RE - INFECTION AND RELAPSE - Fondazione MISI

MariosKoutsakos et al.

SARS-CoV-2 breakthrough infection induces rapid memory and de novo T cell responses

Cell, February 2023; doi.org/10.1016/j.immuni.2023.02.017

Abstract

While the protective role of neutralising antibodies against COVID-19 is well-established, questions remain about the relative importance of cellular immunity. Using 6 pMHC-multimers in a cohort with early and frequent sampling, we define the phenotype and kinetics of recalled and primary T cell responses following Delta or Omicron breakthrough infection in previously vaccinated individuals. Recall of spike-specific CD4+ T cells was rapid, with cellular proliferation and extensive activation evident as early as 1 day post-symptom onset. Similarly, spike-specific CD8+ T cells were rapidly activated but showed variable degrees of expansion. The frequency of activated SARS-CoV-2-specific CD8+ T cells at baseline and peak inversely correlated with peak SARS-CoV-2 RNA levels in nasal swabs and accelerated viral clearance. Our study demonstrates rapid and extensive recall of memory T cell populations occurs early after breakthrough infection and suggests that CD8+ T cells contribute to the control of viral replication in breakthrough SARS-CoV-2 infections.

Brian P Epling et al.

Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment

CID, February 2023; doi.org/10.1093/cid/ciac663

Abstract

Background

Nirmatrelvir/ritonavir, the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, reduces the risk of hospitalization and death by coronavirus disease 2019 (COVID-19) but has been associated with symptomatic rebound after therapy completion.

Methods

Six individuals with relapse of COVID-19 symptoms after treatment with nirmatrelvir/ritonavir, 2 individuals with rebound symptoms without prior antiviral therapy and 7 patients with acute Omicron infection (controls) were studied. Soluble biomarkers and serum SARS-CoV-2 nucleocapsid protein were measured. Nasal swabs positive for SARS-CoV-2 underwent viral isolation and targeted viral sequencing. SARS-CoV-2 anti-spike, anti–receptor-binding domain, and anti-nucleocapsid antibodies were measured. Surrogate viral neutralization tests against wild-type and Omicron spike protein, as well as T-cell stimulation assays, were performed.

Results

High levels of SARS-CoV-2 anti-spike immunoglobulin G (IgG) antibodies were found in all participants. Anti-nucleocapsid IgG and Omicron-specific neutralizing antibodies increased in patients with rebound. Robust SARS-CoV-2–specific T-cell responses were observed, higher in rebound compared with early acute COVID-19 patients. Inflammatory markers mostly decreased during rebound. Two patients sampled longitudinally demonstrated an increase in activated cytokine-producing CD4+ T cells against viral proteins. No characteristic resistance mutations were identified. SARS-CoV-2 was isolated by culture from 1 of 8 rebound patients; Polybrene addition increased this to 5 of 8.

Conclusions

Nirmatrelvir/ritonavir treatment does not impede adaptive immune responses to SARS-CoV-2. Clinical rebound corresponds to development of a robust antibody and T-cell immune response, arguing against a high risk of disease progression. The presence of infectious virus supports the need for isolation and assessment of longer treatment courses.

COVID-19 Forecasting Team

Past SARS-CoV-2 infection protection against re-infection: a systematic review and meta-analysis

The Lancet, February 2023; doi.org/10.1016/S0140-6736(22)02465-5

Abstract

Background

Understanding the level and characteristics of protection from past SARS-CoV-2 infection against subsequent re-infection, symptomatic COVID-19 disease, and severe disease is essential for predicting future potential disease burden, for designing policies that restrict travel or access to venues where there is a high risk of transmission, and for informing choices about when to receive vaccine doses. We aimed to systematically synthesise studies to estimate protection from past infection by variant, and where data allow, by time since infection.

Interpretation

Protection from past infection against re-infection from pre-omicron variants was very high and remained high even after 40 weeks. Protection was substantially lower for the omicron BA.1 variant and declined more rapidly over time than protection against previous variants. Protection from severe disease was high for all variants. The immunity conferred by past infection should be weighed alongside protection from vaccination when assessing future disease burden from COVID-19, providing guidance on when individuals should be vaccinated, and designing policies that mandate vaccination for workers or restrict access, on the basis of immune status, to settings where the risk of transmission is high, such as travel and high-occupancy indoor settings.

Chemaitelly H et al.

Protection against Reinfection with the Omicron BA.2.75 Subvariant

NEJM, February 2023; DOI: 10.1056/NEJMc2214114

Abstract

The BA.2.75 sublineage of the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may escape neutralizing antibodies. The BA.2.75 sublineage (primarily the BA.2.75.2 subvariant) became the predominant sublineage in Qatar by September 10, 2022 (Section S1 and Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). We estimated the effectiveness of previous infection with SARS-CoV-2 in preventing reinfection with BA.2.75 using a test-negative, case–control study design (Section S2).1

The effectiveness of previous infection against reinfection with BA.2.75.2 appears to be lower than that against BA.4 or BA.5 reinfection.2 Protection afforded by a previous pre-omicron infection is negligible at this stage of the pandemic, a finding that confirms that pre-omicron–conferred immunity against omicron infection may not last beyond approximately 1 year.5 Protection conferred by a previous omicron infection was moderate, at approximately 50%, when the previous infection was with a BA.1 or BA.2 subvariant but was approximately 80% when the previous infection was more recent (i.e., caused by a BA.4 or BA.5 subvariant); these results may reflect a combination of progressive immune-system evasion and gradual waning of immune protection. Immunity resulting from a combination of pre-omicron and omicron infection was most protective against BA.2.75 reinfection. Viral immune-system evasion may have accelerated recently to overcome high immunity in the global population, thereby also accelerating the waning of natural immunity.

