Michael Jäger et al.
Immunity of Heterologously and Homologously Boosted or Convalescent Individuals Against Omicron BA.1, BA.2, and BA.4/5 Variants
Academic.oup ;July 2023 ; doi.org/10.1093/infdis/jiad057
Abstract
The emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants BA.1, BA.2, and BA.4/5 demonstrate higher transmission and infection rates than previous variants of concern. To evaluate effectiveness of heterologous and homologous booster vaccination, we directly compared cellular and humoral immune responses as well as neutralizing capacity against replication-competent SARS-CoV-2 wild type, Delta, and Omicron variants BA.1, BA.2, and BA.4/5.
Methods
Peripheral blood mononuclear cells and serum samples from 137 participants were investigated, in 3 major groups. Individuals in the first group were vaccinated twice with ChAdOx1 and boosted with a messenger RNA (mRNA) vaccine (BNT162b2 or mRNA-1273); the second group included triple mRNA–vaccinated participants, and the third group, twice-vaccinated and convalescent individuals.
Results
Vaccination and convalescence resulted in the highest SARS-CoV-2–specific antibody levels, stronger T-cell responses, and best neutralization against wild type, Delta Omicron BA.2, and BA.4/5, while a combination of ChAdOx1 and BNT162b2 vaccination elevated neutralizing capacity against Omicron BA.1. In addition, heterologous booster regimens, compared with homologous regimens, showed higher efficacy against Omicron BA.2 as well as BA.4/5.
Conclusions
We showed that twice-vaccinated and convalescent individuals demonstrated the strongest immunity against Omicron BA.2 and BA.4/5 variant, followed by those receiving heterologous and homologous booster vaccine regimens.
Scott J. C. Pallett et al.
Hybrid immunity in older adults is associated with reduced SARS-CoV-2 infections following BNT162b2 COVID-19 immunisation
Nature, June 2023 ; doi.org/10.1038/s43856-023-00303-y
Abstract
Older adults, particularly in long-term care facilities (LTCF), remain at considerable risk from SARS-CoV-2. Data on the protective effect and mechanisms of hybrid immunity are skewed towards young adults precluding targeted vaccination strategies.
Methods
A single-centre longitudinal seroprevalence vaccine response study was conducted with 280 LCTF participants (median 82 yrs, IQR 76-88 yrs; 95.4% male). Screening by SARS-CoV-2 polymerase chain reaction with weekly asymptomatic/symptomatic testing (March 2020-October 2021) and serology pre-/post-two-dose Pfizer-BioNTech BNT162b2 vaccination for (i) anti-nucleocapsid, (ii) quantified anti-receptor binding domain (RBD) antibodies at three time-intervals, (iii) pseudovirus neutralisation, and (iv) inhibition by anti-RBD competitive ELISA were conducted. Neutralisation activity: antibody titre relationship was assessed via beta linear-log regression and RBD antibody-binding inhibition: post-vaccine infection relationship by Wilcoxon rank sum test.
Results
Here we show neutralising antibody titres are 9.2-fold (95% CI 5.8–14.5) higher associated with hybrid immunity (p < 0.00001); +7.5-fold (95% CI 4.6-12.1) with asymptomatic infection; +20.3-fold, 95% (CI 9.7-42.5) with symptomatic infection. A strong association is observed between antibody titre: neutralising activity (p < 0.00001) and rising anti-RBD antibody titre: RBD antibody-binding inhibition (p < 0.001), although 18/169 (10.7%) participants with high anti-RBD titre (>100BAU/ml), show inhibition <75%. Higher RBD antibody-binding inhibition values are associated with hybrid immunity and reduced likelihood of infection (p = 0.003).
Conclusions
Hybrid immunity in older adults was associated with considerably higher antibody titres, neutralisation and inhibition capacity. Instances of high anti-RBD titre with lower inhibition suggests antibody quantity and quality as independent potential correlates of protection, highlighting added value of measuring inhibition over antibody titre alone to inform vaccine strategy.
Thomas Althaus et al.
The Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination and Infection on Neutralizing Antibodies: A Nation-wide Cross-sectional Analysis
Academic.oup, February 2023; doi.org/10.1093/infdis/jiad030
Abstract
Neutralising antibodies (nAbs) play a critical role in the protection against severe COVID-19. In the era of vaccine boosters and repeated SARS-CoV-2 outbreaks, identifying individuals at risk represents a public health priority.
Method
Relying on the Monaco COVID Public Health Programme, we evaluated nAbs from July 2021-June 2022 in 8,080 SARS-CoV-2 vaccinated and/or infected children and adults, at their inclusion visit. We stratified by infection status and investigated variables associated with nAbs using a generalised additive model.
Results
Infected and vaccinated participants had high and consistent nAbs (>800 IU/mL), which remained stable over time since injection, regardless of the number of vaccine doses, body mass index, sex, or age. By contrast, uninfected participants showed larger variability (two doses [V2] median 157.6; interquartile range [IQR] 43.3-439.1 IU/mL) versus three doses [V3] median 882.5; [829.5-914.8] IU/mL). NAbs decreased by 20% per month after V2 (adjusted ratio 0.80; 95%CI [0.79-0.82]), but remained stable after V3 (adjusted ratio 0.98; 95%CI [0.92-1.05]).
Conclusions
Hybrid immunity provided stable, high and consistent nAbs over time. The benefit of boosters was marked to restore decaying nAbs in uninfected participants. NAbs could identify individuals at risk of severe COVID-19 and provide more targeted vaccine boosters’ campaigns.
