Several studies have shown that SARS-CoV-2 BA.1 omicron is an immune escape variant. Meanwhile, however, omicron BA.2 and BA.5 became dominant in many countries and replaced BA.1. As both have several mutations compared to BA.1, we analyzed whether BA.2 and BA.5 show further immune escape relative to BA.1. Here, we characterized neutralization profiles against the BA.2 and BA.5 omicron sub-variants in plasma samples from individuals with different history of exposures to infection/vaccination and found that unvaccinated individuals after a single exposure to BA.2 had limited cross-neutralizing antibodies to pre-omicron variants and to BA.1. Consequently, our antigenic map including all Variants of Concern and BA.1, BA.2 and BA.5 omicron sub-variants, showed that all omicron sub-variants are distinct to pre-omicron variants, but that the three omicron variants are also antigenically distinct from each other. The antibody landscapes illustrate that cross-neutralizing antibodies against the current antigenic space, as described in our maps, are generated only after three or more exposures to antigenically close variants but also after two exposures to antigenically distant variants. Here, we describe the antigenic space inhabited by the relevant SARS-CoV-2 variants, the understanding of which will have important implications for further vaccine strain adaptations.
Several COVID-19 vaccines have been approved. The mRNA vaccine from Pfizer/BioNTech (Comirnaty, BNT162b2; BNT) and the vector vaccine from AstraZeneca (Vaxzevria, ChAdOx1; AZ) have been widely used. mRNA vaccines induce high antibody and T cell responses, also to SARS-CoV-2 variants, but are costlier and less stable than the slightly less effective vector vaccines. For vector vaccines, heterologous vaccination schedules have generally proven more effective than homologous schedules.
Abstract We investigated antibody titers and avidity after heterologous versus homologous coronavirus disease 2019 vaccination over 6 months after the second dose. We found a significantly higher avidity in regimens including at least 1 dose of the adenoviral vector vaccine ChAdOx1-S compared with 2 doses of the mRNA vaccine BNT162b2.
Complementing the adult seroprevalence data collected at the time of the rapid SARS-CoV-2 mass vaccination in the district of Schwaz in 2021, we set out to establish the seroprevalence of SARS-CoV-2 among the pediatric population of the district. A total of 369 children, mean age 9.9 (SD 3.4), participated in the study, answering a structured questionnaire on the history of SARS-CoV-2 infection, household contacts, symptoms and history of vaccination. We determined binding and neutralizing antibody levels using plasma samples provided. We estimated the overall prevalence of SARS-CoV-2 infection in the general pediatric population at the time of the study using the census data from Statistik Austria and daily reports of officially confirmed cases. Excluding study participants who reported a history of PCR-confirmed infection, the age-standardized seroprevalence of previously unknown SARS-CoV-2 infection among the general pediatric population of the district was 27% (95% CI: 26.1–27.8). Adding this to the officially documented cases, the true overall prevalence was 32.8% (95% CI: 31.9–33.6) in contrast to the officially documented 8.0% (95% CI: 7.5–8.5) by June 2021. This translated into a proportion of 75.7% (95% CI: 74.4–77.0) of cases being officially undocumented, suggesting a high extent of silent SARS-CoV-2 infections in the pediatric population and possibly silent transmission.
Abstract It is uncertain to which extent antibody and T-cell responses after vaccination against SARS-CoV-2 are associated with reduced risk of breakthrough infection and whether their measurement enhances risk prediction. We conducted a phase-4 open-label clinical trial in the pre-omicron era, enrolling 2,760 individuals aged ≥16 years 35±8 days after having received the second dose of BNT162b2 (baseline 15-21 May 2021). Over a median 5.9-month of follow-up, we identified incident SARS-CoV-2 breakthrough infections using weekly antigen tests, a confirmatory PCR test, and/or serological evidence for incident infection. We quantified relative risks adjusted for age, sex, and prior SARS-CoV-2 infection for different immunological parameters and assessed improvements in risk discrimination. In contrast to the T-cell response, higher plasma levels of binding antibodies and antibodies in a surrogate neutralization assay were associated with reduced risk of breakthrough infection. Furthermore, assessment of anti-spike IgG levels enhanced prediction of breakthrough infection and may therefore be a suitable measurable correlate of protection in practice.
In order to curb the rapid dissemination of the B.1.351 variant of SARS-CoV-2 in the district of Schwaz and beyond, the EU allocated additional vaccine doses at the beginning of March 2021 to implement a rapid mass vaccination of the population (16+). The aim of our study was to determine the seroprevalence of SARS-CoV-2 among the adult population in the district of Schwaz at the time of the implementation. Data on previous history of infections, symptoms and immunization status were collected using a structured questionnaire. Blood samples were used to determine SARS-CoV-2 specific anti-spike, anti-nucleocapsid and neutralizing antibodies. We recruited 2,474 individuals with a median age (IQR) of 42 (31-54) years. Using the official data on distribution of age and sex, we found a standardized prevalence of undocumented infections at 15.0% (95% CI: 13.2-16.7). Taken together with the officially documented infections, we estimated that 24.0% (95% CI: 22.5-25.6) of the adult population had prior SARS-CoV-2 infection. Hence, the proportion of undocumented infections identified by our study was 55.8% (95% CI: 52.7-58.5). With a vaccination coverage of 10% among the adults population at that time, we imply that a minimum of two-thirds of the target popuation was susceptible to the circulating threat when this unique campaign started.
