Yang Yang et al.

Viral and antibody dynamics of acute infection with SARS-CoV-2 omicron variant (B.1.529): a prospective cohort study from Shenzhen, China

The Lancet, July 2023; doi.org/10.1016/S2666-5247(23)00139-8

Abstract

Elucidating viral dynamics within the host is important for designing public health measures against SARS-CoV-2, particularly during the early stages of infection when transmission potential rapidly increases. We aimed to analyse the viral and antibody dynamics of the omicron variant in relation to symptom onset or laboratory confirmation and replication dynamics throughout the infection course.

Methods

In this prospective cohort study, patients with laboratory-confirmed SARS-CoV-2 infection who were admitted to Shenzhen Third People's Hospital (Shenzhen, China) between Jan 11, 2020, and April 24, 2022, were screened for eligibility. We included immunocompetent individuals with acute SARS-CoV-2 infection without antiviral agents targeting SARS-CoV-2. Serial nasopharyngeal swabs and plasma samples were analysed for viral RNAs and specific IgG antibodies of SARS-CoV-2. The comparative viral and antibody kinetics in association with symptom onset or laboratory confirmation and replication dynamics throughout the infection course were calculated by the locally estimated scatterplot smoothing curve fitting polynomial regression. The associations between viral and antibody dynamics and vaccination, age, sex, disease severity, and underlying health conditions were analysed using the Mann-Whitney U test and the Gehan-Breslow-Wilcoxon method.

Findings

15 406 serial nasopharyngeal swabs and 2324 plasma samples were taken from 2043 individuals with acute SARS-CoV-2 infection (n=217 prototype [A.1] and D614G [B.1] variant [wild-type]; n=105 delta variant [B.1.617.2]; n=1721 omicron variant [B.1.529]) and were included for the analyses. The mean Ct value of omicron variant on the first day post symptom onset (dpo; defined as the first day post laboratory confirmation in asymptomatic participants) was 22·65 (95% CI 22·05–23·26). Peak viral load was reached with a mean Ct value of 17·63 (17·47–17·79) at a mean of 3·19 dpo (95% CI 3·09–3·28), and viral clearance (Ct values ≥35) was reached at a mean of 13·50 dpo (95% CI 13·32–13·67). Omicron variant showed faster viral replication and clearance than wild-type SARS-CoV-2 and delta variant, and the viral load at the first dpo and the peak viral load was lower than delta variant but higher than wild-type SARS-CoV-2. Age, sex, disease severity, and underlying health conditions were associated with the viral dynamics of omicron variant, with faster viral clearance found in young (aged 0–14 years), male, and asymptomatic participants, and those without underlying health conditions. Replication dynamics thoughout the infection course showed that peak viral load was reached at a mean of 5·06 dpo (4·76–5·36) and viral clearance took a mean of 14·27 days (13·6–14·93) for omicron variant. SARS-CoV-2-specific IgG increased earlier and faster to significantly higher concentrations in breakthrough infection than naive infection with omicron variant, despite long intervals (≥7 months) between the last dose of vaccination and infection.

Interpretation

Our data provide a comprehensive overview of the longitudinal viral and antibody dynamics of omicron variant in people with acute SARS-CoV-2 infection, with important implications for public health strategies, including population screening, antiviral treatment, isolation periods, and vaccination.

Martin Law et al

Efficacy and effectiveness of inactivated vaccines against symptomatic COVID-19, severe COVID-19, and COVID-19 clinical outcomes in the general population: a systematic review and meta-analysis

The Lancet, May 2023; doi.org/10.1016/j.lanwpc.2023.100788

Abstract

Inactivated, whole-virion vaccines have been used extensively in the SARS-CoV-2 pandemic. Its efficacy and effectiveness across regions have not been systematically evaluated. Efficacy refers to how well a vaccine performs in a controlled environment. Effectiveness refers to how well it performs in real world settings.

Methods

This systematic review and meta-analysis reviewed published, peer-reviewed evidence on all WHO-approved inactivated vaccines and evaluated their efficacy and effectiveness against SARS-CoV-2 infection, symptomatic infection, severe clinical outcomes, and severe COVID-19. We searched Pubmed (including MEDLINE), EMBASE (via OVID), Web of Science Core Collection, Web of Science Chinese Science Citation Database, and Clinicaltrials.gov.

Findings

The final pool included 28 studies representing over 32 million individuals reporting efficacy or effectiveness estimates of complete vaccination using any approved inactivated vaccine between January 1, 2019 and June 27, 2022. Evidence was found for efficacy and effectiveness against symptomatic infection (OR 0.21, 95% CI 0.16–0.27, I2 = 28% and OR 0.32, 95% CI 0.16–0.64, I2 = 98%, respectively) and infection (OR 0.53, 95% CI 0.49–0.57, I2 = 90% and OR 0.31, 95% CI 0.24–0.41, I2 = 0%, respectively) for early SARS-CoV-2 variants of concern (VoCs) (Alpha, Delta), and for waning of vaccine effectiveness with more recent VoCs (Gamma, Omicron). Effectiveness remained robust against COVID-related ICU admission (OR 0.21, 95% CI 0.04–1.08, I2 = 99%) and death (OR 0.08, 95% CI 0.00–2.02, I2 = 96%), although effectiveness estimates against hospitalization (OR 0.44, 95% CI 0.37–0.53, I2 = 0%) were inconsistent.

Interpretation

This study showed evidence of efficacy and effectiveness of inactivated vaccines for all outcomes, although inconsistent reporting of key study parameters, high heterogeneity of observational studies, and the small number of studies of particular designs for most outcomes undermined the reliability of the findings. Findings highlight the need for additional research to address these limitations so that more definitive conclusions can be drawn to inform SARS-CoV-2 vaccine development and vaccination policies.

Xiaolei Wang et al.

Vaccine-induced protection against SARS-CoV-2 requires IFN-γ-driven cellular immune response

Nature, June 2023; doi.org/10.1038/s41467-023-39096-y

Abstract

The overall success of worldwide mass vaccination in limiting the negative effect of the COVID-19 pandemics is inevitable, however, recent SARS-CoV-2 variants of concern, especially Omicron and its sub-lineages, efficiently evade humoral immunity mounted upon vaccination or previous infection. Thus, it is an important question whether these variants, or vaccines against them, induce anti-viral cellular immunity. Here we show that the mRNA vaccine BNT162b2 induces robust protective immunity in K18-hACE2 transgenic B-cell deficient (μMT) mice. We further demonstrate that the protection is attributed to cellular immunity depending on robust IFN-γ production. Viral challenge with SARS-CoV-2 Omicron BA.1 and BA.5.2 sub-variants induce boosted cellular responses in vaccinated μMT mice, which highlights the significance of cellular immunity against the ever-emerging SARS-CoV-2 variants evading antibody-mediated immunity. Our work, by providing evidence that BNT162b2 can induce significant protective immunity in mice that are unable to produce antibodies, thus highlights the importance of cellular immunity in the protection against SARS-CoV-2.

Joel N Blankson.

Bivalent COVID-19 Vaccines: Can the Original Antigenic Sin Be Forgiven?

Academic.oup, April 2023; doi.org/10.1093/infdis/jiad073

Abstract

On 31 August 2022, the United States (US) Food and Drug Administration authorized bivalent formulations of the Moderna and Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccines [1]. These modified vaccines contain messenger RNA (mRNA) encoding for both the ancestral WA1/2020 and the Omicron BA.4/BA.5 spike proteins. The hope was that they would provide immunity to the BA.5 virus, which differs from WA1/2020 by >30 mutations in the spike protein and was the predominant variant in circulation at the time. Unfortunately, studies have shown that the levels of neutralizing antibodies to the BA.5 variant were not significantly higher in patients who received the bivalent vaccine than those who received the monovalent vaccine with WA1/2020 mRNA [2, 3]. In other words, vaccination with BA.5 spike protein did not lead to an appreciably better antibody response. The reason for this disappointing result has not yet been determined, but antigenic imprinting, also known as the “original antigenic sin,” has been invoked as a potential cause for these results.

To fully explain this tenant of immunotheology, one has to review some basic principles. While there are some notable exceptions [4], the process of extensive gene segment recombination leads to the production of diverse T- and B-cell receptors that should be capable of recognizing almost any conceivable pathogen we will ever encounter. The drawback is that there are very few cells with any given receptor and so when we first see a pathogen, naive cells with receptors specific for the pathogen's antigens have to proliferate extensively before we can mount an effective primary adaptive immune response. Some of these naive cells will become memory cells that circulate at higher levels so that if the same antigen is encountered again, a faster, more effective secondary adaptive immune response will occur.

The original antigenic sin occurs when we encounter antigens on a pathogen that is similar to one we have previously encountered [5, 6]. It is thought that rather than initiating a primary immune response where rare naive lymphocytes that have high-affinity receptors for the new antigens proliferate, a secondary response occurs where memory cells with receptors that are cross-reactive for both the original and new antigens are stimulated. This could potentially be advantageous if the targeted epitopes of the 2 pathogens are identical or very similar because then the 2 epitopes will be equally recognized. However, in many cases, because the cross-reactive memory cells were primed to respond to the antigen on the first pathogen, the cross-reactive receptors will have a higher affinity for the first pathogen, leading to a suboptimal response to the newer pathogen….

Natalia Martin-Orozco et al.

Phase I randomized, observer-blinded, placebo-controlled study of a SARS-CoV-2 mRNA vaccine PTX-COVID19-B

Nature, May 2023; doi.org/10.1038/s41598-023-35662-y

Abstract

Access to vaccines against SARS-CoV-2 virus was limited in poor countries during the COVID-19 pandemic. Therefore, a low-cost mRNA vaccine, PTX-COVID19-B, was produced and evaluated in a Phase 1 trial. PTX-COVID19-B encodes Spike protein D614G variant without the proline-proline (986–987) mutation present in other COVID-19 vaccines. The aim of the study was to evaluate safety, tolerability, and immunogenicity of PTX-COVID19-B vaccine in healthy seronegative adults 18–64 years old. The trial design was observer-blinded, randomized, placebo-controlled, and tested ascending doses of 16-µg, 40-µg, or 100-µg in a total of 60 subjects who received two intramuscular doses, 4 weeks apart. Participants were monitored for solicited and unsolicited adverse events after vaccination and were provided with a Diary Card and thermometer to report any reactogenicity during the trial. Blood samples were collected on baseline, days 8, 28, 42, 90, and 180 for serum analysis of total IgG anti-receptor binding domain (RBD)/Spike titers by ELISA, and neutralizing antibody titers by pseudovirus assay. Titers in BAU/mL were reported as geometric mean and 95% CI per cohort. After vaccination, few solicited adverse events were observed and were mild to moderate and self-resolved within 48 h. The most common solicited local and systemic adverse event was pain at the injection site, and headache, respectively. Seroconversion was observed in all vaccinated participants, who showed high antibody titers against RBD, Spike, and neutralizing activity against the Wuhan strain. Neutralizing antibody titers were also detected against Alpha, Beta, and Delta variants of concerns in a dose dependent manner. All tested doses of PTX-COVID19-B were safe, well-tolerated, and provided a strong immunogenicity response. The 40-µg dose showed fewer adverse reactions than the 100-µg dose, and therefore was selected for a Phase 2 trial, which is currently ongoing.

Nazmul Islam et al

Comparative effectiveness of the sars-CoV-2 vaccines during delta dominance

Cell, May 2023; doi.org/10.1016/j.heliyon.2023.e16006

Abstract

Several vaccines with demonstrated efficacy for coronavirus disease 2019 (Covid-19) are available. The purpose of this study was to evaluate the COVID mRNA based and adenovector based vaccines’ differential effectiveness during the time of circulation of the Delta variant and determine what impact this would have on population health and cost effectiveness.

Methods

We used de-identified claims in a research database that included vaccination status and Covid-positivity status. Individuals ≥18 years, fully vaccinated with Ad26.COV2·S/J&J/Janssen, mRNA-1273/Moderna, or BNT162b2/Pfizer-BioNTech by September 30, 2021, were included. Outcomes were SARS-CoV-2-infection, emergency department visits, outpatient visits, inpatient hospitalizations, intensive care unit (ICU) transfers, death, and hospice transfers through September 30, 2021.

Results

Among ∼6.5 million fully vaccinated individuals in the UHC Medicare Advantage and our commercially insured research database, mRNA-1273 performed better than BNT162b2 for infection, composite-hospitalization (hospitalization/ICU transfer/hospice transfer/death), and composite-ICU transfer (ICU transfer/hospice transfer/death) caused by B.1.612.7 (delta) variant infection. 26 CE.COV2.S performed worse than BNT162b2 for infection, composite-hospitalization, and composite-ICU transfers. The number needed to vaccinate (NNV) with mRNA1273 to prevent one hospitalization at 90 days was 3130 compared to 26 CE.COV2·S and 15,472 compared to BNT162b2. The NNV with mRNA1273 to prevent one ICU transfer at 90 days was 6358 compared to 26 CE.COV2·S and 34,279 compared to BNT162b2. For every one million individuals vaccinated with BNT162b compared to mRNA-1273, the approximate incremental inpatient cost would be $405,000 and the approximate incremental ICU cost would be $662,000.

Conclusions

The two-dose mRNA vaccines' effectiveness significantly exceeded the single-dose Ad26.COV2·S vaccine's effectiveness from population health and cost-effectiveness perspectives. The mRNA1273 vaccine showed slightly more effectiveness than the BNT162b vaccine.

Matthew L Robinson et al.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Variants on Inpatient Clinical Outcome

CID, December 2022; doi.org/10.1093/cid/ciac957

Abstract

Prior observation has shown differences in COVID-19 hospitalization risk between SARS-CoV-2 variants, but limited information describes hospitalization outcomes.

Methods

Inpatients with COVID-19 at 5 hospitals in the eastern United States were included if they had hypoxia, tachypnea, tachycardia, or fever, and SARS-CoV-2 variant data, determined from whole-genome sequencing or local surveillance inference. Analyses were stratified by history of SARS-CoV-2 vaccination or infection. The average effect of SARS-CoV-2 variant on 28-day risk of severe disease, defined by advanced respiratory support needs, or death was evaluated using models weighted on propensity scores derived from baseline clinical features.

Results

Severe disease or death within 28 days occurred for 977 (29%) of 3369 unvaccinated patients and 269 (22%) of 1230 patients with history of vaccination or prior SARS-CoV-2 infection. Among unvaccinated patients, the relative risk of severe disease or death for Delta variant compared with ancestral lineages was 1.30 (95% confidence interval [CI]: 1.11–1.49). Compared with Delta, the risk for Omicron patients was .72 (95% CI: .59–.88) and compared with ancestral lineages was .94 (.78–1.1). Among Omicron and Delta infections, patients with history of vaccination or prior SARS-CoV-2 infection had half the risk of severe disease or death (adjusted hazard ratio: .40; 95% CI: .30–.54), but no significant outcome difference by variant.

Conclusions

Although risk of severe disease or death for unvaccinated inpatients with Omicron was lower than with Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated inpatients, with no difference between Delta and Omicron infections.

EhsanMostafavi et al.

Efficacy and Safety of a Protein-Based SARS-CoV-2 Vaccine

A Randomized Clinical Trial

JAMA, May 2023; doi:10.1001/jamanetworkopen.2023.10302

Abstract

Importance The protein-based SARS-CoV-2 vaccines FINLAY-FR-2 (Soberana 02) and FINLAY-FR-1A (Soberana Plus) showed good safety and immunogenicity in phase 1 and 2 trials, but the clinical efficacy of the vaccine remains unknown.

Objective To evaluate the efficacy and safety of a 2-dose regimen of FINLAY-FR-2 (cohort 1) and a 3-dose regimen of FINLAY-FR-2 with FINLAY-FR-1A (cohort 2) in Iranian adults.

Design, Setting, and Participants Amulticenter, randomized, double-blind, placebo-controlled, phase 3 trial was conducted at 6 cities in cohort 1 and 2 cities in cohort 2. Participants included individuals aged 18 to 80 years without uncontrolled comorbidities, coagulation disorders, pregnancy or breastfeeding, recent immunoglobulin or immunosuppressive therapy, and clinical presentation or laboratory-confirmed COVID-19 on enrollment. The study was conducted from April 26 to September 25, 2021.

Interventions In cohort 1, 2 doses of FINLAY-FR-2 (n = 13 857) or placebo (n = 3462) were administered 28 days apart. In cohort 2, 2 doses of FINLAY-FR-2 plus 1 dose of FINLAY-FR-1A (n = 4340) or 3 placebo doses (n = 1081) were administered 28 days apart. Vaccinations were administered via intramuscular injection.

Main Outcomes and Measures The primary outcome was polymerase chain reaction–confirmed symptomatic COVID-19 infection at least 14 days after vaccination completion. Other outcomes were adverse events and severe COVID-19. Intention-to-treat analysis was performed.

Results In cohort 1 a total 17 319 individuals received 2 doses and in cohort 2 5521 received 3 doses of the vaccine or placebo. Cohort 1 comprised 60.1% men in the vaccine group and 59.1% men in the placebo group; cohort 2 included 59.8% men in the vaccine group and 59.9% in the placebo group. The mean (SD) age was 39.3 (11.9) years in cohort 1 and 39.7 (12.0) years in cohort 2, with no significant difference between the vaccine and placebo groups. The median follow-up time in cohort 1 was 100 (IQR, 96-106) days and, in cohort 2, 142 (137-148) days. In cohort 1, 461 (3.2%) cases of COVID-19 occurred in the vaccine group and 221 (6.1%) in the placebo group (vaccine efficacy: 49.7%; 95% CI, 40.8%-57.3%) vs 75 (1.6%) and 51 (4.3%) in cohort 2 (vaccine efficacy: 64.9%; 95% CI, 49.7%-59.5%). The incidence of serious adverse events was lower than 0.1%, with no vaccine-related deaths.

Conclusions and Relevance In this multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of the efficacy and safety of FINLAY-FR-2 and FINLAY-FR-1A, 2 doses of FINLAY-FR-2 plus the third dose of FINLAY-FR-1A showed acceptable vaccine efficacy against symptomatic COVID-19 as well as COVID-19–related severe infections. Vaccination was generally safe and well tolerated. Therefore, Soberana may have utility as an option for mass vaccination of the population, especially in resource-limited settings, because of its storage condition and affordable price.

Soyoung Oh, HaesookSeo

Dietary intervention with functional foods modulating gut microbiota for improving the efficacy of COVID-19 vaccines

Cell, April 2023; doi.org/10.1016/j.heliyon.2023.e15668

Abstract

Dysbiosis of the gut microbiota with aging contributes to a reduction in important cross-feeding bacterial reactions in the gut and immunosenescence, which could contribute to a decrease in vaccine efficacy. Fever, cough, and fatigue are the main signs of coronavirus disease 2019 (COVID-19); however, some patients with COVID-19 present with gastrointestinal symptoms. COVID-19 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the best measures to reduce SARS-CoV-2 infection rates and the severity of COVID-19. The immunogenicity of COVID-19 vaccines is influenced by the composition of the gut microbiota, and the immune response to COVID-19 vaccines decreases with age. In this review, we discuss gut microbiota dysbiosis and immunosenescence in the older adults, the role of gut microbiota in improving the efficacy of COVID-19 vaccines, and dietary interventions to improve the efficacy of COVID-19 vaccines in the older adults.

Stefania Arsuffi et al.

Timing and implications for immune response to vaccine in SARS-CoV-2 breakthrough infections

Cell, April 2023; doi.org/10.1016/j.isci.2023.106716

Abstract

COVID-19 vaccines elicit a strong anti-S antibodies response. We aim to describe antibody titers in peri-vaccination SARS-CoV-2 infections. This is a retrospective longitudinal single-cohort study. Serological tests were performed at the time of the first SARS-CoV-2 vaccine dose (T0) and 60 (T1), 120 (T2) and 240 (T3) days after.

The study included 4682 subjects. Group A had the infection without an anti-S Ig response. Group B and C seroconverted for anti-N Ig between T0 and T1 and between T1 and T2, respectively. Group D was persistently anti-N Ig negative. Group B showed an initial suboptimal response, reaching the highest titer at T3. Those who received the second dose 120 days after the infection had higher titers compared to those who received it 21 days after the first dose. The immune response depends on the number and the timing of vaccine doses, highlighting the need for a more personalized approach to vaccination.

Jeffrey I Cohen et al.

Comparison of Levels of Nasal, Salivary, and Plasma Antibody to Severe Acute Respiratory Syndrome Coronavirus 2 During Natural Infection and After Vaccination

CID, December 2022; doi.org/10.1093/cid/ciac934

Abstract

Most studies of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) measure antibody or cellular responses in blood; however, the virus infects mucosal surfaces in the nose and conjunctivae and infectious virus is rarely if ever present in the blood.

Methods

We used luciferase immunoprecipitation assays to measure SARS-CoV-2 antibody levels in the plasma, nose, and saliva of infected persons and vaccine recipients. These assays measure antibody that can precipitate the SAR-CoV-2 spike and nucleocapsid proteins.

Results

Levels of plasma anti-spike antibody declined less rapidly than levels of anti-nucleocapsid antibody in infected persons. SARS-CoV-2 anti-spike antibody levels in the nose declined more rapidly than antibody levels in the blood after vaccination of infected persons. Vaccination of previously infected persons boosted anti-spike antibody in plasma more than in the nose or saliva. Nasal and saliva anti-spike antibody levels were significantly correlated with plasma antibody in infected persons who had not been vaccinated and after vaccination of uninfected persons.

Conclusions

Persistently elevated SARS-CoV-2 antibody in plasma may not indicate persistence of antibody at mucosal sites such as the nose. The strong correlation of SARS-CoV-2 antibody in the nose and saliva with that in the blood suggests that mucosal antibodies are derived primarily from transudation from the blood rather than local production. While SARS-CoV-2 vaccine given peripherally boosted mucosal immune responses in infected persons, the increase in antibody titers was higher in plasma than at mucosal sites. Taken together, these observations indicate the need for development of mucosal vaccines to induce potent immune responses at sites where SARS-CoV-2 infection occurs.

Robyn Mitchell et al.

Trends in Severe Outcomes Among Adult and Pediatric Patients Hospitalized With COVID-19 in the Canadian Nosocomial Infection Surveillance Program, March 2020 to May 2022

JAMA, April 2023; doi:10.1001/jamanetworkopen.2023.9050

Abstract

Importance Trends in COVID-19 severe outcomes have significant implications for the health care system and are key to informing public health measures. However, data summarizing trends in severe outcomes among patients hospitalized with COVID-19 in Canada are not well described.

Objective To describe trends in severe outcomes among patients hospitalized with COVID-19 during the first 2 years of the COVID-19 pandemic.

Design, Setting, and Participants Active prospective surveillance in this cohort study was conducted from March 15, 2020, to May 28, 2022, at a sentinel network of 155 acute care hospitals across Canada. Participants included adult (aged ≥18 years) and pediatric (aged 0-17 years) patients hospitalized with laboratory-confirmed COVID-19 at a Canadian Nosocomial Infection Surveillance Program (CNISP)–participating hospital.

Exposures COVID-19 waves, COVID-19 vaccination status, and age group.

Main Outcomes and Measures The CNISP collected weekly aggregate data on the following severe outcomes: hospitalization, admission to an intensive care unit (ICU), receipt of mechanical ventilation, receipt of extracorporeal membrane oxygenation, and all-cause in-hospital death.

Results Among 1 513 065 admissions, the proportion of adult (n = 51 679) and pediatric (n = 4035) patients hospitalized with laboratory-confirmed COVID-19 was highest in waves 5 and 6 of the pandemic compared with waves 1 to 4 (77.3 vs 24.7 per 1000 patient admissions). Despite this, the proportion of patients with positive test results for COVID-19 who were admitted to an ICU, received mechanical ventilation, received extracorporeal membrane oxygenation, and died were each significantly lower in waves 5 and 6 when compared with waves 1 through 4. Admission to the ICU and in-hospital all-cause death rates were significantly higher among those who were unvaccinated against COVID-19 when compared with those who were fully vaccinated (incidence rate ratio, 4.3 and 3.9, respectively) or fully vaccinated with an additional dose (incidence rate ratio, 12.2 and 15.1, respectively).

Conclusions and Relevance The findings of this cohort study of patients hospitalized with laboratory-confirmed COVID-19 suggest that COVID-19 vaccination is important to reduce the burden on the Canadian health care system as well as severe outcomes associated with COVID-19.

Laure F. Pittet et al.

Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers

NEJM, April 2023; DOI: 10.1056/NEJMoa2212616

Abstract

The bacilleCalmette–Guérin (BCG) vaccine has immunomodulatory “off-target” effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19).

METHODS

In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline.

RESULTS

A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], −0.7 to 5.5; P=0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, −1.2 to 3.5; P=0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safetyconcernswereidentified.

CONCLUSIONS

Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo.

Shaofeng Deng et al.

An intranasal influenza virus-vectored vaccine prevents SARS-CoV-2 replication in respiratory tissues of mice and hamsters

Nature, doi.org/10.1038/s41467-023-37697-1

Abstract

Current available vaccines for COVID-19 are effective in reducing severe diseases and deaths caused by SARS-CoV-2 infection but less optimal in preventing infection. Next-generation vaccines which are able to induce mucosal immunity in the upper respiratory to prevent or reduce infections caused by highly transmissible variants of SARS-CoV-2 are urgently needed. We have developed an intranasal vaccine candidate based on a live attenuated influenza virus (LAIV) with a deleted NS1 gene that encodes cell surface expression of the receptor-binding-domain (RBD) of the SARS-CoV-2 spike protein, designated DelNS1-RBD4N-DAF. Immune responses and protection against virus challenge following intranasal administration of DelNS1-RBD4N-DAF vaccines were analyzed in mice and compared with intramuscular injection of the BioNTech BNT162b2 mRNA vaccine in hamsters. DelNS1-RBD4N-DAF LAIVs induced high levels of neutralizing antibodies against various SARS-CoV-2 variants in mice and hamsters and stimulated robust T cell responses in mice. Notably, vaccination with DelNS1-RBD4N-DAF LAIVs, but not BNT162b2 mRNA, prevented replication of SARS-CoV-2 variants, including Delta and Omicron BA.2, in the respiratory tissues of animals. The DelNS1-RBD4N-DAF LAIV system warrants further evaluation in humans for the control of SARS-CoV-2 transmission and, more significantly, for creating dual function vaccines against both influenza and COVID-19 for use in annual vaccination strategies.

BirknehTilahunTadesse, et al.

Impact of Vaccination With the SCB-2019 Coronavirus Disease 2019 Vaccine on Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Household Contact Study in the Philippines

CID, November 2022; doi.org/10.1093/cid/ciac914

Abstract

Background

An exploratory household transmission study was nested in SPECTRA, the phase 2/3 efficacy study of the adjuvanted recombinant protein-based COVID-19 vaccine SCB-2019. We compared the occurrence of confirmed COVID-19 infections between households and household contacts of infected SPECTRA placebo or SCB-2019 recipients.

Methods

SPECTRA participants at 8 study sites in the Philippines who developed real-time reverse transcriptase–polymerase chain reaction (rRT-PCR)–confirmed COVID-19 were contacted by a study team blinded to assignment of index cases to vaccine or placebo groups to enroll in this household transmission study. Enrolled households and household contacts were monitored for 3 weeks using rRT-PCR and anti–SARS-CoV-2 N-antigen IgG/IgM testing to detect new COVID-19 infections.

Results

One hundred fifty-four eligible COVID-19 index cases (51 vaccinees, 103 placebo) were included. The secondary attack rate per household for symptomatic COVID-19 infection was 0.76% (90% CI: .15–3.90%) if the index case was an SCB-2019 vaccinee compared with 5.88% (90% CI: 3.20–10.8%) for placebo index cases, a relative risk reduction (RRR) of 79% (90% CI: −28% to 97%). The RRR of symptomatic COVID-19 per household member was similar: 84% (90% CI: 28–97%). The impact on attack rates in household members if index cases were symptomatic (n = 130; RRR = 80%; 90% CI: 7–96%) or asymptomatic (n = 24; RRR = 100%; 90% CI: −76% to 100%) was measurable but the low numbers undermine the clinical significance.

Conclusions

In this prospective household contact study vaccination with SCB-2019 reduced SARS-CoV-2 transmission compared with placebo in households and in household members independently of whether or not index cases were symptomatic.

Jane M. Knisely et al.

Mucosal vaccines for SARS-CoV-2: scientific gaps and opportunities—workshop report

Nature, April 2023; doi.org/10.1038/s41541-023-00654-6

Abstract

On November 7th and 8th, 2022, The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), The Coalition for Epidemic Preparedness Innovation (CEPI), The Bill & Melinda Gates Foundation (BMGF), The Biomedical Advanced Research and Development Authority (BARDA), and the Wellcome Trust hosted a virtual workshop entitled “Mucosal Vaccines for SARS-CoV-2: Scientific Gaps and Opportunities.” During the workshop, researchers and vaccine developers from around the world discussed the potential of mucosal vaccines to block SARS-CoV-2 transmission and reviewed the status of SARS-CoV-2 mucosal vaccine research. Here, we summarize key challenges and opportunities in basic, translational, and clinical research that were highlighted during the meeting. We also provide recommendations to advance the field and accelerate the development of mucosal vaccines for SARS-CoV-2.

Christopher A. Martin et al.

Ethnic differences in cellular and humoral immune responses to SARS-CoV-2 vaccination in UK healthcare workers: a cross-sectional analysis

The Lancet, April 2023; doi.org/10.1016/j.eclinm.2023.101926

Abstract

Few studies have compared SARS-CoV-2 vaccine immunogenicity by ethnic group. We sought to establish whether cellular and humoral immune responses to SARS-CoV-2 vaccination differ according to ethnicity in UK Healthcare workers (HCWs).

Methods

In this cross-sectional analysis, we used baseline data from two immunological cohort studies conducted in HCWs in Leicester, UK. Blood samples were collected between March 3, and September 16, 2021. We excluded HCW who had not received two doses of SARS-CoV-2 vaccine at the time of sampling and those who had serological evidence of previous SARS-CoV-2 infection. Outcome measures were SARS-CoV-2 spike-specific total antibody titre, neutralising antibody titre and ELISpot count. We compared our outcome measures by ethnic group using univariable (t tests and rank-sum tests depending on distribution) and multivariable (linear regression for antibody titres and negative binomial regression for ELISpot counts) tests. Multivariable analyses were adjusted for age, sex, vaccine type, length of interval between vaccine doses and time between vaccine administration and sample collection and expressed as adjusted geometric mean ratios (aGMRs) or adjusted incidence rate ratios (aIRRs). To assess differences in the early immune response to vaccination we also conducted analyses in a subcohort who provided samples between 14 and 50 days after their second dose of vaccine.

Interpretation

This study provides evidence that, in an infection naïve cohort, humoral and cellular immune responses to SARS-CoV-2 vaccination are stronger in South Asian HCWs than White HCWs. These differences are most clearly seen in the early period following vaccination. Further research is required to understand the underlying mechanisms, whether differences persist with further exposure to vaccine or virus, and the potential impact on vaccine effectiveness.

Rebecca Kahn et al.

The effectiveness of COVID-19 vaccines in Latin America, 2021: a multicenter regional case–control study

The Lancet, march 2023; doi.org/10.1016/j.lana.2023.100474

Abstract      

As of September 2022, nearly 1.3 billion doses of COVID-19 vaccine products have been administered in Latin America and the Caribbean, where 27% of global COVID-19 deaths have occurred. This study aimed to estimate the effectiveness of COVID-19 vaccines against lab-confirmed COVID-19 related hospitalizations and deaths among adults in Argentina, Brazil, Chile, and Colombia.

Methods

Using a test-negative case control design, we evaluated the effectiveness of a primary vaccination series considering six COVID-19 vaccine products (Sputnik V, mRNA-1273, CoronaVac, ChAdOx1, BNT162b2, Ad26.COV2.S) against lab-confirmed COVID-19 hospitalizations and deaths among 83,708 hospitalized adults from February–December, 2021. Data from hospitalization records, COVID surveillance, and vaccination registries were used. Vaccine effectiveness was estimated using logistic regression ((1-OR) x 100).

Findings

The average age of participants was 56.7 (SD = 17.5), and 45,894 (54.8%) were male. Adjusted VE (aVE) estimates for full vaccination against hospitalization were 82% for mRNA-1273 (95% confidence interval (CI) = −30 to 98%), 76% (71%–81%) for BNT162b2, 65% (61–68%) for ChAdOx1, 57% (10–79%) for Sputnik V, 53% (50–56%) for CoronaVac, and 46% (23–62%) for Ad26.COV2.S. Estimates, particularly for CoronaVac, varied by variant. Decreasing aVEwas estimated as age increased, particularly for CoronaVac and ChAdOx1. aVE estimates against death were generally higher, with 100% (CI not estimated) for mRNA-1273, 82% (69–90%) for BNT162b2, 73% (69–77%) for ChAdOx1, 65% (60–67%) for CoronaVac, 38% (−75 to 78%) for Sputnik V, 6% (−58 to 44%) for Ad26.COV2.S.