Thomas Althaus et al
The Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination and Infection on Neutralizing Antibodies: A Nation-wide Cross-sectional Analysis
Academic.oup, February 2023; doi.org/10.1093/infdis/jiad030
Abstract
Neutralising antibodies (nAbs) play a critical role in the protection against severe COVID-19. In the era of vaccine boosters and repeated SARS-CoV-2 outbreaks, identifying individuals at risk represents a public health priority.
Method
Relying on the Monaco COVID Public Health Programme, we evaluated nAbs from July 2021-June 2022 in 8,080 SARS-CoV-2 vaccinated and/or infected children and adults, at their inclusion visit. We stratified by infection status and investigated variables associated with nAbs using a generalised additive model.
Results
Infected and vaccinated participants had high and consistent nAbs (>800 IU/mL), which remained stable over time since injection, regardless of the number of vaccine doses, body mass index, sex, or age. By contrast, uninfected participants showed larger variability (two doses [V2] median 157.6; interquartile range [IQR] 43.3-439.1 IU/mL) versus three doses [V3] median 882.5; [829.5-914.8] IU/mL). NAbs decreased by 20% per month after V2 (adjusted ratio 0.80; 95%CI [0.79-0.82]), but remained stable after V3 (adjusted ratio 0.98; 95%CI [0.92-1.05]).
Conclusions
Hybrid immunity provided stable, high and consistent nAbs over time. The benefit of boosters was marked to restore decaying nAbs in uninfected participants. NAbs could identify individuals at risk of severe COVID-19 and provide more targeted vaccine boosters’ campaigns.
Javier Perez-Saez et al
Long term anti-SARS-CoV-2 antibody kinetics and correlate of protection against Omicron BA.1/BA.2 infection
Nature, May 2023; doi.org/10.1038/s41467-023-38744-7
Abstract
Binding antibody levels against SARS-CoV-2 have shown to be correlates of protection against infection with pre-Omicron lineages. This has been challenged by the emergence of immune-evasive variants, notably the Omicron sublineages, in an evolving immune landscape with high levels of cumulative incidence and vaccination coverage. This in turn limits the use of widely available commercial high-throughput methods to quantify binding antibodies as a tool to monitor protection at the population-level. Here we show that anti-Spike RBD antibody levels, as quantified by the immunoassay used in this study, are an indirect correlate of protection against Omicron BA.1/BA.2 for individuals previously infected by SARS-CoV-2. Leveraging repeated serological measurements between April 2020 and December 2021 on 1083 participants of a population-based cohort in Geneva, Switzerland, and using antibody kinetic modeling, we found up to a three-fold reduction in the hazard of having a documented positive SARS-CoV-2 infection during the Omicron BA.1/BA.2 wave for anti-S antibody levels above 800 IU/mL (HR 0.30, 95% CI 0.22-0.41). However, we did not detect a reduction in hazard among uninfected participants. These results provide reassuring insights into the continued interpretation of SARS-CoV-2 binding antibody measurements as an independent marker of protection at both the individual and population levels.
Otávio Melo Espíndola et al.
Reduced ability to neutralize the Omicron variant among adults after infection and complete vaccination with BNT162b2, ChAdOx1, or CoronaVac and heterologous boosting
Nature, May 2023; doi.org/10.1038/s41598-023-34035-9
Abstract
COVID-19 vaccines have dramatically reduced rates of severe infection requiring hospitalization. However, SARS-CoV-2 variants have reduced vaccine effectiveness at preventing any symptomatic infection. This real-world study analyzed binding and neutralizing antibodies generated after complete vaccination and boosting across three vaccine platforms. Binding antibodies decayed most slowly in people under 60 with hybrid immunity. Neutralizing antibodies against Omicron BA.1 were reduced compared to other variants. The anamnestic anti-spike IgG response to the first boost was more pronounced than after the second boost. Monitoring of the effects of SARS-CoV-2 mutations on disease severity and the effectiveness of therapeutics is warranted.
Dan-Yu Lin et al.
Durability of Bivalent Boosters against Omicron Subvariants
NEJM, April 2023; DOI: 10.1056/NEJMc2302462
Abstract
On September 1, 2022, the Moderna and Pfizer–BioNTech bivalent vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) containing equal amounts of spike messenger RNA from the ancestral and omicron BA.4–BA.5 subvariants replaced their monovalent counterparts as booster doses for persons who are 12 years of age or older in the United States. We previously reported surveillance data from North Carolina on the effectiveness of these two bivalent boosters against coronavirus disease 2019 (Covid-19) during the first 3 months after deployment (September 1 to December 8, 2022); the BA.4–BA.5 subvariants were predominant during the first 2.5 months of this period.1 Here, we present two additional months of data that were obtained during a period when the omicron BQ.1–BQ.1.1 and XBB–XBB.1.5 subvariants had become predominant to show the durability of protection conferred by these two bivalent boosters against a wider range of clinical outcomes than were included in our previous report.
We considered four outcome measures: infection, severe infection resulting in hospitalization, severe infection resulting in hospitalization or death, and severe infection resulting in death. We fit the Cox regression model with a time-varying hazard ratio for severe infection and fit the proportional-rates model with a time-varying rate ratio for recurrent infection for each additional booster dose that was received (i.e., first booster vs. primary vaccination, second booster vs. first booster, or third booster vs. second booster); all measures were adjusted for the baseline characteristics shown in Table S1. We estimated the booster effectiveness on a particular day as 1 minus the hazard ratio or rate ratio on that day multiplied by 100%.