Holm Hansen C. et al.

Risk of reinfection, vaccine protection, and severity of infection with the BA.5 omicron subvariant: a nation-wide population-based study in Denmark

The Lancet, October 2022; doi.org/10.1016/S1473-3099(22)00595-3

Abstract

Estimates of immunity and severity for the SARS-CoV-2 omicron subvariant BA.5 are important to assess the public health impact associated with its rapid global spread despite vaccination. We estimated natural and vaccine immunity and severity of BA.5 relative to BA.2 in Denmark, a country with high mRNA-vaccination coverage and free-of-charge RT-PCR testing.

Methods

This nation-wide population-based study in Denmark included residents aged 18 years or older who had taken an RT-PCR test between 10 April and 30 June, 2022 (ie, the outcome period), and who the national COVID-19 surveillance system identified as having information since February 2020 on RT-PCR tests, whole-genome sequencing, vaccinations, and hospitalisation with a positive RT-PCR test and COVID-19 as the main diagnosis. First, we used a case–control design, in which cases were people infected with BA.5 or BA.2 during the outcome period and controls were people who tested negative for SARS-CoV-2 infection during the outcome period. We calculated the protection provided by a previous PCR-confirmed omicron infection against BA.5 and BA.2 infection and hospitalisation among triple-vaccinated individuals. Second, we compared vaccination status in people infected with BA.5 versus BA.2 and estimated relative vaccine protection against each subvariant. Third, we compared rates of hospitalisation for COVID-19 among people infected with BA.5 versus BA.2. We estimated effects using logistic regression with adjustment for sex, age, region, PCR-test date, comorbidity and, as appropriate, vaccination and previous infection status.

Findings

A total of 210 (2·4%) of 8678 of BA.5 cases, 192 (0·7%) of 29 292 of BA.2 cases, and 33 972 (19·0%) of 178 669 PCR-negative controls previously had an omicron infection, which was estimated in the adjusted analyses to offer 92·7% (95% CI 91·6–93·7) protection against BA.5 infection and 97·1% (96·6–97·5) protection against BA.2 infection. We found similarly high amounts of protection against hospitalisation owing to infection with BA.5 (96·4% [95% CI 74·2–99·5]) and BA.2 (91·2% [76·3–96·7]). Vaccine coverage (three mRNA doses vs none) was 9307 (94·2%) of 9878 among BA.5 cases and 30 581 (94·8%) of 32 272 among BA.2 cases, although in the adjusted analysis, there was a trend towards slightly higher vaccination coverage among BA.5 cases than BA.2 cases (OR 1·18 [95% CI 0·99–1·42]; p=0·064), possibly suggesting marginally poorer vaccine protection against BA.5. The rate of hospitalisation due to COVID-19 was higher among the BA.5 cases (210 [1·9%] of 11 314) than among the BA.2 cases (514 [1·4%] of 36 805), with an OR of 1·34 (95% CI 1·14–1·57) and an adjusted OR of 1·69 (95% CI 1·22–2·33), despite low and stable COVID-19 hospitalisation numbers during the study period.

Interpretation

The study provides evidence that a previous omicron infection in triple-vaccinated individuals provides high amounts of protection against BA.5 and BA.2 infections. However, protection estimates greater than 90% might be too high if individuals with a previous infection were more likely than those without one to come forward for a test for reasons other than suspicion of COVID-19. Our analysis also showed that vaccine protection against BA.5 infection was similar to, or slightly weaker than, protection against BA.2 infection. Finally, there was evidence that BA.5 infections were associated with an increased risk of hospitalisation compared with BA.2 infections.

ShoMiyamoto et al.

Non-Omicron breakthrough infection with higher viral load and longer vaccination-infection interval improves SARS-CoV-2 BA.4/5 neutralization

Cell, January 2023; doi.org/10.1016/j.isci.2023.105969

Abstract

The immune responses to SARS-CoV-2 variants in COVID-19 cases are influenced by various factors including pre-existing immunity via vaccination and prior infection. Elucidating the drivers for upgrading neutralizing activity to SARS-CoV-2 in COVID-19 cases with pre-existing immunity will aid in improving COVID-19 booster vaccines with enhanced cross-protection against antigenically distinct variants, including the Omicron sub-lineage BA.4/5. This study revealed that the magnitude and breadth of neutralization activity to SARS-CoV-2 variants after breakthrough infections are determined primarily by upper respiratory viral load and vaccination-infection time interval. Extensive neutralizing breadth, covering even the most antigenically distant BA.4/5, was observed in cases with higher viral load and longer time intervals. Antigenic cartography depicted a critical role of the time interval in expanding the breadth of neutralization to SARS-CoV-2 variants. Our results illustrate the importance of dosing interval optimization as well as antigen design in developing variant-proof booster vaccines.

Tan S.T. et al.

Infectiousness of SARS-CoV-2 breakthrough infections and reinfections during the Omicron wave

Nature, January 2023; doi.org/10.1038/s41591-022-02138-x

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infections in vaccinated individuals and reinfections in previously infected individuals have become increasingly common. Such infections highlight a broader need to understand the contribution of vaccination, including booster doses, and natural immunity to the infectiousness of individuals with SARS-CoV-2 infections, especially in high-risk populations with intense transmission, such as in prisons. Here we show that both vaccine-derived and naturally acquired immunity independently reduce the infectiousness of persons with Omicron variant SARS-CoV-2 infections in a prison setting. Receipt of booster doses and more recent vaccination further reduced infectiousness among vaccinated cases. These findings suggest that, although vaccinated and/or previously infected individuals remain highly infectious upon SARS-CoV-2 infection in this prison setting, their infectiousness is reduced compared to individuals without any history of vaccination or infection. This study underscores benefit of vaccination to reduce, but not eliminate, transmission.