Interpretation

Primary series vaccination with available COVID-19 vaccine products was effective against COVID-19 hospitalization and mortality. Effectiveness varied by product and declined with increasing age.

Geraldine Nouailles et al.

Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters

Nature, April 2023; doi.org/10.1038/s41564-023-01352-8

Abstract

Vaccines play a critical role in combating the COVID-19 pandemic. Future control of the pandemic requires improved vaccines with high efficacy against newly emerging SARS-CoV-2 variants and the ability to reduce virus transmission. Here we compare immune responses and preclinical efficacy of the mRNA vaccine BNT162b2, the adenovirus-vectored spike vaccine Ad2-spike and the live-attenuated virus vaccine candidate sCPD9 in Syrian hamsters, using both homogeneous and heterologous vaccination regimens. Comparative vaccine efficacy was assessed by employing readouts from virus titrations to single-cell RNA sequencing. Our results show that sCPD9 vaccination elicited the most robust immunity, including rapid viral clearance, reduced tissue damage, fast differentiation of pre-plasmablasts, strong systemic and mucosal humoral responses, and rapid recall of memory T cells from lung tissue after challenge with heterologous SARS-CoV-2. Overall, our results demonstrate that live-attenuated vaccines offer advantages over currently available COVID-19 vaccines.

HaogaoGu et al.

Within-host genetic diversity of SARS-CoV-2 lineages in unvaccinated and vaccinated individuals

Nature, March 2023; doi.org/10.1038/s41467-023-37468-y                                           

Abstract      

Viral and host factors can shape SARS-CoV-2 evolution. However, little is known about lineage-specific and vaccination-specific mutations that occur within individuals. Here, we analysed deep sequencing data from 2,820 SARS-CoV-2 respiratory samples with different viral lineages to describe the patterns of within-host diversity under different conditions, including vaccine-breakthrough infections. In unvaccinated individuals, variant of Concern (VOC) Alpha, Delta, and Omicron respiratory samples were found to have higher within-host diversity and were under neutral to purifying selection at the full genome level compared to non-VOC SARS-CoV-2. Breakthrough infections in 2-dose or 3-dose Comirnaty and CoronaVac vaccinated individuals did not increase levels of non-synonymous mutations and did not change the direction of selection pressure. Vaccine-induced antibody or T cell responses did not appear to have significant impact on within-host SARS-CoV-2 sequence diversification. Our findings suggest that vaccination does not increase exploration of SARS-CoV-2 protein sequence space and may not facilitate emergence of viral variants.

BirknehTilahunTadesse et al.

Coronavirus Disease 2019 Vaccine on Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Household Contact Study in the Philippines

CID, November 2022; doi.org/10.1093/cid/ciac914

Abstract

Background

An exploratory household transmission study was nested in SPECTRA, the phase 2/3 efficacy study of the adjuvanted recombinant protein-based COVID-19 vaccine SCB-2019. We compared the occurrence of confirmed COVID-19 infections between households and household contacts of infected SPECTRA placebo or SCB-2019 recipients.

Conclusions

In this prospective household contact study vaccination with SCB-2019 reduced SARS-CoV-2 transmission compared with placebo in households and in household members independently of whether or not index cases were symptomatic.

Kai Wang et al.

Transmission Characteristics and Inactivated Vaccine Effectiveness Against Transmission of SARS-CoV-2 Omicron BA.5 Variants in Urumqi, China

JAMA, March 2023; doi:10.1001/jamanetworkopen.2023.5755

Abstract

Importance In 2022, Omicron variants circulated globally, and Urumqi, China, experienced a COVID-19 outbreak seeded by Omicron BA.5 variants, resulting in the highest number of infections in the city’s record before the exit of the zero COVID-19 strategy. Little was known about the characteristics of Omicron variants in mainland China.

                               

Objective To evaluate transmission characteristics of Omicron BA.5 variants and the effectiveness of inactivated vaccine (mainly BBIBP-CorV) against their transmission.

Design, Setting, and Participants This cohort study was conducted using data from an Omicron-seeded COVID-19 outbreak in Urumqi from August 7 to September 7, 2022. Participants included all individuals with confirmed SARS-CoV-2 infections and their close contacts identified between August 7 and September 7, 2022 in Urumqi.

Exposures A booster dose was compared vs 2 doses (reference level) of inactivated vaccine and risk factors were evaluated.

Main Outcomes and Measures Demographic characteristics, timeline records from exposure to laboratory testing outcomes, contact tracing history, and contact setting were obtained. The mean and variance of the key time-to-event intervals of transmission were estimated for individuals with known information. Transmission risks and contact patterns were assessed under different disease-control measures and in different contact settings. The effectiveness of inactivated vaccine against the tranmission of Omicron BA.5 was estimated using multivariate logistic regression models.

Results Among 1139 individuals diagnosed with COVID-19 (630 females [55.3%]; mean [SD] age, 37.4 [19.9] years) and 51 323 close contacts who tested negative for COVID-19 (26 299 females [51.2%]; mean [SD] age, 38.4 [16.0] years), the means of generation interval, viral shedding period, and incubation period were estimated at 2.8 days (95% credible interval [CrI], 2.4-3.5 days), 6.7 days (95% CrI, 6.4-7.1 days), and 5.7 days (95% CrI, 4.8-6.6 days), respectively. Despite contact tracing, intensive control measures, and high vaccine coverage (980 individuals with infections [86.0%] received ≥2 doses of vaccine), high transmission risks were found in household settings (secondary attack rate, 14.7%; 95% CrI, 13.0%-16.5%) and younger (aged 0-15 years; secondary attack rate, 2.5%; 95% CrI, 1.9%-3.1%) and older age (aged >65 years; secondary attack rate, 2.2%; 95% CrI, 1.5%-3.0%) groups. Vaccine effectiveness against BA.5 variant transmission for the booster-dose vs 2 doses was 28.9% (95% CrI, 7.7%-45.2%) and 48.5% (95% CrI, 23.9%-61.4%) for 15-90 days after booster dose. No protective outcome was detected beyond 90 days after the booster dose.

Conclusions and Relevance This cohort study revealed key transmission characteristics of SARS-CoV-2 as they evolved, as well as vaccine effectiveness against variants. These findings suggest the importance of continuously evaluating vaccine effectiveness against emerging SARS-CoV-2 variants.

Shiv Pillai

Is it bad, is it good, or is IgG4 just misunderstood?

Science, February 2023; doi/10.1126/sciimmunol.adg7327

Abstract

Repeated doses of mRNA vaccines for COVID-19 result in increased proportions of anti-spike antibodies of the IgG4 subclass, which are known to neutralize well and to form mixed immune complexes with IgG1 but, in a pure form, might be less effective than IgG1 or IgG3 antibodies in facilitating opsonization by phagocytes, complement fixation, and NK cell–dependent elimination of infected cells (see related Research Article by Irrgang et al.).

CleberVinicius Brito dos Santos et al.

The effectiveness of COVID-19 vaccines against severe cases and deaths in Brazil from 2021 to 2022: a registry-based study

The Lancet, March 2023; doi.org/10.1016/j.lana.2023.100465

Abstract

Brazil started the COVID-19 mass vaccination in January 2021 with CoronaVac and ChAdOx1, followed by BNT162b2 and Ad26.COV2.S vaccines. By the end of 2021, more than 317 million vaccine doses were administered in the adult population. This study aimed at estimating the effectiveness of the primary series of COVID-19 vaccination and booster shots in protecting against severe cases and deaths in Brazil during the first year of vaccination.

Methods                   

A cohort dataset of over 158 million vaccination and severe cases records linked from official national registries was analyzed via a mixed-effects Poisson model, adjusted for age, state of residence, time after immunization, and calendar time to estimate the absolute vaccine effectiveness of the primary series of vaccination and the relative effectiveness of the booster. The method permitted analysis of effectiveness against hospitalizations and deaths, including in the periods of variant dominance.

Interpretation

This study provides real-world evidence of the effectiveness of COVID-19 vaccination in Brazil, including during the Omicron wave, demonstrating protection even after waning effectiveness. Comparisons of the effectiveness among different vaccines require caution due to potential bias effects related to age groups, periods in the pandemic, and eventual behavioural changes.

GiliRegev-Yochay et al.

Correlates of protection against COVID-19 infection and intensity of symptomatic disease in vaccinated individuals exposed to SARS-CoV-2 in households in Israel (ICoFS): a prospective cohort study

The Lancet, March 2023; doi.org/10.1016/S2666-5247(23)00012-5

Abstract               

Identifying COVID-19 correlates of protection and immunity thresholds is important for policy makers and vaccine development. We aimed to identify correlates of protection of BNT162b2 (Pfizer–BioNTech) vaccination against COVID-19.

Methods

In this prospective cohort study, households within a radius of 40 km of the Sheba Medical Center in Israel in which a new SARS-CoV-2 infection (defined as the index case) was detected within the previous 24 h were approached between July 25 and Nov 15, 2021. We included adults (aged >18 years) who had received one or two vaccine doses, had an initial negative SARS-CoV-2 PCR and no previous infection reported, and had a valid IgG and neutralising antibody result. The exposure of interest was baseline immune status, including IgG antibody concentration, neutralising antibody titre, and T-cell activation. The outcomes of interest were PCR-positive SARS-CoV-2 infection between day 2 and day 21 of follow-up and intensity of disease symptoms (self-reported via a telephone questionnaire) among participants who had a confirmed infection. Multivariable logistic and ordered logit ordinal regressions were used for the adjusted analysis. To identify immunological thresholds for clinical protection, we estimated the conditional probability of infection and moderate or severe disease for individuals with pre-exposure IgG and neutralising antibody concentrations above each value observed in the study data.

Deborah Cromer et al.

Predicting vaccine effectiveness against severe COVID-19 over time and against variants: a meta-analysis

Nature, March 2023; doi.org/10.1038/s41467-023-37176-7

Abstract       

Vaccine protection from symptomatic SARS-CoV-2 infection has been shown to be strongly correlated with neutralising antibody titres; however, this has not yet been demonstrated for severe COVID-19. To explore whether this relationship also holds for severe COVID-19, we performed a systematic search for studies reporting on protection against different SARS-CoV-2 clinical endpoints and extracted data from 15 studies. Since matched neutralising antibody titres were not available, we used the vaccine regimen, time since vaccination and variant of concern to predict corresponding neutralising antibody titres. We then compared the observed vaccine effectiveness reported in these studies to the protection predicted by a previously published model of the relationship between neutralising antibody titre and vaccine effectiveness against severe COVID-19. We find that predicted neutralising antibody titres are strongly correlated with observed vaccine effectiveness against symptomatic (Spearman \(\rho\) = 0.95, p < 0.001) and severe (Spearman \(\rho\) = 0.72, p < 0.001 for both) COVID-19 and that the loss of neutralising antibodies over time and to new variants are strongly predictive of observed vaccine protection against severe COVID-19.

Fei Gao et al.

Robust T cell responses to Pfizer/BioNTech vaccine compared to infection and evidence of attenuated peripheral CD8+ T cell responses due to COVID-19

Cell, march 2023; doi.org/10.1016/j.immuni.2023.03.005

Abstract

T cells are a critical component of the response to SARS-CoV-2, but their kinetics after infection and vaccination are insufficiently understood. Using “spheromer” peptide-MHC multimer reagents, we analyzed healthy subjects receiving two doses of the Pfizer/BioNTech BNT162b2 vaccine. Vaccination resulted in robust Spike-specific T cell responses for the dominant CD4+ (HLA-DRB1∗15:01/S191) and CD8+ (HLA-A∗02/S691) T cell epitopes. Antigen-specific CD4+ and CD8+ T cell responses were asynchronous, with the peak CD4+ T cell responses occurring one week post the second vaccination (boost), whereas CD8+ T cells peaked two weeks later. These peripheral T cell responses were elevated compared to COVID-19 patients. We also found that prior SARS-CoV-2 infection resulted in decreased CD8+ T cell activation and expansion, suggesting that prior infection can influence the T cell response to vaccination.

Peter W. Marks

Bivalent Covid-19 Vaccines

NEJM, March 2023; DOI: 10.1056/NEJMc2301323

Abstract     

Citing preliminary immunogenicity results and one study on effectiveness, Offit (Feb. 9 issue)1 argues in his Perspective article that the bivalent boosters against SARS-CoV-2 omicron subvariants BA.4 and BA.5 as well as the ancestral strain should not be deployed throughout the entire population. Key available evidence that was omitted by Offit suggests otherwise.

Davis-Gardner and colleagues, as well as others, found that the bivalent boosters had better immunogenicity against emerging variants, including BQ.1.1 and XBB, than did the monovalent boosters.2 Coronavirus disease 2019 (Covid-19) has taken a tremendous toll on the entire population and resulted in more than 7500 hospitalizations and 1100 deaths in the United States among persons 18 to 49 years of age between September and December 2022 alone, according to the Centers for Disease Control and Prevention. Several studies indicate that the bivalent boosters are clinically effective in reducing the incidences of symptomatic disease, hospitalization, and death across the age spectrum, including among persons 18 to 49 years of age who had been vaccinated previously.3-5 Given the excellent safety profile of the vaccines, which is similar to that of the influenza vaccine among persons 6 months of age or older, the totality of the available evidence supports the vaccination of all currently eligible persons with updated Covid-19 vaccines as an important public health intervention.

Rong Tang et al.

Safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster following three doses of CoronaVac: a multicentre, open-label, phase 4, randomised trial

The Lancet, March 2023; doi.org/10.1016/S2213-2600(23)00049-8

Abstract

Background

Aerosolised Ad5-nCoV is the first approved mucosal respiratory COVID-19 vaccine to be used as a booster after the primary immunisation with COVID-19 vaccines. This study aimed to evaluate the safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster.

Interpretation

A heterologous fourth dose (second booster) with either aerosolised Ad5-nCoV or intramuscular Ad5-nCoV was safe and highly immunogenic in healthy adults who had been immunised with three doses of CoronaVac

Hiam Chemaitelly et al.

Long-term COVID-19 booster effectiveness by infection history and clinical vulnerability and immune imprinting: a retrospective population-based cohort study

The Lancet, March 2023; doi.org/10.1016/S1473-3099(23)00058-0

Abstract

Background

Long-term effectiveness of COVID-19 mRNA boosters in populations with different previous infection histories and clinical vulnerability profiles is inadequately understood. We aimed to investigate the effectiveness of a booster (third dose) vaccination against SARS-CoV-2 infection and against severe, critical, or fatal COVID-19, relative to that of primary-series (two-dose) vaccination over a follow-up duration of 1 year.

Interpretation

Protection against omicron infection waned after the booster, and eventually suggested a possibility for negative immune imprinting. However, boosters substantially reduced infection and severe COVID-19, particularly among individuals who were clinically vulnerable, affirming the public health value of booster vaccination.

Kate A. Parham et al.

Monovalent and trivalent VSV-based COVID-19 vaccines elicit neutralizing antibodies and CD8+ T-cells against SARS-CoV-2 variants

Cell, February 2023; doi.org/10.1016/j.isci.2023.106292

Abstract

Recombinant vesicular stomatitis virus (rVSV) vaccines expressing Spike proteins of Wuhan, Beta and/or Delta variants of SARS-CoV-2 were generated and tested for induction of antibody and T cell immune responses following intramuscular delivery to mice. rVSV-Wuhan and rVSV-Delta vaccines and a rVSV-Trivalent (mixed rVSV-Wuhan, -Beta, -Delta) vaccine elicited potent neutralizing antibodies (nAbs) against live SARS-CoV-2 Wuhan (USAWA1), Beta (B.1.351), Delta (B.1.617.2) and Omicron (B.1.1.529) viruses. Prime-boost vaccination with rVSV-Beta was less effective in this capacity. Heterologous boosting of rVSV-Wuhan with rVSV-Delta induced strong nAb responses against Delta and Omicron viruses, with rVSV-Trivalent vaccine consistently effective in inducing nAbs against all the SARS-CoV-2 variants tested. All vaccines, including rVSV-Beta, elicited a spike-specific immunodominant CD8+ T cell response. Collectively, rVSV vaccines targeting SARS-CoV-2 variants of concern may be considered in the global fight against COVID-19.

Daniela Sieghart et al.

Multiparametric Prediction Models for Coronavirus Disease 2019 Vaccine Selection: Results of a Comparative Population-Based Cohort Study

CID, November 2022; doi.org/10.1093/cid/ciac840

Abstract

Background

An understanding vaccine-dependent effects on protective and sustained humoral immune response is crucial to planning future vaccination strategies against coronavirus disease 2019 (COVID-19).

Methods

In this multicenter, population-based, cohort study including 4601 individuals after primary vaccination against COVID-19 ≥ 4 months earlier we compared factors associated with residual antibody levels against severe acute respiratory syndrome coronavirus-2 receptor-binding domain (RBD) across different vaccination strategies (BNT162b2, mRNA-1273, or ChAdOx1).

Results

Our main model including 3787 individuals (2 × BNT162b2, n = 2271; 2 × mRNA-1273, n = 251; 2 × ChAdOx1, n = 1265), predicted significantly lower levels of anti-RBD antibodies after 6 months in individuals vaccinated with ChAdOx1 (392.7 binding antibody units per milliliter [BAU/mL]) compared with those vaccinated with BNT162b2 (1179.5 BAU/mL) or mRNA-1273 (2098.2 BAU/mL). Vaccine-dependent association of antibody levels was found for age with a significant predicted difference in BAU/ml per year for BNT162b2 (−21.5; 95% confidence interval [CI], −24.7 to −18.3) and no significant association for mRNA-1273 (−4.0; 95% CI, −20.0 to 12.1) or ChAdOx1 (1.7; 95% CI, .2 to 3.1). The predicted decrease over time since full immunization was highest in mRNA-1273 (−23.4; 95% CI, −31.4 to −15.4) compared with BNT162b2 (−5.9; 95% CI, −7 to −4.8).

Conclusions

Our study revealed population-based evidence of vaccine-dependent effects of age and time since full immunization on humoral immune response. Findings underline the importance of individualized vaccine selection, especially in elderly individuals.

Marc Garnier et al.

Association of preoperative COVID-19 and postoperative respiratory morbidity during the Omicron epidemic wave: the DROMIS-22 multicentre prospective observational cohort study

eClinicalMedicine; March 2023; doi.org/10.1016/j.eclinm.2023.101881

Abstract

Background

Preoperative COVID-19 has been associated with excess postoperative morbi-mortality. Consequently, guidelines were developed that recommended the postponement of surgery for at least 7 weeks after the infection. We hypothesised that vaccination against the SARS-CoV-2 and the large predominance of the Omicron variant attenuated the effect of a preoperative COVID-19 on the occurrence of postoperative respiratory morbidity.

Methods

We conducted a prospective cohort study in 41 French centres between 15 March and 30 May 2022 (ClinicalTrials NCT05336110), aimed at comparing the postoperative respiratory morbidity between patients with and without preoperative COVID-19 within 8 weeks prior to surgery. The primary outcome was a composite outcome combining the occurrence of pneumonia, acute respiratory failure, unexpected mechanical ventilation, and pulmonary embolism within the first 30 postoperative days. Secondary outcomes were 30-day mortality, hospital length-of-stay, readmissions, and non-respiratory infections. The sample size was determined to have 90% power to identify a doubling of the primary outcome rate. Adjusted analyses were performed using propensity score modelling and inverse probability weighting.

Findings

Of the 4928 patients assessed for the primary outcome, of whom 92.4% were vaccinated against the SARS-CoV-2, 705 had preoperative COVID-19. The primary outcome was reported in 140 (2.8%) patients. An 8-week preoperative COVID-19 was not associated with increased postoperative respiratory morbidity (odds ratio 1.08 [95% CI 0.48–2.13]; p = 0.83). None of the secondary outcomes differed between the two groups. Sensitivity analyses concerning the timing between COVID-19 and surgery, and the clinical presentations of preoperative COVID-19 did not show any association with the primary outcome, except for COVID-19 patients with ongoing symptoms the day of surgery (OR 4.29 [1.02–15.8]; p = 0.04).

Interpretation

In our Omicron-predominant, highly immunised population undergoing general surgery, a preoperative COVID-19 was not associated with increased postoperative respiratory morbidity.

Chiara Piubelli et al.

Subjects who developed SARS-CoV-2 specific IgM after vaccination show a longer humoral immunity and a lower frequency of infection

eBioMedicine, February 2023; doi.org/10.1016/j.ebiom.2023.104471

Abstract    

Background

We have previously shown that eliciting SARS-CoV-2-specific IgM after vaccination is associated with higher levels of SARS-CoV-2 neutralizing IgG. This study aims to assess whether IgM development is also associated with longer-lasting immunity.

Methods

We analysed anti-SARS-CoV-2 spike protein IgG and IgM (IgG-S, IgM-S), and anti-nucleocapsid IgG (

Interpretation

The development of anti-SARS-CoV-2 IgM-S following D1 and D2 is associated with higher IgG-S levels. Most individuals who developed IgM-S never became infected, suggesting that IgM elicitation may be associated with a lower risk of infection.

YiJu et al.

Impact of anti-PEG antibodies inducedby SARS-CoV-2 mRNA vaccines

Nature, december 2022; doi.org/10.1038/s41577-022-00825-x

Abstract

The successful mRNA vaccines againstCOVID-19 contain polyethylene glycol (PEG)to stabilize the lipid nanoparticles. Recentdata show that PEG-specific antibodies canbe induced or boosted by mRNA vaccination.Further research is needed to studythe potential links between PEG-specificantibodies, vaccine reactogenicity andenhanced clearance of other PEG-containingmedicines.

SharifaNasreen et al.

Effectiveness of Coronavirus Disease 2019 Vaccines Against Hospitalization and Death in Canada: A Multiprovincial, Test-Negative Design Study

CID, February 2023; doi.org/10.1093/cid/ciac634

Abstract

Background

A major goal of coronavirus disease 2019 (COVID-19) vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of messenger RNA (mRNA) and ChAdOx1 COVID-19 vaccines against severe outcomes in 4 Canadian provinces between December 2020 and September 2021.

Methods             

We conducted this multiprovincial, retrospective, test-negative study among community-dwelling adults aged ≥18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random-effects models.

Results

We included 2 508 296 tested participants, with 31 776 COVID-19 hospitalizations and 5842 deaths. Vaccine effectiveness was 83% after a first dose and 98% after a second dose against both hospitalization and death (separately). Against severe outcomes, effectiveness was 87% (95% confidence interval [CI], 71%–94%) ≥84 days after a first dose of mRNA vaccine, increasing to 98% (95% CI, 96%–99%) ≥112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95% CI, 75%–94%) ≥56 days after a first dose, increasing to 97% (95% CI, 91%–99%) ≥56 days after a second dose. Lower 1-dose effectiveness was observed for adults aged ≥80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules and against Alpha, Gamma, and Delta variants.

Conclusions

Two doses of mRNA or ChAdOx1 vaccine provide excellent protection against severe outcomes.

Pernille Jorgensen et al.

Factors associated with receipt of COVID-19 vaccination and SARS-CoV-2 seropositivity among healthcare workers in Albania (February 2021–June 2022): secondary analysis of a prospective cohort study

The Lancet, February 2023; doi.org/10.1016/j.lanepe.2023.100584

Abstract

Background

Healthcare workers (HCWs) have been disproportionally affected by COVID-19. We investigated factors associated with two- and three-dose COVID-19 vaccine uptake and SARS-CoV-2 seropositivity among 1504 HCWs enrolled (19 February-7 May 2021) in a prospective COVID-19 vaccine effectiveness cohort in Albania through a secondary analysis.

Methods

We collected sociodemographic, occupational, health, prior SARS-CoV-2 infection, and COVID-19 vaccination data from all HCWs at enrollment. Vaccination status was assessed weekly through June 2022. A serum sample was collected from all participants at enrollment and tested for anti-spike SARS-CoV-2 antibodies. We analyzed HCWs characteristics and outcomes using multivariable logistic regression.

Findings

Interpretation

In a large cohort of Albanian HCWs, COVID-19 vaccine booster dose uptake was very low, particularly among younger, female, and non-physician HCWs, despite evidence demonstrating the added benefit of boosters in preventing infection and severe disease. Reasons behind these disparities should be explored to develop targeted strategies in order to promote uptake in this critical population. SARS-CoV-2 seroprevalence was higher among non-physicians and HCWs performing APGs. A better understanding of the factors contributing to these differences is needed to inform interventions that could reduce infections in the future.

Chang-Monteagudo A. et al.

A single dose of SARS-CoV-2 FINLAY-FR-1A vaccine enhances neutralization response in COVID-19 convalescents, with a very good safety profile: An open-label phase 1 clinical trial

The Lancet, https://www.thelancet.com/action/showPdf?pii=S2667-193X%2821%2900075-2

CONTENUTO : trial clinico monocentrico open-label di fase I condotto presso il National Institute of Haematology and Immunology (L’Avana, Cuba), su una popolazione di 30 pazienti affetti da COVID-19, convalescenti, tra i 25-57 anni. I pazienti sono stati divisi in tre gruppi : convalescenti da COVID-19 mild, convalescenti asintomatici (entrambi con PCR positiva al tampone nasofaringeo al momento della diagnosi con negativizzazione almeno due mesi prima dell’inizio dello studio) ed infine individui con infezione subclinica con IgG positive per Sars-CoV2 al test sierologico, in assenza di un test molecolare nasofaringeo positivo. Criteri di esclusione : storia di patologia COVID-19 relata moderata o severa negli ultimi 2 mesi, patologie severe o patologie croniche non compensate, immunodeficit, storia di reazioni allergiche severe, gravidanza, allattamento, trattamenti immunologici nei 30 giorni precedenti l’inizio dello studio. Su tale campione di popolazione è stato testato un vaccino basato su d-RBD ricombinante  (SARS-CoV-2 FINLAY-FR-1°) somministrato intramuscolo ed utilizzato come booster in pazienti convalescenti, con l’obiettivo di valutarne la sicurezza e la presenza di reazioni locali o sistemiche (outcomes primari) e la immunogenicità (outcome secondario). Non è stata riscontrata nessuna reazione avversa grave, le più frequenti (10%) sono state reazioni locali come arrossamento e dolore nella sede di iniezione, perlopiù nelle prime 24h dopo la somministrazione. In 26 pazienti è stato evidenziato un significativo aumento delle IgG anti-RBD a 7 giorni dalla somministrazione, mostrando una stimolazione di una risposta anticorpale secondaria, con un picco dei valori anticorpali a 28 giorni dal vaccino. Tale dose booster si inserisce in un contesto di risposta immunitaria già stimolata dall’infezione pregressa da Sars-CoV2, che porta alla produzione di cellule B della memoria long-term.

COMMENTO:  Una sperimentazione assai risicata (30  soggetti) sulla immunogenicità e sicurezza di un vaccino  fatto col frammento RBD della proteina spike ricombinante in soggetti convalescenti. Molto preliminare, al momento dice poco.

Agrawal U. et al.

COVID-19 hospital admissions and deaths after BNT162b2 and ChAdOx1 nCoV-19 vaccinations in 2·57 million people in Scotland (EAVE II): a prospective cohort study

The Lancet, https://www.thelancet.com/action/showPdf?pii=S2213-2600%2821%2900380-5

CONTENUTO : studio di coorte prospettico, condotto in Scozia su un campione di 2.570.812 persone (8 dicembre 2020-21 Aprile 2021), utilizzando la piattaforma di sorveglianza nazionale Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVEII), contentente informazioni rispetto alle vaccinazioni, cure primarie, risultati dei testo molecolari per Sars-CoV2, ospedalizzazioni e mortalità di 5.4 milioni di persone. I soggetti dello studio sono stati valutati dalla prima somministrazione di vaccino BNT162b2 o ChAdOx1 nCoV-19 fino al ricovero in regime ospedaliero, all’exitus o fino al termine dello studio il 18 aprile 2021.  Utilizzando un modello di regressione di Poisson tempo-dipendente, si sono stimati i rate ratios (RR) di fattori demografici e clinici associati con l’ospedalizzazione o il decesso da COVID-19 in un periodo uguale o superiore alle due settimane dopo la prima dose di vaccino, stratificati per il tipo di vaccinazione ricevuta. 841.090 (32.7%) persone hanno rivevuto la prima dose di BNT162b2, 1.730.918 (67.3%) invece ChAdOx1, 694.915 persone hanno ricevuto la seconda dose nel corso del periodo di studio. I risultati hanno mostrato un basso rischio di ospedalizzazione o decesso COVID-relati a 14 giorni o più dalla prima dose. Fattori di rischio per una patologia severa da Sars-Cov2 si sono dimostrati : età avanzata, comorbidità, recenti ospedalizzazioni nelle 4 settimane precedenti alla dose di vaccino, tabagismo, privazione socio-economica, oppure essere in strutture di lungodegenza. Il tasso di ospedalizzazione o decesso da COVID-19 durante il periodo di studio è stado di 4-6 eventi per 1000 persone-anno (1196 eventi totali) vs 8-57 eventi per 1000 persone anno (10282 eventi totali) nella popolazione non vaccinata. Tale studio mostra in conclusione un basso rischio di ospedalizzazione o decesso legato all’infezione da Sars-CoV2 a 14 giorni o più dalla prima dose di vaccino, tranne nelle classi di popolazione fragile sopraelencate. Tali evidenze potranno essere utilizzate per formulare future politiche vaccinali.

COMMENTO : I numeri sono grandi ed importanti (un bel pò di scozzesi) , tuttavia i risultati delle’effettività clinica delle due dosi vaccinali sono largamente noti da precedenti pubblicazioni. Colpisce però  l’ elevata protezione vaccinale, sia da Cominarti che da ChadOx  dopo la sola prima dose. Ricordo che  in UK hanno molto difeso la loro strategia di dilatare  i tempi della seconda dose per proteggere, almeno parzialmente, il maggior numero di persone in una fase di bassadisponibilità dei vaccini. Dubito , però, che questa strategia possa essere applicata ora con la variante Delta , e gli Autori comunque notano lì elevato rischio di infezione e malattia entro i 15 gitoni dalla prima dose.

El Sahly H.M. et al.

Efficacy of the mRNA-1273 SARS-CoV-2Vaccine at Completion of Blinded Phase

NEJM , https://www.nejm.org/doi/pdf/10.1056/NEJMoa2113017?articleTools=true

CONTENUTO : un analisi ad interim al completamento della fase in cieco di uno studio di fase III observer-blinded controllato verso placebo per la valutazione dell’efficacia, della immunogenicità e della sicurezza del vaccino mRNA-1273 Sars-CoV2 vs. Placebo, condotto su una popolazione di 30.415 volontari. (15.209 vaccinati vs 15.209 placebo) condotto dal 27 giugno al 23 ottobre 2020. Criteri di inclusione : età >18 aa, non precedenti infezioni da Sars-CoV2, alto rischio di infezione o di malattia severa (o entrambe). I partecipanti sono stati assegnati in maniera casuale in un rapporto di 1 :1 nei due gruppi. End-point primario : prevenzione dell’infezione da Sars-CoV2 insorta a 14 giorni dopo la seconda dose di vaccino, in pazienti senza pregressa infezione da Sars-CoV2. L’efficacia nel prevenire la malattia da Sars-CoV2 è stata del 93.2%, (55 confermati nel gruppo dei vaccinati vs. 744 nel gruppo placebo) L’efficacia nel prevenire la malattia severa è stata del 98.2% (2 casi nei vaccinati vs. 106 nel gruppo placebo). L’efficacia nel prevenire un’infezione asintomatica a 14 giorni dalla seconda somministrazione di vaccino è stata del 63% (214 vaccinati vs 498 nel gruppo placebo). Effetti avversi correlati all’iniezione sono stati evidenziati nel 13.9% dei vaccinati vs. 8.5% del gruppo placebo, con 12 casi di eventi avversi severi nel gruppo dei vaccinati vs 4 nel gruppo placebo. In conclusione tale vaccino si dimostra efficace nel prevenire il COVID-19 e la malattia severa oltre 5 mesi dopo la somministrazione, con un profilo di sicurezza accettabile.

COMMENTO : L’alta ’efficacia del vaccino mRNA Spikevac ( Moderna) è perfettamente mantenuta almeno fino a 5 mesi ( col dubbio delle varianti VOC , in particolare della variante delta,perchè questa sperimentazione è precedente alla diffusione delle VOC). Colpisce l’asserita sostanziale eguaglianza degli effetti avversi dopo la prima e seconda dose, cosa che non si era verificata al primo esame della safety ad un mese dalla seconda dose, che è stata alloraparecchio più reattogenica della prima. Questo dato suggerirebbe che nel tempo la maggiore reattività della seconda dose diminuisce, (buon viatico per la terza dose ?). 

Isabelle Montgomerie et al.