The two types of bivalent boosters were associated with an additional reduction in the incidence of omicron infection among participants who had previously been vaccinated or boosted. Although the two bivalent vaccines were designed to target the BA.4–BA.5 subvariants, they were also associated with a lower risk of infection or severe infection with the BQ.1–BQ.1.1 and XBB–XBB.1.5 subvariants. The effectiveness was higher against hospitalization and death than against infection and waned gradually from its peak over time.
Noam Barda et al.
The Association Between Prebooster Vaccination Antibody Levels and the Risk of Severe Acute Respiratory Syndrome Coronavirus 2 Infection
CID, Novembre 2022; doi.org/10.1093/cid/ciac886
Abstract
The correlation between anti–severe acute respiratory syndrome coronavirus 2 antibody levels and infection was reported. Here, we estimated the role of pre–fourth dose levels using data from 1098 healthcare workers. The risk of infection was reduced by 46% (95% confidence interval, 29%–59%) for each 10-fold increase in prebooster levels. Prebooster antibody levels could be used to optimally time boosters.
Emanuele Andreano et al.
mRNA vaccines and hybrid immunity use different B cell germlines against Omicron BA.4 and BA.5
Nature, March 2023; doi.org/10.1038/s41467-023-37422-y
Abstract
Severe acute respiratory syndrome 2 Omicron BA.4 and BA.5 are characterized by high transmissibility and ability to escape natural and vaccine induced immunity. Here we test the neutralizing activity of 482 human monoclonal antibodies isolated from people who received two or three mRNA vaccine doses or from people vaccinated after infection. The BA.4 and BA.5 variants are neutralized only by approximately 15% of antibodies. Remarkably, the antibodies isolated after three vaccine doses target mainly the receptor binding domain Class 1/2, while antibodies isolated after infection recognize mostly the receptor binding domain Class 3 epitope region and the N-terminal domain. Different B cell germlines are used by the analyzed cohorts. The observation that mRNA vaccination and hybrid immunity elicit a different immunity against the same antigen is intriguing and its understanding may help to design the next generation of therapeutics and vaccines against coronavirus disease 2019.
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.
VéroniqueBarateau et al.
Prior SARS-CoV-2 infection enhances and reshapes spike protein–specific memory induced by vaccination
Science, March 2023; DOI: 10.1126/scitranslmed.ade0550
Abstract
The diversity of vaccination modalities and infection history are both variables that have an impact on the immune memory of individuals vaccinated against SARS-CoV-2. To gain more accurate knowledge of how these parameters imprint on immune memory, we conducted a long-term follow-up of SARS-CoV-2 spike protein–specific immune memory in unvaccinated and vaccinated COVID-19 convalescent individuals as well as in infection-naïve vaccinated individuals. Here, we report that individuals from the convalescent vaccinated (hybrid immunity) group have the highest concentrations of spike protein–specific antibodies at 6 months after vaccination. As compared with infection-naïve vaccinated individuals, they also display increased frequencies of an atypical mucosa-targeted memory B cell subset. These individuals also exhibited enhanced TH1 polarization of their SARS-CoV-2 spike protein–specific follicular T helper cell pool. Together, our data suggest that prior SARS-CoV-2 infection increases the titers of SARS-CoV-2 spike protein–specific antibody responses elicited by subsequent vaccination and induces modifications in the composition of the spike protein–specific memory B cell pool that are compatible with enhanced functional protection at mucosal sites.
Edwards Pradenas et al.
Impact of hybrid immunity booster vaccination and Omicron breakthrough infection on SARS-CoV-2 VOCs cross-neutralization
Cell, March 2023; doi.org/10.1016/j.isci.2023.106457
Abstract
The elicitation of cross-variant neutralizing antibodies against SARS-CoV-2 represents a major goal for current COVID-19 vaccine strategies. Additionally, natural infection may also contribute to broaden neutralizing responses. To assess the contribution of vaccines and natural infection, we cross-sectionallyanalyzed plasma neutralization titers of six groups of individuals, organized according to the number of vaccines they received and their SARS-CoV-2 infection history. Two doses of vaccine had a limited capacity to generate cross-neutralizing antibodies against Omicron variants of concern (VOCs) in uninfected individuals, but efficiently synergized with previous natural immunization in convalescent individuals. In contrast, booster dose had a critical impact on broadening the cross-neutralizing response in uninfected individuals, to level similar to hybrid immunity, while still improving cross-neutralizing responses in convalescent individuals. Omicron breakthrough infection improved cross-neutralization of Omicron subvariants in non-previously infected vaccinated individuals. Therefore, ancestral Spike-based immunization, via infection or vaccination, contributes to broaden SARS-CoV-2 humoral immunity.
RamandipGrewal et al.
Effectiveness of mRNA COVID-19 vaccine booster doses against Omicron severe outcomes
Nature, March 2023; doi.org/10.1038/s41467-023-36566-1
Abstract
We estimated the effectiveness of booster doses of monovalent mRNA COVID-19 vaccines against Omicron-associated severe outcomes among adults in Ontario, Canada. We used a test-negative design to estimate vaccine effectiveness (VE) against hospitalization or death among SARS-CoV-2-tested adults aged ≥50 years from January 2 to October 1, 2022, stratified by age and time since vaccination. We also compared VE during BA.1/BA.2 and BA.4/BA.5 sublineage predominance. We included 11,160 cases and 62,880 tests for test-negative controls. Depending on the age group, compared to unvaccinated adults, VE was 91–98% 7–59 days after a third dose, waned to 76–87% after ≥240 days, was restored to 92–97% 7–59 days after a fourth dose, and waned to 86–89% after ≥120 days. VE was lower and declined faster during BA.4/BA.5 versus BA.1/BA.2 predominance, particularly after ≥120 days. Here we show that booster doses of monovalent mRNA COVID-19 vaccines restored strong protection against severe outcomes for at least 3 months after vaccination. Across the entire study period, protection declined slightly over time, but waned more during BA.4/BA.5 predominance.