Grace Lai-Hung Wong et al.

Incidence of Viral Rebound After Treatment With Nirmatrelvir-Ritonavir and Molnupiravir

JAMA, December 2022; doi:10.1001/jamanetworkopen.2022.45086

Abstract

Importance Some patients treated with nirmatrelvir-ritonavir have experienced rebound of COVID-19 infections and symptoms; however, data are scarce on whether viral rebound also occurs in patients with COVID-19 receiving or not receiving molnupiravir. Objective To examine the incidence of viral rebound in patients with COVID-19 who were treated with the oral antiviral agents nirmatrelvir-ritonavir and molnupiravir. Design, Setting, and Participants This cohort study identified 41 255 patients with COVID-19 who were hospitalized from January 1, 2022, to March 31, 2022, in Hong Kong and assessed 12 629 patients with serial cycle threshold (Ct) values measured. Patients were followed up until the occurrence of the clinical end point of interest, death, date of data retrieval (July 31, 2022), or up to 30 days of follow-up, whichever came first. Exposures Molnupiravir or nirmatrelvir-ritonavir treatment. Main Outcomes and Measures Viral rebound, defined as a Ct value greater than 40 that decreased to 40 or less.

Conclusions and Relevance

In this cohort study, viral rebound was uncommon in patients taking molnupiravir or nirmatrelvir-ritonavir and was not associated with increased risk of mortality. Given these findings, novel oral antivirals should be considered as a treatment for more patients with COVID-19 in the early phase of the infection.

Brian P Epling et al.

Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment

CID, October 2022; doi.org/10.1093/cid/ciac663

Abstract

Background

Conclusions

Xiaojuan Zhang et al.

Omicron sublineage recombinant XBB evades neutralising antibodies in recipients of BNT162b2 or CoronaVac vaccines

Lancet, December 2022; doi.org/10.1016/S2666-5247(22)00335-4

Abstract

The SARS-CoV-2 omicron variant XBB sublineage, a BA.2.10.1–BA.2.75 recombinant classified as variant under monitoring by WHO, has been found in 35 countries,1 and has become the dominant strain in Singapore. There is early evidence suggesting that XBB might be associated with a higher risk of reinfection.2 A previous study using a pseudovirus neutralisation test and sera from individuals who received CoronaVac (Sinovac) found that XBB is the most immunoevasive sublineage.

In summary, our data showed that both XBB.1 and XBB.3 were much more immunoevasive than ancestral strain and BA.5.2. This immunoevasion is consistently seen in patients with different history of vaccination or infection. Since patients infected with BA.5.2 might not elicit neutralising antibody against XBB sublineage, patients who have been infected with BA.5 or those with bivalent vaccine might have a higher risk of reinfection or vaccine breakthrough infection from XBB sublineage than previous sublineages.

Bowe B et al.

Acute and postacute sequelae associated with SARS-CoV-2 reinfection

Nature, November 2022; doi.org/10.1038/s41591-022-02051-3

Abstract

First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Compared tononinfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.

Hyung-Joon Kwon et al.

Enhanced virulence and waning vaccine-elicited antibodies account for breakthrough infections caused by SARS-CoV-2 Delta and beyond

CELL, November 2022; doi.org/10.1016/j.isci.2022.105507

Abstract

Summary Here we interrogate the factors responsible for SARS-CoV-2 breakthrough infections in a K18-hACE2 transgenic mouse model. We show that Delta and the closely related Kappa variant cause viral pneumonia and severe lung lesions in K18-hACE2 mice. Human COVID-19 mRNA post-vaccination sera after the 2nd dose are significantly less efficient in neutralizing Delta/Kappa than early 614G virus in vitro and in vivo. By 5 months post-vaccination, ≥50% of donors lack detectable neutralizing antibodies against Delta and Kappa and all mice receiving 5-month post-vaccination sera die after the lethal challenges. Although a 3rd vaccine dose can boost antibody neutralization against Delta in vitro and in vivo, the mean log neutralization titers against the latest Omicron subvariants are 1/3- 1/2 of those against the original 614D virus. Our results suggest that enhanced virulence, greater immune evasion and waning of vaccine-elicited protection account for SARS-CoV-2 variants caused breakthrough infections.

Turbett S.E. et al.

Distinguishing SARS-CoV-2 persistence and reinfection: A retrospective cohort study

CID, October 2022; doi.org/10.1093/cid/ciac830

Abstract

The study aimed to evaluate the characteristics of SARS-CoV-2 reinfection and persistent RNA detection using independent genomic, clinical, and laboratory assessments.

H. Chemaitelly et al.

Immune Imprinting and Protection against Repeat Reinfection with SARS-CoV-2

New England J of Medicine, October 2022; doi: 10.1056/NEJMc2211055

Abstract

The authors investigated the epidemiologic evidence for immune imprinting in persons with specific immune histories related to natural infection. They evaluated the incidence of repeat reinfection in the national cohort of persons in Qatar who had had a documented omicron BA.1 or BA.2 reinfection after a primary infection with non-omicron SARS-CoV-2 (the “double-primed” cohort) as compared with the incidence of reinfection in the national cohort of persons who had had a documented primary infection with omicron BA.1 or BA.2 (the “omicron-primed” cohort).

