Arms race between viral evolution and population immunity - Understanding the impact of antibody pressure on SARS-CoV-2 variants and human endemic coronaviruses.

BackgroundImmense scientific progress has been made during the Covid-19 pandemic, but the future of SARS-CoV-2 remains unpredictable. With the emergence of the Omicron variant of concern (VOC) a new phase of the pandemic was entered. Although genomic surveillance could identify the strongly mutated Omicron quickly, only biological experiments could demonstrate an altered viral phenotype compared to earlier VOCs: A novel SARS-CoV-2 serotype of unknown origin with strong immune-escape from antibodies derived by earlier infection, vaccination and even hybrid immunity. Since then, high infection activity from Omicron BA.1, BA.2 and BA.5 were observed, with negative impacts on health and economy. Within a short time, a very high viral diversity within the Omicron clade developed but with heterogeneous geographical patterns. This suggests that viral evolution towards new variants is currently mainly driven by underling immunity, that is now a heterogeneous background of immunity to earlier variants, vaccination, and breakthrough (re-) infections. An increase in SARS-CoV-2 population immunity may even impact endemic coronaviruses by the same mechanism of immune pressure.Project & AimsIn the proposed project, I will build on work of the last 2.5 years on phenotypic characterization of SARS-CoV-2 and in vivo risk assessment of variants, including earlier experience of complex culture models and research on coronaviruses other than SARS-CoV-2.In this proposal I will focus on 1.) Emergence of immune escape properties in vivo in contemporary SARS-CoV-2 isolates through evolutionary pressure mediated by antibodies derived from prior infection with various VOCs, vaccination and hybrid immunity. We will sequentially passage virus isolates on primary human airway cultures in presence of anti-SARS-CoV-2 antibodies derived from characterized convalescent, post-vaccine and hybrid-immune sera. Isolates of all passages will be fully sequenced to see development of mutations. They will be phenotypically assessed for neutralization by sera representing the complexity of current population immunity (unvaccinated Omicron-exposure, vaccination, multi-exposure after vaccination and reinfection). In addition, we will assess replicative capacity in human primary airway cultures. We will compare them to naturally arising immune escape variants or selected recombinant viruses 2). Intra-host evolution of SARS-CoV-2 in chronically infected patients including their phenotypic characterization as one scenario of evolution of immune escape variants 3.) Intra- and post-pandemic evolution of endemic human coronaviruses (HCoVs) through immune pressure from SARS-CoV-2 immunity and/or disruption in transmission during the pandemic. Pre-, intra and post-pandemic HCoVs will be sequenced and isolated to assess for immune escape by neutralization assays.Impact & RationaleThe transition phase from a pandemic to an endemic state is characterized by the arms race between increasing population immunity and viral evolution. Developing in vitro models to understand the evolution of immune escape is a forward-oriented approach, rather than just assessing new variants when they emerge. The coming years offer a once-in-a lifetime opportunity for a virologist to observe the establishment of a new human virus into the human population, including a possible impact on related viruses. Due to ongoing collection of virus isolates and serum panels, access to patient cohorts and continuous genomic surveillance for SARS-CoV-2 and HCoVs, our Centre is in an ideal position to study this.