Carol Ho-Yan Fong et al
Effect of vaccine booster, vaccine type, and hybrid immunity on humoral and cellular immunity against SARS-CoV-2 ancestral strain and Omicron variant sublineages BA.2 and BA.5 among older adults with comorbidities: a cross sectional study
eBioMedicine, January 2023; doi.org/10.1016/j.ebiom.2023.104446
Abstract
Background
Vaccination reduces COVID-19-related hospitalization among older adults. However, how SARS-CoV-2 infection and vaccine regimens affect vaccine-elicited immunity remain unclear.
Methods
This is a cross-sectional study recruiting adults aged ≥70 years with comorbidities in Hong Kong. Demographic and clinical information were collected using a questionnaire. Neutralizing antibody (nAb) titers (against ancestral and Omicron strains) and SARS-CoV-2-specific T cell response were analyzed according to infection and vaccination status. Multivariable regression analysis was performed to assess the associations of BNT162b2 and booster doses with higher nAbtiters, with adjustment for comorbidities.
Interpretation
Our data support the use of booster doses for older adults with or without prior infection. Non-infected individuals primed with CoronaVac will benefit from heterologous mRNA vaccine booster.
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
The Lancet, 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.
Methods
We did an unmasked post-hoc immunogenicity analysis after the first and second doses of AZD1222 in a randomised, placebo-controlled, phase 1b–2a study done in seven locations in South Africa. AZD1222 recipients who were HIV-uninfected, were stratified into baseline seropositive or seronegative groups using the serum anti-nucleocapsid (anti-N) immunoglobulin G (IgG) electroluminescence immunoassay to establish SARS-CoV-2 infection before the first dose of AZD1222. Binding IgG to spike (anti-S) and receptor binding domain (anti-RBD) were measured before the first dose (day 0), second dose (day 28), day 42, and day 180. Neutralising antibody (NAb) against SARS-CoV-2 variants D614G, beta, delta, gamma, and A.VOI.V2, and omicron BA1 and BA.4 variants, were measured by pseudovirus assay (day 28, day 42, and day 180). This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132.
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.
Funding
The Bill & Melinda Gates Foundation, the South African Medical Research Council, the UK Research and Innovation, the UK National Institute for Health Research, and the South African Medical Research Council.
Cassandra Willyard
How quickly does COVID immunity fade? What scientists know Vaccination, infection with SARS-CoV-2 and a combination of both provide varying degrees of protection
Nature, February 2023; doi.org/10.1038/d41586-023-00124-y
Abstract
Three years into the pandemic, the immune systems of the vast majority of humans have learnt to recognize SARS-CoV-2 through vaccination, infection or, in many cases, both. But just how quickly do these types of immunity fade?
New evidence suggests that ‘hybrid’ immunity, the result of both vaccination and a bout of COVID-19, can provide partial protection against reinfection for at least eight months1. It also offers greater than 95% protection against severe disease or hospitalization for between six months and a year after an infection or vaccination, according to estimates from a meta-analysis2. Immunity acquired by booster vaccination alone seems to fade somewhat faster.
But the durability of immunity is much more complex than the numbers suggest. How long the immune system can fend off SARS-CoV-2 infection depends not only on how much immunity wanes over time but also on how well immune cells recognize their target. “And that has more to do with the virus and how much it mutates,” says Deepta Bhattacharya, an immunologist at the University of Arizona College of Medicine in Tucson. If a new variant finds ways to escape the existing immune response, then even a recent infection might not guarantee protection.
Omicron era
Omicron has presented just such a scenario. In late 2021 and early 2022, the main Omicron subvariants that were causing infections were BA.1 and BA.2. By mid-2022, the BA.5 wave was gathering strength in some countries, raising the prospect that those who’d already had one round of Omicron could soon be exposed to another. Data are now providing a sense of the risk of reinfection over time.
In one study, researchers looking at Portugal’s national database of infections studied vaccinated people who became infected during the BA.1/BA.2 wave. Analysis showed that 90 days after an infection, this population had high immune protection — their risk of becoming infected with BA.5 was just one-sixteenth that of people who had been vaccinated but never infected. After that, hybrid immunity against infection declined steeply for a few months and then stabilized, ultimately providing protection for eight months after infection, the duration of the study.
What the Omicron wave is revealing about human immunity
Another study looked at 338 vaccinated health-care workers in Sweden, some of whom had had a previous SARS-CoV-2 infection. The authors found that workers with hybrid immunity had some level of protection against infection with BA.1, BA.2 and BA.5 for at least eight months. Swabbing of these workers’ noses revealed high levels of ‘mucosal’ antibodies, which are thought to be a better shield against infection than antibodies that circulate in the blood.
A study in Qatar compared the infection risks of people who had never caught SARS-CoV-2 with those of people who’d had a previous infection with Omicron or an earlier variant. Both groups included vaccinated and unvaccinated individuals. The results show that more recent infections provide greater protection than older ones in all cases. But because the virus kept evolving, the authors couldn’t untangle whether those differences were because of waning immunity, the virus’s growing ability to evade the immune response or, more likely, a combination of the two.
Infection reprieve
Taken together, the studies suggest that hybrid immunity provides some protection against infection for at least seven or eight months, and probably longer. “That’s pretty good,” says Charlotte Thålin, an immunologist at the Karolinska Institute in Stockholm and an author of the Swedish study.