S. Carazo et al.

Protection against omicron (B.1.1.529) BA.2 reinfection conferred by primary omicron BA.1 or pre-omicron SARS-CoV-2 infection among health-care workers with and without mRNA vaccination: a test-negative case-control study

Lancet Infectious Diseases, September 2022; doi.org/10.1016/S1473-3099(22)00578-3

Abstract

There is a paucity of data on vaccine-induced or infection-induced (hybrid or natural) immunity against omicron (B.1.1.529) subvariant BA.2, particularly in comparing the effects of previous SARS-CoV-2 infection with the same or different genetic lineage. The authors aimed to estimate the protection against omicron BA.2 associated with previous primary infection with omicron BA.1 or pre-omicron SARS-CoV-2, among health-care workers with and without mRNA vaccination.

N.H. Altarawneh et al.

Protection of SARS-CoV-2 natural infection against reinfection with the Omicron BA.4 or BA.5 subvariants

medRxiv, July 2022; doi.org/10.1101/2022.07.11.22277448

Abstract

This study estimates the effectiveness of previous infection with SARS-CoV-2 in preventing reinfection with Omicron BA.4/BA.5 subvariants using a test-negative, case–control study design. Cases (SARS-CoV-2-positive test results) and controls (SARS-CoV-2-negative test results) were matched according to sex, 10-year age group, nationality, comorbid condition count, calendar week of testing, method of testing, and reason for testing. Effectiveness was estimated using the S-gene “target failure” (SGTF) infections between May 7, 2022-July 4, 2022. SGTF status provides a proxy for BA.4/BA.5 infections, considering the negligible incidence of other SGTF variants during the study. Effectiveness was also estimated using all diagnosed infections between June 8, 2022-July 4, 2022, when BA.4/BA.5 dominated incidence. Effectiveness of a previous pre-Omicron infection against symptomatic BA.4/BA.5 reinfection was 15.1% (95% CI: -47.1-50.9%), and against any BA.4/BA.5 reinfection irrespective of symptoms was 28.3% (95% CI: 11.4-41.9%). Effectiveness of a previous Omicron infection against symptomatic BA.4/BA.5 reinfection was 76.1% (95% CI: 54.9-87.3%), and against any BA.4/BA.5 reinfection was 79.7% (95% CI: 74.3-83.9%). Results using all diagnosed infections when BA.4/BA.5 dominated incidence confirmed the same findings. Sensitivity analyses adjusting for vaccination status confirmed study results. Protection of a previous infection against BA.4/BA.5 reinfection was modest when the previous infection involved a pre-Omicron variant, but strong when the previous infection involved the Omicron BA.1 or BA.2 subvariants. Protection of a previous infection against BA.4/BA.5 was lower than that against BA.1/BA.2, consistent with BA.4/BA.5’s greater capacity for immune-system evasion than that of BA.1/BA.2.

I. Smolenov et al.

Impact of previous exposure to SARS-CoV-2 and of S-Trimer (SCB-2019) COVID-19 vaccination on the risk of reinfection: a randomised, double-blinded, placebo-controlled, phase 2 and 3 trial

The Lancet Infectious Diseases, April 2022; doi.org/10.1016/S1473-3099(22)00144-X

Abstract

Background We previously reported the efficacy of the adjuvanted-protein COVID-19 vaccine candidate S-Trimer (SCB-2019) in adults who showed no evidence of previous exposure to SARS-CoV-2. In this study, we aimed to investigate the extent of protection afforded by previous exposure to SARS-CoV-2 on subsequent COVID-19 infection, as well as the efficacy, safety, and reactogenicity of SCB-2019 in participants who were enrolled in the Study evaluating Protective-Efficacy and safety of Clover’s Trimeric Recombinant protein-based and Adjuvanted COVID-19 vaccine (SPECTRA) trial who had already been exposed to SARS-CoV-2 before vaccination.

Methods In a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial (SPECTRA) done at 31 sites in five countries, participants were randomly assigned 1:1 using the Cenduit Interactive Response Technology system (IQVIA, Durham, NC, USA), with a block size of six, to receive two doses of either SCB-2019 or placebo 21 days apart. The primary outcomes of the SPECTRA trial were vaccine efficacy, measured by real-time PCR (rtPCR)-confirmed COVID-19 of any severity, with onset from 14 days after the second vaccine dose, as well as the safety and solicited local and systemic adverse events in the phase 2 subset. Here, we present secondary analyses to calculate the protective efficacy due to previous exposure to SARS-CoV-2 against reinfection with COVID-19 according to severity in SPECTRA participants who had evidence of exposure to SARS-CoV-2 at baseline, including efficacy against identified viral variants, as well as efficacy of SCB-2019 vaccination in this population.

Findings We enrolled 30174 participants between March 24, 2021, and Aug 10, 2021. In the 14 670 participants who were randomly assigned to receive placebo, there were 418 (2·8%) confirmed cases of COVID-19; 65 (0·9%) of 7339 SARS-CoV-2-exposed participants, and 353 (4·8%) of 7331 SARS-CoV-2-naive participants (attack rates of 5·5 cases per 100 person-years for SARS-CoV-2-exposed participants and 32·4 cases per 100 person-years for SARSCoV-2-naive participants). Protective efficacy due to previous exposure to SARS-CoV-2 was 83·2% (95% CI 78·0–87·3) against any COVID-19, 92·5% (82·9–97·3) against moderate-to-severe COVID-19, and 100% (59·3–100) against severe COVID-19; no SARS-CoV-2-exposed participants had hospitalisation associated with COVID-19. Protective efficacy against variants were 100% for alpha (B.1.1.7) and lambda (C.37) variants, 88·6% (14·9–99·7) for B.1.623, 93·6% (80·1–98·7) for gamma (P.1), and 92·4% (81·2–97·6) for mu (B.1.621) variants, and lowest against beta (B.1.351; 72·2% [33·1–89·9]) and delta (B.1.617.2; 77·2% [61·3–87·2]) variants. In addition, one dose of SCB-2019 had 49·9% (1·5–75·6) efficacy against any symptomatic COVID-19, and two doses had 64·2% (26·5–83·8) efficacy. SCB-2019 was well tolerated in SARS-CoV-2-exposed participants, but was associated with higher rates of injection site pain (89 [33·8%] of 263 participants) than placebo (16 [6·7%] of 239 participants). Rates of solicited systemic adverse events, severe adverse events, and serious adverse events were similar between vaccine and placebo groups, and with rates in SARS-CoV-2-naive vaccine recipients.