Incorporation of SARS-CoV-2 spike NTD to RBD Protein Vaccine Improves Immunity Against Viral Variants

Cell, February 2023; doi.org/10.1016/j.isci.2023.106256

Abstract

Emerging SARS-CoV-2 variants pose a threat to human health worldwide. SARS-CoV-2 receptor binding domain (RBD)-based vaccines are suitable candidates for booster vaccines, eliciting a focused antibody response enriched for virus neutralizing activity. Although RBD proteins are manufactured easily, and have excellent stability and safety properties, they are poorly immunogenic compared to the full-length spike protein. We have overcome this limitation by engineering a subunit vaccine composed of an RBD tandem dimer fused to the N-terminal domain (NTD) of the spike protein. We found that inclusion of the NTD (i) improved the magnitude and breadth of the T cell and anti-RBD response, and (ii) enhanced T follicular helper cell and memory B cell generation, antibody potency, and cross-reactive neutralization activity against multiple SARS-CoV-2 variants, including B.1.1.529 (Omicron BA.1). In summary, our uniquely engineered RBD-NTD-subunit protein vaccine provides a promising booster vaccination strategy capable of protecting against known SARS-CoV-2 variants of concern.

Marianoel Pereira-Gómez et al.

One-year monitoring SARS-CoV-2 RNA surface contamination in hospitals reveals no correlation with organic material and negative pressure as a limiting factor for contamination

Cell, February 2023; doi.org/10.1016/j.heliyon.2023.e13875

Abstract

Understanding transmission routes of SARS-CoV-2 is crucial to establish effective interventions in healthcare institutions. Although the role of surface contamination in SARS-CoV-2 transmission has been controversial, fomites have been proposed as a contributing factor. Longitudinal studies about SARS-CoV-2 surface contamination in hospitals with different infrastructure (presence or absence of negative pressure systems) are needed to improve our understanding of their effectiveness on patient healthcare and to advance our knowledge about the viral spread.

We performed a one-year longitudinal study to evaluate surface contamination with SARS-CoV-2 RNA in reference hospitals. These hospitals have to admit all COVID-19 patients from public health services that require hospitalization. Surfaces samples were molecular tested for SARS-CoV-2 RNA presence considering three factors: the dirtiness by measuring organic material, the circulation of a high transmissibility variant, and the presence or absence of negative pressure systems in hospitalized patients' rooms.

Our results show that: (i) There is no correlation between the amount of organic material dirtiness and SARS-CoV-2 RNA detected on surfaces; (ii) SARS-CoV-2 high transmissible Gamma variant introduction significantly increased surface contamination; (iii) the hospital with negative pressure systems was associated with lower levels of SARS-CoV-2 surface contamination and, iv) most environmental samples recovered from contaminated surfaces were assigned as non-infectious.

This study provides data gathered for one year about the surface contamination with SARS-CoV-2 RNA sampling hospital settings. Our results suggest that spatial dynamics of SARS-CoV-2 RNA contamination varies according with the type of SARS-CoV-2 genetic variant and the presence of negative pressure systems. In addition, we showed that there is no correlation between the amount of organic material dirtiness and the quantity of viral RNA detected in hospital settings. Our findings suggest that SARS CoV-2 RNA surface contamination monitoring might be useful for the understanding of SARS-CoV-2 dissemination with impact on hospital management and public health policies. This is of special relevance for the Latin-American region where ICU rooms with negative pressure are insufficient.

Lidong Gao et al.

Safety and immunogenicity of a protein subunit COVID-19 vaccine (ZF2001) in healthy children and adolescents aged 3–17 years in China: a randomised, double-blind, placebo-controlled, phase 1 trial and an open-label, non-randomised, non-inferiority, phase 2 trial

The Lancet, February 2023; doi.org/10.1016/S2352-4642(22)00376-5

Abstract

Background

ZF2001 is a recombinant protein subunit vaccine against SARS-CoV-2 that has been approved for use in China, Colombia, Indonesia, and Uzbekistan in adults aged 18 years or older, but not yet in children and adolescents younger than 18 years. We aimed to evaluate the safety and immunogenicity of ZF2001 in children and adolescents aged 3–17 years in China.

Interpretation

ZF2001 is safe, well tolerated, and immunogenic in children and adolescents aged 3–17 years. Vaccine-elicited sera can neutralise the omicron BA.2 subvariant, but with reduced activity. The results support further studies of ZF2001 in children and adolescents.

Carreño JM et al.

An inactivated NDV-HXP-S COVID-19 vaccine elicits a higher proportion of neutralizing antibodies in humans than mRNA vaccination

Science, February 2023; DOI: 10.1126/scitranslmed.abo2847

Abstract

NDV-HXP-S is a recombinant Newcastle disease virus–based vaccine against SARS-CoV-2, which expresses an optimized (HexaPro) spike protein on its surface. The vaccine can be produced in embryonated chicken eggs using the same process as that used for the production of the vast majority of influenza virus vaccines. Here, we performed a secondary analysis of the antibody responses after vaccination with inactivated NDV-HXP-S in a phase 1 clinical study in Thailand. The SARS-CoV-2 neutralizing and spike protein binding activity of NDV-HXP-S postvaccination serum samples was compared to that of samples from mRNA BNT162b2 (Pfizer) vaccinees. Neutralizing activity of sera from NDV-HXP-S vaccinees was comparable to that of BNT162b2 vaccinees, whereas spike protein binding activity of the NDV-HXP-S vaccinee samples was lower than that of sera obtained from mRNA vaccinees. This led us to calculate ratios between binding and neutralizing antibody titers. Samples from NDV-HXP-S vaccinees had binding to neutralizing activity ratios that were lower than those of BNT162b2 sera, suggesting that NDV-HXP-S vaccination elicits a high proportion of neutralizing antibodies and low non-neutralizing antibody titers. Further analysis showed that, in contrast to mRNA vaccination, which induces strong antibody titers to the receptor binding domain (RBD), the N-terminal domain, and the S2 domain, NDV-HXP-S vaccination induced an RBD-focused antibody response with little reactivity to S2. This finding may explain the high proportion of neutralizing antibodies. In conclusion, vaccination with inactivated NDV-HXP-S induces a high proportion of neutralizing antibodies and absolute neutralizing antibody titers that are comparable to those elicited by mRNA vaccination.

Paul T Heath et al.

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial

CID, October 2022; doi.org/10.1093/cid/ciac803

Abstract

Background

The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported.

Methods

Adults aged 18–84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses.

Results

Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%–88.8%). Vaccine efficacy was 100% (95% CI, 17.9%–100.0%) against severe disease and 76.3% (95% CI, 57.4%–86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein–specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups.

Conclusions

A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated.

We Y et al.

Estimation of Vaccine Effectiveness of CoronaVac and BNT162b2 Against Severe Outcomes Over Time Among Patients With SARS-CoV-2 Omicron

JAMA, February 2023; doi:10.1001/jamanetworkopen.2022.54777

Abstract

Importance  Few studies have evaluated the waning of vaccine effectiveness against severe outcomes caused by SARS-CoV-2 Omicron infection. Hong Kong is providing inactivated and mRNA vaccines, but the population had limited protection from natural infections before the Omicron variant emerged.

Objective  To examine the change in vaccine effectiveness against hospitalization and mortality due to the Omicron variant over time.

Design, Setting, and Participants  This case-control study included adults with SARS-CoV-2 Omicron variant infection who died or were hospitalized in Hong Kong from January 1 to June 5, 2022 (ie, case participants), and adults with SARS-CoV-2 Omicron, sampled from the public health registry during the study period (ie, control participants), who were matched to case participants by propensity score.

Exposures  Vaccination status of the individuals.

Main Outcomes and Measures  Estimated vaccine effectiveness against death, death or hospitalization, and death among hospitalized patients. Vaccine effectiveness was calculated as 1 − adjusted odds ratio obtained by conditional logistic regression adjusted with covariates for each period following vaccination.

Results  There were 32 823 case participants (25 546 [77.8%] ≥65 years; 16 930 [47.4%] female) and 131 328 control participants (100 041 [76.2%] ≥65 years; 66 625 [46.6%] female) in the sample analyzed for the death or hospitalization outcome. Vaccine effectiveness against death or hospitalization was maintained for at least 6 months after the second dose of both CoronaVac (74.0%; 95% CI, 71.8%-75.8%) and BNT162b2 (77.4%; 95% CI, 75.5%-79.0%) vaccines. Vaccine effectiveness against death in those aged 18 to 49 years was 86.4% (95% CI, 85.8%-87.0%) and 92.9% (95% CI, 92.6%-93.2%) for those receiving 2 doses of CoronaVac and BNT162b2, respectively, while for patients aged 80 years or older, it dropped to 61.4% (95% CI, 59.8%-63.2%) and 52.7% (95% CI, 50.2%-55.6%) for CoronaVac and BNT162b2, respectively. Nevertheless, overall vaccine effectiveness against death at 4 to 6 months after the third dose was greater than 90% for CoronaVac, BNT162b2, and the mixed vaccine schedule (eg, mixed vaccines: vaccine effectiveness, 92.2%; 95% CI, 89.2%-95.1%).

Conclusions and Relevance  While vaccines were generally estimated to be effective against severe outcomes caused by SARS-CoV-2 Omicron infection, this analysis found that protection in older patients was more likely to wane 6 months after the second dose. Hence, a booster dose is recommended for older patients to restore immunity. This is especially critical in a setting like Hong Kong, where third-dose coverage is still insufficient among older residents.

Marking U et al.

7-month duration of SARS-CoV-2 mucosal immunoglobulin-A responses and protection

The Lancet, January 2023; doi.org/10.1016/S1473-3099(22)00834-9

Abstract

Mucosal immunity has a pivotal role in protection from respiratory viral infections.1 The current authors have showed substantial protection from omicron infection by high concentrations of nasal mucosal SARS-CoV-2 WT spike immunoglobulin-A (M-IgA) over a 4-week screening period.2 A sharp increase in M-IgA concentrations following BA.1 or BA.2 breakthrough infection in triple vaccinated health-care workers was also observed.2 Here, we present follow-up data with prospectively collected omicron infection rates and systemic and mucosal antibody concentrations from the same cohort (appendix pp 7–9, 12–14).
The association between M-IgA concentrations at the 75th percentile or higher at enrolment and a reduced risk of symptomatic BA.1, BA.2, or BA.5 breakthrough infection remained over an 8-month follow-up period, with a hazard ratio (HR) of 0•55 (95% CI 0•35–0•87), much due to the initial risk difference (figure A). Serum WT spike-specific IgG (S-IgG) concentrations waned over 8 months following a third vaccine dose in all study participants (appendix p 10), concurrent with previous data.3 However, concentrations of nasal M-IgA in participants with previous SARS-CoV-2 infection, but without omicron breakthrough infection, remained above the amount associated to 65% protection2 over the 8-month study period (figure C). This finding suggests a long-lasting mucosal immunity evoked by SARS-CoV-2 infection.
We next followed systemic and mucosal immune responses in participants that had a BA.1 or BA.2 breakthrough infection during the screening study. 7 months following breakthrough infection, S-IgG concentrations waned to be lower than at baseline (appendix p 10). As previously shown,4 serological responses were lower among participants with a history of SARS-CoV-2 infection before breakthrough infection compared with those without and the difference remained over the 7-months follow-up (appendix p 10). Whether these findings reflect immune imprinting after previous infection5 or a hampered systemic viral replication due to stronger and more rapid mucosal immune responses2 needs further investigation. Interestingly, although nasal M-IgA concentrations waned, they remained above the protective threshold2 in 94% of participants with previous SARS-CoV-2 WT or delta infection and in 58% of previously SARS-CoV-2-naive participants (figure B). In line with this, and in agreement with recent population-based data,6, 7 BA.1 and BA.2 infections were strongly protective against subsequent BA.5 infection in this cohort, with a HR of 0•13 (95% CI 0•04–0•44; figure D).
To assess whether M-IgA in nasal samples originated in the mucosa, we correlated M-IgA to mucosal spike-specific secretory IgA in nasal samples, and M-IgA to spike-specific IgA in serum. Concentrations of M-IgA correlated stronger to mucosal secretory IgA in nasal samples (r=0•9, p<0•001) than to spike-specific IgA in serum (r=0•64, p<0•001) (appendix p 11). Although a spillover from the circulation cannot be ruled out, these results indicate a mucosal origin of nasal IgA.
These findings highlight the key role of antigen presentation at the mucosa and support a protective effect of mucosal immunity for up to 8 months. Whether nasal or oral vaccines can elicit mucosal immune responses and protection similar to those following natural infection in mRNA-vaccinated individuals, will be an important aspect of ongoing clinical trials.Florea A. et al.

Effectiveness of Messenger RNA-1273 Vaccine Booster Against Coronavirus Disease 2019 in Immunocompetent Adults

CID, September 2022; doi.org/10.1093/cid/ciac785

Abstract

We conducted a prospective cohort study at Kaiser Permanente Southern California to evaluate the relative vaccine effectiveness (rVE) of a booster dose vs 2-dose primary series of messenger RNA (mRNA)-1273 in immunocompetent individuals.

Conclusions

Among immunocompetent adults, the mRNA-1273 booster conferred additional protection against SARS-CoV-2 infection and severe COVID-19 disease compared with the 2-dose mRNA-1273 primary series during periods of Delta and Omicron predominance.

Irrgang P. et al.

Class switch toward noninflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination

Science, December 2022; doi/10.1126/sciimmunol.ade2798

Abstract

RNA vaccines are efficient preventive measures to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. High levels of neutralizing SARS-CoV-2 antibodies are an important component of vaccine-induced immunity. Shortly after the initial two mRNA vaccine doses, the immunoglobulin G (IgG) response mainly consists of the proinflammatory subclasses IgG1 and IgG3. Here, we report that several months after the second vaccination, SARS-CoV-2–specific antibodies were increasingly composed of noninflammatory IgG4, which were further boosted by a third mRNA vaccination and/or SARS-CoV-2 variant breakthrough infections. IgG4 antibodies among all spike-specific IgG antibodies rose, on average, from 0.04% shortly after the second vaccination to 19.27% late after the third vaccination. This induction of IgG4 antibodies was not observed after homologous or heterologous SARS-CoV-2 vaccination with adenoviral vectors. Single-cell sequencing and flow cytometry revealed substantial frequencies of IgG4-switched B cells within the spike-binding memory B cell population [median of 14.4%; interquartile range (IQR) of 6.7 to 18.1%] compared with the overall memory B cell repertoire (median of 1.3%; IQR of 0.9 to 2.2%) after three immunizations. This class switch was associated with a reduced capacity of the spike-specific antibodies to mediate antibody-dependent cellular phagocytosis and complement deposition. Because Fc-mediated effector functions are critical for antiviral immunity, these findings may have consequences for the choice and timing of vaccination regimens using mRNA vaccines, including future booster immunizations against SARS-CoV-2.

Jinal N. Bhiman et al.

Novavax NVX-COV2373 triggers neutralization of Omicron sub-lineages

Nature, January 2023; doi.org/10.1038/s41598-023-27698-x

Abstract

The SARS-CoV-2 Omicron (B.1.1.529) Variant of Concern (VOC) and its sub-lineages (including BA.2, BA.4, BA.5, BA.2.12.1) contain spike mutations that confer high level resistance to neutralizing antibodies induced by vaccination with ancestral spike or infection with previously circulating variants. The NVX-CoV2373 vaccine, a protein nanoparticle vaccine containing the ancestral spike sequence, has value in countries with constrained cold-chain requirements. Here we report neutralizing titers following two or three doses of NVX-CoV2373. We show that after two doses, Omicron sub-lineages BA.1 and BA.4/BA.5 were resistant to neutralization by 72% (21/29) and 59% (17/29) of samples respectively. However, after a third dose of NVX-CoV2373, we observed high titers against Omicron BA.1 (GMT: 1,197) and BA.4/BA.5 (GMT: 582), with responses similar in magnitude to those triggered by three doses of an mRNA vaccine. These data are of particular relevance as BA.4/BA.5 is dominating in multiple locations, and highlight the potential utility of the NVX-CoV2373 vaccine as a booster in resource-limited environments.

Rupsha Fraser et al.

Upper respiratory tract mucosal immunity for SARS-CoV-2 vaccines

Cell, January 2023; doi.org/10.1016/j.molmed.2023.01.003

Abstract

SARS-CoV-2 vaccination significantly reduces morbidity and mortality, but has less impact on viral transmission rates, thus aiding viral evolution; and the longevity of vaccine-induced immunity rapidly declines. Immune responses in respiratory tract mucosal tissues are crucial for early control of infection, and can generate long-term antigen-specific protection with prompt recall responses. However, currently approved SARS-CoV-2 vaccines are not amenable to adequate respiratory mucosal delivery, particularly in the upper airways, which could account for the high vaccine breakthrough infection rates and limited duration of vaccine-mediated protection. In view of these drawbacks, we outline a strategy that has the potential to enhance both the efficacy and durability of existing SARS-CoV-2 vaccines, by inducing robust memory responses in the upper respiratory tract mucosa.

Katia Alves et al.

Immunogenicity of a Fourth Homologous Dose of NVX-CoV2373

NEJM, January 2023; doi/full/10.1056/NEJMc2215509

Abstract        

The emergence and rapid propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants — in particular, the B.1.1.529 (omicron) sublineages, which have mutations that increase transmissibility and evasiveness against vaccine-induced immunity — can substantially reduce the efficacy of approved vaccines. The degree to which ancestral strain–based vaccines induced immunity against variants depends on the ability of the vaccine to induce broadly cross-reactive antibodies. The NVX-CoV2373 vaccine (Novavax) consists of full-length, prefusion, recombinant spike (rS) protein trimers with epitopes conserved across variants and is coformulated with a saponin-based adjuvant, Matrix-M, which may enhance antibody avidity, affinity maturation, and epitope spreading.

As part of an ongoing phase 2, randomized, placebo-controlled clinical trial of NVX-CoV2373 that is being conducted in Australia and the United States (ClinicalTrials.gov number, NCT04368988. opens in new tab), two doses of NVX-CoV2373 were administered to participants 21 days apart, followed initially by a single booster dose after approximately 6 months.1 The trial protocol is available with the full text of this letter at NEJM.org. In a continuation of this trial, a second booster dose of the vaccine was administered after another 6 months. Only participants who received four doses of NVX-CoV2373 were included in this analysis.

These data indicate that boosting with the NVX-CoV2373 vaccine resulted in enhanced cross-reactive immunity to SARS-CoV-2 variants, a decreased gap between immune recognition of the variants and the ancestral strain, and the induction of a potentially more universal-like response against SARS-CoV-2 variants. We believe that this phenomenon may be driven by the conserved epitopes found on the recombinant protein vaccine, whereby expression of the full-length trimers of the S protein present epitopes that are conserved across variants for recognition by the immune system.4 This process may be further enhanced by the saponin-based Matrix-M adjuvant by means of epitope spreading.5 Whether the observed antibody responses to additional boosting with the ancestral sequence that was used in the NVX-CoV2373 vaccine translate into meaningful protection against emerging SARS-CoV-2 variants will require clinical studies of efficacy.

Covid Vaccines — Playing the Long Game

https://www.nejm.org/doi/full/10.1056/NEJMp2300222

Dan-Yu Lin et al.

Effectiveness of Bivalent Boosters against Severe Omicron Infection

NEJM, January 2023; DOI:10.1056/NEJMc2215471

Abstract

On August 31, 2022, the Food and Drug Administration (FDA) authorized the Moderna and Pfizer–BioNTech bivalent Covid-19 vaccines, each containing equal amounts of mRNA encoding the spike protein from the ancestral strain and the spike protein from the BA.4 and BA.5 strains of the B.1.1.529 (omicron) variant, for emergency use as a single booster dose at least 2 months after primary or booster vaccination.1 The FDA authorizations were based on nonclinical data for these two bivalent vaccines, safety and immunogenicity data for bivalent vaccines containing mRNA from the BA.1 lineage of the omicron variant, and safety and effectiveness data for the monovalent mRNA Covid-19 vaccines.1 Since September 1, these two bivalent mRNA vaccines have replaced their monovalent counterparts as booster doses for persons 12 years of age or older in the United States and in other countries. Here, we report data from a large cohort study on the effectiveness of these two bivalent vaccines against severe infection with omicron BA.4.6, BA.5, BQ.1, and BQ.1.1.

Estimates of Effectiveness of One Monovalent or Bivalent Booster Dose against Severe Omicron Infection.

The results are shown in Table 1 and Figures S2 and S3. Booster effectiveness peaked at approximately 4 weeks and waned afterward. For all participants 12 years of age or older, vaccine effectiveness against severe infection resulting in hospitalization over days 15 to 99 after receipt of one monovalent booster dose was 25.2% (95% confidence interval [CI], –0.2 to 44.2), and the corresponding vaccine effectiveness for one bivalent booster dose was 58.7% (95% CI, 43.7 to 69.8); the difference in vaccine effectiveness against this outcome between the bivalent booster and the monovalent booster was 33.5 percentage points (95% CI, 2.9 to 62.1). Vaccine effectiveness against severe infection resulting in hospitalization or death was 24.9% (95% CI, 1.4 to 42.8) for one monovalent booster dose and 61.8% (95% CI, 48.2 to 71.8) for one bivalent booster dose; the difference in vaccine effectiveness against this outcome between the bivalent booster and the monovalent booster was 36.9 percentage points (95% CI, 12.6 to 64.3) (Fig. S3 and Table 1). We obtained similar vaccine effectiveness estimates when the analysis was restricted to participants who were 18 years of age or older or 65 years of age or older, to participants who received an mRNA vaccine as their primary vaccine, or to previously uninfected participants (Table 1). In addition, estimates of vaccine effectiveness were similar for the Moderna and Pfizer–BioNTech boosters and similar among the first, second, and third booster doses (Table 1).

Bivalent boosters provided substantial additional protection against severe omicron infection in persons who had previously been vaccinated or boosted, although the effectiveness waned over time. The effectiveness of bivalent boosters was higher than that of monovalent boosters.

We adjusted for measured confounders, including vaccination history, previous infection, and demographic variables. However, estimates of booster effectiveness would be biased if boosted persons were more likely or less likely to seek Covid-19 testing than nonboosted persons. For this reason, we focused on severe infection, which was more likely to be reported than mild infection. Very strong unmeasured confounders would be required in order to fully explain away the observed effectiveness of bivalent boosters.

Hung Fu Tseng et al.

Effectiveness of mRNA-1273 vaccination against SARS-CoV-2 omicron subvariants BA.1, BA.2, BA.2.12.1, BA.4, and BA.5

Nature, January 2023; doi.org/10.1038/s41467-023-35815-7

Abstract

Studies have reported reduced natural SARS-CoV-2 infection- and vaccine-induced neutralization against omicron BA.4/BA.5 compared with earlier omicron subvariants. This test-negative case–control study evaluates mRNA-1273 vaccine effectiveness (VE) against infection and hospitalization with omicron subvariants. The study includes 30,809 SARS-CoV-2 positive and 92,427 SARS-CoV-2 negative individuals aged ≥18 years tested during 1/1/2022-6/30/2022. While 3-dose VE against BA.1 infection is high and wanes slowly, VE against BA.2, BA.2.12.1, BA.4, and BA.5 infection is initially moderate to high (61.0%-90.6% 14-30 days post third dose) and wanes rapidly. The 4-dose VE against infection with BA.2, BA.2.12.1, and BA.4 ranges between 64.3%-75.7%, and is low (30.8%) against BA.5 14-30 days post fourth dose, disappearing beyond 90 days for all subvariants. The 3-dose VE against hospitalization for BA.1, BA.2, and BA.4/BA.5 is 97.5%, 82.0%, and 72.4%, respectively; 4-dose VE against hospitalization for BA.4/BA.5 is 88.5%. Evaluation of the updated bivalent booster is warranted.

Azzi L et al.

Mucosal immune response after the booster dose of the BNT162b2 COVID-19 vaccine

The Lancet, January 2023; doi.org/10.1016/j.ebiom.2022.104435

Abstract

Background

To date, only a few studies reported data regarding the development of mucosal immune response after the BNT162b2-booster vaccination.

Methods

Samples of both serum and saliva of 50 healthcare workers were collected at the day of the booster dose (T3) and after two weeks (T4). Anti-S1-protein IgG and IgA antibody titres and the neutralizing antibodies against the Wuhan wild-type Receptor-Binding Domain in both serum and saliva were measured by quantitative and competitive ELISA, respectively. Data were compared with those recorded after the primary vaccination cycle (T2). Neutralizing antibodies against the variants of concern were measured in those individuals with anti-Wuhan neutralizing antibodies in their saliva.

The BNT162b2-booster vaccination elicits a strong systemic immune response but fails in activating an effective mucosal immunity against the Omicron BA.1 variant.

Liew F et al.

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

The Lancet, December 2022; doi.org/10.1016/j.ebiom.2022.104402

Abstract                                                                              

Background

Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced.

Methods

In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data.

Interpretation

The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity.

SuadHannawi et al.

Safety and immunogenicity of a bivalent SARS-CoV-2 protein booster vaccine, SCTV01C, in adults previously vaccinated with mRNA vaccine: a randomized, double-blind, placebo-controlled phase 1/2 clinical trial

The Lancet, December 2022; doi.org/10.1016/j.ebiom.2022.104386

Abstract

Background

Booster vaccination is an efficient way to address the waning protection of vaccines and immune escape of SARS-CoV-2 variants. We aimed to assess the safety and immunogenicity of SCTV01C, a novel bivalent protein vaccine as a booster for people who previously received two doses of mRNA vaccine.

Methods

In this randomized, phase 1/2 trial, adults fully vaccinated with mRNA vaccines 3–24 month earlier were enrolled. Participants received SCTV01C at 20 μg, 40 μg or placebo. The primary endpoints were adverse reactions within 7 days and immunogenicity on Day 28 after vaccination. This trial was registered with ClinicalTrials.gov (NCT05043311).

Interpretation

The heterologous booster of SCTV01C was safe, and induced uniformly high cross-neutralization antibody responses against Delta and Omicron variants.

Nicolas A. et al.

Extended SARS-CoV-2 mRNA vaccine prime-boost intervals enhances B cell immunity with limited impact on T cells

Cell, December 2022; doi.org/10.1016/j.isci.2022.105904

Abstract

Spacing the first two doses of SARS-CoV-2 mRNA vaccines beyond 3-4 weeks raised initial concerns about vaccine efficacy. While studies have since shown that long-interval regimens induce robust antibody responses, their impact on B and T cell immunity is poorly known. Here, we compare in SARS-CoV-2 naïve donors B and T cell responses to two mRNA vaccine doses administered 3-4 versus 16 weeks apart. After boost, the longer interval results in higher magnitude and a more mature phenotype of RBD-specific B cells. While the two geographically distinct cohorts present quantitative and qualitative differences in T cell responses at baseline and after priming, the second dose led to convergent features with overall similar magnitude, phenotype and function of CD4+ and CD8+ T cell responses at post-boost memory time points. Therefore, compared to standard regimens, a 16-week interval has a favorable impact on the B cell compartment but minimally affects T cell immunity.

Aurisicchio L et al.

A first-in-human trial on the safety and immunogenicity of COVID-eVax, a cellular response-skewed DNA vaccine against COVID-19

Cell, December 2022; doi.org/10.1016/j.ymthe.2022.12.017

Abstract

The COVID-19 pandemic and the need for additional safe, effective, and affordable vaccines gave new impetus into development of vaccine genetic platforms. Here we report the findings from the phase 1, first-in-human, dose-escalation study of COVID-eVax, a DNA vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. However, the vaccine did not induce neutralizing antibodies, while particularly relevant was the T cell-mediated immunity, with a robust Th1 response. This T cell-skewed immunological response adds significant information to the DNA vaccine platform and should be assessed in further studies for its protective capacity and potential usefulness also in other therapeutic areas, such as oncology.

Andreano E. et al.

B cell analyses after SARS-CoV-2 mRNA third vaccination reveals a hybrid immunity like antibody response

Nature, January 2023; doi.org/10.1038/s41467-022-35781-6

Abstract

The continuous evolution of SARS-CoV-2 generated highly mutated variants able to escape natural and vaccine-induced primary immunity. The administration of a third mRNA vaccine dose induces a secondary response with increased protection. Here we investigate the longitudinal evolution of the neutralizing antibody response in four donors after three mRNA doses at single-cell level. We sorted 4100 spike protein specific memory B cells identifying 350 neutralizing antibodies. The third dose increases the antibody neutralization potency and breadth against all SARS-CoV-2 variants as observed with hybrid immunity. However, the B cell repertoire generating this response is different. The increases of neutralizing antibody responses is largely due to the expansion of B cell germlines poorly represented after two doses, and the reduction of germlines predominant after primary immunization. Our data show that different immunization regimens induce specific molecular signatures which should be considered while designing new vaccines and immunization strategies.

SohamSinha, R. Tamara Konetzka

Association of COVID-19 Vaccination Rates of Staff and COVID-19 Illness and Death     Among Residents and Staff in US Nursing Homes

JAMA, December 2022;  doi:10.1001/jamanetworkopen.2022.49002       

Abstract

Importance  It is important to understand the association between staff vaccination rates and adverse COVID-19 outcomes in nursing homes.

Objective  To assess the extent to which staff vaccination was associated with preventing COVID-19 cases and deaths among residents and staff in nursing homes.

Conclusions and Relevance  The findings of this cohort study suggest that before the Omicron variant wave, increasing staff vaccination rates was associated with lower incidence of COVID-19 cases and deaths among residents and staff in US nursing homes. However, as newer, more infectious and transmissible variants of the virus emerged, the original 2-dose regimen of the COVID-19 vaccine as recommended in December 2020 was no longer associated with lower rates of adverse COVID-19 outcomes in nursing homes. Policy makers may want to consider longer-term policy options to increase the uptake of booster doses among staff in nursing homes.

Toledo-Romaní M.E et al.

Safety and efficacy of the two doses conjugated protein-based SOBERANA-02 COVID-19 vaccine and of a heterologous three-dose combination with SOBERANA-Plus: a double-blind, randomised, placebo-controlled phase 3 clinical trial

Lancet, December 2022; doi.org/10.1016/j.lana.2022.100423

Abstract

SOBERANA-02 is a COVID-19 conjugate vaccine (recombinant RBD conjugated to tetanus toxoid). Phases 1/2 clinical trials demonstrated high immunogenicity, promoting neutralising IgG and specific T-cell response. A third heterologous dose of SOBERANA-Plus (RBD-dimer) further increased neutralising antibodies. The aim of this study is to evaluate the safety and efficacy of two immunisation regimes: two doses of SOBERANA-02 and a heterologous three-dose combination with SOBERANA-Plus added to it.

Interpretation

Our results indicate that the straightforward to manufacture SOBERANA vaccines are efficacious in a context of Beta and Delta VOC circulation, have a favourable safety profile, and may represent an attractive option for use in COVID-19 vaccination programmes.

Na Fan et al.

Manganese-coordinated mRNA vaccines with enhanced mRNA expression and immunogenicity induce robust immune responses against SARS-CoV-2 variants

Science, December 2022; doi/10.1126/sciadv.abq3500

Abstract

It is urgent to develop more effective mRNA vaccines against the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants owing to the immune escape. Here, we constructed a novel mRNA delivery system [IC8/Mn lipid nanoparticles (IC8/Mn LNPs)]with high immunogenicity, via introducing a stimulator of interferon genes (STING) agonist [manganese (Mn)] based on a newly synthesized ionizable lipid (IC8). It was found that Mn can not only promote maturation of antigen-presenting cells via activating STING pathway but also improve mRNA expression by facilitating lysosomal escape for the first time. Subsequently, IC8/Mn LNPs loaded with mRNA encoding the Spike protein of SARS-CoV-2 Delta or Omicron variant (IC8/Mn@D or IC8/) were prepared. Both mRNA vaccines induced substantial specific immunoglobulin G responses against Delta or Omicron. IC8/Mn@D displayed strong pseudovirus neutralization ability, T helper 1–biased immune responses, and good safety. It can be concluded that IC8/Mn LNPs have great potential for developing Mn-coordinated mRNA vaccines with robust immunogenicity and good safety.

Rezaul Karim Ripon et al.

A meta-analysis of COVID-19 vaccines acceptance among Black /African American

Cell, December 2022; doi.org/10.1016/j.heliyon.2022.e12300

Abstract

The COVID-19 pandemic had harmed Black /African Americans disproportionately. Mortality and morbidity can reduce by increasing vaccination acceptability and availability. We conducted a meta-analysis of 20 studies that show the prevalence of Black /African Americans who embrace COVID-19 vaccination between 2020 and September, 2022. Investigations conducted before and after the availability of COVID-19 vaccines found the vaccinations effective. The heterogeneity was examined using stratified analyses, the meta-regression approach, and sensitivity analysis in R programming language. This meta-analysis showed that the overall COVID-19 vaccine hesitancy among Black/African Americans is 35% (95% CI: 26%- 45%). That means 65% of Black African Americans received vaccines without any hesitancy. According to correlation analysis, there was a negative relationship (r=-0.392, P=0.021) between the prevalence of vaccine hesitancy and the survey year. Evidence suggests ethnic health disparities in Black/ African Americans were for lower socioeconomic status. Some initiatives had to address health disparities, while ethnicity had not consistently been a focus. Only vaccines can prevent COVID-19 like infectious diseases. Policy makers and health educators should concern on vaccine acceptance or hesitancy related programs among Black/African American.