Other data suggest that in people whose immunity arises only from vaccination, a booster dose provides relatively short-lived protection against infection. Researchers in Israel studied more than 10,000 health-care workers who had not previously been infected; all received either three or four doses of the vaccine made by Pfizer and BioNTech5. The authors found that the fourth dose’s efficacy against infection fell rapidly. In fact, after four months, the fourth dose was no better than three doses at preventing infection.
Immunity against Omicron from breakthrough infection could be a matter of timing
However, “we are talking just about what we call relatively mild disease”, says study co-author GiliRegev-Yochay, an epidemiologist at Sheba Medical Center Tel Hashomer in Ramat Gan, Israel. None of the people in the study developed severe COVID-19.
What about those who haven’t been vaccinated? Another study6 in Qatar suggests that if the virus doesn’t change, infection-based immunity against reinfection can last up to three years. But that immunity can fade faster if the virus mutates. The authors studied data from unvaccinated people who were infected with a pre-Omicron variant. Fifteen months later, those infections were less than 10% effective at protecting against Omicron infection. And it is much riskier to rely on immunity from infection than to get immunized.
But it’s nearly impossible to apply the study results to predict an individual’s risk of becoming infected in future. Immunity depends on a variety of factors, including genetics, age and sex. And past risk of infection isn’t necessarily a good predictor of the risk of future infection, because new variants are continually arising.
Booster break
How growing global hybrid immunity will affect the timing and frequency of infection surges isn’t yet clear. Neither is it clear how this will influence health officials’ decisions about when to offer future booster doses.
For people who are at high risk of developing severe COVID-19, it might make sense to get boosters frequently. Younger individuals without any risk factors who live in regions where the virus has been circulating freely “may already have very significant protection that may not require as frequent boosters”, says LuísGraça, an immunologist in the Faculty of Medicine at the University of Lisbon and a co-author of the Portuguese study. Another option might be to give a booster when antibody levels fall below a certain threshold, says Regev-Yochay.
Thålin understands how frustrating the caveats and uncertainty can be, but says that researchers aren’t likely to pin down an answer anytime soon. “The virus is evolving so fast,” she says. “What’s true today might not be true tomorrow?”.
Bobrovitz N et al.
Protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression
The Lancet, January 2023; doi.org/10.1016/S1473-3099(22)00801-5
Abstract
Background
The global surge in the omicron (B.1.1.529) variant has resulted in many individuals with hybrid immunity (immunity developed through a combination of SARS-CoV-2 infection and vaccination). We aimed to systematically review the magnitude and duration of the protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against infection and severe disease caused by the omicron variant.
Methods
For this systematic review and meta-regression, we searched for cohort, cross-sectional, and case–control studies in MEDLINE, Embase, Web of Science, ClinicalTrials.gov, the Cochrane Central Register of Controlled Trials, the WHO COVID-19 database, and Europe PubMed Central from Jan 1, 2020, to June 1, 2022, using keywords related to SARS-CoV-2, reinfection, protective effectiveness, previous infection, presence of antibodies, and hybrid immunity. The main outcomes were the protective effectiveness against reinfection and against hospital admission or severe disease of hybrid immunity, hybrid immunity relative to previous infection alone, hybrid immunity relative to previous vaccination alone, and hybrid immunity relative to hybrid immunity with fewer vaccine doses. Risk of bias was assessed with the Risk of Bias In Non-Randomized Studies of Interventions Tool. We used log-odds random-effects meta-regression to estimate the magnitude of protection at 1-month intervals. This study was registered with PROSPERO (CRD42022318605).
Findings
11 studies reporting the protective effectiveness of previous SARS-CoV-2 infection and 15 studies reporting the protective effectiveness of hybrid immunity were included. For previous infection, there were 97 estimates (27 with a moderate risk of bias and 70 with a serious risk of bias). The effectiveness of previous infection against hospital admission or severe disease was 74·6% (95% CI 63·1–83·5) at 12 months. The effectiveness of previous infection against reinfection waned to 24·7% (95% CI 16·4–35·5) at 12 months. For hybrid immunity, there were 153 estimates (78 with a moderate risk of bias and 75 with a serious risk of bias). The effectiveness of hybrid immunity against hospital admission or severe disease was 97·4% (95% CI 91·4–99·2) at 12 months with primary series vaccination and 95·3% (81·9–98·9) at 6 months with the first booster vaccination after the most recent infection or vaccination. Against reinfection, the effectiveness of hybrid immunity following primary series vaccination waned to 41·8% (95% CI 31·5–52·8) at 12 months, while the effectiveness of hybrid immunity following first booster vaccination waned to 46·5% (36·0–57·3) at 6 months.
Interpretation
All estimates of protection waned within months against reinfection but remained high and sustained for hospital admission or severe disease. Individuals with hybrid immunity had the highest magnitude and durability of protection, and as a result might be able to extend the period before booster vaccinations are needed compared to individuals who have never been infected.
Recalling ancestral SARS-CoV-2 variants: is it an original sin with benefits?