Interpretation Previous exposure to SARS-CoV-2 decreased the risk and severity of subsequent COVID-19 infection, even against newly emerging variants. Protection is further enhanced by one or two doses of SCB-2019.

Z. Al-Aly et al.

Outcomes of the SARS-CoV-2 reinfection

Research Square, June 2022; doi.org/10.21203/rs.3.rs-1749502/v1

Abstract

First infection with SARS-CoV-2 is associated with increased risk of acute and post-acute death and sequelae in the pulmonary and extrapulmonary organ systems. However, whether reinfection adds to the risk incurred after the first infection is not clear. Here we use the national health care databases of the US Department of Veterans Affairs to build a cohort of people with first infection (n = 257,427), reinfection (2 or more infections, n = 38,926), and a non-infected control group (n = 5,396,855) to estimate risks and 6-month burdens of all-cause mortality, hospitalization, and a set of pre-specified incident outcomes. We show that compared to people with first infection, reinfection contributes additional risks of all-cause mortality, hospitalization, and adverse health outcomes in the pulmonary and several extrapulmonary organ systems (cardiovascular disorders, coagulation and hematologic disorders, diabetes, fatigue, gastrointestinal disorders, kidney disorders, mental health disorders, musculoskeletal disorders, and neurologic disorders); the risks were evident in those who were unvaccinated, had 1 shot, or 2 or more shots prior to the second infection; the risks were most pronounced in the acute phase, but persisted in the post-acute phase of reinfection, and most were still evident at 6 months after reinfection. Compared to non-infected controls, assessment of the cumulative risks of repeated infection showed that the risk and burden increased in a graded fashion according to the number of infections. The constellation of findings show that reinfection adds non-trivial risks of all-cause mortality, hospitalization, and adverse health outcomes in the acute and post-acute phase of the reinfection. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.

R. Rubin

From positive to negative to positive again—the mystery of why covid-19 rebounds in some patients who take Paxlovid

JAMA, June 2022; doi:10.1001/jama.2022.9925

Abstract

Director of the Aaron Diamond AIDS Research Center at Columbia University managed to avoid contracting COVID-19 for more than 2 years. But SARS-CoV-2 finally got the best of the pioneering HIV researcher on an April trip to Paris for, of all things, a 2-day COVID-19 conference.

jama_rubin_2022_mn_220048_1655397810.78549.pdf

J. Quandt et al.

Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes

Science Immunology, June 2022 ; doi: 10.1126/sciimmunol.abq2427

Abstract

Omicron is the evolutionarily most distinct SARS-CoV-2 variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2 and previous SARS-CoV-2 VOCs, but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding BMEM cells against epitopes shared broadly amongst variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted BMEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. While selective amplification of BMEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.

M. Charness et al.

Rapid Relapse of Symptomatic SARS-CoV-2 Infection Following Early Suppression with Nirmatrelvir/Ritonavir

Research Square, May 2022; doi.org/10.21203/rs.3.rs-1588371/v2

Abstract

We describe relapse of COVID-19 symptoms and SARS-CoV-2 viral load following nirmatrelvir/ritonavir (NM/R) in 8 non-immunocompromised patients aged 31 to 71-years-old. Most patients improved rapidly after treatment with NM/R and had negative antigen or PCR tests prior to relapse on Days 9-12 of their illness. Relapse symptoms were described most frequently as cold symptoms, though some patients experiencing a recurrence of fatigue and headache. All relapses resolved without additional antiviral treatment. Viral load during relapse was comparable to levels during initial infection. Sequencing in three patients indicated that relapse was not due to a treatment-emergent mutation or infection with a different viral strain. One patient transmitted SARS-CoV-2 to two family members during relapse. The presence of high viral load and the occurrence of one transmission event suggest that patients with relapse should isolate until antigen testing is negative.

G. Arbor et al.

SARS-CoV-2 vaccination diversifies the CD4+ spike-reactive T cell repertoire in patients with prior SARS-CoV-2 infection

eBioMedicine, May 2022; doi.org/10.1016/j. ebiom.2022.104048

Abstract

Background COVID-19 mRNA vaccines elicit strong T and B cell responses to the SARS-CoV-2 spike glycoprotein in both SARS-CoV-2 nay¨ve and experienced patients. However, it is unknown whether the post-vaccine CD4+ T cell responses seen in patients with a history of COVID-19 are due to restimulation of T cell clonotypes that were first activated during natural infection or if they are the result of new clones activated by the vaccine.

Methods To address this question, we analyzed the SARS-CoV-2 spike glycoprotein-specific CD4+ T cell receptor repertoire before and after vaccination in 10 COVID-19 convalescent patients and 4 SARS-CoV-2 nayive healthy donor vaccine recipients. We used the viral Functional Expansion of Specific T cells (ViraFEST) assay to quantitatively identify specific SARS-CoV-2 and common cold coronavirus CD4+ T cell clonotypes post COVID-19 disease resolution and post mRNA SARS-CoV-2 vaccination.