Maeda H. et al.

Effectiveness of Messenger RNA Coronavirus Disease 2019 Vaccines Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infections During the Delta Variant Epidemic in Japan: Vaccine Effectiveness Real-time Surveillance for SARS-CoV-2 (VERSUS)

CID, December 2022 ; doi.org/10.1093/cid/ciac292

Abstract

Background

Although high vaccine effectiveness of messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines has been reported in studies in several countries, data are limited from Asian countries, especially against the Delta (B.1.617.2) variant.

Conclusions

mRNA COVID-19 vaccines had high effectiveness against symptomatic SARS-CoV-2 infections in Japan during July–September 2021, when the Delta variant was dominant nationwide.

Nicole Ngai Yung Tsang et al.

Effectiveness of BNT162b2 and CoronaVac COVID-19 vaccination against asymptomatic and symptomatic infection of SARS-CoV-2 omicron BA.2 in Hong Kong: a prospective cohort study

Lancet, December 2022 ; doi.org/10.1016/S1473-3099(22)00732-0

Abstract

Background :COVID-19 vaccines provide protection against symptomatic infection that might require medical attention and against severe outcomes; however, there is a paucity of evidence regarding the effectiveness of the BNT162b2 and CoronaVac vaccines and their booster regimens against asymptomatic or mild omicron infections in the community. We aimed to measure the effectiveness of BNT162b2 and CoronaVac vaccines against asymptomatic and symptomatic SARS-CoV-2 omicron infections, during a period of omicron BA.2 predominance in Hong Kong.

Methods : In this prospective cohort study in a population that was generally infection-naive before the large omicron BA.2 wave between January and late May, 2022, we established a public health surveillance platform to monitor the evolving activity of SARS-CoV-2 infections in the community. We recruited a cohort of individuals aged 5 years and older between March 1 and March 7, 2022, from the general population. tions.

Interpretation

Two doses of either vaccine did not provide significant protection against COVID-19 infection. However, receipt of a BNT162b2 booster or CoronaVac booster was associated with a significantly lower risk of omicron BA.2 infection and symptomatic infection. Our findings confirm the effectiveness of booster doses to protect against mild and asymptomatic infection.

Gang Wang et al.

mRNA vaccines elicit potent neutralization against multiple SARS-CoV-2 Omicron subvariants and other variants of concern

CELL, November 2022; doi.org/10.1016/j.isci.2022.105690

Abstract

SARS-CoV-2 variants of concern (VOCs) have shown resistance to vaccines targeting the original virus strain. An mRNA vaccine encoding the spike protein of Omicron BA1 (BA1-S-mRNA) was designed, and its neutralizing activity, with or without the original receptor-binding domain (RBD)-mRNA, was tested against SARS-CoV-2 VOCs. First-dose of BA1-S-mRNA followed by two-boosts of RBD-mRNA elicited potent neutralizing antibodies (nAbs) against pseudotyped and authentic original SARS-CoV-2; pseudotyped Omicron BA1, BA2, BA2.12.1 and BA5 subvariants, and Alpha, Beta, Gamma and Delta VOCs; authentic Omicron BA1 subvariant and Delta VOC. By contrast, other vaccination strategies, including RBD-mRNA first-dose plus BA1-S-mRNA two-boosts, RBD-mRNA or BA1-S-mRNA three-doses, or their combinations, failed to elicit high nAb titers against all of these viruses. Overall, this vaccination strategy was effective for inducing broadly and potent nAbs against multiple SARS-CoV-2 VOCs, particularly Omicron BA5, and may guide the rational design of next-generation mRNA vaccines with greater efficacy against future variants.

Markus Hoffmann et al.

Effect of hybrid immunity and bivalent booster vaccination on omicron sublineage neutralisation

Lancet, December 2022; doi.org/10.1016/S1473-3099(22)00792-7

Abstract

Vaccination is the central strategy to control the COVID-19 pandemic. Vaccination-induced antibodies that target the viral spike (S) protein and neutralise SARS-CoV-2 are crucial for protection against infection and disease. However, most vaccines encode for the S protein of the virus that circulated early in the pandemic (eg, the B.1 lineage), and emerging SARS-CoV-

2 variants have mutations in the S protein that reduce neutralisation sensitivity. In particular, the omicron variant (B.1.1.529 lineage and sublineages) is highly mutated and efficiently evades antibodies.1, 2, 3 Therefore, bivalent mRNA vaccines have been developed that include the genetic information for S proteins of the B.1 lineage and the currently dominating omicron BA.5 lineage. These vaccines have shown increased immunogenicity and protection in mice,4 but information on potential differences in the effectiveness of monovalent and bivalent vaccine boosters in humans is scarce.

Collectively, our results show that the emerging omicron sublineages BQ.1.1 and particularly BA.2.75.2 efficiently evade neutralisation independent of the immunisation history. Although monovalent and bivalent vaccine boosters both induce high neutralising activity and increase neutralisation breadth, BA.2.75.2-specific and BQ.1.1-specific neutralisation activity remained relatively low. This finding is in keeping with the concept of immune imprinting by initial immunisation with vaccines targeting the ancestral SARS-CoV-2 B.1 lineage.9, 10 Furthermore, the observation that neutralisation of BA.2.75.2pp and BQ.1.1pp was most efficient in the cohort that had a breakthrough infection during the BA.1 and BA.2 wave and later received a bivalent booster vaccination, but was still less efficient than neutralisation of B.1pp, implies that affinity maturation of antibodies and two-time stimulation with different omicron antigens might still not be sufficient to overcome immune imprinting. As a consequence, novel vaccination strategies have to be developed to overcome immune imprinting by ancestral SARS-CoV-2 antigen.

Milligan E.C. et al.

Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge one year later

Science; December 2022; doi/10.1126/scitranslmed.add6383

Abstract

The U.S. Food and Drug Administration only gave emergency-use-authorization of the BNT162b2 and the mRNA-1273 SARS-CoV-2 vaccines for infants 6 months and older in June 2022. Yet, questions regarding the durability of vaccine efficacy, especially against emerging variants, in this age group remain. We demonstrated previously that a two-dose regimen of stabilized prefusion Washington SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or purified S-2P mixed with 3 M-052, a synthetic toll-like receptor (TLR) 7/8 agonist, in a squalene emulsion (Protein+3 M-052-SE) was safe and immunogenic in infant rhesus macaques. Here, we demonstrate that broadly neutralizing and spike-binding antibodies against variants of concern (VOC), as well as T cell responses, persisted for 12 months. At one year, corresponding to human toddler age, we challenged vaccinated rhesus macaques and age-matched non-vaccinated controls intranasally and intratracheally with a high-dose of heterologous SARS-CoV-2 B.1.617.2 (Delta). Seven of eight control rhesus macaques exhibited severe interstitial pneumonia and high virus replication in the upper and lower respiratory tract. In contrast, vaccinated rhesus macaques had faster viral clearance with mild to no pneumonia. Neutralizing and binding antibody responses to the B.1.617.2 variant at the day of challenge correlated with lung pathology and reduced virus replication. Overall, the Protein+3 M-052-SE vaccine provided superior protection to the mRNA-LNP vaccine, emphasizing opportunities for optimization of current vaccine platforms. Notably, the observed efficacy of both vaccines one year after vaccination supports the implementation of an early life SARS-CoV-2 vaccine.

Amjadi M. F et al.

Anti-membrane Antibodies Persist at Least One Year and Discriminate Between Past Coronavirus Disease 2019 Infection and Vaccination

The journal of Infectious Diseases¸ June 2022; doi.org/10.1093/infdis/jiac263

Abstract

Background

The consequences of past coronavirus disease 2019 (COVID-19) infection for personal and population health are emerging, but accurately identifying distant infection is a challenge. Anti-spike antibodies rise after both vaccination and infection and anti-nucleocapsid antibodies rapidly decline.

Methods

We evaluated anti-membrane antibodies in COVID-19 naive, vaccinated, and convalescent subjects to determine if they persist and accurately detect distant infection.

Results

We found that anti-membrane antibodies persist for at least 1 year and are a sensitive and specific marker of past COVID-19 infection.

Conclusions

Thus, anti-membrane and anti-spike antibodies together can differentiate between COVID-19 convalescent, vaccinated, and naive states to advance public health and research.

Shira Doron, Monica Gandhi

New boosters are here! Who should receive them and when?

The Lancet, October 2022; doi.org/10.1016/S1473-3099(22)00688-0

The FDA has authorised bivalent booster vaccines containing mRNA for the ancestral SARS-CoV-2 variant as well as B.1.1.529.4 (BA.4) and B.1.1.529.5 (BA.5), the latter being the most prevalent omicron subvariant circulating now.

The US CDC recommends everyone 12 years and older receive these bivalent boosters at least 2 months after their last vaccine dose, regardless of number of previous boosters. Is this the best strategy based on what we know from boosters with the ancestral spike If we clarify the goals of our booster strategy to prevent severe disease  (as recommended by WHO), the annual booster campaign that the FDA has stated is the new strategy going forward will probably only be needed for people who are at highest risk (as defined by age, comorbidities, and whether they are immunocompromised). In fact, once a year might not be enough for some risk groups.

As for timing, we agree with the Canadian National Advisory Committee on Immunization to recommend the updated vaccine at an interval of 6 months after previous vaccination or infection.

Antibody levels stabilise 6–9 months after vaccination for individuals with and those without previous infection.8 Giving a booster too soon (within 60 days) after a recent infection interferes with effective B-cell responses, and extended intervals between vaccine doses increase both neutralising antibodies and memory B cells.8 If one of the aims of omicron-specific boosters is to increase antibodies and prevent even mild infections, the antibody level plateau at the 6-month mark would signal an ideal time to boost with a variant-focused vaccine.

We are excited about the ability of the mRNA vaccines to be updated as new variants emerge. However, focusing our booster recommendations on those most clinically vulnerable to severe disease first, and timing vaccine administration to optimise the immune response, is a good public health strategy.

Romero-Ibarguengoiti M. E et al.

Analysis of immunization time, amplitude, and adverse events of seven different vaccines against SARS-CoV-2 across four different countries

Frontiers, July 2022; doi.org/10.3389/fimmu.2022.894277

Abstract

Background: Scarce information exists in relation to the comparison of seroconversion and adverse events following immunization (AEFI) with different SARS-CoV-2 vaccines. Our aim was to correlate the magnitude of the antibody response to vaccination with previous clinical conditions and AEFI.

Conclusions: The magnitude of seroconversion is predicted by age, vaccine type and SARS-CoV-2 exposure. AEs are correlated with age, sex, and vaccine type. The delta of the antibody response only correlates with AEs in patients previously exposed to SARS-CoV-2.

MUIK A. et al.

Omicron BA.2 breakthrough infection enhances cross-neutralization of BA.2.12.1 and BA.4/BA.5

Science, September 2022; doi/10.1126/sciimmunol.ade2283

Abstract

BNT162b2-vaccinated individuals after Omicron BA.1 breakthrough infection have strong serum- neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 variants of concern (VOCs) yet less against the highly contagious Omicron sublineages BA.4 and BA.5 that have displaced previous variants. Because the latter sublineages are derived from Omicron BA.2, we characterized serum-neutralizing activity of COVID-19 mRNA vaccine triple-immunized individuals who experienced BA.2 breakthrough infection. We demonstrate that sera of these individuals have broadly neutralizing activity against previous VOCs and all tested Omicron sublineages, including BA.2-derived variants BA.2.12.1 and BA.4/BA.5.

Chalkias S. et al.

Neutralization of Omicron Subvariant BA.2.75 after Bivalent Vaccination

NEJM, November 2022, doi/full/10.1056/NEJMc2212772

Bivalent messenger RNA (mRNA) vaccines containing the ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and B.1.1.529 (omicron) variant spike sequences were recently made available to address the waves of infection and coronavirus disease 2019 (Covid-19) caused by omicron variants. The omicron BA.1–containing bivalent vaccine mRNA-1273.214, currently authorized for use in multiple countries, elicits strong neutralizing antibody responses against omicron BA.1 and the epidemiologically dominant BA.4 and BA.5 subvariants.1 The omicron BA.2.75 subvariant, which has steadily increased in prevalence in at least 36 countries, contains potential antibody-escape spike mutations.2 We aimed to characterize the neutralization of BA.2.75 after mRNA-1273.214 boosting and to further elucidate the cross-neutralization potential of this bivalent vaccine against multiple omicron variants.1

These data further support the cross-neutralization ability of the omicron-containing bivalent booster vaccine against emerging omicron subvariants that are not contained in the vaccine. Real-world data on the effectiveness of booster vaccines are needed to evaluate whether the potent and broad neutralizing antibody responses elicited by bivalent vaccines confer enhanced protection against Covid-19.

Liu J. et al.

CD8 T cells contribute to vaccine protection against SARS-CoV-2 inmacaques

Science, August 2022; doi/10.1126/sciimmunol.abq7647

Abstract

Spike-specific neutralizing antibodies (NAbs) are generally considered key correlates of vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recently, robust vaccine prevention of severe disease with SARS-CoV-2 variants that largely escape NAb responses has been reported, suggesting a role for other immune parameters for virologic control. However, direct data demonstrating a role of CD8+ T cells in vaccine protection have not yet been reported. In this study, we show that vaccine-elicited CD8+ T cells contribute substantially to virologic control after SARS-CoV-2 challenge in rhesus macaques. We vaccinated 30 macaques with a single immunization of the adenovirus vector–based vaccine Ad26.COV2.S or sham and then challenged them with 5 × 105 median tissue culture infectious dose SARS-CoV-2 B.1.617.2 (Delta) by the intranasal and intratracheal routes. All vaccinated animals were infected by this high-dose challenge but showed rapid virologic control in nasal swabs and bronchoalveolar lavage by day 4 after challenge. However, administration of an anti-CD8α– or anti-CD8β–depleting monoclonal antibody in vaccinated animals before SARS-CoV-2 challenge resulted in higher levels of peak and day 4 virus in both the upper and lower respiratory tracts. These data demonstrate that CD8+ T cells contribute substantially to vaccine protection against SARS-CoV-2 replication in macaques.

Canetti M et al.

Six-Month Follow-up after a Fourth BNT162b2 Vaccine Dose

NEJM, November 2022; doi/full/10.1056/NEJMc2211283

Abstract

In a prospective cohort study involving health care workers that was described previously,1 we evaluated the humoral response and vaccine effectiveness of a fourth dose of the BNT162b2 vaccine (Pfizer–BioNTech) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during a 6- month follow-up period in which omicron (mostly BA.1 and BA.2) was the predominant variant in Israel.2 The absence of previous SARS-CoV-2 infection was verified by SARS-CoV-2 testing and serologic follow-up testing (see Table S1 and the Supplementary Methods in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The humoral response (as assessed by the measurement of IgG and neutralizing antibodies) after receipt of the fourth vaccine dose was compared with that after receipt of the second and third doses. Vaccine effectiveness was assessed by comparing infection rates among participants who had received a fourth vaccine dose during various time periods (days 7 through 35, days 36 through 102, or days 103 through 181 after receipt of the fourth dose) with infection rates among those who had received three doses. Participants were to have received the third vaccine dose at least 4 months earlier. A Cox proportional hazards regression model was used, with adjustment for age, sex, and professional role; calendar time was used as the time scale to account for differences in the prevalence of infection over time (details are provided in the Supplementary Appendix). No participants died or were lost to follow-up. Among the participants who had not had previous SARS-CoV-2 infection, 6113 were included in the analysis of humoral response and 11,176 in the analysis of vaccine effectiveness (Fig. S1 and Tables S2 and S3). Antibody response peaked at approximately 4 weeks, waned to levels seen before the fourth dose by 13 weeks, and stabilized thereafter. Throughout the 6-month follow-up period, the adjusted weekly levels of IgG and neutralizing antibodies were similar after receipt of the third and fourth doses and were markedly higher than the levels seen after receipt of the second dose (Figure 1A and 1B and Table S4). The cumulative incidence curve is shown in Figure S2, and vaccine effectiveness is shown in Figure 1C. Receipt of the fourth BNT162b2 vaccine dose conferred more protection against SARS-CoV-2 infection than that afforded by the receipt of three vaccine doses (with receipt of the third dose having occurred at least 4 months earlier) (overall vaccine effectiveness, 41%; 95% confidence interval [CI], 35 to 47). Time-specific vaccine effectiveness (which, in our analysis, compared infection rates among participants who had not yet been infected since vaccination) waned with time, decreasing from 52% (95% CI, 45 to 58) during the first 5 weeks after vaccination to −2% (95% CI, −27 to 17) at 15 to 26 weeks. The study has several limitations. First, although our cohort consisted of a diverse population that included older-adult volunteers, a cohort consisting of health care workers may not be representative of the general population. Furthermore, only health care workers who had not had previous SARS-CoV-2 infection were included, which further limited generalizability. Second, possible confounding of unrecognized hybrid immunity may have remained, despite thorough history-taking and serologic assessment. Third, the decision to receive the fourth dose could be linked to healthseeking behaviors that were not well-captured in our data, thus possibly resulting in additional residual confounding. Fourth, we were unable to estimate effectiveness against severe outcomes of infection owing to the absence of such outcomes in our study cohort; a third dose of the BNT162b2 vaccine has been shown to confer durable protection against such outcomes.3 Previous studies have shown increased effectiveness of a fourth dose against severe outcomes during short-term followup,4,5 but whether this additional effectiveness wanes similarly to the protection against infection has yet to be determined. In this prospective cohort study, a third dose of the BNT162b2 vaccine led to an improved and sustained immunologic response as compared with two doses, but the additional immunologic advantage of the fourth dose was much smaller and had waned completely by 13 weeks after vaccination. This finding correlated with waning vaccine effectiveness among recipients of a fourth dose, which culminated in no substantial additional effectiveness over a third dose at 15 to 26 weeks after vaccination. These results suggest that the fourth dose, and possibly future boosters, should be timed wisely to coincide with disease waves or to be available seasonally, similar to the influenza vaccine. Whether multivalent booster doses will result in longer durability remains to be seen.

Pai Peng et al.

Extensive neutralization against SARS-CoV-2 variants elicited by Omicron-specific subunit vaccine as a heterologous booster

Cell, November 2022; doi.org/10.1016/j.isci.2022.105465

Abstract

To overcome the increased risk of SARS-CoV-2 reinfection or post-vaccination infection caused by the Omicron variant, Omicron-specific vaccines were considered a potential strategyResults suggest that Omicron-specific subunit booster shows its advantages in the immune protection from both WT and current VOCs and that SARS-CoV-2 vaccines including two or more virus lineages might improve the NAb response.

Kurhade C et al.

Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1, and XBB.1 by 4 doses of parental mRNA vaccine or a BA.5-bivalent booster

BioRxiv, November 2022;  doi.org/10.1101/2022.10.31.514580

Abstract

The newly emerged SARS-CoV-2 Omicron BQ.1.1, XBB.1, and other sublineages have accumulated additional spike mutations that may affect vaccine effectiveness. Here we report neutralizing activities of three human serum panels collected from individuals 1-3 months after dose 4 of parental mRNA vaccine (post-dose-4), 1 month after a BA.5-bivalent-booster (BA.5-bivalent-booster), or 1 month after a BA.5-bivalent-booster with previous SARS-CoV-2 infection (BA.5-bivalent-booster-infection .Thus, although BA.5-bivalent-booster elicits better neutralization than parental vaccine, it does not produce robust neutralization against the newly emerged Omicron BA.2.75.2, BQ.1.1, and XBB.1. Previous infection enhances the magnitude and breadth of BA.5-bivalent-booster-elicited neutralization.

Maringer Y. et al.

Durable spike-specific T-cell responses after different COVID-19 vaccination regimens are not further enhanced by booster vaccination

Science, November 2022; doi/10.1126/sciimmunol.add3899

Abstract

Several COVID-19 vaccines are approved to prevent severe disease outcome following SARS-CoV-2 infection. Whereas the induction and functionality of anti-viral antibody response is largely studied, the induction of T cells upon vaccination with the different approved COVID-19 vaccines is less studied. Here, we reported on T-cell immunity four weeks and six months after different vaccination regimens and four weeks after an additional booster vaccination, in comparison to SARS-CoV-2 T-cell responses in convalescents and prepandemic donors using interferon-gamma ELISpot assays and flow cytometry. Increased T-cell responses and cross-recognition of B.1.1.529 Omicron variant-specific mutations were observed ex vivo in mRNA- and heterologous-vaccinated

donors compared to vector-vaccinated donors. Nevertheless, potent expandability of T cells targeting the spike protein was observed for all vaccination regimens with frequency, diversity and the ability to produce several cytokines of vaccine-induced T-cell responses comparable to those in convalescent donors. T-cell responses for all vaccinated donors significantly exceeded preexisting cross-reactive T-cell responses in prepandemic donors. Booster vaccination led to a significant increase of anti-spike IgG responses, which showed a marked decline 6 month after complete vaccination. In contrast, T-cell responses remained stable over time following complete vaccination with no significant effect of booster vaccination on T-cell responses and cross-recognition of Omicron BA.1 and BA.2 mutations.This suggested that booster vaccination is of particular relevance for the amelioration of antibody response. Together, our work shows that different vaccination regimens induce broad and long-lasting spike-specific CD4+ and CD8+ T-cell immunity to SARS-CoV-2.

Woodbridge Y. et al.

Viral load dynamics of SARS-CoV-2 Delta and Omicron variants following multiple vaccine doses and previous infection

Nature Communications, November 2022; doi.org/10.1038/s41467-022-33096-0

Abstract

An important aspect of vaccine effectiveness is its impact on pathogen transmissibility, harboring major implications for public health policies. As viral load is a prominent factor affecting infectivity, its laboratory surrogate, qRT-PCR cycle threshold (Ct), can be used to investigate the infectivity-related component of vaccine effectiveness. While vaccine waning has previously been observed for viral load during the Delta wave, less is known regarding how Omicron viral load is affected by vaccination status, and whether vaccine-derived and natural infection protection are sustained. By analyzing results of more than 460,000 individuals, we show that while recent vaccination reduces Omicron viral load, its effect wanes rapidly. In contrast, a significantly slower waning rate is demonstrated for recovered COVID-19 individuals. Thus, while the vaccine is effective in decreasing morbidity and mortality, its relatively small effect on transmissibility of Omicron (as measured here by Ct) and its rapid waning call for reassessment of future booster campaigns.

Shabir A Madhi et al.

Durability of ChAdOx1 nCoV-19 (AZD1222) vaccine and hybrid humoral immunity against variants including omicron BA.1 and BA.4 6 months after vaccination (COV005): a post-hoc analysis of a randomised, phase 1b–2a trial

Lancet Infectious Diseases, October 2022; doi.org/10.1016/S1473-3099(22)00596-5

Abstract

Background

COVID-19 vaccine rollout is lagging in Africa, where there has been a high rate of SARS-CoV-2 infection. We aimed to evaluate the effect of SARS-CoV-2 infection before vaccination with the ChAdOx-nCoV19 (AZD1222) vaccine on antibody responses through to 180 days.

Also D614G NAb geometric mean titres (GMTs) were higher in the seropositive group than the seronegative group, as was the percentage with titres of at least 185 (80% putative risk reduction threshold [PRRT] against wild-type–alpha COVID-19), including at day 180 (92·0% [74·0–99·0] vs 18·2% [2·3–51·8). Similar findings were observed for beta, A.VOI.V2, and gamma. For delta, BA.1, and BA.4, NAb GMTs and the proportion with titres above the PRRT were substantially higher in the seropositive compared with seronegative group at day 28 and day 42, but no longer differed between the groups by day 180.

Interpretation

A single dose of AZD1222 in the general African population, where COVID-19 vaccine coverage is low and SARS-CoV-2 seropositivity is 90%, could enhance the magnitude and quality of antibody responses to SARS-CoV-2.

Kerr S. et al.

Severity of BA.2 variant and vaccine effectiveness against symptomatic disease in Scotland

Lancet, November 2022; doi.org/10.1016/j.lanepe.2022.100533

Abstract

Il The first confirmed case of SARS-CoV-2 omicron BA.2 was identified in Scotland on December 23, 2021.1 BA.2 was the dominant variant in Scotland, replacing omicron BA.1.1.529 (BA.1) and accounting for >90% of new cases as of March 23, 2022 (Fig. S1, Supplementary Appendix).1 Initial research suggested that BA.2 was associated with an increase in the odds ratio of infection for both unvaccinated and fully vaccinated individuals compared to BA.1.2 Since then, other studies from Qatar have shown that vaccination can provide protection against symptomatic BA.1 and BA.2 infection,3 but vaccination effectiveness is stronger after a third ‘booster’ dose. Our Cox regression model showed that the adjusted hazard ratio (aHR) for COVID-19 hospitalisation or death was similar for BA.2 relative to BA.1 (aHR: 0.84, 95% CI 0.60–1.18, Table 1), with three doses of any vaccine associated with a 48% reduction in the risk of COVID-19 associated hospitalisation or death among those who tested positive (aHR: 0.52, 95% CI 0.39–0.70, Table 1). We also tested for an interaction between vaccination status and infection with BA.1 or BA.2 and found no overall difference between vaccination status and HR (Likelihood ratio p = 0.34).

In summary, our analysis shows that BA.2 is associated with comparable risk of serious COVID-19 outcomes to BA.1, and that three vaccination doses (including a booster dose) provide reasonable protection against symptomatic BA.2 infection and COVID-19 hospitalisation or death.

Chin E.T. et al.

Protection against Omicron from Vaccination and Previous Infection in a Prison System

NEJM, November 2022; DOI: 10.1056/NEJMoa2207082

Abstract

BACKGROUND

Information regarding the protection conferred by vaccination and previous infection against infection with the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is limited.

METHODS

We evaluated the protection conferred by mRNA vaccines and previous infection against infection with the omicron variant in two high-risk populations: residents and staff in the California state prison system

CONCLUSIONS

Our findings in two high-risk populations suggest that mRNA vaccination and previous infection were effective against omicron infection, with lower estimates among those infected before the period of delta predominance. Three vaccine doses offered significantly more protection than two doses, including among previously infected persons.

Tianyang Mao et al

Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses

Science Immunology, October 2022; doi/10.1126/science.abo2523

Abstract

The SARS-CoV-2 pandemic has highlighted the need for vaccines that not only prevent disease, but also prevent transmission. The authors describe the development of a vaccine strategy that leverages existing immunity generated by primary vaccination (prime) to elicit mucosal immune memory within the respiratory tract using unadjuvanted intranasal spike boosters (spike).

Tang G J et al.

Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination

Science Immunology, July 2022; doi/10.1126/sciimmunol.add4853

Abstract

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation. The authors compared the SARS-CoV-2 S–specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19–vaccinated individuals and hospitalized patients. The study shows that the mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.

Howard-Williams M. et al.

Association between state-issued Covid-19 vaccine mandates and vaccine administration rates in 12 US states and the district of Columbia

JAMA, October 2022; doi:10.1001/jamahealthforum.2022.3810

Abstract

Some US states have issued COVID-19 vaccine mandates;the association of these mandates with vaccination rates remains unknown.

Grasselli G. et al.

Association of Covid-19 vaccinations with intensive care unit admissions and outcome of critically ill patients with Covid-19 pneumonia in Lombardy, Italy

JAMA, October 2022;doi:10.1001/jamanetworkopen.2022.38871

Abstract

In this cohort study of more than 10 million people, vaccines based on mRNA technology or adenoviral vectors significantly decreased the risk of ICU admission for COVID-19 pneumonia. ICU and hospital mortality, adjusted for age, heart disease and Pao₂/FiO₂ at ICU admission, were similar between vaccinated and unvaccinated patients.

Lianhan Shang, Bin Cao

Protein-based vaccine as the booster dose for adults: evidence and beyond

Lancet, August 2022; doi.org/10.1016/S1473-3099(22)00447-9

Abstract

There are many potential reasons that might contribute to the ongoing pandemic, such as the waning of immune protection from vaccine or past infection with time, immune escape of the emerging variants, vaccine hesitancy, and the global inequity of vaccine distribution. Booster dose vaccines have been shown to reinforce the immune reaction and elicit increased protective antibodies.

Vo A.D. et al.

Factors Associated With Severe COVID-19 Among Vaccinated Adults Treated in US Veterans Affairs Hospitals

JAMA, October 2022; doi:10.1001/jamanetworkopen.2022.40037

Abstract

With a large proportion of the US adult population vaccinated against SARS-CoV-2, it is important to identify who remains at risk of severe infection despite vaccination.

Madhi S.A. et al.

Durability of ChAdOx1 nCoV-19 (AZD1222) vaccine and hybrid humoral immunity against variants including omicron BA.1 and BA.4 6 months after vaccination (COV005): a post-hoc analysis of a randomised, phase 1b–2a trial

Lancet, October 2022;doi.org/10.1016/S1473-3099(22)00596-5

Abstract

In Africa there has been a high rate of SARS-CoV-2 infection. The study aims to evaluate the effect of SARS-CoV-2 infection before vaccination with the ChAdOx-nCoV19 (AZD1222) vaccine on antibody responses through to 180 days.

U. Agrawal et al.

Severe COVID-19 outcomes after full vaccination of primary schedule and initial boosters: pooled analysis of national prospective cohort studies of 30 million individuals in England, Northern Ireland, Scotland, and Wales

The Lancet, October 2022; doi.org/10.1016/S0140-6736(22)01656-7

Abstract

Current UK vaccination policy is to offer future COVID-19 booster doses to individuals at high risk of serious illness from COVID-19, but it is still uncertain which groups of the population could benefit most. In response to an urgent request from the UK Joint Committee on Vaccination and Immunisation, the authors aimed to identify risk factors for severe COVID-19 outcomes in individuals who had completed their primary COVID-19 vaccination schedule and had received the first booster vaccine.

S.A. Irving & M.E. Sundaram

Prioritisation of COVID-19 boosters in the omicron era

The Lancet.com, October 2022; Vol. 400

Abstract

Bivalent vaccines optimised for BA.4 and BA.5 omicron sublineages have been developed for use as a booster dose, but roll-out of these new vaccines will be slow. To prioritise the limited supply of bivalent boosters, it is imperative to enhance our understanding of the populations at highest risk of severe COVID-19 breakthrough infections.

R.L. Hajnik et al.

Dual spike and nucleocapsid mRNA vaccination confer protection against SARS-CoV-2 Omicron and Delta variants in preclinical models

Science Translational Medicine, September 2022; doi: 10.1126/scitranslmed.abq1945

Abstract

Emergence of SARS-CoV-2 variants of concern (VOCs), including the highly transmissible Omicron and Delta strains, has posed constant challenges to the current COVID-19 vaccines that principally target the viral spike protein (S). In this study the authors report a nucleoside-modified messenger RNA (mRNA) vaccine that expresses the more conserved viral nucleoprotein (mRNA-N) and show that mRNA-N vaccination alone can induce modest control of SARS-CoV-2.

C. M. Buckner et al.

Interval between prior SARS-CoV-2 infection and booster vaccination impacts magnitude and quality of antibody and B cell responses

Cell, September 2022; doi.org/10.1016/j.cell.2022.09.032

Abstract

SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination.

Spyros Chalkias et al.

A bivalent Omicron-containing booster vaccine against Covid-19

New England J of Medicine, October 2022; doi: 10.1056/NEJMoa2208343

Abstract

The safety and immunogenicity of the bivalent omicron-containing mRNA-1273.214 booster vaccine are not known. The authors compared the 50-μg bivalent vaccine mRNA-1273.214 with the previously authorized 50-μg mRNA-1273 booster.

J. D. Kelly et al.

Incidence of severe COVID-19 illnessfollowing vaccination and booster with BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines.

JAMA, September 2022; doi:10.1001/jama.2022.17985

Abstract

Evidencedescribing the incidence of severe COVID-19 illness following vaccination and booster with BNT162b2, mRNA-1273, and Ad26.COV2.S vaccinesisneeded, particularly for high-risk populations.  In a US cohort, therewas a low incidence of hospitalization with COVID-19 pneumonia or death following vaccination and booster during a period of Delta and Omicron variantpredominance.

S. S. Hameed et al.

Characterisingadults in Scotland who are notvaccinatedagainst COVID-19

The Lancet, September 2022; doi.org/10.1016/ S0140-6736(22)01780-9

Abstract

By Aug 10, 2022, 3 497 208 of the estimated 4·4 millionadults living in Scotland hadreceivedthreedoses of a COVID-19 vaccine. A proportion of the adultpopulationremainsunvaccinated and susceptible to severe COVID-19 outcomes. Characterisingthispopulation can help to understand gaps in vaccine coverage and determinants of vaccine hesitancy and could support targeted public health messaging.