The Lancet, January 2023; doi.org/10.1016/S1473-3099(23)00007-5
Abstract
Immune imprinting was first described in the contextof influenza as “original antigenic sin” by Thomas Francis Jr in 1960.1 Influenza imprinting might nudgethe immune response towards conserved regions ofcurrently circulating influenza virus strains, rather thanthe most immunogenic region of the dominant strainof the future influenza epidemics. Similar concernshave been raised for SARS-CoV-2, in particular,whether previous vaccination or infection with preomicronvariants might impair responses againstcurrently circulating strains. Have we committed anoriginal sin by vaccinating with the spike protein ofa now outcompeted variant of SARS-CoV-2, that willhenceforth stunt our immune response to the variantsand vaccines of the future, leading to higher morbidityand mortality? In other words, is this a scenario for usto overcome, as Hoffmann and colleagues2 concludein their recent correspondence in The Lancet InfectiousDiseases?There is a lot of evidence that underpins the notion that the immune response to viruses is guided byprevious exposure to similar antigens. This response is also the case for SARS-CoV-2, whereby previousexposure to other human coronaviruses, such asHKU-1, appears to guide the antibody response towardsepitopes that are conserved, rather than novel andSARS-CoV-2 specific epitopes.3Several studies examined the immune responseto infections with omicron variants, and these, too,revealed evidence of immune imprinting. In individualsprimed with ancestral strains of SARS-CoV-2 throughinfection or vaccination, titres of neutralisingantibodies, an established marker of protection,are boosted against ancestral strains and to a lesserdegree against omicron itself.4 Infections with omicronvariants did not transition the immune responsetowards proficient neutralisation of newer variantsof omicron, such as BA.2.75.2 and BQ.1.1, whileupholding strong titres against wildtype SARS-CoV-2.2The upholding of strong titres is despite all omicronvariants sharing only a small minority of unalteredneutralising B-cell epitopes with the earliest variant ofSARS-CoV-2.5A similar observation can be made for bivalent vaccineboosters containing the spike of omicron variants BA.5,in addition to wildtype SARS-CoV-2. Wildtype SARSCoV-2 is neutralised most effectively, even though abroadening of the immune response towards neweromicron variants also occurs, but in a much lessermagnitude.6 If this broadening of the immune responseoffers long-lived improved protection from infection,especially by emerging omicron variants, remains to beseen. But the insights gained through studies of neutralisingantibodies do not seem to translate into highermortality. Priming with wildtype SARS-CoV-2 throughthree vaccine doses upholds efficacy against the mostimportant outcomes of vaccination, severe disease, anddeath in the case of an omicron infection,7 potentiallyaided by upheld T-cell immunity. And priming with preomicronvariants of SARS-CoV-2, before an infectionwith the first omicron variants BA.1 or BA.2, reduced therisk of re-infection, rather than promoted it.8Considering that infections with omicron variantswere associated with less, albeit still considerable,serious adverse outcomes than the ancestral deltavariant,9 it appears to be a beneficial population strategyto maintain high memory B-cell immunity againstancestral strains. The action of immune imprinting,by upholding high neutralising antibody titres againstancestral SARS-CoV-2 strains in the population, mighthelp eradicate ancestral strains, in favour of attenuatedstrains circulating in consecutive waves. A novel(hypothetical) strain derived from the delta variantthat shares the predisposition to cause lethal outcomesmight be the worst-case scenario going forward in thepandemic in regions with high population-immunity.And immune imprinting might help protect us from thisprospect.We agree with Hoffmann and colleagues thatovercoming immune imprinting might be neededto optimise vaccine efficacy against reinfection withomicron variants emerging today and in the future.We can learn from the observation that the responsetowards newer omicron variants is enhanced inmagnitude and breadth through previous infection,which exposes the immune system to wider range ofnon-neutralising epitopes. The frequency of vaccinationand the time intervals between them also play animportant role. Alternative strategies, such as mucosalvaccines, might also help in broadening the immuneresponse.Meanwhile, it should be considered that immuneimprinting might be offering a wall of protection fromeven more severe variants derived from ancestralstrains.
Van Coillie J. et al.
The BNT162b2 mRNA SARS-CoV-2 vaccine induces transient afucosylated IgG1 in naive but not in antigen-experienced vaccinees
The Lancet, December 2022; doi.org/10.1016/j.ebiom.2022.104408
Abstract
Afucosylated IgG1 responses have only been found against membrane-embedded epitopes, including anti-S in SARS-CoV-2 infections. These responses, intrinsically protective through enhanced FcγRIIIa binding, can also trigger exacerbated pro-inflammatory responses in severe COVID-19. We investigated if the BNT162b2 SARS-CoV-2 mRNA also induced afucosylated IgG responses.
Methods
Blood from vaccinees during the first vaccination wave was collected. Liquid chromatography-Mass spectrometry (LC-MS) was used to study anti-S IgG1 Fc glycoprofiles. Responsiveness of alveolar-like macrophages to produce proinflammatory cytokines in presence of sera and antigen was tested. Antigen-specific B cells were characterized and glycosyltransferase levels were investigated by Fluorescence-Activated Cell Sorting (FACS).
Findings
Initial transient afucosylated anti-S IgG1 responses were found in naive vaccinees, but not in antigen-experienced ones. All vaccinees had increased galactosylated and sialylated anti-S IgG1. Both naive and antigen-experienced vaccinees showed relatively low macrophage activation potential, as expected, due to the low antibody levels for naive individuals with afucosylated IgG1, and low afucosylation levels for antigen-experienced individuals with high levels of anti-S. Afucosylation levels correlated with FUT8 expression in antigen-specific plasma cells in naive individuals. Interestingly, low fucosylation of anti-S IgG1 upon seroconversion correlated with high anti-S IgG levels after the second dose.
Interpretation
Here, we show that BNT162b2 mRNA vaccination induces transient afucosylated anti-S IgG1 responses in naive individuals. This observation warrants further studies to elucidate the clinical context in which potent afucosylated responses would be preferred.
Eddy Fadlyana, et al.
