Responding to an Evolving Pandemic: Characterisation of Emerging Evolving Viruses and Population Immunity by the Example of SARS-CoV-2

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.

Gates Cambridge Trust