Y. Zhang et al.

Immunogenicity, durability, and safety of an mRNA and threeplatform-based COVID-19 vaccinesas a third dose following twodoses of CoronaVac in China: arandomised, doubleblinded, placebo-controlled, phase 2 trial.

eClinicalMedicine, October 2022; doi.org/10.1016/j. eclinm.2022.101680

Abstract

More effective vaccine candidatesagainstvariants of concernas a booster dose are needed in people primed with two-dose inactivated COVID-19 vaccines. Thisrandomised, double-blinded, investigator-initiatedphase 2 trial aims to evaluateimmunogenicity, durability, and safety of an mRNA vaccine candidate (RQ3013) and threeotherplatformvaccines (an adenovirus-vectored vaccine candidate [ChAdTS-S], a recombinantprotein vaccine candidate [ZR202-CoV], and an inactivated vaccine [CoronaVac]) as a booster.

P.I.Más-Bermejo et al.

Cuban Abdala vaccine: effectiveness in preventing severe disease and death from COVID-19 in Havana, Cuba; acohort study.

The Lancet Regional Health – Americas, October 2022; doi.org/10.1016/j.lana.2022.100366

Abstract

COVID-19 vaccineshaveproven safe and efficacious in reducing severe illness and death. Cuban pro-

tein subunit vaccine Abdala has shown safety, tolerability and efficacy (92¢3% [95% CI: 85¢7‒95¢8]) against SARS-CoV-2 in clinical trials. This study aimed to estimate Abdala’sreal-world vaccine effectiveness (VE).

J.P. Ridgway et al.

Odds of hospitalization for Covid-19 after 3 vs 2 doses of MrNA covid-19 vaccine by time since booster dose

JAMA, September 2022; doi:10.1001/jama.2022.17811

Abstract

Vaccination with a booster dose of COVID-19 mRNA vaccine has been associated with decreased risk of developing severe COVID-19 compared with no vaccination. However, among individuals already fully vaccinated with the primary series of an mRNA vaccine, less is known about how much protection is added by a booster and how long that protection lasts. The authors assessed the association between COVID-19 mRNA booster immunization compared with vaccination with the primary mRNA vaccination series alone and the odds of hospitalization for COVID-19.

D.S. Hui

Hybrid immunity and strategies for COVID-19 vaccination

Lancet Infectious Diseases, September 2022; doi.org/10.1016/ S1473-3099(22)00640-5

Abstract

Since April, 2022, BA.2.12.1, BA.4, and BA.5 subvariants of the omicron (B.1.1.529) SARS-CoV-2 variant of concern have been spreading globally with increased viral fitness and transmissibility. Omicron BA.5 subvariant is currently the predominant COVID-19 threat worldwide. With the emergence of the antigenically distinct variants of concern, either natural immunity or first-generation vaccine-induced immunity has failed to prevent transmission effectively. Booster (third or fourth) doses of vaccine play an important role in preventing symptomatic infection, although the boosting effect only lasts for several months.

R.L. Hajnik et al.

Dual spike and nucleocapsid mRNA vaccination confer protection against SARS-CoV-2 Omicron and Delta variants in preclinical models

SciencTranslational Medicine, September 2022; doi/10.1126/scitranslmed.abq1945

Abstract

Emergence of SARS-CoV-2 variants of concern (VOCs), including the highly transmissible Omicron and Delta strains, has posed constant challenges to the current COVID-19 vaccines that principally target the viral spike protein (S). the study reports a nucleoside-modified messenger RNA (mRNA) vaccine that expresses the more conserved viral nucleoprotein (mRNA-N) and show that mRNA-N vaccination alone can induce modest control of SARS-CoV-2.

P. Qu et al.

Durability of Booster mRNA Vaccine against SARS-CoV-2 BA.2.12.1, BA.4, and BA.5 Subvariants

The New England J of Medicine, September 2022; doi: 10.1056/NEJMc2210546

Abstract

Mounting concern about the long-term efficacy of messenger RNA (mRNA) booster vaccines against coronavirus disease 2019 (Covid-19) has been exacerbated by the recent emergence of the B.1.1.529 (omicron) subvariants BA.2.12.1 and BA.4 and BA.5 (hereafter, BA.4/5) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which have high degrees of immune escape.

Hardt K et al.

Efficacy, safety, and immunogenicity of a booster regimen of Ad26.COV2.S vaccine against COVID-19 (ENSEMBLE2): results of a randomised, double-blind, placebo-controlled, phase 3 trial

Lancet InfectiousDiseases, September2022; doi: 10.1016/S1473-3099(22)00506-0

Abstract

Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose.

S. Havervallet al.

Anti-Spike MucosalIgAProtectionagainst SARS-CoV-2 Omicron Infection

New England J of Medicine, September 2022; doi: 10.1056/NEJMc2209651

Abstract

Mucosal IgA can provide immunity against respiratory viruses.Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) boosts mucosal IgA responses,and neutralizing IgA, including neutralizing IgA against the B.1.1.529 (omicron) variant of SARS-CoV-2, has been detected after infection with wild-type SARS-CoV-2. However, the potential role of mucosal IgA in protection against SARS-CoV-2 infection is still largely unknown.

M. Karachaliou et al.

SARS-CoV-2 infection, vaccination, and antibody response trajectories in adults: a cohort study in Catalonia

BMC Medicine, September 2022; doi.org/10.1186/s12916-022-02547-2

Abstract

Heterogeneity of the population in relation to infection, COVID-19 vaccination, and host characteristics is likely reflected in the underlying SARS-CoV-2 antibody responses.These data support that infected people would benefit from vaccination. Results also indicate that hybrid immunity results in superior antibody responses and infection-naïve people would need a booster dose earlier than previously infected people. Mental diseases are associated with less efficient responses to vaccination.

S. Afkhami et al.

Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2

Cell, March 2022; doi: 10.1016/j.cell.2022.02.005

Abstract

The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, the authors evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. Theisfindings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.

A. F.Crawshaw et al.

Defining the determinants of vaccine uptake and undervaccination in migrant populations in Europe to improve routine and COVID-19 vaccine uptake: a systematic review

Lancet Infectious Diseases, September 2022; doi: 10.1016/S1473-3099(22)00066-4

Abstract

Understanding why some migrants in Europe are at risk of underimmunisation and show lower vaccination uptake for routine and COVID-19 vaccines is critical if we are to address vaccination inequities and meet the goals of WHO's new Immunisation Agenda 2030. The authors did a systematic review (PROSPERO: CRD42020219214) exploring barriers and facilitators of vaccine uptake (categorised using the 5As taxonomy: access, awareness, affordability, acceptance, activation) and sociodemographic determinants of undervaccination among migrants in the EU and European Economic Area, the UK, and Switzerland. 

F.P. Havers et al.

COVID-19-Associated Hospitalizations Among Vaccinated and Unvaccinated Adults 18 Years or Older in 13 US States, January 2021 to April 2022

JAMA Intern Med, September 2022; doi: 10.1001/jamainternmed.2022.4299

Abstract

To determine characteristics of COVID-19-associated hospitalizations among vaccinated persons and comparative hospitalization rates in unvaccinated and vaccinated persons.

Main outcomes and measures: COVID-19-associated hospitalization rates among vaccinated vs unvaccinated persons and factors associated with COVID-19-associated hospitalization in vaccinated persons were assessed.In this cross-sectional study of US adults hospitalized with COVID-19, unvaccinated adults were more likely to be hospitalized compared with vaccinated adults; hospitalization rates were lowest in those who had received a booster dose. Hospitalized vaccinated persons were older and more likely to have 3 or more underlying medical conditions and be long-term care facility residents compared with hospitalized unvaccinated persons. The study results suggest that clinicians and public health practitioners should continue to promote vaccination with all recommended doses for eligible persons.

Z. Qin et al.

Pre-exposure to mRNA-LNP inhibits adaptive immune responses and alters innate immune fitness in an inheritable fashion

bioRxiv, August 2022; doi: 10.1101/2022.03.16.484616

Abstract

Hundreds of millions of SARS-CoV-2 mRNA-LNP vaccine doses have already been administered to humans. The mRNA-LNP-based SARS-CoV-2 vaccine is highly inflammatory, and its synthetic ionizable lipid component responsible for the induction of inflammation has a long in vivo half-life. Since chronic inflammation can lead to immune exhaustion and non-responsiveness, the authors sought to determine the effects of pre-exposure to the mRNA-LNP on adaptive immune responses and innate immune fitness. The pre-exposure to mRNA-LNPs or LNP alone led to long-term inhibition of the adaptive immune responses, which could be overcome using standard adjuvants. In summary, the mRNA-LNP vaccine platform induces long-term unexpected immunological changes affecting both adaptive immune responses and heterologous protection against infections. These  studies highlight the need for more research to determine this platform's true impact on human health.

R. Lazarus et al.

Immunogenicity and safety of an inactivated whole-virus COVID-19 vaccine (VLA2001) compared with the adenoviral vector vaccine ChAdOx1-S in adults in the UK (COV-COMPARE): interim analysis of a randomised, controlled, phase 3, immunobridging trial

Lancet Infect Dis, September 2022; doi: 10.1016/S1473-3099(22)00502-3

Abstract

The Valneva COVID-19 vaccine (VLA2001; Valneva Austria, Vienna, Austria) is an inactivated whole-virus, adjuvanted SARS-CoV-2 vaccine. We aimed to assess the safety and immunogenicity of primary vaccination with VLA2001 versus the ChAdOx1-S (Oxford-AstraZeneca) adenoviral-vectored vaccine.

In this immunobridging phase 3 trial (COV-COMPARE), participants aged 18 years and older who were medically stable (as determined by an investigator) were enrolled at 26 sites in the UK. In the double-blind, randomised, controlled arm of the trial, participants aged 30 years and older were randomly assigned (2:1) to receive two doses of VLA2001 (0·5 mL; with 33 antigen units [AU] per dose) or ChAdOx1-S (0·5 mL; with 2·5 × 10 infectious units per dose) on days 1 and 29. In another arm, participants aged 18-29 years received two doses of VLA2001 (same dose) open label on days 1 and 29.

 VLA2001 has a favourable tolerability profile and met superiority criteria for neutralising antibodies and non-inferiority criterion for seroconversion rates compared with ChAdOx1-S. The data presented here formed the basis of successful marketing approval for use of VLA2001 in primary vaccination in the EU, the UK, Bahrain, and United Arab Emirates.

D. H. Barouch

Covid-19 Vaccines - Immunity, Variants, Booster

New England J of Medicine, August 2022; doi: 10.1056/NEJMra2206573

Abstract

The coronavirus disease 2019 (Covid-19) pandemic has claimed an estimated 15 million lives, including more than 1 million lives in the United States alone. The rapid development of multiple Covid-19 vaccines has been a triumph of biomedical research, and billions of vaccine doses have been administered worldwide. Challenges facing the Covid-19 vaccine field include inequitable vaccine distribution, vaccine hesitancy, waning immunity, and the emergence of highly transmissible viral variants that partially escape antibodies. This review summarizes the current state of knowledge about immune responses to Covid-19 vaccines and the importance of both humoral and cellular immunity for durable protection against severe disease

J. Lai et al.

Evolution of SARS-CoV-2 Shedding in Exhaled Breath Aerosols

medRxiv, August 2022; doi.org/10.1101/2022.07.27.22278121

Abstract

Aerosol inhalation is increasingly well recognized as a major if not primary mode of transmission of SARS-CoV-21^,2. Over the course of the COVID-19 pandemic, three highly transmissible lineages evolved and became globally dominant3. One hypothesis to explain increased transmissibility is that natural selection favours variants with higher rates of viral aerosol shedding. However, the extent of aerosol shedding of successive SARS-CoV-2 variants is unknown. Here, we demonstrate that viral shedding (measured as RNA copies) into exhaled breath aerosol was significantly greater during infections with Alpha, Delta, and Omicron than with ancestral strains and variants not associated with increased transmissibility. The three highly transmissible variants independently evolved a high viral aerosol shedding phenotype, demonstrating convergent evolution. We did not observe statistically significant differences in rates of shedding between Alpha, Delta, and Omicron infections. The highest shedder in our study, however, had an Omicron infection and shed three orders of magnitude more viral RNA copies than the maximum observed for Delta and Alpha4. Our results also show that fully vaccinated and boosted individuals, when infected, can shed infectious SARS-CoV-2 via exhaled breath aerosols. These findings provide additional evidence that inhalation of infectious aerosols is the dominant mode of transmission and emphasize the importance of ventilation, filtration, and air disinfection to mitigate the pandemic and protect vulnerable populations. We anticipate that monitoring aerosol shedding from new SARS-CoV-2 variants and emerging pathogens will be an important component of future threat assessments and will help guide interventions to prevent transmission via inhalation exposure.

A. Martner et al.

Transient and durable T cell reactivity after COVID-19

Proc Natl Acad Sci USA, July 2022; doi: 10.1073/pnas.2203659119

Abstract

This study analyzed whole blood samples (n = 56) retrieved from 30 patients at 1 to 21 (median 9) mo after verified COVID-19 to determine the polarity and duration of antigen-specific T cell reactivity against severe acute respiratory syndrome coronavirus 2-derived antigens. Multimeric peptides spanning the entire nucleocapsid protein triggered strikingly synchronous formation of interleukin (IL)-4, IL-12, IL-13, and IL-17 ex vivo until ∼70 d after confirmed infection, whereafter this reactivity was no longer inducible. In contrast, levels of nucleocapsid-induced IL-2 and interferon-γ remained stable and highly correlated at 3 to 21 mo after infection. Similar cytokine dynamics were observed in unvaccinated, convalescent patients using whole-blood samples stimulated with peptides spanning the N-terminal portion of the spike 1 protein. These results unravel two phases of T cell reactivity following natural COVID-19: an early, synchronous response indicating transient presence of multipolar, antigen-specific T helper (T_H) cells followed by an equally synchronous and durable T_H1-like reactivity reflecting long-lasting T cell memory.

L.B. Hartwell et al.

Intranasal vaccination with lipid-conjugated immunogens promotes antigen transmucosal uptake to drive mucosal and systemic immunity

Sci Transl Med, July 2022; doi: 10.1126/scitranslmed.abn1413

Abstract

To combat the HIV epidemic and emerging threats such as SARS-CoV-2, immunization strategies are needed that elicit protection at mucosal portals of pathogen entry. Immunization directly through airway surfaces is effective in driving mucosal immunity, but poor vaccine uptake across the mucus and epithelial lining is a limitation. The major blood protein albumin is constitutively transcytosed bidirectionally across the airway epithelium through interactions with neonatal Fc receptors (FcRn). Exploiting this biology, here, we demonstrate a strategy of "albumin hitchhiking" to promote mucosal immunity using an intranasal vaccine consisting of protein immunogens modified with an amphiphilic albumin-binding polymer-lipid tail, forming amph-proteins. Amph-proteins persisted in the nasal mucosa of mice and nonhuman primates and exhibited increased uptake into the tissue in an FcRn-dependent manner, leading to enhanced germinal center responses in nasal-associated lymphoid tissue. Intranasal immunization with amph-conjugated HIV Env gp120 or SARS-CoV-2 receptor binding domain (RBD) proteins elicited 100- to 1000-fold higher antigen-specific IgG and IgA titers in the serum, upper and lower respiratory mucosa, and distal genitourinary mucosae of mice compared to unmodified protein. Amph-RBD immunization induced high titers of SARS-CoV-2-neutralizing antibodies in serum, nasal washes, and bronchoalveolar lavage. Furthermore, intranasal amph-protein immunization in rhesus macaques elicited 10-fold higher antigen-specific IgG and IgA responses in the serum and nasal mucosa compared to unmodified protein, supporting the translational potential of this approach. These results suggest that using amph-protein vaccines to deliver antigen across mucosal epithelia is a promising strategy to promote mucosal immunity against HIV, SARS-CoV-2, and other infectious diseases.

R. Link-Gelles et al.

Effectiveness of 2, 3, and 4 covid-19 mrna vaccine doses among immunocompetent adults during periods when sars-cov-2 omicron ba.1 and ba.2/ba.2.12.1 sublineages predominated — vision Network, 10 States, December 2021–June 2022

MMWR Morb Mortal Wkly Rep, July 2022; doi: 10.15585/mmwr.mm7129e1

Abstract

The Omicron variant (B.1.1.529) of SARS-CoV-2, the virus that causes COVID-19, was first identified in the United States in November 2021, with the BA.1 sublineage (including BA.1.1) causing the largest surge in COVID-19 cases to date. Omicron sublineages BA.2 and BA.2.12.1 emerged later and by late April 2022, accounted for most cases. Estimates of COVID-19 vaccine effectiveness (VE) can be reduced by newly emerging variants or sublineages that evade vaccine-induced immunity, protection from previous SARS-CoV-2 infection in unvaccinated persons, or increasing time since vaccination. Real-world data comparing VE during the periods when the BA.1 and BA.2/BA.2.12.1 predominated (BA.1 period and BA.2/BA.2.12.1 period, respectively) are limited. The VISION network examined 214,487 emergency department/urgent care (ED/UC) visits and 58,782 hospitalizations with a COVID-19-like illness diagnosis among 10 states during December 18, 2021-June 10, 2022, to evaluate VE of 2, 3, and 4 doses of mRNA COVID-19 vaccines (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) compared with no vaccination among adults without immunocompromising conditions. VE against COVID-19-associated hospitalization 7-119 days and ≥120 days after receipt of dose 3 was 92% (95% CI = 91%-93%) and 85% (95% CI = 81%-89%), respectively, during the BA.1 period, compared with 69% (95% CI = 58%-76%) and 52% (95% CI = 44%-59%), respectively, during the BA.2/BA.2.12.1 period. Patterns were similar for ED/UC encounters. Among adults aged ≥50 years, VE against COVID-19-associated hospitalization ≥120 days after receipt of dose 3 was 55% (95% CI = 46%-62%) and ≥7 days (median = 27 days) after a fourth dose was 80% (95% CI = 71%-85%) during BA.2/BA.2.12.1 predominance. Immunocompetent persons should receive recommended COVID-19 booster doses to prevent moderate to severe COVID-19, including a first booster dose for all eligible persons and second booster dose for adults aged ≥50 years at least 4 months after an initial booster dose. Booster doses should be obtained immediately when persons become eligible.

J. Newman et al.

Neutralizing antibody activity against 21 SARS-CoV-2 variants in older adults vaccinated with BNT162b2

Nature Microbiology, July 2022; doi.org/10.1038/s41564-022-01163-3

Abstract

SARS-CoV-2 variants may threaten the effectiveness of vaccines and antivirals to mitigate serious COVID-19 disease. This is of most concern in clinically vulnerable groups such as older adults. We analysed 72 sera samples from 37 individuals, aged 70–89 years, vaccinated with two doses of BNT162b2 (Pfizer–BioNTech) 3 weeks apart, for neutralizing antibody responses to wildtype SARS-CoV-2. Between 3 and 20 weeks after the second vaccine dose, neutralizing antibody titres fell 4.9-fold to a median titre of 21.3 (neutralization dose 80%), with 21.6% of individuals having no detectable neutralizing antibodies at the later time point. Next, we examined neutralization of 21 distinct SARS-CoV-2 variant spike proteins with these sera, and confirmed substantial antigenic escape, especially for the Omicron (B.1.1.529, BA.1/BA.2), Beta (B.1.351), Delta (B.1.617.2), Theta (P.3), C.1.2 and B.1.638 spike variants. By combining pseudotype neutralization with specific receptor-binding domain (RBD) enzyme-linked immunosorbent assays, we showed that changes to position 484 in the spike RBD were mainly responsible for SARS-CoV-2 neutralizing antibody escape. Nineteen sera from the same individuals boosted with a third dose of BNT162b2 contained higher neutralizing antibody titres, providing cross-protection against Omicron BA.1 and BA.2. Despite SARS-CoV-2 immunity waning over time in older adults, booster vaccines can elicit broad neutralizing antibodies against a large number of SARS-CoV-2 variants in this clinically vulnerable cohort.

M.E. McMenamin et al.

Vaccine effectiveness of one, two, and three doses of BNT162b2 and CoronaVac against COVID-19 in Hong Kong: a population-based observational study

The Lancet Infectious Diseases, July 2022; doi.org/10.1016/ S1473-3099(22)00345-0

Abstract

Background Hong Kong maintained low circulation of SARS-CoV-2 until a major community epidemic of the omicron (B.1.1.529) sublineage BA.2 began in January, 2022. Both mRNA (BNT162b2 [Fosun Pharma-BioNTech]) and inactivated CoronaVac (Sinovac, Beijing, China) vaccines are widely available; however, vaccination coverage has been low, particularly in older adults aged 70 years or older. We aimed to assess vaccine effectiveness in this predominantly infection-naive population.

Methods In this observational study, we used individual-level case data on mild or moderate, severe or fatal, and fatal disease in patients hospitalised with COVID-19 along with census information and coverage data of BNT162b2 and CoronaVac. We used a negative binomial model, adjusting for age, sex, and calendar day to estimate vaccine effectiveness of one, two, and three doses of both BNT162b2 and CoronaVac vaccines, and relative effectiveness by number of doses and vaccine type.

Findings Between Dec 31, 2020, and March 16, 2022, 13·2 million vaccine doses were administered in Hong Kong’s 7·4-million population. We analysed data from confirmed cases with mild or moderate (n=5566), severe or fatal (n=8875), and fatal (n=6866) COVID-19. Two doses of either vaccine protected against severe disease and death within 28 days of a positive test, with higher effectiveness among adults aged 60 years or older with BNT162b2 (vaccine effectiveness 89·3% [95% CI 86·6–91·6]) compared with CoronaVac (69·9% [64·4–74·6]). Three doses of either vaccine offered very high levels of protection against severe or fatal outcomes (97·9% [97·3–98·4]).

Interpretation Third doses of either BNT162b2 or CoronaVac provide substantial additional protection against severe COVID-19 and should be prioritised, particularly in older adults older than 60 years and others in high-risk populations who received CoronaVac primary schedules. Longer follow-up is needed to assess duration of protection across different vaccine platforms and schedules.

P. Nordström et al.

Effectiveness of a fourth dose of mRNA COVID-19 vaccine against all-cause mortality in long-term care facility residents and in the oldest old: A nationwide, retrospective cohort study in Sweden

The Lancet Regional Health - Europe; July 2022; doi.org/10.1016/j.lanepe.2022.100466

Abstract

Background

The effect of a fourth dose of COVID-19 vaccine on the risk of death in the oldest and frailest individuals is unknown.

Methods

Two matched cohorts were formed using Swedish nationwide registers. In the first, residents of long-term care facilities (LTCFs) given a fourth dose of an mRNA vaccine from 1 January 2022 onwards were matched 1:1 on birth year and county of residence to residents given at least a third dose (N = 24,524). In the second, all individuals aged ≥80 years given a fourth dose were matched 1:1 to individuals given at least a third dose (N = 394,104). Cox regression models were used to estimate hazard ratios for all-cause mortality in fourth-dose recipients as compared with in third-dose recipients, with relative vaccine effectiveness (VE) estimated as 1 minus the hazard ratio.

Findings

From 7 days after baseline and onwards, there were 1119 deaths in the LTCF cohort during a median follow-up of 77 days and a maximum follow-up of 126 days. During days 7 to 60, the VE of the fourth dose was 39% (95% CI, 29-48), which declined to 27% (95% CI, -2-48) during days 61 to 126. In the cohort of all individuals aged ≥80 years, there were 5753 deaths during a median follow-up of 73 days and a maximum follow-up of 143 days. During days 7 to 60, the VE of the fourth dose was 71% (95% CI, 69-72), which declined to 54% (95% CI, 48-60) during days 61 to 143. The VE of the fourth dose seemed stronger when it was compared to third-dose recipients where at least four months had passed since vaccination (P < 0·001 for interaction).

Interpretation

As compared with a third dose, a fourth dose of an mRNA COVID-19 vaccine, administered during the Omicron era, was associated with reduced risk of death from all causes in residents of LTCFs and in the oldest old during the first two months, after which the protection became slightly lower. These findings suggest that a fourth dose may prevent premature mortality in the oldest and frailest even after the emergence of the Omicron variant, although the timing of vaccination seems to be important with respect to the slight waning observed after two months.

M.J. Cohen et al.

Association of Receiving a Fourth Dose of the BNT162b Vaccine With SARS-CoV-2 Infection Among Health Care Workers in Israel

JAMA Netw Open., August 2022; doi:10.1001/jamanetworkopen.2022.24657

 Abstract

Importance  Despite the high 3-dose vaccination rate among health care workers (HCWs) in Israel, a high rate of SARS-CoV-2 breakthrough infections in this group was observed during the Omicron wave. As a result, the Israeli Ministry of Health decided to recommend a fourth vaccine dose to medical staff.

Objective  To evaluate the benefit of a fourth BNT162b2 vaccine dose on the breakthrough infection rate among HCWs.

Design, Setting, and Participants  This multicenter cohort study was performed in January 2022, the first month of the 4-dose vaccination campaign, during a surge of the Omicron variant wave. All health care workers at 11 general hospitals in Israel who had been vaccinated with 3 doses up to September 30, 2021, and had not contracted COVID-19 before the vaccination campaign were included.

Exposures  Vaccination with a fourth dose of the BNT162b2 vaccine during January 2022.

Main Outcomes and Measures  Breakthrough COVID-19 infections in 4-dose recipients vs 3-dose recipients measured by a polymerase chain reaction test result positive for SARS-CoV-2. Health care workers were tested based on symptoms or exposure.

Results  A total of 29 611 Israeli HCWs (19 381 [65%] female; mean [SD] age, 44 [12] years) had received 3 vaccine doses between August and September 2021; of these, 5331 (18%) received the fourth dose in January 2022 and were not infected by the first week after vaccination. Overall breakthrough infection rates were 368 of 5331 (7%) in the 4-dose group and 4802 of 24280 (20%) in the 3-dose group (relative risk, 0.35; 95% CI, 0.32-0.39). Similar reductions were found in a matched analysis by the exact day of receiving the third vaccine (relative risk, 0.61; 95% CI, 0.54-0.71) and in a time-dependent Cox proportional hazards regression model (adjusted hazard ratio, 0.56; 95% CI, 0.50-0.63). In both groups, no severe disease or death occurred.

Conclusions and Relevance  In this cohort study, the fourth BNT162b2 vaccine dose resulted in a reduced breakthrough infection rate among hospital staff. This reduction was lower than that observed after the third dose; nevertheless, considering the high infectivity of the Omicron variant, which led to critical medical staff shortages, a fourth vaccine dose should be considered to mitigate the infection rate among HCWs.

O.J. Watson et al.

Global impact of the first year of COVID-19 vaccinationa mathematically modelling study

The Lancet Infectious Diseases, June 2022; doi.org/10.1016/S1473-3099(22)00320-6

Abstract

Background

The first COVID-19 vaccine outside a clinical trial setting was administered on Dec 8, 2020. To ensure global vaccine equity, vaccine targets were set by the COVID-19 Vaccines Global Access (COVAX) Facility and WHO. However, due to vaccine shortfalls, these targets were not achieved by the end of 2021. We aimed to quantify the global impact of the first year of COVID-19 vaccination programmes.

Methods

A mathematical model of COVID-19 transmission and vaccination was separately fit to reported COVID-19 mortality and all-cause excess mortality in 185 countries and territories. The impact of COVID-19 vaccination programmes was determined by estimating the additional lives lost if no vaccines had been distributed. We also estimated the additional deaths that would have been averted had the vaccination coverage targets of 20% set by COVAX and 40% set by WHO been achieved by the end of 2021.

Findings

Based on official reported COVID-19 deaths, we estimated that vaccinations prevented 14·4 million (95% credible interval [Crl] 13·7–15·9) deaths from COVID-19 in 185 countries and territories between Dec 8, 2020, and Dec 8, 2021. This estimate rose to 19·8 million (95% Crl 19·1–20·4) deaths from COVID-19 averted when we used excess deaths as an estimate of the true extent of the pandemic, representing a global reduction of 63% in total deaths (19·8 million of 31·4 million) during the first year of COVID-19 vaccination. In COVAX Advance Market Commitment countries, we estimated that 41% of excess mortality (7·4 million [95% Crl 6·8–7·7] of 17·9 million deaths) was averted. In low-income countries, we estimated that an additional 45% (95% CrI 42–49) of deaths could have been averted had the 20% vaccination coverage target set by COVAX been met by each country, and that an additional 111% (105–118) of deaths could have been averted had the 40% target set by WHO been met by each country by the end of 2021.

Interpretation

COVID-19 vaccination has substantially altered the course of the pandemic, saving tens of millions of lives globally. However, inadequate access to vaccines in low-income countries has limited the impact in these settings, reinforcing the need for global vaccine equity and coverage.

U. Storz

The COVID-19 vaccine patent race

Nature Biotechnology, July 2022; doi.org/10.1038/s41587-022-01376-1

Abstract

COVID-19 has kept the world in its grip for two years and counting. The unfolding of the pandemic came with some remarkable — and in part concerning — developments, including the speed with which the SARS-CoV-2 virus spread across the globe, the rapid development and approval of vaccines, the unexpected vaccine skepticism, and finally the inequitable distribution of the vaccines in different regions of the world.

COVID-19 is also historic in terms of its patent background. Several aspects regarding the patent protection of COVID-19 vaccines have been discussed, including disputes over patent ownership and the role of patents in limiting vaccine access to developing countries1^,2. Here, we discuss the development of mRNA vaccine technology, the race to the vaccine and the issues surrounding securing patent rights.

C.J. Reynolds et al .

Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure

Science, June 2022; doi: 10.1126/science.abq1841

Abstract

The Omicron, or Pango lineage B.1.1.529, variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection against severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple BioNTech BNT162b2 messenger RNA–vaccinated health care workers (HCWs) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple-vaccinated individuals, but the magnitude of T and B cell responses against B.1.1.529 spike protein was reduced. Immune imprinting by infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529. Previously infection-naïve HCWs who became infected during the B.1.1.529 wave showed enhanced immunity against earlier variants but reduced nAb potency and T cell responses against B.1.1.529 itself. Previous Wuhan Hu-1 infection abrogated T cell recognition and any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529.

M. Dennis

Pfizer, BioNTech's Omicron-adapted COVID-19 candidate vaccines show promise

First Word Pharma, June 2022; https://firstwordpharma.com/story/5602941

Abstract

Pfizer and BioNTech announced that booster doses of two different Omicron-adapted COVID-19 vaccine candidates elicited a substantially higher immune response against Omicron BA.1 than the companies' current mRNA-based shot Comirnaty. Pfizer CEO Albert Bourla said "based on these data, we believe we have two very strong Omicron-adapted candidates."

The vaccine candidates tested in the Phase II/III trial include an Omicron-adapted monovalent immunisation and a bivalent shot, which combines Comirnaty with a vaccine candidate targeting the spike protein of the Omicron BA.1 variant of concern. The study included 1234 participants aged 56 years and older who received a fourth booster dose with either the monovalent or bivalent vaccine candidate at a dose of 30µg or 60µg.

Adams et al.

Vaccine Effectiveness of Primary Series and Booster Doses against Omicron Variant COVID-19-Associated Hospitalization in the United States

medRxiv, June 2022; doi.org/10.1101/2022.06.09.22276228

Abstract

Objectives: To compare the effectiveness of a primary COVID-19 vaccine series plus a booster dose with a primary series alone for the prevention of Omicron variant COVID-19 hospitalization.

Design: Multicenter observational case-control study using the test-negative design to evaluate vaccine effectiveness (VE).

Setting: Twenty-one hospitals in the United States (US).

Participants: 3,181 adults hospitalized with an acute respiratory illness between December 26, 2021 and April 30, 2022, a period of SARS-CoV-2 Omicron variant (BA.1, BA.2) predominance. Participants included 1,572 (49%) case-patients with laboratory confirmed COVID-19 and 1,609 (51%) control patients who tested negative for SARS-CoV-2. Median age was 64 years, 48% were female, and 21% were immunocompromised; 798 (25%) were vaccinated with a primary series plus booster, 1,326 (42%) were vaccinated with a primary series alone, and 1,057 (33%) were unvaccinated.

Main Outcome Measures: VE against COVID-19 hospitalization was calculated for a primary series plus a booster and a primary series alone by comparing the odds of being vaccinated with each of these regimens versus being unvaccinated among cases versus controls. VE analyses were stratified by immune status (immunocompetent; immunocompromised) because the recommended vaccine schedules are different for these groups. The primary analysis evaluated all COVID-19 vaccine types combined and secondary analyses evaluated specific vaccine products.

Results: Among immunocompetent patients, VE against Omicron COVID-19 hospitalization for a primary series plus one booster of any vaccine product dose was 77% (95% CI: 71–82%), and for a primary series alone was 44% (95% CI: 31–54%) (p<0.001). VE was higher for a boosted regimen than a primary series alone for both mRNA vaccines used in the US (BNT162b2: primary series plus booster VE 80% (95% CI: 73-85%), primary series alone VE 46% (95% CI: 30-58%) [p<0.001]; mRNA-1273: primary series plus booster VE 77% (95% CI: 67-83%), primary series alone VE 47% (95% CI: 30-60%) [p<0.001]). Among immunocompromised patients, VE for a primary series of any vaccine product against Omicron COVID-19 hospitalization was 60% (95% CI: 41-73%). Insufficient sample size has accumulated to calculate effectiveness of boosted regimens for immunocompromised patients.