Immunogenicity and safety in healthy adults of full dose versus half doses of COVID-19 vaccine (ChAdOx1-S or BNT162b2) or full-dose CoronaVac administered as a booster dose after priming with CoronaVac: a randomised, observer-masked, controlled trial in Indonesia
The lancet, January 2023, doi.org/10.1016/S1473-3099(22)00800-3
Abstract
Inactivated COVID-19 vaccines effectively prevent death, but their effectiveness for preventing infection or severe illness is known to decrease within 3–6 months following the second priming dose. Here we aimed to evaluate the immunogenicity and safety of three potential booster vaccines administered as a full-dose homologous booster or full-dose or half-dose heterologous boosters among individuals primed with CoronaVac. We did an observer and participant masked, randomised controlled trial study of healthy Indonesian adults from five recruitment sites in Bandung and Jakarta, Indonesia, aged 18 years and older who had previously received two doses of CoronaVac within 3 to less than 6 months or 6 to 9 months before the booster dose. Participants were randomly assigned (1:1:1:1:1) by means of stratified randomisation with random block size to a homologous booster with full-dose CoronaVac or heterologous boosters with ChAdOx1-S or BNT162b2 in full dose or half dose. The primary outcome was to evaluate the seropositive, seroconversion rate, and the geometric mean titres of IgG anti-spike-receptor binding domain and neutralising antibodies, 28 days after booster dose vaccination in the per-protocol population. Safety was assessed as a secondary outcome in all vaccinated booster participants by the incidence rate and intensity of adverse events within 24 h, 7 days, and 28 days after the booster dose. This study is registered with ina-registry.org, INA-GO0HLGB, and is complete. Geometric mean titre values between participants in the 6 to 9 months priming group and the 3 to less than 6 months priming group before the booster dose and between half-dose and full-dose groups 28 days before the booster were not significantly different for half-dose ChAdOx1-S, full-dose BNT162b2, and CoronaVac and were significantly different for full-dose ChAdOx1-S and half-dose BNT162b2. Among individuals primed with CoronaVac, boosting with BNT162b2 (full dose or half dose) or ChAdOx1-S (full dose or half dose) produces substantially better immune responses than in those boosted with CoronaVac. Full-dose and half-dose boosting with either BNT162b2 or ChAdOx1-S produced similar responses. Heterologous booster with half-dose might be considered in adults primed with two doses of CoronaVac vaccine.
Sacco C. et al.
Impatto della vaccinazione e della pregressa diagnosi sul rischio di infezione e di malattia severa associata a SARS-CoV-2: un’analisi dei casi diagnosticati nel mese di ottobre 2022
Abstract
In Italia, l’epidemia di infezioni da SARS-CoV-2 nel corso del 2022 è stata influenzata dalla predominanza della variante Omicron, caratterizzata da alta trasmissibilità, e dalla progressiva eliminazione di quasi tutte le misure non farmacologiche di prevenzione. La combinazione di questi due elementi ha determinato una notevole circolazione virale di SARS-CoV-2 con oltre 24,5 milioni di casi da inizio epidemia. Dato l’alto numero di persone che ha superato almeno una infezione da SARS-CoV-2 e l’alta copertura vaccinale nella popolazione è necessario stimare il ruolo protettivo dell’immunità associata sia al vaccino che all’infezione pregressa nel prevenire l’infezione e la malattia severa da COVID-19. Il presente rapporto fornisce una stima del rischio di infezione e di malattia grave, per il mese di ottobre 2022, sulla base della vaccinazione e della precedente infezione. La massima protezione contro la diagnosi di infezione da SARS-CoV-2 e la malattia severa si realizza attraverso una immunità ibrida (l’effetto combinato della vaccinazione e della pregressa infezione) mentre livelli di rischio più alto si riscontrano sempre tra le persone non vaccinate e senza una precedente diagnosi di infezione. A parità di fascia di età e di pregressa infezione, si osserva una tendenza alla riduzione del rischio di malattia severa associata alla vaccinazione, in particolare se recente.
Bobrovitz N. et al.
Protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression
The Lancet, January 2023; doi.org/10.1016/S1473-3099(22)00801-5
Abstract
The global surge in the omicron (B.1.1.529) variant has resulted in many individuals with hybrid immunity (immunity developed through a combination of SARS-CoV-2 infection and vaccination). We aimed to systematically review the magnitude and duration of the protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against infection and severe disease caused by the omicron variant.
Interpretation
All estimates of protection waned within months against reinfection but remained high and sustained for hospital admission or severe disease. Individuals with hybrid immunity had the highest magnitude and durability of protection, and as a result might be able to extend the period before booster vaccinations are needed compared to individuals who have never been infected.
Tauzin A. et al.
Spike recognition and neutralization of SARS-CoV-2 Omicron subvariants Spike elicited after the third dose of mRNA vaccine
ScienceDirect, January 2023; doi.org/10.1016/j.celrep.2023.111998
Several SARS-CoV-2 Omicron subvariants have recently emerged, becoming the dominant circulating strains in many countries. These variants contain a large number of mutations in their Spike glycoprotein, raising concerns about vaccine efficacy. In this study, we evaluate the ability of plasma from a cohort of individuals that received three doses of mRNA vaccine to recognize and neutralize these Omicron subvariant Spikes. We observed that BA.4/5 and BQ.1.1 Spikes are markedly less recognized and neutralized compared to the D614G and the other Omicron subvariant Spikes tested. Also, individuals who have been infected before or after vaccination present better humoral responses than SARS-CoV-2 naïve vaccinated individuals, thus indicating that hybrid immunity generates better humoral responses against these subvariants.