BackgroundCorrelates of protection could help to assess the extent to which a person is protected from SARS-CoV-2 infection after vaccination (so-called breakthrough infection). We aimed to clarify associations of antibody and T-cell responses after vaccination against COVID-19 with risk of a SARS-CoV-2 breakthrough infection and whether measurement of these responses enhances risk prediction.MethodsWe did an open-label, phase 4 trial in two community centres in the Schwaz district of the Federal State of Tyrol, Austria, before the emergence of the omicron (B.1.1.529) variant of SARS-CoV-2. We included individuals (aged ≥16 years) a mean of 35 days (range 27–43) after they had received a second dose of the BNT162b2 (Pfizer–BioNTech) COVID-19 vaccine. We quantified associations between immunological parameters and breakthrough infection and assessed whether information on these parameters improves risk discrimination. The study is registered with the European Union Drug Regulating Authorities Clinical Trials Database, 2021-002030-16.Findings2760 individuals (1682 [60·9%] female, 1078 [39·1%] male, mean age 47·4 years [SD 14·5]) were enrolled into this study between May 15 and May 21, 2021, 712 (25·8%) of whom had a previous SARS-CoV-2 infection. Over a median follow-up of 5·9 months, 68 (2·5%) participants had a breakthrough infection. In models adjusted for age, sex, and previous infection, hazard ratios for breakthrough infection for having twice the immunological parameter level at baseline were 0·72 (95% CI 0·60–0·86) for anti-spike IgG, 0·80 (0·70–0·92) for neutralising antibodies in a surrogate virus neutralisation assay, 0·84 (0·58–1·21) for T-cell response after stimulation with a CD4 peptide pool, and 0·77 (0·54–1·08) for T-cell response after stimulation with a combined CD4 and CD8 peptide pool. For neutralising antibodies measured in a nested case-control sample using a pseudotyped virus neutralisation assay, the corresponding odds ratio was 0·78 (0·62–1·00). Among participants with previous infection, the corresponding hazard ratio was 0·73 (0·61–0·88) for anti-nucleocapsid Ig. Addition of anti-spike IgG information to a model containing information on age and sex improved the C-index by 0·085 (0·027–0·143).InterpretationIn contrast to T-cell response, higher levels of binding and neutralising antibodies were associated with a reduced risk of breakthrough SARS-CoV-2 infection. The assessment of anti-spike IgG enhances the prediction of incident breakthrough SARS-CoV-2 infection and could therefore be a suitable correlate of protection in practice. Our phase 4 trial measured both humoral and cellular immunity and had a 6-month follow-up period; however, the longer-term protection against emerging variants of SARS-CoV-2 remains unclear.FundingNone.
Abstract Background Several studies have shown that SARS-CoV-2 BA.1 omicron is an immune escape variant and current vaccines and infection with pre-omicron variants provide limited protection against BA.1. Meanwhile, however, omicron BA.2 has become the dominant variant in many countries and has replaced BA.1. As BA.2 has several mutations especially in the receptor binding and the N terminal domain compared to BA.1, we analyzed whether BA.2 shows further immune escape relative to BA.1. Methods We characterized neutralization profiles against the new BA.2 omicron variant in plasma samples from a variety of individuals with different numbers of exposures to infection/vaccination, including samples from previously virus-naïve, BA.2 omicron-infected individuals. To illustrate antigenic differences of the two omicron sub-variants and pre-omicron variants we performed antigenic cartography and generated antibody landscapes. Results Unvaccinated individuals after a single exposure to BA.2 had limited cross-neutralizing antibodies to pre-omicron variants and to BA.1. Consequently, our antigenic map, which included all Variants of Concern and both BA.1 and BA.2 omicron sub-variants, showed that both omicron sub-variants are distinct to pre-omicron variants, but that the two omicron variant are also antigenically distinct from each other. The antibody landscapes illustrate that cross-neutralizing antibodies against the whole antigenic space, as described in our maps, are generated only after three or more exposures to antigenically close variants but also after two exposures to antigenically distinct variants. Conclusions Here, we describe the antigenic space inhabited by the relevant SARS-CoV-2 variants, the understanding of which will have important implications for further vaccine strain adaptations.
In response to a large outbreak of the SARS-CoV-2 Beta (B.1.351) variant in the district Schwaz, Austria, a rapid mass vaccination campaign with BNT162b2 was carried out in spring 2021, immunizing more than 70% of the adult population within one week. Subsequent analysis revealed that the mass vaccination was associated with a significant reduction in new SARS-CoV-2 infections compared to control districts. Here, we aimed to evaluate both SARS-CoV-2-specific T- and B-cell responses at 35 ± 8 and 215 ± 7 days after the second dose in 600 study subjects who participated at both time points. Overall, a robust antibody and T-cell response was measured at day 35, which waned over time. Nevertheless, all persons preserved seropositivity and T cell response could still be detected in about half of the participants at day 215. Further, antibody response correlated negatively with age; however, in persons who experienced SARS-CoV-2 infection prior to study enrolment, the serum levels of both S- and N-specific antibodies surprisingly increased with age. In contrast, there was no correlation of T cell response with age. We could not detect any sex-related difference in the immune responses. SARS-CoV-2 infections prior to study enrolment or incident infections before day 215 resulted in higher antibody levels and T cell responses at day 215 compared to study participants with no history of infection. Collectively, our data support that vaccination with BNT162b2 against COVID-19 provides a durable immune response and emphasize the usefulness of vaccination even after a natural infection.
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