Conclusions: Among immunocompetent people, a booster dose of COVID-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing COVID-19 hospitalization due to the Omicron variant.

Comunicato stampa, 17 Giugno 2022

Coronavirus (COVID-19) Update: FDA Authorizes Moderna and Pfizer-BioNTech COVID-19 Vaccines for Children Down to 6 Months of Age

https://www.fda.gov/news-events/press-announcements/coronaviruscovid-19-update-fda-authorizes-moderna-and-pfizer-biontech-covid-19-vaccines-children 11.

Abstract

Today, the U.S. Food and Drug Administration authorized emergency use of the Moderna COVID-19 Vaccine and the Pfizer-BioNTech COVID-19 Vaccine for the prevention of COVID-19 to include use in children down to 6 months of age. 

• For the Moderna COVID-19 Vaccine, the FDA amended the emergency use authorization (EUA) to include use of the vaccine in individuals 6 months through 17 years of age. The vaccine had been authorized for use in adults 18 years of age and older.
• For the Pfizer-BioNTech COVID-19 Vaccine, the FDA amended the EUA to include use of the vaccine in individuals 6 months through 4 years of age. The vaccine had been authorized for use in individuals 5 years of age and older. 

K. Mohan Vadrevu et al.

Immunogenicity and reactogenicity of an inactivated SARS-CoV-2 vaccine (BBV152) in children aged 2–18 years: interim data from an open-label, non-randomised, age deescalation phase 2/3 study

Lancet; June 2022; doi.org/10.1016/ S1473-3099(22)00307-3

Abstract

Background Despite having milder symptoms than adults, children are still susceptible to and can transmit SARSCoV-2. Vaccination across all age groups is therefore necessary to curtail the pandemic. Among the available COVID-19 vaccine platforms, an inactivated vaccine platform has the advantage of excellent safety profile across all age groups; hence, we conducted an age de-escalation study to assess the safety, reactogenicity, and immunogenicity of an inactivated COVID-19 vaccine, BBV152 (COVAXIN; Bharat Biotech International, Hyderabad, India), in children aged 2–18 years.

Methods In this phase 2/3 open-label, non-randomised, multicentre study done in six hospitals in India, healthy children (male or female) aged 2–18 years were eligible for inclusion into the study. Children who had positive SARSCoV-2 nucleic acid and serology tests at baseline, or any history of previous SARS-CoV-2 infection, or with known immunosuppressive condition were excluded. Children were sequentially enrolled into one of three groups (>12 to ≤18 years [group 1], >6 to 12 years [group 2], or ≥2 to 6 years [group 3]) and administered with adult formulation of BBV152 as two 0·5 mL intramuscular doses on days 0 and 28. Co-primary endpoints were solicited adverse events for 7 days post-vaccination and neutralising antibody titres on day 56, 28 days after the second dose. Immunogenicity endpoints were compared with Biodefense and Emerging Infections, Research Resources Repository (BEI) reference serum samples and from adults who received two doses of BBV152 in the same schedule in a previously reported phase 2 study. The trial is registered with the Clinical Trials Registry, India (CTRI/2021/05/033752) and ClinicalTrials. gov (NCT04918797).

Findings From May 27, 2021, to July 10, 2021, we enrolled 526 children sequentially into groups 1 (n=176), 2 (n=175), and 3 (n=175). Vaccination was well tolerated, with no differences in reactogenicity between the three age groups, and no serious adverse events, deaths, or withdrawals due to an adverse event. Local reactions mainly consisted of mild injection site pain in 46 (26%) of 176 participants in group 1, 61 (35%) of 175 in group 2, and 39 (22%) of 175 in group 3 after dose 1; and 39 (22%) of 176 in group 1, 43 of 175 (25%) in group 2, and 14 of 175 (8%) in group 3 after dose 2; there were no cases of severe pain and few reports of other local reactions. After dose 1, the most frequent solicited systemic adverse event was mild-to-moderate fever, reported in eight (5%) of 176 participants in group 1, 17 (10%) of 175 in group 2, and 22 (13%) of 175 in group 3. No case of severe fever was reported, and rates of all fever were all 4% or less after dose 2. Geometric mean titres (GMTs) of microneutralisation antibodies at day 56 in groups 1 (138·8 [95% CI 111·0–173·6]), 2 (137·4 [99·1–167·5]), and 3 (197·6 [176·4–221·4]) were similar to titres in vaccinated adults (160·1 [135·8–188·8]) and with BEI reference serum samples (103·3 [50·3–202·1]). Similar results were obtained using the plaque reduction neutralisation test (PRNT), in which 166 (95%) of 175 participants in group 1, 165 (98%) of 168 in group 2, and 169 (98%) of 172 in group 3 seroconverted at day 56. The GMT ratio of PRNT titres in children and adults was 1·76 (95% CI 1·32–2·33), indicating a superior response in children compared with adults.

Interpretation BBV152 was well tolerated in children aged 2–18 years, and induced higher neutralising antibody responses than those observed in adults, in whom the efficacy (ie, the prevention or decrease in the severity of COVID-19 infection) has been demonstrated.

R. Ochoa-Azze et al.

Safety and immunogenicity of the FINLAY-FR-1A vaccine in COVID-19 convalescent participants: an open-label phase 2a and double-blind, randomised, placebo-controlled, phase 2b, seamless, clinical trial

Lancet Respir. Med., June 2022; doi.org/10.1016/ S2213-2600(22)00100-X

Abstract

Background A phase 1, clinical trial to evaluate FINLAY-FR-1A vaccine in COVID-19 convalescent individuals was completed. Here, we report results of the phase 2, clinical trial.

Methods We studied 450 convalescent participants with a history of asymptomatic, mild, or moderate COVID-19 at the National Institute of Hematology and Immunology and the National Centre for Sexual Education in Havana, Cuba. The study included adults aged 19–78 years who had recovered from COVID-19 and had had a negative PCR test at least 2 months before the initiation of the study. Phase 2 was done sequentially in two stages. The first stage to assess safety comprised an open, non-controlled phase 2a study in participants aged 60–78 years who received a single dose of the FINLAY-FR-1A vaccine (50 µg of recombinant dimeric receptor binding domain [RBD]). The second stage comprised the placebo-controlled, double-blind, phase 2b trial in participants aged 19–78 years, where participants were randomly assigned (4:1) into two groups: an experimental group vaccinated with a single dose of the FINLAY-FR-1A vaccine, and a control (placebo) group injected with vaccine excipient. The primary outcomes were safety, evaluated 28 days after vaccination by the occurrence of serious adverse events in all participants, and successful immune response, assessed by neutralising antibody ELISA, and defined as half-maximal surrogate virus neutralisation titres of 250 or more. Secondary endpoints included vaccine immunogenicity assessed by ELISA anti-RBD and live-virus neutralisation test.All randomly assigned participants were included in the safety analysis (safety population), and immunogenicity was evaluated in participants without study interruptions (per-protocol population). The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000366-En and WHO-ICTRP and is complete.

Findings From April 9, 2021, to April 17, 2021, 663 COVID-19 convalescent participants were enrolled in the study; 213 participants did not meet the selection criteria and 450 volunteers were recruited. 20 participants aged 60–78 years were included in the open, single-group, phase 2a study and 430 participants were randomly assigned to the experimental (n=344) or control groups (n=86) in the phase 2b study of participants aged 19–78 years. 19 (95%) of 20 phase 2a volunteers achieved a successful immune response after vaccination. No vaccine-associated serious adverse events were reported in the whole study population. Minor adverse events were found, the most common being pain at the injection site (105 [29%] of 364 in the intervention group; 13 [15%] of 86 in the placebo group). A successful immune response was found in 289 (81%) of 358 participants 28 days after vaccination. The vaccine elicited a greater than 31-times increase in anti-RBD-IgG antibodies compared with prevaccination rates, and the seroconversion rate was 302 (84%) of 358 on day 28 after vaccination; the geometric mean titres of live-virus neutralisation test increased from 15·4 (95% CI 10·3–23·2) to 400·3 (272·4–588·1) and high response was found against alpha, beta, and delta variants of concern.

Interpretation A single dose of the FINLAY-FR-1A vaccine against SARS-CoV-2 strengthened the pre-existing natural immunity, with excellent safety profile.

R. Vikkurthi et al.

Inactivated whole-virion vaccine BBV152/Covaxin elicits robust cellular immune memory to SARS-CoV-2 and variants of concern

Nature Microbiology, June 2022; doi.org/10.1038/s41564-022-01161-5

Abstract

BBV152 is a whole-virion inactivated vaccine based on the Asp614Gly variant. BBV152 is the first alum-imidazoquinolin-adjuvanted vaccine authorized for use in large populations. Here we characterized the magnitude, quality and persistence of cellular and humoral memory responses up to 6 months post vaccination. We report that the magnitude of vaccine-induced spike and nucleoprotein antibodies was comparable with that produced after infection. Receptor binding domain-specific antibodies declined against variants in the order of Alpha (B.1.1.7; 3-fold), Delta (B.1.617.2; 7-fold) and Beta (B.1.351; 10-fold). However, pseudovirus neutralizing antibodies declined up to 2-fold against the Delta followed by the Beta variant (1.7-fold). Vaccine-induced memory B cells were also affected by the Delta and Beta variants. The SARS-CoV-2-specific multicytokine-expressing CD4⁺ T cells were found in ~85% of vaccinated individuals. Only a ~1.3-fold reduction in efficacy was observed in CD4⁺ T cells against the Beta variant. We found that antigen-specific CD4⁺ T cells were present in the central memory compartment and persisted for at least up to 6 months post vaccination. Vaccine-induced CD8⁺ T cells were detected in ~50% of individuals. Importantly, the vaccine was capable of inducing follicular T helper cells that exhibited B-cell help potential. These findings show that inactivated vaccine BBV152 induces robust immune memory to SARS-CoV-2 and variants of concern that persists for at least 6 months after vaccination.

S. Monge et al.

Effectiveness of mRNA vaccine boosters against infection with the SARS-CoV-2 omicron (B.1.1.529) variant in Spain: a nationwide cohort study

The Lancet, June 2022; doi.org/10.1016/ S1473-3099(22)00292-4

Abstract

Background     The omicron (B.1.1.529) variant of SARS-CoV-2 has increased capacity to elude immunity and cause breakthrough infections. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters (third dose) against infection with the omicron variant by age, sex, time since complete vaccination, type of primary vaccine, and type of booster.

Methods     In this nationwide cohort study, we linked data from three nationwide population registries in Spain (Vaccination Registry, Laboratory Results Registry, and National Health System registry) to select community-dwelling individuals aged 40 years or older, who completed their primary vaccine schedule at least 3 months before the start of follow-up, and had not tested positive for SARS-CoV-2 since the start of the pandemic. On each day between Jan 3, and Feb 6, 2022, we matched individuals who received a booster mRNA vaccine and controls of the same sex, age group, postal code, type of vaccine, time since primary vaccination, and number of previous tests. We estimated risk of laboratory-confirmed SARS-CoV-2 infection using the Kaplan-Meier method and compared groups using risk ratios (RR) and risk differences. Vaccine effectiveness was calculated as one minus RR. Findings Between Jan 3, and Feb 6, 2022, 3 111 159 matched pairs were included in our study. Overall, the estimated effectiveness from day 7 to 34 after a booster was 51·3% (95% CI 50·2–52·4). Estimated effectiveness was 52·5% (51·3–53·7) for an mRNA-1273 booster and 46·2% (43·5–48·7) for a BNT162b2 booster. Effectiveness was 58·6% (55·5–61·6) if primary vaccination had been with ChAdOx1 nCoV-19 (Oxford–AstraZeneca), 55·3% (52·3–58·2) with mRNA-1273 (Moderna), 49·7% (48·3–51·1) with BNT162b2 (Pfizer–BioNTech), and 48·0% (42·5–53·7) with Ad26.COV2.S (Janssen). Estimated effectiveness was 43·6% (40·0–47·1) when the booster was administered between 151 days and 180 days after complete vaccination and 52·2% (51·0–53·3) if administered more than 180 days after primary scheduled completion.

Interpretation     Booster mRNA vaccine-doses were moderately effective in preventing infection with the omicron variant of SARS-CoV-2 for over a month after administration, which indicates their suitability as a strategy to limit the health effects of COVID-19 in periods of omicron variant domination. Estimated effectiveness was higher for mRNA-1273 compared with BNT162b2 and increased with time between completed primary vaccination and booster.

Moderna

Moderna announces Omicron-containing bivalent booster candidate mRNA-1273.214 demonstrates superior antibody response against Omicron

June 2022; https://investors.modernatx.com/news/news-details/2022/Moderna-Announces-Omicron-Containing-Bivalent-Booster-Candidate-mRNA-1273.214-Demonstrates-Superior-Antibody-Response-Against-Omicron/default.aspx

Moderna, Inc., (NASDAQ:MRNA) a biotechnology company pioneering messenger RNA (mRNA)therapeutics and vaccines, announced new clinical data on its Omicron-containing bivalent COVID boostercandidate, mRNA-1273.214, containing mRNA-1273 (Spikevax) and a vaccine candidate targeting theOmicron variant of concern. A 50 µg booster dose of mRNA-1273.214 met all pre-specified endpoints including superior neutralizing antibody response (geometric mean ratio) against the Omicron variant one month after administration when compared to the original mRNA-1273 vaccine.The booster dose of mRNA-1273.214 was generally well-tolerated, with side effects comparable to a booster dose of mRNA-1273 at the 50 µg dose level.

M. Patel

Increasing children's global access to COVID-19 vaccines

The Lancet, June 2022; Vol 399, pp 2171-2173

Abstract

Expanding COVID-19 vaccination to children is an issue for parents and decision makers worldwide. Among nine vaccines with WHO Emergency Use Listing (EUL), only two are authorised for children: Pfizer-BioNTech’s BNT162b2 and Moderna’s mRNA-1273. The WHO EUL is required for vaccines purchased through the COVAX mechanism, but other vaccines without EUL for paediatric use, such as BBIBP-CorV (SinoPharm), CoronaVac (SinoVac), and Covaxin (Bharat Biotech), are used in children with local approvals. Because of lower rates of severe COVID-19 in children than in older adults, and inequities in vaccine supply, the WHO SAGE Roadmap for prioritising the use of COVID-19 vaccines classifies children as a lower priority group. However, a COVID-19 risk in children does exist. Complications in children with COVID-19 have included respiratory failure, neurological involvement, cardiovascular dysfunction, multisystem inflammatory syndrome, and long COVID.

C. Buddy Creech et al.

Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6 to 11 Years of Age

New England Journal of Medicine, May 2022; doi: 10.1056/NEJMoa2203315

Abstract

BACKGROUND

Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown.

METHODS

Part 1 of this ongoing phase 2–3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 μg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported.

RESULTS

In part 1 of the trial, 751 children received 50-μg or 100-μg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-μg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 μg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-μg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-μg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant.

CONCLUSIONS

Two 50-μg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults.

Grace Li et al

Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in children aged 12-17 years: a preliminary report of a phase 2, single-blind, randomised controlled trial (COV006)

The Lancet, June 2022;  doi: 10.1016/S0140-6736(22)00770-X.

Abstract

Background: Vaccination of children and young people against SARS-CoV-2 is recommended in some countries. Scarce data have been published on immune responses induced by COVID-19 vaccines in people younger than 18 years compared with the same data that are available in adults.

Methods: COV006 is a phase 2, single-blind, randomised, controlled trial of ChAdOx1 nCoV-19 (AZD1222) in children and adolescents at four trial sites in the UK. Healthy participants aged 6-17 years, who did not have a history of chronic respiratory conditions, laboratory-confirmed COVID-19, or previously received capsular group B meningococcal vaccine (the control), were randomly assigned to four groups (4:1:4:1) to receive two intramuscular doses of 5 × 10¹⁰ viral particles of ChAdOx1 nCoV-19 or control, 28 days or 84 days apart. Participants, clinical investigators, and the laboratory team were masked to treatment allocation. Study groups were stratified by age, and participants aged 12-17 years were enrolled before those aged 6-11 years. Due to the restrictions in the use of ChAdOx1 nCoV-19 in people younger than 30 years that were introduced during the study, only participants aged 12-17 years who were randomly assigned to the 28-day interval group had received their vaccinations at the intended interval (day 28). The remaining participants received their second dose at day 112. The primary outcome was assessment of safety and tolerability in the safety population, which included all participants who received at least one dose of the study drug. The secondary outcome was immunogenicity, which was assessed in participants who were seronegative to the nucleocapsid protein at baseline and received both prime and boost vaccine. This study is registered with ISRCTN (15638344).

Findings: Between Feb 15 and April 2, 2021, 262 participants (150 [57%] participants aged 12-17 years and 112 [43%] aged 6-11 years; due to the change in the UK vaccination policy, the study terminated recruitment of the younger age group before the planned number of participants had been enrolled) were randomly assigned to receive vaccination with two doses of either ChAdOx1 nCoV-19 (n=211 [n=105 at day 28 and n=106 at day 84]) or control (n=51 [n=26 at day 28 and n=25 at day 84]). One participant in the ChAdOx1 nCoV-19 day 28 group in the younger age bracket withdrew their consent before receiving a first dose. Of the participants who received ChAdOx1 nCoV-19, 169 (80%) of 210 participants reported at least one solicited local or systemic adverse event up to 7 days following the first dose, and 146 (76%) of 193 participants following the second dose. No serious adverse events related to ChAdOx1 nCoV-19 administration were recorded by the data cutoff date on Oct 28, 2021. Of the participants who received at least one dose of ChAdOx1 nCoV-19, there were 128 unsolicited adverse events up to 28 days after vaccination reported by 83 (40%) of 210 participants. One participant aged 6-11 years receiving ChAdOx1 nCoV-19 reported a grade 4 fever of 40·2°C on day 1 following first vaccination, which resolved within 24 h. Pain and tenderness were the most common local solicited adverse events for all the ChAdOx1 nCoV-19 and capsular group B meningococcal groups following both doses. Of the 242 participants with available serostatus data, 14 (6%) were seropositive at baseline. Serostatus data were not available for 20 (8%) of 262 participants. Among seronegative participants who received ChAdOx1 nCoV-19, anti-SARS-CoV-2 IgG and pseudoneutralising antibody titres at day 28 after the second dose were higher in participants aged 12-17 years with a longer interval between doses (geometric means of 73 371 arbitrary units [AU]/mL [95% CI 58 685-91 733] and 299 half-maximal inhibitory concentration [IC₅₀; 95% CI 230-390]) compared with those aged 12-17 years who received their vaccines 28 days apart (43 280 AU/mL [95% CI 35 852-52 246] and 150 IC₅₀ [95% CI 116-194]). Humoral responses were higher in those aged 6-11 years than in those aged 12-17 years receiving their second dose at the same 112-day interval (geometric mean ratios 1·48 [95% CI 1·07-2·07] for anti-SARS-CoV-2 IgG and 2·96 [1·89-4·62] for pseudoneutralising antibody titres). Cellular responses peaked after a first dose of ChAdOx1 nCoV-19 across all age and interval groups and remained above baseline after a second vaccination.

Interpretation: ChAdOx1 nCoV-19 is well tolerated and immunogenic in children aged 6-17 years, inducing concentrations of antibody that are similar to those associated with high efficacy in phase 3 studies in adults. No safety concerns were raised in this trial.

J. Weitzer et al.

Willingness to receive an annual COVID-19 booster vaccine in the German-speaking D-A-CH region in Europe: A cross-sectional study

The Lancet Regional Health – Europe, June 2022;  doi.org/10.1016/j.lanepe.2022.100414

Abstract

Background Emergence of new coronavirus variants and waning immunity may necessitate regular COVID-19 vaccine boosters, but empirical data on population willingness for regular vaccination are limited.

Methods In August 2021, we surveyed 3,067 quota-sampled German-speaking adults residing in the D-A-CH region (Germany, Austria, Switzerland). Using multivariable adjusted ordered logistic regression models we calculated odds ratios (OR) and 95% confidence intervals (95% CIs) to assess factors associated with willingness to vaccinate annually against COVID-19.

Findings Among 2,480 participants vaccinated or planning to get vaccinated, 82·4% indicated willingness to receive annual COVID-19 boosters. This willingness was higher in Austria (OR=1·47, 95% CI, 1·19–1·82; p < 0·001) and Germany (OR=1·98, 95% CI, 1·60–2·45; p < 0·001) versus Switzerland and increased with age. Having voted in the last national election (OR_{opposition party voters}=1·51, 95% CI=1·18–1·92; p = 0·001 and OR_{governing party voters}=1·57, 95% CI=1·28–1·93; p < 0·001, versus non-voters) and not regularly participating in religious meetings (OR=1·37, 95% CI=1·08–1·73; p = 0·009, versus participation at least monthly) were significantly associated with willingness to vaccinate, as was partial (OR=1·97, 95% CI=1·43–2·72; p < 0·001) or total (OR=5·20, 95% CI=3·76–7·19; p < 0·001) approval of COVID-19 mitigation measures (versus non-approval). By country, Austrians showed the strongest association of voting behavior and mitigation measure approval with willingness to vaccinate.

Interpretation Targeted promotion programs informed by political and religious engagement and mitigation measure approval are needed to increase willingness to receive regular COVID-19 boosters.

G. Lorenzoni et al.

COVID-19 Vaccination Status Among Adults Admitted to Intensive Care Units in Veneto, Italy

Jama, May 2022; doi:10.1001/jamanetworkopen.2022.13553

Abstract

Effectiveness of vaccination to prevent severe COVID-19 requiring admission to the intensive care unit (ICU) has been reported to be approximately 90%. However, few data are available regarding duration of vaccination coverage to prevent ICU admission for severe COVID-19 and outcomes in patients who require ICU admission despite prior vaccination. This study aimed to provide a descriptive analysis of ICU admissions for severe COVID-19 after a vaccination campaign in the Veneto region of Italy that started at the end of December 2020 and prioritized health care workers, older individuals, nursing home residents, and patients with severe comorbidities.

Methods

This cohort study included all consecutive patients aged 18 years or older admitted to the Veneto ICU Network from May to December 2021 for COVID-19–associated acute respiratory distress syndrome. The Institutional Ethical Committee of Padova University Hospital approved the study; informed consent was waived because of the observational design and retrospective analysis of data from an anonymous database. The study followed the STROBE guideline.

Vaccination status (vaccinated [≥2 doses], partially vaccinated [1 dose], or not vaccinated), date of vaccine administration, age, hospital and ICU admission date, and ICU outcome (death or discharge) were collected for each patient. Data were analyzed using R, version 4.1.0, and 2-sided P < .05 was significant. A full description of statistical methods is available in the eMethods in Supplement 1.

Results

A total of 748 patients were admitted to ICUs of the Veneto ICU Network during the study period (mean [SD] age, 62 [14] years); 138 (18%) were vaccinated, 58 (8%) were partially vaccinated, and 552 (74%) were not vaccinated. Vaccinated patients were more often older than 80 years (29 [21%]) compared with partially vaccinated patients (3 [5%]) and nonvaccinated patients (19 [3%]) (P < .001) (Table). Median time from vaccine administration to ICU admission for partially vaccinated patients was 22.5 days (IQR, 16.0-49.8 days) and for vaccinated patients, 159.0 days (IQR, 112.0-192.0 days).

The Figure shows ICU admissions per million inhabitants during the study period. A statistically significant increasing trend was detected for ICU admissions among nonvaccinated patients. Conversely, the trend remained stable for vaccinated patients. Overall, 145 patients died in the ICU: 93 nonvaccinated (17%; 95% CI, 14%-20%), 19 partially vaccinated (33%; 95% CI, 21%-46%), and 33 vaccinated (24%; 95% CI, 17%-32%) patients.

Discussion

The study data revealed that vaccinated patients received the second dose of vaccine a median of 5 months before admission to the ICU, whereas for partially vaccinated patients, the median ICU admission time occurred while they awaited the second dose. A statistically significant increase in ICU admissions was observed only for nonvaccinated patients. The data suggest that mortality was higher among vaccinated patients than among nonvaccinated patients, and the proportion of patients older than 80 years was greater among vaccinated patients than among partially vaccinated and nonvaccinated patients. The data are consistent with recent work showing that among 1585 ICU patients, only 7% were vaccinated and hospital mortality was higher among vaccinated individuals than among nonvaccinated individuals.⁴

This study has limitations. Patients could not be characterized according to clinical characteristics and type of vaccine administered because this information was not available. Furthermore, confounding by indication may be problematic given that the priority schemes used in vaccination programs were often determined by health outcomes among nonvaccinated patients. The study’s findings suggest that vaccination was associated with fewer ICU admissions and that a COVID-19 booster campaign⁵ and a fourth dose of mRNA vaccine may be warranted, especially for older patients and individuals with comorbidities.

J.X. Li et al.

Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, openlab

The Lancet , May 2022;  doi.org/10.1016/ S2213-2600(22)00087-X

Abstract

Background Due to waning immunity and protection against infection with SARS-CoV-2, a third dose of a homologous or heterologous COVID-19 vaccine has been proposed by health agencies for individuals who were previously primed with two doses of an inactivated COVID-19 vaccine.

Methods We did a randomised, open-label, controlled trial to evaluate the safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in Chinese adults (≥18 years old) who had previously received two doses of an inactivated SARS-CoV-2 vaccine—Sinovac CoronaVac. Eligible participants were randomly assigned (1:1:1) to receive a heterologous booster vaccination with a low dose (1·0×10¹¹ viral particles per mL; 0·1 mL; low dose group), or a high dose (1·0×10¹¹ viral particles per mL; 0·2 mL; high dose group) aerosolised Ad5-nCoV, or a homologous intramuscular vaccination with CoronaVac (0·5 mL). Only laboratory staff were masked to group assignment. The primary endpoint for safety was the incidence of adverse reactions within 14 days after the booster dose. The primary endpoint for immunogenicity was the geometric mean titres (GMTs) of serum neutralising antibodies (NAbs) against live SARS-CoV-2 virus 14 days after the booster dose. This study was registered with ClinicalTrials.gov, NCT05043259.

Findings Between Sept 14 and 16, 2021, 420 participants were enrolled: 140 (33%) participants per group. Adverse reactions were reported by 26 (19%) participants in the low dose group and 33 (24%) in the high dose group within 14 days after the booster vaccination, significantly less than the 54 (39%) participants in the CoronaVac group (78·5 [60·5–101·7]; p<0·0001).

Interpretation We found that a heterologous booster vaccine with an orally administered aerosolised Ad5-nCoV is safe and highly immunogenic in adults who have previously received two doses of CoronaVac as the primary series vaccination.

Lustig et al.

Superior immunogenicity and effectiveness of the third compared to the second BNT162b2 vaccine dose

Nature immunology, May 2022; doi.org/10.1038/s41590-022-01212-3

Abstract

As the effectiveness of a two-dose messenger RNA (mRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine regimen decreases with time, a third dose has been recommended. Here, we assessed immunogenicity, vaccine effectiveness and safety of the third BNT162b2 vaccine dose in a prospective cohort study of 12,413 healthcare workers (HCWs). Anti-RBD immunoglobulin G (IgG) levels were increased 1.7-fold after a third dose compared with following the second dose. Increased avidity from 61.1% (95% confidence interval (CI), 56.1–66.7) to 96.3% (95% CI, 94.2–98.5) resulted in a 6.1-fold increase in neutralization titer. Peri-infection humoral markers of 13 third-dose Delta variant of concern (VOC) breakthrough cases were lower compared with 52 matched controls. Vaccine effectiveness of the third dose relative to two doses was 85.6% (95% CI, 79.2–90.1). No serious adverse effects were reported. These results suggest that the third dose is superior to the second dose in both quantity and quality of IgG antibodies and safely boosts protection from infection.

Islam et al.

Comparative effectiveness over time of themRNA-1273 (Moderna) vaccine and the BNT162b2 (Pfizer-BioNTech) vaccine

Nature communications, May 2022; doi.org/10.1038/s41467-022-30059-3

Abstract

Real-world analysis of the incidence of SARS-CoV-2 infection post vaccination is important in determining the comparative effectiveness of the available vaccines. In this retrospective cohort study using deidentified administrative claims for Medicare Advantage and commercially insured individuals in a research database we examine over 3.5 million fully vaccinated individuals, including 8,848 individuals with SARS-CoV-2 infection, with a follow-up period between 14 and 151 days after their second dose. Our primary outcome was the rate of Covid-19 infection occurring at 30, 60, and 90 days at least 14 days after the second dose of either the mRNA-1273 vaccine or the BNT162b2 vaccine. Sub-analyses included the incidence of hospitalization, ICU admission, and death/hospice transfer. Separate analysis was conducted for individuals above and below age 65 and those without a prior diagnosis of Covid-19. We show that immunization with mRNA-1273, compared to BNT162b2, provides slightly more protection against SARS-CoV-2 infection that reaches statistical significance at 90 days with a number needed to vaccinate of >290. There are no differences in vaccine effectiveness for protection against hospitalization, ICU admission, or death/hospice transfer (aOR 1.23, 95% CI (0.67, 2.25).

A.C. Garfinkel et al.

From Resentment to Reconnection — Reflections on Caring for the Unvaccinated

New England J Medicine, April 2022; doi: 10.1056/NEJMp2119720

Abstract

As cautious, fully vaccinated, but immunocompromised people die of Covid, a physician finds herself resenting the patients filling up the hospital after declining vaccination. Then an encounter with one very ill and frightened patient changes her perspective.

H.C. Meissner

Understanding Vaccine Safety and the Roles of the FDA and the CDC

New England J Medicine, April 2022;doi: 10.1056/NEJMra2200583

Abstract

Throughout human history, epidemics and pandemics have resulted in untold suffering, localized reductions in population size, and damaged economies. Often, economic harm has caused greater loss of wellbeing than the infection itself. Increasing population density and economic and social changes, such as population shifts and the requirement for increased food production, have resulted in human encroachment into less populated areas of the globe. These factors bring people into closer contact with wildlife and arthropod vectors, as well as livestock and poultry, which increases the risk that zoonotic pathogens will spill over to humans. In the past two decades, bats have been reservoirs of three betacoronaviruses that have crossed the species barrier, causing severe acute respiratory syndrome (SARS)–like disease in humans. Recent outbreaks caused by noncoronaviruses such as pandemic influenza A (H1N1), Ebola, and Zika viruses underscore the threat of future outbreaks (Table 1). In the decades ahead, diseases caused by currently unknown viruses are likely to emerge as changes in human behavior continue to increase exposure to infectious organisms in the environment. The development and widespread acceptance of vaccines will be crucial for controlling disease caused by pathogenic organisms, especially those that acquire the capability of efficient human-to-human transmission. As existing microbes evolve and new microbes emerge, nonpharmacologic interventions, including containment, isolation, and quarantine, will play a role in outbreak control, but vaccines will form the foundation for converting a viral pandemic into manageable endemic disease. Containment of past viral pandemics has been accomplished without vaccines, but minimizing the morbidity and mortality associated with future pandemics is likely to be difficult to achieve without high rates of vaccine acceptance, especially for viruses that use the respiratory tract as a portal of entry. A widespread understanding and acceptance of vaccines will be an integral aspect of public health strategies for limiting the consequences of future pandemics. This review discusses how vaccine safety and efficacy are evaluated, the pathways by which vaccines become authorized or licensed, and considerations addressed by advisory bodies in establishing vaccine recommendations.

O. Magen et al.

Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting

New England J Medicine, 2022; doi: 10.1056/NEJMoa2201688

Abstract

Background

With large waves of infection driven by the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), alongside evidence of waning immunity after the booster dose of coronavirus disease 2019 (Covid-19) vaccine, several countries have begun giving at-risk persons a fourth vaccine dose.

Methods

To evaluate the early effectiveness of a fourth dose of the BNT162b2 vaccine for the prevention of Covid-19–related outcomes, we analyzed data recorded by the largest health care organization in Israel from January 3 to February 18, 2022. We evaluated the relative effectiveness of a fourth vaccine dose as compared with that of a third dose given at least 4 months earlier among persons 60 years of age or older. We compared outcomes in persons who had received a fourth dose with those in persons who had not, individually matching persons from these two groups with respect to multiple sociodemographic and clinical variables. A sensitivity analysis was performed with the use of parametric Poisson regression.