Findings We found that while some preexisting T cell receptor clonotypes persisted, the post-vaccine repertoire consisted mainly of vaccine-induced clones and was largely distinct from the repertoire induced by natural infection. Vaccination-induced clones led to an overall maintenance of the total number of SARS-CoV-2 reactive clonotypes over time through expansion of novel clonotypes only stimulated through vaccination. Additionally, we demonstrated that the vaccine preferentially induces T cells that are only specific for SARS-CoV-2 antigens, rather than T cells that cross-recognize SARS-CoV-2/common cold coronaviruses.

Interpretation These data demonstrate that SARS-CoV-2 vaccination in patients with prior SARS-CoV-2 infection induces a new antigen-specific repertoire and sheds light on the differential immune responses induced by vaccination versus natural infection.

M.P. Sormani et al.

Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy

eBioMedicine, May 2022; doi.org/10.1016/j. ebiom.2022.104042

Abstract

Background In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection.

Methods This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose.

Findings 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave.

Interpretation The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response.

P.Nordström et al.

Risk of SARS-CoV-2 reinfection and COVID-19 hospitalisation in individuals with natural and hybrid immunity: a retrospective, total population cohort study in Sweden

The Lancet, March 2022; doi.org/10.1016/ S1473-3099(22)00143-8

Abstract

Background: Real-world evidence supporting vaccination against COVID-19 in individuals who have recovered from a previous SARS-CoV-2 infection is sparse. We aimed to investigate the long-term protection from a previous infection (natural immunity) and whether natural immunity plus vaccination (hybrid immunity) was associated with additional protection.

Methods: In this retrospective cohort study, we formed three cohorts using Swedish nationwide registers managed by the Public Health Agency of Sweden, the National Board of Health and Welfare, and Statistics Sweden. Cohort 1 included unvaccinated individuals with natural immunity matched pairwise on birth year and sex to unvaccinated individuals without natural immunity at baseline. Cohort 2 and cohort 3 included individuals vaccinated with one dose (one-dose hybrid immunity) or two doses (two-dose hybrid immunity) of a COVID-19 vaccine, respectively, after a previous infection, matched pairwise on birth year and sex to individuals with natural immunity at baseline. Outcomes of this study were documented SARS-CoV-2 infection from March 20, 2020, until Oct 4, 2021, and inpatient hospitalisation with COVID-19 as main diagnosis from March 30, 2020, until Sept 5, 2021.

Findings: Cohort 1 was comprised of 2 039 106 individuals, cohort 2 of 962 318 individuals, and cohort 3 of 567 810 individuals. During a mean follow-up of 164 days (SD 100), 34 090 individuals with natural immunity in cohort 1 were registered as having had a SARS-CoV-2 reinfection compared with 99 168 infections in non-immune individuals; the numbers of hospitalisations were 3195 and 1976, respectively. After the first 3 months, natural immunity was associated with a 95% lower risk of SARS-CoV-2 infection (adjusted hazard ratio [aHR] 0·05 [95% CI 0·05–0·05] p<0·001) and an 87% (0·13 [0·11–0·16]; p<0·001) lower risk of COVID-19 hospitalisation for up to 20 months of follow-up. During a mean follow-up of 52 days (SD 38) in cohort 2, 639 individuals with one-dose hybrid immunity were registered with a SARS-CoV-2 reinfection, compared with 1662 individuals with natural immunity (numbers of hospitalisations were eight and 113, respectively). One-dose hybrid immunity was associated with a 58% lower risk of SARS-CoV-2 reinfection (aHR 0·42 [95% CI 0·38–0·47]; p<0·001) than natural immunity up to the first 2 months, with evidence of attenuation thereafter up to 9 months (p<0·001) of follow-up. During a mean follow-up of 66 days (SD 53) in cohort 3, 438 individuals with two-dose hybrid immunity were registered as having had a SARS-CoV-2 reinfection, compared with 808 individuals with natural immunity (numbers of hospitalisations were six and 40, respectively). Two-dose hybrid immunity was associated with a 66% lower risk of SARS-CoV-2 reinfection (aHR 0·34 [95% CI 0·31–0·39]; p<0·001) than natural immunity, with no significant attenuation up to 9 months (p=0·07). To prevent one reinfection in the natural immunity cohort during follow-up, 767 individuals needed to be vaccinated with two doses. Both one-dose (HR adjusted for age and baseline date 0·06 [95% CI 0·03–0·12]; p<0·001) and two-dose (HR adjusted for age and baseline date 0·10 [0·04–0·22]; p<0·001) hybrid immunity were associated with a lower risk of COVID-19 hospitalisation than natural immunity.

Interpretation: The risk of SARS-CoV-2 reinfection and COVID-19 hospitalisation in individuals who have survived and recovered from a previous infection remained low for up to 20 months. Vaccination seemed to further decrease the risk of both outcomes for up to 9 months, although the differences in absolute numbers, especially in hospitalisations, were small. These findings suggest that if passports are used for societal restrictions, they should acknowledge either a previous infection or vaccination as proof of immunity, as opposed to vaccination only.

Moreira E.D. et al.

