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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. SARS-CoV-2 omicron variant BA.1 has shown increased transmissibility and immune escape, relative to previous SARS-CoV-2 variants. In this study, authors utilise antigenic cartography to characterise the neutralisation profiles of omicron sub-lineages, BA.2 and BA.5, in comparison to BA.1 and pre-omicron variants.

Since emergence of the initial SARS-CoV-2 BA.1, BA.2 and BA.5 variants, Omicron has diversified substantially. Antigenic characterization of these new variants is important to analyze their potential immune escape from population immunity and implications for future vaccine composition. Here, we describe an antigenic map based on human single-exposure sera and live-virus isolates that includes a broad selection of recently emerged Omicron variants such as BA.2.75, BF.7, BQ, XBB and XBF variants. Recent Omicron variants clustered around BA.1 and BA.5 with some variants further extending the antigenic space. Based on this antigenic map we constructed antibody landscapes to describe neutralization profiles after booster immunization with bivalent mRNA vaccines based on ancestral virus and either BA.1 or BA.4/5. Immune escape of BA.2.75, BQ, XBB and XBF variants was also evident in bivalently boosted individuals, however, cross-neutralization was improved for those with hybrid immunity. Our results indicate that future vaccine updates are needed to induce cross-neutralizing antibodies against currently circulating variants. Antigenic characterization of new SARS-CoV-2 variants is important to evaluate population immunity and the need for vaccine updates. Here, neutralizing antibodies against newly emerged Omicron variants were analysed in bivalently boosted individuals.

The rapid spread of the Omicron BA.1 (B.1.1.529.1) SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) variant in 2021 resulted in international efforts to quickly assess its escape from immunity generated by vaccines and previous infections. Numerous laboratories published BA.1 neutralization data as preprints and reports. We collated this data in real time and regularly presented updates of the aggregated results in US, European and WHO research and advisory settings. Here, we retrospectively analyzed the accuracy of these aggregations from 85 different sources published during a time period from 2021/12/08 up to 2022/08/14. We found that the mean titer fold change from wild type-like variants to BA.1, a standard measure of a variant’s immune escape, remained stable after the first 15 days of data reporting in people who were twice vaccinated, and incoming data increased the confidence in this quantity. Further, it is possible to build reliable, stable antigenic maps from this collated data already after one month of incoming data. We here demonstrate that combining early reports from variable, independent sources can rapidly indicate a new virus variant’s immune escape and can therefore be of immense benefit for public health.

Antigenic characterization of newly emerging SARS-CoV-2 variants is important to assess their immune escape and judge the need for future vaccine updates. To bridge data obtained from animal sera with human sera, we analyzed neutralizing antibody titers in human and hamster single infection sera in a highly controlled setting using the same authentic virus neutralization assay performed in one laboratory. Using a Bayesian framework, we found that titer fold changes in hamster sera corresponded well to human sera and that hamster sera generally exhibited higher reactivity.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the human population in 2019 presented extraordinary challenges to the scientific community, and at the same time unique opportunities. Following the evolution of a novel human virus, together with the development of population immunity against it, allowed us to test knowledge acquired through decades of influenza virus research on SARS-CoV-2. In this thesis, I will describe how I used computational methods developed for the antigenic characterisation of influenza virus to answer scientific and public health questions about SARS-CoV-2's evolution and population immunity, from the achievement of protection with the original vaccine designed against the ancestral Wuhan strain to a time when vaccine strain updates became standard practice for SARS-CoV-2. Antigenic cartography is an integral tool for influenza virus characterisation and vaccine strain selection. In this thesis, I demonstrate its suitability for mapping the evolution of SARS-CoV-2 virus variants from the Wuhan strain of 2019 up to Variants of Concern (VoC) in 2024. I show Omicron variants as the first vaccine escape variants, and that subsequently emerging variants further escaped prior immunity. With SARS-CoV-2's antigenic evolution, its ability to escape immunity elicited by exposures to previously circulating strains, came the need to update the vaccine composition. I show that information on a variant's vaccine escape ability can be obtained rapidly from summarising publicly available data, giving a timely advantage to public health decisions. I further describe early evidence of the benefit of exposure to antigenically distant SARS-CoV-2 strains on the breadth of antibody neutralisation, as well as results from a controlled clinical trial that contributed to the first SARS-CoV-2 vaccine strain update. Mapping immunity after the vaccine strain update together with variant circulation at the time revealed the escape of these variants from updated vaccine-elicited immunity, and that SARS-CoV-2 vaccines will need to be repeatedly updated like influenza vaccines. Additionally, I found that immunity against earlier circulating strains was backboosted after exposure to an antigenically evolved strain, as was previously described for influenza. The need for animal models to characterise SARS-CoV-2's ongoing evolution became urgent when it transitioned from a pandemic to an endemic. I used Bayesian modelling and antigenic cartography to show that both hamster and nonhuman primate sera correspond well with human single exposure sera, and that samples from both animals can substitute human samples for antigenic cartography in the future. This thesis provides practical examples for responding to an evolving pandemic, from its early pandemic stages to its endemic phase. Key to the successful response to SARS-CoV-2 was global collaboration, open science and cooperation of scientists and policy makers. SARS-CoV-2 was not stopped by political borders, and neither will the next pandemic.