Results

The primary analysis included 182,122 matched pairs. Relative vaccine effectiveness in days 7 to 30 after the fourth dose was estimated to be 45% (95% confidence interval [CI], 44 to 47) against polymerase-chain-reaction–confirmed SARS-CoV-2 infection, 55% (95% CI, 53 to 58) against symptomatic Covid-19, 68% (95% CI, 59 to 74) against Covid-19–related hospitalization, 62% (95% CI, 50 to 74) against severe Covid-19, and 74% (95% CI, 50 to 90) against Covid-19–related death. The corresponding estimates in days 14 to 30 after the fourth dose were 52% (95% CI, 49 to 54), 61% (95% CI, 58 to 64), 72% (95% CI, 63 to 79), 64% (95% CI, 48 to 77), and 76% (95% CI, 48 to 91). In days 7 to 30 after a fourth vaccine dose, the difference in the absolute risk (three doses vs. four doses) was 180.1 cases per 100,000 persons (95% CI, 142.8 to 211.9) for Covid-19–related hospitalization and 68.8 cases per 100,000 persons (95% CI, 48.5 to 91.9) for severe Covid-19. In sensitivity analyses, estimates of relative effectiveness against documented infection were similar to those in the primary analysis.

Conclusions

A fourth dose of the BNT162b2 vaccine was effective in reducing the short-term risk of Covid-19–related outcomes among persons who had received a third dose at least 4 months earlier.

J. Lang-meli et al.

SARS-CoV-2-specific T-cell epitope repertoire in convalescent and mRNA-vaccinated individual

Nature Microbiology, April 2022; doi.org/10.1038/s41564-022-01106-y

Abstract

Continuously emerging variants of concern (VOCs) sustain the SARS-CoV-2 pandemic. The SARS-CoV-2 Omicron/B.1.1.529 VOC harbours multiple mutations in the spike protein associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. By performing in-depth comparisons of the SARS-CoV-2-specific T-cell epitope repertoire after infection and messenger RNA vaccination, we demonstrate that spike-derived epitopes were not dominantly targeted in convalescent individuals compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T-cell response compared to convalescent individuals. Booster vaccination increased the breadth of the spike-specific T-cell response in convalescent individuals but not in vaccinees with complete initial vaccination. In convalescent individuals and vaccinees, the targeted T-cell epitopes were broadly conserved between wild-type SARS-CoV-2 variant B and Omicron/B.1.1.529. Hence, our data emphasize the relevance of vaccine-induced spike-specific CD8⁺ T-cell responses in combating VOCs including Omicron/B.1.1.529 and support the benefit of boosting convalescent individuals with mRNA vaccines.

H.M. El Sahly et al.

Is a fourth dose of covid-19 mRNA vaccine needed?

N Engl J Med, Journal Watch, April 2022;

Abstract

Two retrospective Israeli cohort studies suggest that, after a fourth dose of BNT162b2, participants aged ≥60 had reduced risk for infection and severe disease in the short term.

In the wake of the surging SARS-CoV-2 Omicron variant, a fourth dose of the Pfizer-BioNTech (BNT162b2) vaccine in those aged ≥60 was approved in Israel. Now, two retrospective cohort studies have evaluated its effectiveness at preventing COVID-19 outcomes. Using public health data from 1.2 million eligible adults, Bar-On et al. evaluated the incidence of severe COVID-19 (respiratory rate >30 breaths per minute, oxygen saturation <94%, or ratio of partial pressure of arterial oxygen to fraction of inspired oxygen <300) in 623,000 persons who received a fourth dose (8–14 days previously) compared with three doses (629,000 recipients) and an internal control (days 3–7 after a fourth dose). From week 4 through week 6, adjusted rates of severe disease ranged from 3.5–4.3-fold lower in the four-dose group than in the three-dose group, and from 2.3–2.8-fold lower than in the internal control group. From week 4 through week 8, adjusted rates of confirmed SARS-CoV-2 infection were 2.0–1.1-fold lower in the four-dose group than in the three-dose group and 1.8–1.0-fold lower than in the internal control.

In a second study, Magen et al. used data from an Israeli healthcare organization to match a cohort of 182,000 members aged ≥60 who received a fourth dose with those who received three doses. Between days 7 and 30 postvaccination, the relative effectiveness of a fourth versus third dose was 45% against SARS-CoV-2 infection, 55% against symptomatic COVID-19, 68% against COVID-19–related hospitalization, 62% against severe COVID-19, and 74% against COVID-19–related death.

A.S. Brett et al.

Second Booster for COVID-19 Vaccination: Early Results

N Engl J Med, Journal Watch, April 2022

Abstract

Studies provide data on short-term effectiveness of a second booster (i.e., the fourth dose of an mRNA vaccine).

The U.S. CDC recently authorized a second mRNA COVID-19 vaccine booster (i.e., a fourth dose overall) for middle-aged and older adults (age, ≥50). In part, the CDC's decision was informed by two observational studies from Israel, where a fourth dose of the BNT162b2 vaccine (Pfizer-BioNTech) was approved on January 2, 2022, for older adults and others at high risk.

Taken together, the two studies involved more than 1 million older people (age, ≥60); short-term outcomes for those receiving a fourth dose between January and March 2022 were compared with outcomes among those who had received only 3 doses. The B.1.1.529 (Omicron) variant was dominant during this period. Findings were as follows:

• The fourth dose began to show protection against confirmed SARS-CoV-2 infection during the second week after vaccination; the peak effect occurred at roughly 4 weeks (a roughly 50% reduction in infection, compared with infections in 3-dose recipients), but the effect had disappeared by 8 weeks.
• Protection against a global category of severe COVID-19 also was noted by the second week after the fourth dose; protection was still peaking at 6 weeks (the last time-point for this observation), when the rate of severe infection was lower by roughly two thirds among four-dose recipients, compared with three-dose recipients.
• Between days 7 and 30 after the fourth dose, relative reductions in COVID-19–related hospitalization and death were both roughly 70%; absolute reductions were 180 fewer hospitalizations and 23 fewer deaths per 100,000 people.

COMMENT

Although general protection against testing positive for SARS-CoV-2 had waned by 8 weeks after a fourth dose of mRNA vaccine, it afforded substantial protection against severe COVID-19 for 1 or 2 months during the B.1.1.529 Omicron-variant wave; however, that variant is no longer dominant in the U.S., new variants likely will emerge, and longer-term effects remain unclear. An editorialist discusses the potential tradeoffs and even detriments of too-frequent boosting; clinicians whose patients are seeking advice about additional boosting might find it worthwhile to read his discussion.

J. D. Altman

T cells in COVID-19 — the kids are all right

Nature Immunology, April 2022; doi.org/10.1038/s41590-022-01190-6

Thomas and colleagues describe how multiple mRNA vaccine boosters, with or without natural SARS-CoV-2 infection, shape T cell immunity.

A. Minervina et al.

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memoryCD8+ T cells

MedRxiv, January 2022: doi: 10.1101/2021.07.12.21260227

Abstract

Although mRNA vaccine efficacy against severe COVID-19 remains high, variant emergence and breakthrough infections have changed vaccine policy to include booster immunizations. However, the effect of diverse and repeated antigen exposures on SARS-CoV-2 memory T cells is poorly understood. Here, we utilize DNA-barcoded MHC-multimers combined with scRNAseq and scTCRseq to capture the ex vivo profile of SARS-CoV-2-responsive T cells within a cohort of individuals with one, two, or three antigen exposures, including vaccination, primary infection, and breakthrough infection. We found that the order of exposure determined the relative distribution between spike- and non-spike-specific responses, with vaccination after infection leading to further expansion of spike-specific T cells and differentiation to a CCR7-CD45RA+ effector phenotype. In contrast, individuals experiencing a breakthrough infection mount vigorous non-spike-specific responses. In-depth analysis of over 4,000 epitope-specific T cell receptor sequences demonstrates that all types of exposures elicit diverse repertoires characterized by shared, dominant TCR motifs, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and that current vaccination protocols continue to expand and differentiate spike-specific memory responses.

N. Andrews et al.

Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant

N Engl J Med 2022; doi: 10.1056/NEJMoa2119451

Abstract

BACKGROUND

A rapid increase in coronavirus disease 2019 (Covid-19) cases due to the omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 in highly vaccinated populations has aroused concerns about the effectiveness of current vaccines.

METHODS

We used a test-negative case–control design to estimate vaccine effectiveness against symptomatic disease caused by the omicron and delta (B.1.617.2) variants in England. Vaccine effectiveness was calculated after primary immunization with two doses of BNT162b2 (Pfizer–BioNTech), ChAdOx1 nCoV-19 (AstraZeneca), or mRNA-1273 (Moderna) vaccine and after a booster dose of BNT162b2, ChAdOx1 nCoV-19, or mRNA-1273.

RESULTS

Between November 27, 2021, and January 12, 2022, a total of 886,774 eligible persons infected with the omicron variant, 204,154 eligible persons infected with the delta variant, and 1,572,621 eligible test-negative controls were identified. At all time points investigated and for all combinations of primary course and booster vaccines, vaccine effectiveness against symptomatic disease was higher for the delta variant than for the omicron variant. No effect against the omicron variant was noted from 20 weeks after two ChAdOx1 nCoV-19 doses, whereas vaccine effectiveness after two BNT162b2 doses was 65.5% (95% confidence interval [CI], 63.9 to 67.0) at 2 to 4 weeks, dropping to 8.8% (95% CI, 7.0 to 10.5) at 25 or more weeks. Among ChAdOx1 nCoV-19 primary course recipients, vaccine effectiveness increased to 62.4% (95% CI, 61.8 to 63.0) at 2 to 4 weeks after a BNT162b2 booster before decreasing to 39.6% (95% CI, 38.0 to 41.1) at 10 or more weeks. Among BNT162b2 primary course recipients, vaccine effectiveness increased to 67.2% (95% CI, 66.5 to 67.8) at 2 to 4 weeks after a BNT162b2 booster before declining to 45.7% (95% CI, 44.7 to 46.7) at 10 or more weeks. Vaccine effectiveness after a ChAdOx1 nCoV-19 primary course increased to 70.1% (95% CI, 69.5 to 70.7) at 2 to 4 weeks after an mRNA-1273 booster and decreased to 60.9% (95% CI, 59.7 to 62.1) at 5 to 9 weeks. After a BNT162b2 primary course, the mRNA-1273 booster increased vaccine effectiveness to 73.9% (95% CI, 73.1 to 74.6) at 2 to 4 weeks; vaccine effectiveness fell to 64.4% (95% CI, 62.6 to 66.1) at 5 to 9 weeks.

CONCLUSIONS

Primary immunization with two doses of ChAdOx1 nCoV-19 or BNT162b2 vaccine provided limited protection against symptomatic disease caused by the omicron variant. A BNT162b2 or mRNA-1273 booster after either the ChAdOx1 nCoV-19 or BNT162b2 primary course substantially increased protection, but that protection waned over time.

D. Abbass et al.

BNT162b2 vaccine induces antibody release in saliva: a possible role for mucosal viral protection?

Embo Molecular Medicine, April 2022; doi.org/10.15252/emmm.202115326

Abstract

Vaccination against an airborne pathogen is very effective if it induces also the development of mucosal antibodies that can protect against infection. The mRNA-based vaccine-encoding SARS-CoV-2 full-length spike protein (BNT162b2, Pfizer/BioNTech) protects also against infection despite being administered systemically. Here, we show that upon vaccination, cognate IgG molecules are also found in the saliva and are more abundant in SARS-CoV-2 previously exposed subjects, paralleling the development of plasma IgG. The antibodies titer declines at 3 months from vaccination. We identified a concentration of specific IgG in the plasma above which the relevant IgG can be detected in the saliva. Regarding IgA antibodies, we found only protease-susceptible IgA1 antibodies in plasma while they were present at very low levels in the saliva over the course of vaccination of SARS-CoV-2-naïve subjects. Thus, in response to BNT162b2 vaccine, plasma IgG can permeate into mucosal sites and participate in viral protection. It is not clear why IgA1 are detected in low amount, they may be proteolytically cleaved.

S. May Sidik et al.

COVID vaccine plus infection can lead to months of immunity

Nature, News 06 April 2022; doi: https://doi.org/10.1038/d41586-022-00961-3

Findings from Brazil, Sweden and the United Kingdom show that before the advent of Omicron, vaccination benefited even those who had had a bout of COVID-19.

K. Kobiyama et al.

Making innate sense of mRNA vaccine adjuvanticity

Nat Immunol., 2022; doi.org/10.1038/s41590-022-01168-4

Abstract

mRNA vaccines such as those used to prevent COVID-19 owe part of their success to methylation that masks immunostimulatory properties of the mRNA, but the immunological mechanisms of adjuvanticity are unclear. Two new studies reveal distinct mechanisms for innate sensing of this hidden adjuvant.

Tangye SG et al.

Getting to the (germinal) center of humoral immune responses to SARS-CoV-2   

Cell, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8928419/pdf/main.pdf

CONTENUTO E COMMENTO: La protezione a lungo termine contro SARS-CoV-2 richiede una risposta immunitaria efficace e duratura. In questo numero di Cell due articoli esaminano i centri germinativi linfonodali (luogo di nascita e sviluppo dell’immunità adattativa) per quantificare la specificità, l’intensità e la persistenza delle risposte immunitarie umorali locali e sistemiche indotte dall’infezione o dalla vaccinazione contro SARS-CoV-2. Entrambi gli studi ipotizzano che la vaccinazione, rispetto all’infezione naturale, produca una risposta umorale superiore, dovuta alla formazione di centri germinativi spike-specifici.

Regev-Yochay G. et al.

Efficacy of a Fourth Dose of Covid-19 mRNA Vaccine against Omicron

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMc2202542

CONTENUTO E COMMENTO: Studio clinico non randomizzato open-label condotto con lo scopo di valutare l’immunogenicità e la sicurezza di una quarta dose di vaccino per Sars-CoV2 a mRNA (BNT162b2 e mRNA-1273) somministrata a 4 mesi dalla terza dose di vaccino (nell’ambito di un protocollo a tre dosi di BNT162b2). Dei 1050 operatori sanitari arruolati nel protocollo Sheba, 155 hanno ricevuto la quarta dose di vaccino Pfizer e, una settimana dopo, 120 persone hanno ricevuto invece mRNA-1273. Dopo la quarta dose in entrambi i gruppi è stato riscontrato un aumento degli anticorpi IgG contro il RBD di Sars-Cov2 e del titolo di anticorpi neutralizzanti. Tale crescita è risultata essere maggiore rispetto al valore di partenza di un fattore 9-10, maggiore anche a quella riscontrata dopo la terza dose, in assenza di particolari differenze tra i due composti utilizzati. In entrambi i gruppi inoltre è stata riscontrata una maggiore risposta in vivo alla variante omicron, attualmente predominante. Non sono stati riscontrati particolari eventi avversi nel corso del follow-up, se non reazioni sistemiche moderate o lievi del sito di iniezione. Nel gruppo di controllo il 25% dei partecipanti si è infettato con la variante omicron vs. il 18.3% del gruppo ricevente la quarta dose. Questi ultimi in ogni caso hanno presentato sintomi trascurabili anche se tutti in corso di infezione sono stati probabilmente infettivi, con una carica virale relativamente alta riscontrata. Le limitazioni dello studio riguardano in particolare la non randomizzazione, la differenza di una settimana nell’arruolamento dei due gruppi di intervento e il campione ridotto.

Peng Q. et al.

Waning immune responses against SARS-CoV-2 variants of concern among vaccinees in Hong Kong

EBioMedicine, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8893246/pdf/main.pdf

CONTENUTO E COMMENTO: In questo studio longitudinale prospettico condotto ad Hong Kong viene comparata l’immunogenicità e la « durability » della risposta immunitaria di due vaccini, BNT162b2, (a mRNA) e CoronaVac (inattivato). Sono state valutate in soggetti pienamente vaccinati la capacità di produrre anticorpi neutralizzanti e la risposta CD4 T spike-specifica. In particolare, nei pazienti sottoposti a vaccinazione con BNT162b2 è stata riscontrata una produzione di anticorpi neutralizzanti nel 100% dei casi, mentre in quelli sottoposti a vaccinazione con CoronaVac nell’85.7% dei casi. In media la produzione di anticorpi neutralizzanti e la frequenza media di subset di CD4 reattivi è stata significativamente più bassa nei soggetti vaccinati con CoronaVac. Inoltre CoronaVac non ha indotto livelli misurabili di IFN-γ al test di stimolazione con la proteina nucleocapsidica specifica. Per quanto riguarda le varianti Delta e Omicron, la produzione di anticorpi neutralizzanti nei loro confronti è stata significativamente più bassa nei vaccinati con CoronaVac rispetto a quelli con BNT162b2 e dopo 3 mesi dalla vaccinazione nel gruppo CoronaVac i livelli di anticorpi neutralizzanti e la risposta delle cellule T della memoria tendono a diminuire fino a raggiungere il limite di detettabilità.

Gli autori dello studio mettono in luce evidenti differenze per quanto riguarda la stimolazione della risposta immunitaria conseguente al completamento della vaccinazione con i due vaccini in esame : CoronaVac sembra stimolare una risposta cellulare e umorale complessivamente inferiore rispetto a  BNT162b2, specialmente nei confronti delle variant of concern Delta e Omicron.

Abu-Rabbad L.J. et al.

Effect of mRNA Vaccine Boosters against  SARS-CoV-2 Omicron Infection in Qatar

The NEJM , https://www.nejm.org/doi/pdf/10.1056/NEJMoa2200797?articleTools=true

CONTENUTO E COMMENTO : Due studi retrospettivi di coorte con matching condotti in Qatar nel dicembre 2021 fino al gennaio 2022, per valutare l’efficacia della dose booster dei vaccini per Sars-CoV2 a mRNA, comparata con l’efficacia delle sole due prime dosi, nei confronti dell’infezione sintomatica, dell’ ospedalizzazione COVID-relata e dell’exitus dovuti alla variante Omicron. Sono state appaiate nel corso dello studio due coorti (1 :1 ratio a seconda del sesso, intervalli di età di 10 anni e nazionalità), una di persone boosterate da almeno sette giorni con BNT162b2 o mRNA-1273 e una coorte di persone vaccinate con due dosi. Un totale di 1.299.010 tra il gennaio 2021 e il gennaio 2022 hanno ricevuto almeno due dosi di vaccino. Pfizer, e di queste 281.093 anche la dose booster. Nella coorte di persone con booster sono state registrate nel periodo di studio 17.745 infezioni, di cui 12 progredite verso una malattia severa ma nessuna ha portato al decesso. Nel gruppo dei non boosterati invece sono state riscontrate 25.266 infezioni, di cui 45 progredite a COVID severo, 4 a malattia critica da COVID e nessuna al decesso. A 35 giorni dalla somministrazione della terza dose l’incidenza cumulativa di infezioni sintomatiche stimata è stata del 2.4% contro il 4.5% del gruppo dei non-booster. La riduzione stimata dell’incidenza di infezione sintomatica dovuta alla variante Omicron dopo la dose booster di BNT162b2, rispetto alle sole due dosi, è stata del 49.4%, mentre nei confronti della malattia severa e dell’exitus del 76.5%.

Stesso tipo di studio è stato effettuato per il vaccino mRNA-1273, con il riscontro di una efficacia nei confronti dell’infezione sintomatica, rispetto alle prime due dosi, del 47.3%, mentre non sono stati riscontrati casi di malattia severa o exitus. Sicuramente lo studio dimostra in entrambi i gruppi una protezione nei confronti della malattia severa e dell’ospedalizzazione, anche dopo due sole dosi, con una minore efficacia anche del booster nei confronti dell’Omicron rispetto alle precedenti varianti, aprendo iil dibattito su un possibile cambio di strategia vaccinale nel futuro, con composti differenti rispetto ad ulteriori dosi booster. Lo studio ha delle limitazioni legate all’età media giovane della popolazione del Qatar, alla minore severità della variante Omicron rispetto alle precedenti, all’efficacia duratura anche del ciclo vaccinale primario nei confronti dell’ospedalizzazione e dell’exitus, tutte variabili influenti sui dati ottenuti.

Bar-On Y. M. et al.

Preprint not peer reviewed

Protection by 4th dose of BNT162b2 against Omicron in Israel  

https://www.medrxiv.org/content/10.1101/2022.02.01.22270232v1

CONTENUTO E COMMENTO : analisi condotta in Israele su partecipanti dai 60 anni in su che abbiano ricevuto 3 dosi di vaccino BNT162b2 da almeno 4 prima dell’inizio dello studio nel periodo tra il 15 e il 27 gennaio 2022 (periodo a prevalenza omicron) per indagare infezione da SARS-CoV2 e patologia severa, studiando stato vaccinale, variabili demografiche e area di residenza. Sui 1 138 681 soggetti studiati, si e’ effettuata una regressione di Poisson per calcolare i tassi di infezione e patologia severa per 100 000 persone-giorni di rischio in ogni gruppo (3 gruppi : individui eleggibili per non abbiano ricevuto la quarta dose, individui a 3-7 giorni dalla quarta dose, individui a 12 giorni o piu’ dalla quarta dose).

Il tasso di infezione confermata nel gruppo vaccinato da 12 giorni o piu’ era piu’ basso di 2 volte (95% confidence interval [CI], 2.0 a 2.1) rispetto al gruppo eleggibile non vaccinato e di 1,9 (95% CI, 1.8 a 1.9) rispetto a coloro che avevano ricevuto la quarta dose 3-7 giorni prima. Le differenze aggiustate dei tassi erano 279 (95% CI, 271 a 287) e 234 (95% CI, 219 a 247) casi per 100,000 persone-giorni a rischio tra il gruppo di trattamento e gli altri due gruppi.  Il tasso di patologia severa nel gruppo di persone che avevano ricevuto la quarta dose 12 o piu’ giorni prima era piu’ basso di 4.3 (95% CI 2.4 a 7.6) rispetto al gruppo vaccinato con 3 dosi e di 4.0 volte (95% CI 2.2 a 7.5) rispetto a coloro che avevano ricevuto la quarta dose 3-7 giorni prima. Le differenze aggiustate dei tassi erano di 3.8 (95% CI, 2.8 a 4.8) e 3.5 (95% CI, 2.1 a 5.1) casi per 100,000 persone-giorni di rischio rispetto ai due gruppi di controllo, rispettivamente. Il rapporto di incidenza durante I primi 3-7 giorni dopo la vaccinazione e’ circa 1, aumentando di 2-3 volte 2 settimane dopo la vaccinazione.

I dati dimostrano che una quarta dose ad almeno 4 mesi dalla terza puo’ aumentare la protezione verso la patologia severa, specialmente in popolazioni a rischio.

LIMITAZIONI : differenze di comorbidita’ nei gruppi non analizzate in quanto dati non disponibili ; non analizzate differenze comportamentali (richiesta di supporto medico ecc) ; modifica delle linee guida nazionali per il testing nello stesso periodo che puo’ sovra o sottostimare l’effetto osservato nello studio.

Andrews N. et al.

Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2119451?articleTools=true

CONTENUTO E COMMENTO : :  studio caso controllo, a design test-negativo per valutare l’efficacia del vaccino contro la malattia sintomatica dovuta alle varianti delta ed omicron nel Regno Unito (novembre 2021-gennaio2022). Tale efficacia è stata valutata dopo due dosi di BNT162b2 (Pfizer–BioNTech), ChAdOx1 nCoV-19 (AstraZeneca), o mRNA-1273 (Moderna) e dopo una dose booster di BNT162b2, ChAdOx1 nCoV-19, o mRNA-1273. La popolazione di studio contava 886.774 persone con variante omicron, 204.154 con variante delta e 1.572.621 controlli test-negativi. I risultati hanno mostrato, in ogni momento dello studio, una superiorità della protezione vaccinale nei confronti della malattia sintomatica contro la variante delta rispetto alla omicron. A 20 settimane dalle due dosi di ChAdOx1 nCoV-19 non sono stati evidenziati effetti contro Omicron, mentre per BNT162b2 la protezione risultava del 65.5% fino a 4 settimane dalla seconda dose vs. 8.8% oltre le 25 settimane. Nei pazienti vaccinati con ChAdOx1 nCoV19 e riceventi il booster BNT162b2 si oscillava tra il 62.4% dopo 2-4 settimane fino al 39.6% oltre le 10 settimane. In pazienti con ciclo vaccinale omologo con BNT162b2 si riscontrava il 67.2% di protezione nel primo periodo per poi decrescere fino al 45.7% oltre le 10 settimane. Quando la dose booster considerata era mRNA-1273 nei pazienti con ciclo primario con Astrazeneca la protezione risultava maggiore, del 70.1% dopo 2-4 settimane per poi ridursi al 60.9% fino alla nona settimana dalla somministrazione booster. La combinazione con i migliori dati di protezione risulta essere quella con ciclo iniziale Pfizer e booster Moderna (73.9% nelle prime 4 settima e 64.4% fino a 9 settimane dal booster). Lo studio evidenzia come il ciclo vaccinale con due dosi, indipendentemente dal composto ricevuto, non garantisce una immunizzazione efficace nei confronti della variante omicron ed inoltre che anche la protezione garantita da una dose booster decresce significativamente con il passare del tempo.

Hongjie X. et al.

Neutralization and durability of 2 or 3 doses of the BNT162b2 vaccine against Omicron SARS-CoV-2 (journal pre-proof)

Cell Host and Microbe, https://doi.org/10.1016/j.chom.2022.02.015     

CONTENUTO E COMMENTO: studio che indaga l’attivita’ neutralizzante anticorpale dei sieri di pazienti vaccinati, testandola contro la variante wild-type USA-WA1/2020 e una variante USA-WA1/2020 ingegnerizzata per esprimere la glicoproteina spike di Omicron. Tramite test in vitro, come ad esempio l’analisi su cellule Vero E6, entrambi i virus hanno mostrato rapporti di genoma virale RNA/PFU equivalenti, suggerendo infettivita’ specifiche comparabili. I sieri sono stati testati a 2 o 4 settimane dopo la seconda dose, somministrata a 3 settimane dalla prima, e per quanto riguarda la terza dose, testati il giorno prima della stessa, 1 e 4 mesi dopo. A 2 o 4 settimane post seconda dose, i titoli medi geometrici di neutralizzazione (GMTs) contro il virus wild-type e il virus Omicron-spike erano rispettivamente 511 e 20; a 1 mese post terza dose, la neutralizzazione GMTs e’ incrementata a 1342 e 336; a 4 mesi dalla terza dose, i GMTs sono calati a 820 e 171.

A 2 o 4 settimane dopo la seconda dose, i GMT contro il virus Omicron-spike erano 25,6 volte piu’ bassi che contro la variante wild-type, come gia’ dimostrato in studi in letteratura.

A 1 mese dopo la terza dose, i GMTs sia contro variante wild-type che contro Omicron-spike sono aumentati di 2,6 e 16,8 volte rispetto ai corrispettivi dalle 2 alle 4 settimane post seconda dose, supportando dati preliminari che una terza dose di BNT162b2 aumenti la magnitudine e l’ampiezza della neutralizzazione gia’ mostrata contro le varianti Delta e Beta. Da 1 a 4 mesi dopo la terza dose, i GMTs contro il virus wild-type e Omicron e’ diminuito di 1,6 e 2 volte, suggerendo una dinamica di decadimento articorpale simile per entrambe le varianti, seppur sia necessario un campione piu’ grande e osservazioni piu’ lunghe per confermare il dato. Da cio’ deriva il fatto che la terza dose di vaccino BNT162b2 possa ridurre l’impatto sulla salute della variante Omicron, specialmente sull’ospedalizzazione, come gia’ dimostrato in altri studi.

L’utilizzo di varianti USA-WA1/2020 ingegnerizzate per esprimere la glicoproteina spike di Omicron rispetto alla variante Omicron naturale e’ giustificata dagli autori per la rapidita’ di analisi rispetto agli isolati clinici e perche’ il vaccino BNT162b2 colpisce solo la proteina spike (unica differenza tra le due varianti in studio), eliminando tramite questa metodica le variazioni legate a mutazioni virali su altri bersagli non spike.

LIMITAZIONI: non utilizzo di isolati clinici, non dati real-word, corto periodo di osservazione, piccolo campione, analisi solo umorale e non indagata immunita’ cellulo-mediata.

Shinde V. et al.

Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant

NEJM,

https://www.nejm.org/doi/10.1056/NEJMoa2103055?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

CONTENUTO E COMMENTO: studio clinico randomizzato controllato di fase 1-2 mirato a testare efficacia e sicurezza del vaccino NVX-CoV2373 vaccine (5 μg di proteina spike ricombinante e 50 μg di adiuvante Matrix-M1) verso placebo (rapporto 1 :1), studiato su partecipanti sani tra i 18 e gli 84 anni, seronegativi o HIV positivi con infezione controllata, in Sud Africa, arruolati tra agosto 2020 e novembre 2020. Dei 6324 partecipanti sottoposti a screening, 4387 hanno ricevuto almeno una iniezione di NVXCoV2373 o placebo (rispettivamente 2199 e 2188); 4332 partecipanti hanno ricevuto entrambe le iniezioni previste.

Caratteristiche demografiche: l’eta’ media di tutti i partecipanti era di 32.0 anni, 20% era obeso, 5.6% iperteso, 1.6% era affetto da diabete mellito. 30% circa era sieropositivo albaseline tramite valutazione degli anticorpi IgG antiSpike.

Sicurezza: dopo la prima dose, l’evento avverso locale piu’ frequente era dolore nel sito di iniezione, descritto nel 37% dei partecipanti sieronegativi e 39% dei sieropositivi nel gruppo dei vaccinati e 15% e 16% nel gruppo placebo, rispettivamente. Dopo la seconda dose, il tasso di eventi avversi locali era simile, con una durata lievemente maggiore, comunque sotto ai 3 giorni. Nel gruppo vaccinato, l’evento avverso sistemico piu’ comune dopo la prima dose e’ stato cefalea (20-25%), mialgie (17-20%), astenia (12-16%), con una durante lievemente maggiore dopo la seconda dose, comunque sotto i 3 giorni. Eventi avversi di grado 3 sono stati infrequenti, con tassi simili nel gruppo placebo (13 vs. 6 eventi avversi con necessita’ di intervento medico nel gruppo vaccinato vs placebo e 2 vs. 1 eventi avversi gravi rispettivamente).

Efficacia: dei 2684 partecipanti sieronegativi per SARS-CoV2 al baseline (94% HIV-negativi e 6% HIV-positivi) e che potessero essere valutati nell’analisi di efficacia dopo 28 giorni, si sono osservati 15 casi sintomatici COVID19 nel gruppo vaccino e 29 nel gruppo placebo, corrispondendo a una efficacia vaccinale di 49.4% (95% confidence interval [CI], 6.1 a 72.8), che incontra il criterio primario di efficacia nella valutazione di fase 2b. Tutti i casi di COVID nell’analisi per-protocol erano lievi-moderati, eccetto per un caso grave nel gruppo placebo. Tra i partecipanti HIV negativi, si sono osservati 11 casi COVID sintomatici nel gruppo vaccino e 27 nel placebo nei seronegativi per SARS-CoV2 al baseline, corrispondendo a un’efficacia vaccinale di 60,1%. Nei partecipanti HIV+, si sono osservati 4 casi sintomatici nel gruppo vaccino (sui 76 partecipanti) e 2 su 72 nel gruppo placebo. Tra i partecipanti seronegativi per SARS-CoV2 al baseline, si sono osservati 44 casi sintomatici nei due gruppi tra il 23 novembre 2020 e il 30 dicembre 2020. Dei 41 campioni testati tramite whole-genome sequencing, 38 sono stati indentificati come attribuibili alla variante B.1.351, ampiamente diffusa nel territorio sudafricano in quel momento. L’efficacia vaccinale contro la variante B.1.351 era 51.0% (95% CI, −0.6 a 76.2) tra i partecipanti HIV negativi (11 nei vaccinati e 22 nei placebo) e 43.0% (95% CI, −9.8 a 70.4) nella popolazione combinata HIV negativa e positiva (14 e 24 rispettivamente). Pur se necessario la conferma con ulteriori studi, il vaccino NVX-CoV2373 sembra conferire un grado di cross-protezione contro varianti ad escape immune.

LIMITAZIONI: risultati di efficacia preliminary (follow-up di 66 giorni dopo la prima dose e 45 dopo la seconda), piccolo campione per le analisi in sottogruppi, popolazione giovane e poco comorbida.

Yunkai Yu et al.

mRNA vaccine‑induced antibodies more efective than natural immunity in neutralizing SARS‑CoV‑2 and its high afnity variants

Nature, https://www.nature.com/articles/s41598-022-06629-2.pdf

CONTENUTO E COMMENTO : Studio in vitro volto a quantificare il titoloanticorpale e la capacitàneutralizzante di due popolazioni : vaccinati con due dosi di composto a m-RNA e pazienticonvalescenti COVID-19, in un contestoepidemiologicocaratterizzato da numerosevarianti del virus, alcune delle quali con mutazioni del RBD-ACE2, particolamente virulente. Un totale di 41 campioni di siero sono statiacquisiti da pazienti con COVID-19 accertato e ulterioricampioni sono statiprelevati ad unapopolazione di 28 personevaccinate con due dosi di Pfizer o Moderna. Neicampioni di siero di questiultimi sono statiriscontrati valori di anticorpi anti-RBD con unamediana 17 volte superiore rispetto a quelli di pazienti con infezionenaturale, con unasovrapponibilecapacitàneutralizzantecontro RBD-ACE2. Inoltre è stata valutata la capacità di neutralizzazioneneiconfrontidella variante N501Y dei convalescenti e dei pazientivaccinati. I risultatihannomostratounaridottacapacità di neutralizzazionecontro il RBD di N501Y in tutti i campioni di sangue dei pazienticonvalescenti, controunaelevatacapacità di neutralizzazioneneipazientivaccinati. Le limitazionidello studio riguardano l’impossibilità di rappresentarenelmodelloutilizzato la strutturatridimensionaledellaproteinaspike virale e dell’ACE2, la densitàsuperficiale di entrambe le molecole e il processo di ingressonellacellula del virus. Inoltre i profiili di mutazione del virus sono estremamentesemplificati in tale modello.