Safety and Efficacy of a Third Dose of BNT162b2 Covid-19 Vaccine

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2200674?articleTools=true

CONTENUTO E COMMENTO: Trial clinico controllato randomizzato di fase 3 (giugno-agosto 2021), finalizzato a valutare l’efficacia e la sicurezza di una terza dose booster di vaccino per Sars-CoV2 BNT162b2. In particolare, 5081 partecipanti allo studio hanno ricevuto una terza dose di vaccino e 5044 invece il placebo, almeno a 6 mesi dalle precedenti due dosi di vaccino Pfizer. Per quanto riguarda il profilo di sicurezza nel corso del follow-up (mediana di 2.5 mesi) non sono state riscontrate segnalazioni di nuove reazioni avverse, con la maggior parte delle reazioni di grado lieve e moderato, perlopiù correlate al sito di iniezione. Le reazioni avverse severe sono state riscontrate con maggiore frequenza nel gruppo dei vaccinati rispetto al placebo (0.5% vs 0.3%) Nessun caso di miocardite o pericardite è stato riportato. Per quanto riguarda l’efficacia della dose booster, nel gruppo ricevente il vaccino, solo 6 pazienti sono risultati positivi ad almeno una settimana dalla somministrazione. Viceversa, nel gruppo ricevente il placebo, sono stati 123 i casi di infezione da Sars-CoV2 segnalati. I dati finora acquisiti in fase 2-3 di questo trial mostrano una efficacia complessiva della dose booster del 90%, da 7 giorni fino a 6 mesi dalla somministrazione con una efficacia del 95.3% ad una mediana di 2.5 mesi di follow-up in pazienti senza storia di pregressa infezione. Non sono stati osservati casi di COVID-19 severo nel gruppo di pazienti vaccinati. Sicuramente i risultati preliminari dimostrano l’importanza e l’efficacia di una terza dose booster di vaccino, seppur in tal caso i dati riguardano un periodo storico in cui la variante predominate era la Delta, con limitazioni legate inoltre ai differenti tempi di ricezione della dose booster nella popolazione di studio e alla perdita di partecipanti nel gruppo placebo per permettere la ricezione della terza dose in casi speciifici.

Poopalasingam N. et al.

Determining the reliability of rapid SARS-CoV-2 antigen detection in fully vaccinated individuals

J Clin Virol.,

https://reader.elsevier.com/reader/sd/pii/S1386653222000555?token=D94DF78CF507A4B7DDFC572CCE8B43798838AE7FA0E09A9F5BAE93C528261A4A6107D7A4E328040FCD9E56ADD4069D10&originRegion=eu-west-1&originCreation=20220311154957

CONTENUTO E COMMENTO : Questo studio valuta la capacità diagnostica del test antigenico rapido in soggetti vaccinati. Sono stati arruolati individui vaccinati ai quali sono stati effettuati due tamponi nasofaringei, uno per il test molecolare e l’altro per il test antigenico ; per la comparazione fra vaccinati e non vaccinati è stato utilizzato come riferimento un dataset precedentemente pubblicato dallo stesso gruppo di studio. Sono stati rilevati 76 campioni positivi mediante test molecolare e 45 campioni positivi mediante test antigenico. La sensibilità stratificata in base al numero di cicli (≤20, ≤25 e ≤30) è stata rispettivamente del 100.0%, 94.4% e 81.1% ; nessuno dei 23 campioni risultati positivi all’esame molecolare con cicli ≥30 è stato rilevato come positivo dal test antigenico. Per bassi valori di cicli di amplificazione non è stata documentata differenza di sensibilità in vaccinati o non vaccinati ; per valori medi ed elevati di cicli è stata documentata una ridotta sensibilità del test nei non vaccinati. La specificità del test antigenico è stata del 99.7% e la performance del test non è stata influenzata dalla presenza o meno di sintomi.

I risultati dello studio confermano l’estrema utilità del test antigenico per valori elevati valori di carica virale, mantenendo un eccellente potere diagnostico anche nei soggetti vaccinati, mentre, come già ampiamente osservato in precedenti studi, si conferma essere poco sensibile in presenza di basse cariche virali.

Miyamoto S. Et al.

Vaccination-infection interval determines cross-neutralization potency to SARS-CoV-2 Omicron after breakthrough infection by other variants

Med 2022, https://linkinghub.elsevier.com/retrieve/pii/S2666634022000897

CONTENUTO E COMMENTO: : Studio condotto su 30 campioni di individui con 2 dosi di vaccino BNT162b2 testati tramite neutralization assay su VSV pseudovirus e virus vivo. Da questo studio emerge un’importante perdita della potenza neutralizzante nel tempo contro omicron in entrambi gli assay (di 18,5 e 8 volte per gli assay a pseudovirus e virus vivo al tempo precoce (30 giorni) e 5,4 e 3 volte al tempo tardivo (10 giorni). I sieri degli individui con infezioni breakthrough sostenute da variani alpha e delta e vaccinazione BNT162b2 hanno potenza crossneutralizzante maggiore contro la variante omicron e a livelli comparabili a quelli di altre varianti, mentre i sieri dei vaccinati senza infezione breakthrough hanno una potenza neutralizzante contro omicron molto minore. Sembrerebbe inoltre che i sieri degli individui con infezione delta abbiano una attivita’ crossneutralizzante contro omicron maggiore che coloro con infezione alpha. In piu’, un piu’ lungo intervallo tra vaccinazione e infezione breakthrough si e’ mostrato ottimale per una migliore risposta anticorpale contro la variante omicron nei sieri di individui con infezione breakthrough non omicron, sia come potenza che come ampiezza della risposta. Il grado di correlazione tra attivita’ neutralizzante e intervallo di vaccinazione-infezione e’ maggiore per le varianti beta e omicron, mentre per la variante delta il pattern e’ completamente diverso. Le infezioni breakthrough dopo vaccinazione hanno sviluppato una robusta risposta crossneutralizzante contro molte varianti di SARS-CoV2, dovuta in larga parte alle cellule B della memoria indotte dalla precedente vaccinazione.