Previous exposure to one severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant influences neutralizing antibody responses induced by subsequent exposures. Consecutive exposures predominantly back-boost pre-existing immunity and expand cross-neutralizing antibodies while de novo variant-specific responses are poorly induced. In this study, we analyzed neutralizing antibodies against a panel of variants in plasma samples from individuals after exactly two exposures: twice pre-Omicron variant (either two dose vaccinated or infected and one dose vaccinated), pre-Omicron followed by early Omicron variant, or twice early Omicron variant. We found that exposure to two antigenically distinct variants, either pre-Omicron followed by Omicron or two different Omicron variants, increased the neutralization breadth. However, no significant cross-neutralization against the genetically closely related human coronavirus SARS-CoV was induced. Using depletion experiments, we showed that the first exposed variant strongly influences the specificity of antibodies. The second exposure primarily expanded cross-reactive antibodies rather than inducing a variant-specific response against the later variant, highlighting the phenomenon of immune imprinting in the context of SARS-CoV-2. Overall, our results indicate that multiple exposures to SARS-CoV-2 improve cross-neutralization against a variety of variants, but also underscore the lack of de novo antibody production against the more recently encountered variant.

The rapid spread of the Omicron BA.1 (B.1.1.529.1) SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) variant in 2021 resulted in international efforts to quickly assess its escape from immunity generated by vaccines and previous infections. Numerous laboratories published BA.1 neutralization data as preprints and reports. We collated this data in real time and regularly presented updates of the aggregated results in US, European and WHO research and advisory settings. Here, we retrospectively analyzed the accuracy of these aggregations from 85 different sources published during a time period from 2021/12/08 up to 2022/08/14. We found that the mean titer fold change from wild type-like variants to BA.1, a standard measure of a variant's immune escape, remained stable after the first 15 days of data reporting in people who were twice vaccinated, and incoming data increased the confidence in this quantity. Further, it is possible to build reliable, stable antigenic maps from this collated data already after one month of incoming data. We here demonstrate that combining early reports from variable, independent sources can rapidly indicate a new virus variant's immune escape and can therefore be of immense benefit for public health.Competing Interest StatementThe authors have declared no competing interest.Footnotes* The manuscript was updated to include a retrospective analysis of the incoming data to show how soon after variant emergence escape measures, such as fold change from wild type titers, approach a level of certainty relevant for public health guidance. In addition, data up to August 2022 was used. All figures and text were updated accordingly.* https://docs.google.com/spreadsheets/d/1IvUwoWMAtJULnN-pohUoPio0RmHZIRj8OTtv9r4RFl4/edit?gid=0#gid=0

The antigenic evolution of SARS-CoV-2 requires ongoing monitoring to judge the immune escape of newly arising variants. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal sera. We compared 18 datasets generated using human, hamster, and mouse sera, and six different neutralization assays. Titer magnitude was lowest in human, intermediate in hamster, and highest in mouse sera. Fold change, immunodominance patterns and antigenic maps were similar among sera. Most assays yielded similar results, except for differences in fold change in cytopathic effect assays. Not enough data was available for conclusively judging mouse sera, but hamster sera were a consistent surrogate for human first-infection sera.

During the SARS-CoV-2 pandemic, multiple variants escaping pre-existing immunity emerged, causing concerns about continued protection. Here, we use antigenic cartography to analyze patterns of cross-reactivity among a panel of 21 variants and 15 groups of human sera obtained following primary infection with 10 different variants or after mRNA-1273 or mRNA-1273.351 vaccination. We find antigenic differences among pre-Omicron variants caused by substitutions at spike protein positions 417, 452, 484, and 501. Quantifying changes in response breadth over time and with additional vaccine doses, our results show the largest increase between 4 weeks and >3 months post-2nd dose. We find changes in immunodominance of different spike regions depending on the variant an individual was first exposed to, with implications for variant risk assessment and vaccine strain selection.

Antigenic characterization of newly emerging SARS-CoV-2 variants is important to assess their immune escape and judge the need for future vaccine updates. As exposure histories for human sera become more and more complex, animal sera may provide an alternative for antigenic characterization of new variants. To bridge data obtained from animal sera with human sera, we here analyzed neutralizing antibody titers in human and hamster first infection sera in a highly controlled setting using the same live-virus neutralization assay performed in one laboratory. Using a Bayesian framework, we found that titer fold changes in hamster sera corresponded well to human sera and that hamster sera generally exhibited higher reactivity. Our results indicate that sera from infected hamsters are a good surrogate for the antigenic characterization of new variants.