Matusali G. et al

Differential Dynamics of SARS-CoV-2 Binding and Functional Antibodies upon BNT162b2 Vaccine: A 6-Month Follow-Up

MDPI Viruses, https://doi.org/10.3390/v14020312

CONTENUTO E COMMENTO : : Studio in vitro finalizzato a valutare la associazione dinamica tra i binding e functional antibodies per Sars-Cov2 in operatori sanitari vaccinati con due dosi di BNT162b2 a sei mesi dalla seconda dose di vaccino. Un totale di 152 campioni di siero sono stati prelevati da 52 operatori sanitari tra gennaio e giugno 2021. Tali campioni sono stati testati per la ricerca di IgG anti-RBD, IgG anti-Trimeric Spike e anticorpi neutralizzanti per Sars-Cov2 a due settimane, tre mesi e sei mesi dalla seconda somministrazione di Comirnaty. Il livello maggiore di IgG anti-spike è stato registrato a due settimane dal vaccino. Una significativa riduzione di tali livelli è stata osservata già a tre mesi (anti-RBD IgG: median 479.7, IQR 283.7–920.8; anti-Trimeric S IgG: median 970.5, IQR 551.3–1598) e ulteriormente a sei mesi (anti-RBD IgG: median 171.8, IQR 84.6–281.9; anti-Trimeric S IgG, median 578.5, IQR 288.5–991.0). Il dato interessante riguarda il decadimento più rapido delle IgG anti-RBD rispetto alle anti-Trimeric S nel corso del follow-up ( riduzione IgG anti RBD pari a 4.5 volte a 3 mesi e a 13 volte dopo 6 mesi vs. riduzione anti-Trimeric S a 3 mesi pari a 2.8 a 3 mesi e 4.7 volte a 6 mesi). Una differente. dinamica è stata riscontrata per la riduzione degli anticopri neutralizzanti, con valori comprarabili tra loro  a tre e sei mesi. La mutevole relazione tra le IgG anti-RBD e anti-Trimeric S ed anticorpi neutralizzanti sta ad indicare che l’affinità degli stessi per la proteina virale Spike si evolve nel tempo in pazienti vaccinati con Comirnaty, così come è stato osservato nell’infezione da Sars-CoV2. Sicuramente una limitazione dello studio è legata al ridotto numero di campioni analizzati e alla prevalenza di soggetti di sesso femminile nella popolazione di studio.

Sadoff J. et al.

Final Analysis of Efficacy and Safety of Single-Dose Ad26.COV2.S

The NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2117608

CONTENUTO E COMMENTO : studio di fase 3 randomizzato, doppio cieco, controllato con placebo, multicentrico in cui e’ stata effettuata vaccinazione crossover nel gruppo di controllo (una volta autorizzato il vaccino negli stati dei partecipanti) con il fine di valutare l’efficacia di una singola dose di  Ad26.COV2.S  nel prevenire la comparsa di infezioni da SARS-CoV2 moderato-severe confermate tramite test molecolare RT-PCR con esordio ad almeno 14 giorni dalla somministrazione e 28, con una sottopopolazione di studio di sicurezza con 6000 partecipanti circa con valutazione degli effetti avversi a 7 e 28 giorni dalla somministrazione. I partecipanti sono stati assegnati in maniera random in gruppi 1 :1 con l’uso di gruppi random permutati per ricevere o una dose di Ad26.COV2.S (5x1010 viral particles) o un placebo salino intramuscolo (0.5 ml). Nella popolazione di partecipanti trattati per-protocol (39185), l’efficacia vaccinale nella protezione contro la COVID19 moderata-severa ad almeno 14 giorni dalla somministrazione e’ stata 56,3% (95% confidence interval [CI], 51.3 a 60.8; 484 casi nel gruppo vaccinato vs. 1067 nel gruppo placebo). Una singola dose di vaccino Ad26.COV2.S ad almeno 28 giorni dalla somministrazione e’ rimasta efficace nella prevenzione della COVID19 moderata-severa (52,9%, 95% CI, 47.1 a 58.1)  e di tutte le forme COVID sintomatiche (52,4%, 95% CI, 46.6 a 57.6), nonostante l’emergenza di nuove varianti (dati pre emergenza di Omicron). L’efficacia contro le forme severe e critiche e’ rimasta alta (74,6%), in minor misura per le nuove varianti (93.1% efficacia contro il ceppo di riferimento e 71.8% verso le varianti non di riferimento). La riduzione dell’efficacia nei dati finali rispetto all’analisi primaria (efficacia vaccinale per l’endpoint primario ad almeno 28 giorni dall’amministrazione, 66,1% nell’analisi primaria e 52,9% nell’analisi finale) e’ verosimilmente attribuibile a una minore efficacia vaccinale verso le varianti (ad esempio, 10.1% contro la variante lambda e 36.5% contro la gamma, dati non disponibili per omicron). L’efficacia vaccinale contro l’infezione sintomatica nelle persone che vivono con HIV in questo trial e’ stata bassa, con ampi intervalli di confidenza (23,5%, 95% CI, −78.3 a 68.2).

Nei partecipanti con pregressa infezione asintomatica (serologia positiva per proteina N SARS-CoV2 all’arruolamento), la pregressa infezione da sola provvedeva a una protezione del 90.4% contro l’infezione sintomatica e dopo la somministrazione di Ad26.COV2.S, 97.7% di protezione rispetto ai partecipanti placebo seronegativi.

Le infezioni da SARS-CoV2 nei partecipanti che hanno ricevuto una dose di Ad26.COV2.S si sono mostrate piu’ brevi, meno severe e con piu’ basse cariche virali con una minore necessita’ di intervento medico (90% di protezione iniziale, fino ad arrivare al 70% a 6 settimane, rimanendo a tale livello per I successive 5-6 mesi).

Gli eventi avversi sono stati rari, con eventi avversi gravi in circa l’1% e si e’ osservato nel periodo di post autorizzazine il tinnito, classificato come evento molto raro. Non ci sono stati casi di anafilassi o capillary leak syndrome e si e’ osservato un solo caso di VITT.

Barin B. et Al.

Comparison of SARS-CoV-2 anti-spike receptor binding domain IgG antibody responses after CoronaVac, BNT162b2, ChAdOx1 COVID-19 vaccines, and a single booster dose: a prospective, longitudinal population-based study

The Lancet,

 https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(21)00305-0/fulltext

CONTENUTO E COMMENTO : studio longitudinale prospettico per esaminare le concentrazioni di IgG SARS-CoV-2 anti-spike RBD dopo vaccinazione con BNT162b2, ChAdOx1, e CoronaVac o dopo dose booster, svoltosi nel nord di Cipro. Le valutazioni sono state effettuate a 1 mese e 3 mesi dalla seconda dose di ciascun vaccino nella coorte principale con gli intervalli temporali tra le dosi di 4 settimane per CoronaVac, 3 per BNT162b2, 12 per ChAdOx1.

Sono state inoltre valutati sottocoorti di partecipanti che hanno ricevuto inizialmente due dosi di CoronaVac e 6 mesi dopo una dose di BNT162b2 o di CoronaVac e un gruppo indipendente di riferimento che ha avuto il covid nei 3 mesi precedenti e non abbia ricevuto vaccino.

Si e’ osservato un alto tasso di seropositivita’ e di titoli anticorpali in tutti i timepoint testati per i vaccini BNT162b2 e ChAdOx1 rispetto a CoronaVac per tutti i gruppi di eta’ (gruppo BNT162b2 : 100% di tasso di sieroposivita’ in pazienti sopra e sotto i 60 anni e si e’ mantenuto stabile a 3 mesi; gruppo ChAdOx1 : tasso di sieropositivita’ ad un mese dalla seconda dose di 100% nei piu’ giovani e 96% nei piu’ anziani con una riduzione a 3 mesi  dalla seconda dose a 97% nei piu’ giovani e  90% nei piu’ anziani; gruppo CoronaVac, tasso di sieropositivita’ a un mese di 97% nei piu’ giovani e 88% nei piu’ anziali, con un calo a 76% nei giovani e 60% nei piu’ anziani a 3 mesi) e i titoli IgG indotti da BNT162b2 erano maggiori quando comparati con ChAdOx1.

Per gli soggetti piu’ anziani ad alto rischio, il tasso di seropositivita’ a 3 mesi dalla seconda dose era del 100% per BNT162b2, 90% per ChAdOx1 e 60% per CoronaVac.

Nonostante l’eta’, il tasso di declino degli anticorpi da 1 a 3 mesi dalla vaccinazione completa e’ stato piu’ veloce nel gruppo CoronaVac, seguito da ChAdOx1, e poi da BNT162b2.

Negli individui piu’ anziani (eta’ maggiore di 60 anni) vaccinati con ciclo primario di CoronaVac, una singola dose booster di BNT162b2 ha comportato un significativo incremento dei titoli di IgG (gruppo BNT162b2: la mediana dei titoli anticorpali era di 5·0 (1·8–13·9) a un mese e 1·2 (0·5–3·1) a 3 mesi, con tassi di seropositivita’ a 86·5% a 1 mese e  59·6% a 3 mesi) rispetto a una singola dose booster di CoronaVac  (gruppo CoronaVac: la mediana dei titoli anticorpali era di 3·2 (0·9–8·6) ad un mese e 0·9 (0·4–1·3) a 3 mesi con un tasso di sieropositivita’ del 75% a un mese e 50% a 3 mesi): nonostante i titoli anticorpali ad uno e 3 mesi dopo la seconda dose di CoronaVac fossero simili tra i due gruppi maggiormente anziani (Wilcoxon two-sample test; p=0·25 a un mese e p=0·41 a 3 mesi), una singola dose booster di of BNT162b2 ha indotto un maggior titolo di anticorpi IgG anti-spike RBD rispetto al booster CoronaVac (p<0·0001; figure 2A).

I risultati dello studio sono consistenti con precedenti studi: il sesso maschile e la eta’ avanzata sono associati a un piu’ basso livello generale di anticorpi.

Si e’ osservata una forte relazione tra gli alti titoli di anticorpi IgG anti-spike e un ridotto stato di malattia come anche una piu’ bassa incidenza di infezioni breakthrough, dove un piu’ alto livello di IgG leganti l’antigene ha comportato una maggiore protezione: da qui l’assunto che i titoli anticorpali possano servire da correlato di protezione contro l’infezione e come surrogato della risposta generale immune allo specifico vaccino.

Una dose booster di CoronaVac somministrato a 6 mesi dal ciclo primario di CoronaVac ha indotto un piu’ modesto incremento dei titoli IgG rispetto a booster con BNT162b2 (l’aumento della media geometrica e’ stato di circa 3 volte per

CoronaVac vs 8x per BNT162b2).

Limitazioni: singola nazionalita’, campione piccolo (384 di cui 222 CoronaVac, 106 BNT162b2, 56 ChAdOx1), metodo di campionamento “convenience” rispetto ad un vero arruolamento, studio effettuato in periodo non Omicron (1 marzo 2021-settembre 2021).

Corrao G. et al.

Persistence of protection against SARS-CoV-2 clinical outcomes up to 9 months since vaccine completion: a retrospective observational analysis in Lombardy, Italy

The Lancet, https://doi.org/10.1016/ S1473-3099(21)00813-6

CONTENUTO E COMMENTO : : Studio osservazionel retrospettivo, finalizzato a valutare la persistenza della protezione nei confronti degli otucomes clinici (infezione e malattia severa) del Sars-Cov2, a nove mesi dal completamento del ciclo vaccinale. In questo studio, 5.351.085 individui sono stati seguiti a 14 giorni dal completamento del ciclo vaccinale tra il gennaio ed il giugno 2021 e poi fino all’ ottobre dello stesso anno. In tale lasso di tempo sono stati valutati i cambiamenti nel tempo degli outcomes considerati, come l’infezione e la gravità della stessa nella popolazione vaccinata ed il trend dell’efficacia dei vaccini. In totale sono state osservate 14.140 infezioni e 2450 malattie severe (1.2 casi/10000 persone). Dal primo mese di follow-up fino al mese di ottobre si è osservato un aumento di questo tasso fino al 6.7/10000. Le infezioni più severe sono state riscontrate nella popolazione over60, senza una particolare variazione nella popolazione ricevente un vaccino a mRNA o con vettore virale. Ovviamente tale dato è direttamente proporzionale alla riduzione dell’efficacia della protezione vaccinale nel tempo, ponendo l’attenzione sull’importanza della necessità di una dose booster, con tempistiche non eccessivamente prolungate.

Shuo Feng et al.

Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection

Nature, https://doi.org/10.1038/s41591-021-01540-1

CONTENUTO E COMMENTO : Trial randomizzato di efficacia, condotto nel Regno Unito, per determinare i livelli anticorpali in pazienti vaccinati con ChAdOx1 nCoV19 (vettore virale), a 28 giorni dalla seconda dose in pazienti infetti (171 pazienti) e non infetti (1404) da Sars-Cov2. Il proposito di tale studio era appunto valutare la correlazione della protezione anticorpale in pazienti vaccinati, infetti, con infezione sintomatica e non. Elevati livelli anticorpali sono stati correlati ad una riduzione del rischio di infezioni sintomatiche, con una protezione dell’89% nei confronti della stessa a 28 giorni dalla seconda dose. La limitazione principale dello studio riguarda la popolazione presa in considerazione e l’intervallo di tempo considerato, predominante la variante Beta nei pazienti considerati. 

Atmar R.L. et al.

Homologous and Heterologous Covid-19 Booster Vaccinations

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2116414?articleTools=true

CONTENTUO E COMMENTO : : Trial clinico open-label di fase 1-2, condotto in 10 siti degli Stati Uniti, finalizzato a valutare la sicurezza, la immunogenicità e la reattogenicità al giorno 15 e 29 del trial di una dose booster omologa o eterologa (9 possibili combinazioni tra prima vaccinazione e booster) di mRNA-1273, Ad26.COV2.S o BNT162b2 in pazienti con ciclo vaccinale completo da almeno 12 settimane, senza precedenti infezioni da Sars-Cov2. 458 pazienti hanno partecipato al trial, di questi 154 hanno ricevuto mRNA-1273, 150 Ad26.COV2.s e 153 BNT162b2. Non vi sono state differenze nella reattogenicità rispetto al ciclo vaccinale iniziale con due reazioni avverse severe dopo la dose booster con Ad.26.COV2.S. Tutte le combinazioni vaccinali hanno dimostrato un netto aumento del titolo di anticorpi neutralizzanti (booster omologhi hanno portato ad un amento del titolo di un fattore da 4 a 20, gli eterologhi da 6 a 73). Un livello maggiore e persistente di T-cell CD8+ è stato riscontrato nei riceventi il vaccino Janssen sia come booster etereologo che omologo. In conclusione, tutte le combinazioni di vaccini booster hanno dimostrato un profilo di sicurezza accettabile e di efficacia. Sicuramente la mancanza di un gruppo di controllo costituisce un limite importante per lo studio.

Cheng S.M.S. et al.

Neutralizing  antibodies against the SARS-CoV-2 Omicron variant following homologous  and heterologous CoronaVac or BNT162b2 vaccination

Nature, https://www.nature.com/articles/s41591-022-01704-7_reference.pdf

CONTENUTO E COMMENTO : :  Studio in vitro condotto per valutare  e confrontare il plaque reduction neutralization (PRNT50) e PRNT90 GMT antibody titre contro la variante Omicron in pazienti vaccinati con due dosi di CoronaVac (n=30) o con BNT162b2 (n=31) mai affetti da Sars-CoV2, in pazienti vaccinati con dose booster CoronaVac o con booster eterologo BNT162b2 ed infine pazienti con dose booster BNT162b2 omologa. Inoltre è stato valutato il siero di pazienti guariti dal COVID-19 non vaccinati e pazienti convalescenti vaccinati con una solo dose dei sopracitati composti. I dati hanno mostrato una  riduzione  marcata del titolo anticorpale contro la variante  Omicron (comparta con il virus wild-type)  dopo due dosi di BNT162b2 ( GMT 218.8) o CoronaVac (GMT 32.5). Una dose booster di BNT162b2 ha elicitato un titolo PRNT50 >25.6 contro Omicron nell’88% dei riceventi il ciclo vaccinale omologo e nell’80% nei riceventi CoronaVac nelle prime due somministrazioni. Nei cicli vaccinali omologhi con CoronaVac solo un paziente su trenta ha raggiunto tali livelli. Tali risultati suggeriscono di procedere alla somministrazione della dose booster con vaccini a mRNA nei paesi ad alta prevalenza di vaccinati con CoronaVac, al fine di garantire una maggiore protezione contro la variante Omicron.

Franco-Paredes C. Knol M.J. et al. Ko H.H.T.

Transmissibility of SARS-CoV-2 among fully vaccinated individuals

The Lancet,

https://www.thelancet.com/journals/laninf/article/PIIS14733099(21)007684/fulltext?fbclid=IwAR2DVUiGh16mPpNFRJk5ngugpsGcg7u1FhR008aEAq3RgTnvLfOYOa68m5M

CONTENUTO E COMMENTO: 3 correspondences in risposta allo studio prospettico di coorte condotto nel Regno Unito da Anika Singanayagam et al sulla trasmissione comunitaria di SARS-CoV2 tra individui vaccinati e non.

Franco-Paredes evidenzia come i dati presentati indeboliscano il razionale scientifico sottostante l’obbligo vaccinale in quanto non si e’ mostrato un impatto significativamente differente della vaccinazione sulla circolazione del virus. Questi dati sono stati inoltre confermati in altri studi, come, ad esempio, gli studi attestanti rispettivamente la presenza di breakthrough infection in personale sanitario vaccinato in israele, titoli virali delle alte vie respiratorie e colture virali al picco dell’infezione sovrapponibili tra vaccinati e non, nonche’ la sovrapponibile carica virale di SARS-CoV2 a livello nasofaringeo in vaccinati e non, persino nei soggetti con infezione asintomatica provata.

Knol MJ et al affrontano invece l’importanza dell’aggiustamento per eta’ nel confronto tra soggetti vaccinati e non vaccinati, in quanto fattore confondente associato sia allo stato vaccinale che al rischio di trasmissione di SARS-CoV2 (incremento del picco di carica virale medio con l’aumentare dell’eta’ e dunque una minore contagiosita’ dei bambini o la maggiore propensione a vaccinare i soggetti anziani). Per questa ragione, l’efficacia del vaccino contro la trasmissione dello studio di Singanayagam et al e’ verosimilmente sottostimata.

HHT Ko esplora invece l’eventualita’ che i vaccini possano favorire l’accumulo di grandi cariche virali e dunque comportare un aumentato rischio di escape immune, in quando non conferiscono un’immunita’ totalmente neutralizzante. Tracciando con tecniche di whole-genome sequencing, si potrebbero confrontare nel tempo per evidenziare possibili mutazioni i dati dei partecipanti vaccinati e non dello studio Singanayagam et al. Se queste mutazioni sono occorse principalmente nei contatti vaccinati rispetto ai non vaccinati, questo suggerirebbe una mutazione indotta da vaccino.

Andrews N. et al.

Duration of Protection against Mild and Severe Disease by Covid-19 Vaccines

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2115481?articleTools=true

CONTENUTO E COMMENTO :  Studio caso-controllo (dicembre 2020-ottobre 2021, Regno Unito) finalizzato a stimare l’efficacia di due dosi dei vaccini per Sars-CoV-2 ChAdOx1-S, BNT162b2 e mRNA-1273 contro l’infezione sintomatica, l’ospedalizzazione entro 14 giorni da un test molecolare positivo e control’exitus a28 giorni dal tampone nasofaringeo positivo. Per tutti glioutcomes sono stati confrontati i dati di pazienti vaccinati, sintomatici e con molecolare positivo per Sars-Cov-2 e di pazienti vaccinati con sintomi da COVID-19 ma con test molecolare negativi(n. tot=6,056,673). L’efficacia dei vaccini nei confronti della variante delta ha mostrato la massima efficacia nei confronti dell’infezione sintomatica nelle prime settimane dopo la seconda dose con una riduzione a 5 mesi fino al 44.3% con ChAdOx-1-S ed al66.3% con BNT162b2. A 5 mesi dalla seconda dose vaccinale si è invece osservato un tasso minore di riduzione di efficacia nei confronti dell’ospedalizzazione (80%. ChAdOx-1-se. 91.7% BNT162b2) e dei decessi da Sars-CoV-2 (84.8% vs 91.9%). Lo studio fornisce dati importanti sul timing della terza dose di vaccino, alla luce dell’elevata protezione nei confronti dell’ospedalizzazione e del decesso a 5 mesi dalla seconda somministrazione. Le limitazioni dello studio sono in primis legate allo stesso disegno test-negative case-control, uno studio osservazionale soggetto a bias potenziali.

Roos S.G. Sablerolles et al

Immunogenicity and Reactogenicityof Vaccine Boosters afterAd26.COV2.S Priming

The NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2116747

CONTENUTO E COMMENTO : Trial clinico randomizzato controllato multicentrico in singolo cieco in operatori sanitari (HCW) nei Paesi Bassi : sono stati selezionati HCW tra i 18 e 65, senza fattori coesistenti/comorbidita’ gravi, nessuna storia di infezione da SARS CoV-2, vaccinati con Ad26.COV2.S 3 mesi prima dell’arruolamento e assegnati in maniera casuale (ratio 1:1:1:1) a booster con Ad26.COV2.S, mRNA-1273, BNT162b2 o nessun booster (n=434 partecipanti).

L’endpoint primario, ossia il livello di anticorpi IgG contro la subunita’ S1 della proteina spike dopo booster, e’ stato significamente superiore nei pazienti che hanno ricevuto booster rispetto a chi non lo ha ricevuto e questo maggiormente dopo booster con mRNA 1273 (beta coefficient, 0.21; 98.3% CI, 0.13 to 0.37). La vaccinazione eterologa con booster a mRNA hanno avuto livelli di anticorpi leganti superiori alla vaccinazione omologa, con una maggiore quota di anticorpi neutralizzanti.

Per quanto riguarda le risposte cellulari T-mediate, queste sono state maggiori nel gruppo che ha ricevuto il booster a mRNA:  risposta al 91.7% con il booster mRNA-1273 e 91.5%con il booster BNT162b2; entrambi con migliori performance del booster omologo (risposta 72.7%).

Sul versante reattogenicita’, il booster mRNA1273 e’ stato associato a una piu’ grande percezione di severita’ e durata delle reazioni locali e sistemiche (comunque lievi-moderate senza necessita’ di ospedalizzazione, risoltesi nelle 48 ore).

Nawal Al Kaabi et al.

The incidence of COVID‑19 infection following emergency use authorization of BBIBP‑CORV inactivated vaccine in frontline workers in the United Arab Emirates

Nature, https://www.nature.com/articles/s41598-021-04244-1.pdf

CONTENUTO E COMMENTO : Studio di coorte prospettico condotto tra i lavoratori degli Emirati Arabi, esposti in prima linea al rischio di contagio da Sars-CoV2 e sottoposti ad un ciclo vaccinale con due dosi di BBIBP-CORV (settembre-dicembre 2020). Si tratta di un vaccino inattivato, approvato dalla WHO nella Emergency Use Listing. 11.322 individui sono stati sottoposti alla vaccinazione con due dosi di tale composto, con un’incidenza di infezioni sintomatiche pari allo 0.08 per 1000 persone al giorno, con un rischio assoluto di sviluppare un’infezione sintomatica dello 0.97%. Il tasso di sierconversione è risultato essere del 92.8%. Non sono stati riportati eventi avversi severi dopo la somministrazione, e nessuno dei vaccinati ha sviluppato una patologia severa da Sars-CoV2. In conclusione i dati dello studio risultano promettenti, con la forte limitante di un’assenza di un gruppo di controllo di non vaccinati e considerando che in assoluto molte altre variabili possono ridurre il tasso di infezioni osservato nel periodo dello studio.

Eyre D.W. et al.

Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants

The NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2116597?query=featured_coronavirus

CONTENUTO E COMMENTO:  Studio osservazionale retrospettivo di coorte, svolto nel Regno Unito (1 gennaio-31 luglio 2021) nel quale sono stati studiati adulti di età maggiore di 18 anni, contatti di casi e casi indice(146243 contatti testati, 108498 indici testati) al fine di investigare associazioni tra trasmissione e stato vaccinale tra casi indice e contatti e studiare come queste cambino con le diverse varianti virali (alpha e delta) e la distanza temporale dal termine della vaccinazione.

Dei 146,243 contatti testa, 52,667 (37%) sono risultati positivi al test PCR per SARS-CoV2. I vaccini BNT e ChAd si sono dimostrati associati a una minore trasmissione di SARS-CoV2 dai casi che si sono infettati nonostante la vaccinazione (adjusted rate ratio BNT162b2, 0.32; 95% confidence interval [CI], 0.21 to 0.48; and with ChAdOx1 nCoV-19, 0.48; 95% CI, 0.30 to 0.78), seppur nei casi vaccinati con BNT e in maggiormente con ChAd, questa riduzione e’ stata minore sulla trasmissione della variante delta che sulla variante alfa (adjusted rate ratio BNT, 0.50; 95% CI, 0.39 to 0.65; adjusted rate ratio ChAdOx1, 0.76; 95% CI, 0.70 to 0.82).).

La vaccinazione e’ stata associata a piu’ basse cariche virali (alte Ct) nella variante alfa (non vaccinati median Ct value, 18.4; interquartile range, 15.7 to 22.5; BNT nei pazienti sintomatici,Valore mediano Ct, 27.4; interquartile range, 19.7 to 32.1 : ChAdOx, Ct mediano, 23.9; interquartile range, 18.1 to 32.5) e minor misura nella variante delta (BNT Ct mediano 18.0 (interquartile range, 15.8 to 21.8), ChAd Ct mediano 17.3 (interquartile range, 15.3 to 20.6), Non vaccinato Ct mediano 17.0 (interquartile range, 15.1 to 20.3): lo studio ha pero’ mostrato che la differenza nei valori Ct alla diagnosi dei casi era attribuibile solo per il 7/23% all’effetto della vaccinazione.

L’incidenza delle infezioni con la variante alfa e quelle con la delta erano minori nei contatti vaccinati con 2 dosi di BNT che in coloro vaccinati con 2 dosi di ChAd.

La protezione verso la trasmissione ai contatti e’ andata scemando nel periodo di 3 mesi dopo la seconda vaccinazione, in misura maggiore verso la variante delta, specialmente nei vaccinati con ChAd. I contatti erano piu’ soggetti a infettarsi maggiore il tempo trascorso della seconda vaccinazione.

Limitazioni : bias comportamentale (non investigati i soggetti che non avessero eseguito un test PCR), possibili altre fonti di contagio per i contatti altri che il caso, dati insufficienti su precedenti infezioni, utilizzati come proxy il periodo (10 maggio come spartiacque) e il S-gene target failure, non aggiustamenti su comorbidita’ e condizioni coesistenti.

Eyre, D. W., et al.

Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants

NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2116597?articleTools=true

 CONTENUTO E COMMENTO: Studio osservazionale su contatti di casi accertati di COVID che valuta gli effetti dei vaccini Pfizer ed AstraZeneca sulla trasmissione della variante alpha e Delta di SARS-CoV-2. I contatti stretti di casi di COVID-19 che avevano ricevuto il vaccino BNT162b2 avevano un rischio  inferiore di risultare positivi durante le 14 settimane dopo la seconda vaccinazione rispetto a coloro che avevano ricevuto ChAdOx1 nCoV-19, anche se l'effetto protettivo di BNT162b2 svaniva più rapidamente.

Bar-On Y.M. et al.

The NEJM

Protection against Covid-19 by BNT162b2 Booster across Age Groups

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2115926?articleTools=true

CONTENUTO E COMMENTO : Studio analitico retrospettivo, condotto in Israele, utilizzando i dati del Ministero della Salute nel periodo di tempo tra il 30 luglio ed il 10 ottobre 2021, di 4.696.865 persone di età >16aa che avevano ricevuto almeno due dosi di vaccino BNT162b2 per Sars-CoV2 nei 5 mesi precedenti.  Tali dati sono stati poi utilizzati in una analisi primaria per comparare il tasso di casi di COVID-19, di malattia severa e di morte nel gruppo denominato booster, in persone sottoposte alla terza dose almeno 12 giorni prima dell’infezione vs un gruppo nonbooster. In una analisi secondaria sono state comparate le medesime variabili nel booster group vs. un early postbooster group, ovvero pazienti vaccinati con la terza dose dai 3 ai 7 giorni prima, il tutto stratificato per 5 diverse fasce di età. I risultati hanno mostrato che il tasso di infezioni da Sars-CoV2 confermate era inferiore di circa 10 volte nel booster group rispetto al nonbooster, e altresì minore nel booster rispetto all’early postbooster (da 4.9 fino 10.8 volte a seconda delle fasce di età considerate). Il tasso di malattie severe nel booster group era inferiore rispetto al nonbooster ed all’early postbooster rispettivamente di 17.9 e 6.5 volte nelle persone di età superiore ai 60 aa e di 21.7 e 3.7 rispettivamente nella popolazione tra i 40 e i 59 aa. Nella popolazione >60 aa la mortalità nel booster group era inferiore di 14.7 nell’analisi primaria e di 4.9 volte nella secondaria. Risulta quindi che il tasso di infezioni, di malattia severa e mortalità, risultano inferiori nella popolazione vaccinata con tre dosi, a distanza di 12 giorni dal booster.

Stuart A. S. V. et al.

Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trial

The Lancet, https://www.thelancet.com/action/showPdf?pii=S0140-6736%2821%2902718-5

CONTENUTO : Trial di non inferiotità, randomizzato, in singolo cieco di fase 2, svolto nel Regno Unito (19 aprile-14 maggio 2021) nel quale adulti di età maggiore di 50 anni (1072 partecipanti), precedentemente vaccinati con una singola dose di BNT o ChAd sono stati randomizzati in tre gruppi con un rapporto di 1 :1 :1 al fine di ricevere una seconda dose I.M. dello stesso vaccino, di m1273 o di NVX (8-12 settimane dopo la prima dose). L’end point primario era una non inferiorità del GMR (superiore 0.63 per il one-sided 98·75% CI, criterio di non inferiorità) delle IgG anti spike nei riceventi il vaccino eterologo vs omologo a 28 giorni dalla seconda dose. Nel gruppo vaccinato con ChAd (prima dose) la GMC a 28 giorni dalla seconda dose con m 1273 o NVX risultava non inferiore a quello dei riceventi la dose omologa (GMR 10.2, one-sided 98·75% CI 8·4 to ∞ per m1273 e 2.8 per NVX). Nella popolazione vaccinata con BNT veniva dimostrata allo stesso modo una non inferiorità nei riceventi m1273 vs. 2 dosi di BNT ma non nel gruppo vaccinato con NVX come seconda dose, nonostante una buona risposta anticorpale elicitata da quest’ultimo a 28 giorni. In totale sono stati segnalati 15 eventi avversi severi, con un profilo di sicurezza buono per entrambi i gruppi eterologhi. I risultati mostrano che un ciclo vaccinale eterologo, in particolare con m1273 come seconda dose in vaccinati con BNT e ChAd risulta essere una strategia percorribile ed efficace al fine di rendere più rapida una immunizzazione a livello globale.

COMMENTO :  Studio molto interessante che dimostra la possibilità di immunizzazione primaria eterologa, cioè una seconda dose con vaccino diverso dalla prima. L’end point è la non inferiorità in termini di risposte immuni fra recipienti vaccinazione eterologa rispetto all’omologa. Come seconda dose viene usato il vaccino Novavax, od il vaccino Moderna mentre come prima dose sono usat i vaccini Asta-Zeneca (ChadOx) e Pfizer Biontechancora non approvato in Europa o negli States.  In termini immunologici, l’eterologa Astra-Zeneca-Novavx  è non inferiore all’omologa ma la non inferiorità non è raggiunta da Novavax come seconda dose quando la prima è Pfizer. Comunque sempre, la secinda di Novavax è meno reattogenica. I dati suggeriscono che Novavax può anche potenziare immunologicamente l’immunizzazione con Chadox e la rende più sicura, delineando per questo vaccino proteico sopratutto l’uso come richiamo.