Malato J. et al.
Stability of hybrid versus vaccine immunity against BA.5 infection over 8 months
Lancet, January 2023; doi.org/10.1016/S1473-3099(22)00833-7
Abstract
The coverage of SARS-CoV-2 vaccination in large parts of the world, together with the high number of breakthrough infections, especially following the emergence of Omicron subvariants, makes hybrid immunity (resulting from vaccine and infection) common. Hybrid immunity, particularly after BA.1 or BA.2 infection, confers substantial protection against the BA.5 infection.1, 2, 3 However, although the waning of protection afforded by natural infection in non-vaccinated individuals or by vaccination has been well documented,4, 5 the stability of hybrid immunity, specifically against the BA.5 subvariant, now dominant in many countries, has not been thoroughly addressed.
However, our results of increased protection with hybrid immunity versus vaccine immunity, agrees with the overall conclusion of that study that “imprinting effects are unlikely to negate the overall public health value of booster vaccinations”.7
This study shows that hybrid immunity following infection with Omicron BA.1 or BA.2 when compared with vaccine-only immunity leads to substantially increased protection against BA.5 reinfection for up to 8 months.
Runhong Zhou et al.
Three-dose vaccination-induced immune responses protect against SARS-CoV-2 Omicron BA.2: A population-based study in Hong Kong
Lancet, December 2022; doi.org/10.1016/j.lanwpc.2022.100660
Abstract
Background
The ongoing outbreak of SARS-CoV-2 Omicron BA.2 infections in Hong Kong, the model city of universal masking of the world, has resulted in a major public health crisis. Although the third vaccination resulted in strong boosting of neutralization antibody, vaccine efficacy and correlate of immune protection against the major circulating Omicron BA.2 remain to be investigated.
Interpretation
Our results imply that the timely third vaccination and immune responses are likely required for vaccine-mediated protection against Omicron BA.2 pandemic. Although BA.2 conferred the highest neutralization resistance compared with variants of concern tested before the emergence of BA.2.12.1 and BA.4/5, the third dose vaccination-activated S-specific memory B cells and Omicron cross-reactive T cell responses contributed to reduced frequencies of breakthrough infection and disease severity. Neutralizing antibody potency enhanced by BA.2 breakthrough infection in vaccinees with prior 3 doses of CoronaVac or BNT162b2 may reduce the risk of infection against ongoing BA.2.12.1 and BA.4/5.
Martinuzzi E. et al
A Single Dose of BNT162b2 Messenger RNA Vaccine Induces Airway Immunity in Severe Acute Respiratory Syndrome Coronavirus 2 Naive and Recovered Coronavirus Disease 2019 Subjects
CID, May. 2022; doi.org/10.1093/cid/ciac378
Abstract
Mucosal antibodies can prevent virus entry and replication in mucosal epithelial cells and therefore virus shedding. Parenteral booster injection of a vaccine against a mucosal pathogen promotes stronger mucosal immune responses following prior mucosal infection compared with injections of a parenteral vaccine in a mucosally naive subject. We investigated whether this was also the case for the BNT162b2 coronavirus disease 2019 (COVID-19) messenger RNA vaccine.
Conclusions
Mucosal immune response to the SARS-CoV-2 Spike protein is higher in RCSs after a single vaccine dose compared with SARS-CoV-2–naive subjects after 2 doses.
Shrestha N.K. et al.
Coronavirus Disease 2019 Vaccine Boosting in Previously Infected or Vaccinated Individuals
CID, April 2022; doi.org/10.1093/cid/ciac327
Abstract
The purpose of this study was to determine whether boosting previously infected or vaccinated individuals with a vaccine developed for an earlier variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protects against the Omicron variant.
Conclusions
Administering a COVID-19 vaccine not designed for the Omicron variant >6 months after prior infection or vaccination protects against Omicron variant infection. There is no advantage to administering more than 1 dose of vaccine to previously infected persons.
Rita W. Y. Ng et al.
Cross-Clade Memory Immunity in Adults Following SARS-CoV-1 Infection in 2003
JAMA, December 2022; doi:10.1001/jamanetworkopen.2022.47723
Abstract
Importance Knowledge of the longevity and breath of immune response to coronavirus infection is crucial for the development of next-generation vaccines to control the COVID-19 pandemic.
Objectives To determine the profile of SARS-CoV-2 antibodies among persons infected with the closely related virus, SARS-CoV-1, in 2003 (SARS03 survivors) and to characterize their antibody response soon after the first and second doses of COVID-19 vaccines.
Design, Setting, and Participants This prospective cohort study examined SARS-CoV-2 antibodies among SARS03 survivors compared with sex- and age-matched infection-naive controls. Participants received the COVID-19 vaccines between March 1 and September 30, 2021.
Interventions One of the 2 COVID-19 vaccines (inactivated [CoronaVac] or messenger RNA [BNT162b2]) available in Hong Kong. Two doses were given according to the recommended schedule. The vaccine type administered was known to both participants and observers.
Main Outcomes and Measures SARS-CoV-2 antibodies were measured prevaccination, 7 days after the first dose, and 14 days after the second dose.
Conclusions and Relevance The findings of this prospective cohort study suggest that infection with SARS-CoV-1 was associated with detectable levels of antibodies that cross-react and cross-neutralize SARS-CoV-2, which belongs to a distinct clade under the same subgenus Sarbecovirus. These findings support the development of broadly protective vaccines to cover sarbecoviruses that caused 2 devastating zoonotic outbreaks in humans over the last 2 decades.