LIMITI: piccolo campione, fattori confondenti come la severita’ di patologia non affrontati, non accurate stima degli ordini di grandezza dei titoli neutralizzanti nei partecipanti senza infezioni breakthrough, non considerati sieri raccolti immediatamente dopo l’infezione breakthrough, non studiata correlazione tra attivita’ neutralizzante e replicazione in vivo, non studiata la dose booster.

Stegger M, et al.

Occurrence and significance of Omicron BA.1 infection followed by BA.2 reinfection

MedRxiv, https://www.medrxiv.org/content/10.1101/2022.02.19.22271112v1

CONTENUTO E COMMENTO: Grosso studio danese (non ancora peer-reviewed) condotto sui dati raccolti da diversi registri nazionali tra il 22 novembre 2021 e il 11 febbraio 2022.

In questo lasso di tempo, su un totale di 1,8 milioni di casi di infezione, 187 individui hanno sviluppato reinfezione (definita come il riscontro di due tamponi positivi a distanza di minimo 20 - 60 giorni l’uno dall’altro) e, tra questi, 47 sono stati reinfettati dalla sottovariante BA.2 dopo infezione da BA.1.

Tale studio conferma la possibilità di re-infezione precoce da BA.2 in seguito a infezione da BA.1. Inoltre, lo studio mette in risalto come la popolazione di re-infetti fosse costituita principalmente da soggetti giovani non vaccinati, e come nessuna di queste reinfezioni sia evoluta verso ricovero o malattia severa.

Hammerman A. et al.

Effectiveness of the BNT162b2 Vaccine after Recovery from Covid-19

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2119497

CONTENUTO E COMMENTO : : studio osservazionale retrospettivo di coorte effettuato sui dati medici elettronici di partecipanti iscritti al sistema Clalit Health Services che fossero guariti da un’infezione da SARS-CoV2 documentata da almeno 100 giorni e prima di aver ricevuto qualunque vaccinazione, nel il 23 agosto 2020 e il 31 maggio 2021.

Dei 149032 inclusi, 65676 non eranovaccinati alla fine dellostudio mentre 83356 loerano (BNT162b2) : analizzando l’outcomeprimario (tasso di reinfezione) dell’interacoorte, ci sono stati 354 reinfezionineivaccinati (2,46 casi per 100 000 persone al giorno) e 2168 nei non vaccinati (10,21 casi per 100 000 persone al giorno).

Neipazientisopra i 65 anni, ci sono state 28 reinfezionisu 9384 vaccinati (1,4 casi/100 000 persone/giorno) e 48 su 4799 nei non vaccinati (3,02). L’HR aggiustato per reinfezione nei vaccinati vs non vaccinatiera di 0.18 (95% intervallo di confidenza [CI], 0.16 a 0.20) neipazientitra i 16 e I 64 anni e 0.40 (95% CI, 0.24 a 0.64) tracolorodai 65 anni in su. Pertanto l’efficacia vaccinale stimataera 82% (95% CI, 80 a 84) neipazienti piu’ giovani e 60% (95% CI, 36 a 76) neipartecipantidai 65 anni in su.

Focalizzandosiinvecesul’outcome secondario (efficacia vaccinale tracolorocheavesseropoiricevutouna o due dosi), 67560 (81%) hannoricevutouna dose, 15251 (0.7%) due, e 545 (0.7%) tre. L’HR aggiustato per reinfezioneneipazienti con una dose rispetto a quelli con due era di 0.98 (95% CI, 0.64 a 1.50).

E’ evidente come la vaccinazione con BNT162b2 protegga contro la reinfezioneneipazienticheabbianogia’ avuto l’infezione, sebbene in misura minore neipazientisopra i 65 anni. L’analisi secondaria ha mostrato come l’aumento del numero di dosi in questocampione non siaassociato a unamiglioreefficacia.

LIMITAZIONI : studio real world con molti fattori confondenti non controllati ; esposizione a SARS-CoV2 variabilenel corso dello studio ; casidefiniti da RTqPCR per cuipossibileesclusione dei pazientipositivi ma non testati (ipotesiche i vaccinati con patologia piu’ lieve non si sianotestati, ma effettuandoun’analisisultasso di testinggenerale, questoera piu’ frequentenelgruppovaccinato); non analisi di gravita’, ospedalizzazione o morte ; analizzata la solaefficacia del vaccino BNT162b2.

Altarawneh HN; et al.

Protection against the Omicron Variant from Previous SARS-CoV-2 Infection

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMc2200133

CONTENUTO E COMMENTO : Grosso studio caso-controllo condotto in Qatar su dati estratti da un database nazionale, analizzante il rischio di re-infezione (definito come tampone PCR nuovamente positivo a distanza di almeno 90 giorni da una positività precedente) da variante Omicron in seguito ad infezione da una diversa variante, escludendo dall’analisi gli individui vaccinati. Casi (PCR + con meno di 30 cicli di replicazione) e controlli (PCR -) sono stati appaiati per genere, classe di età, nazionalità, e data di positivizzazione.

Nei risultati, l’intervallo di tempo mediano tra infezione iniziale e reinfezione è stato, rispettivamente, 279, 254 e 314 giorni per le varianti Alpha, Delta e Omicron. Invece, l’efficacia di una iniziale infezione nel prevenire l’incidenza di re-infezione si è dimostrata del 90% e 96% nei confronti delle varianti Alpha e Delta, mentre solo del 56% nei confronti della variante Omicron. Infine, l’efficacia nel prevenire la malattia severa si è dimostrata essere, rispettivamente, del 70%, 100% e 88% per le varianti Alpha, Delta e Omicron.

ariant associated with escape from neutralizing antibodies.