Monitoring antibody protection against SARS-CoV-2 variants

Vaccines were rapidly developed following the SARS-CoV-2 pandemic, and the protection from infection and more importantly from severe disease they afford has saved may lives. Antibody responses to the spike protein following vaccination or natural infection are believed, along with T cell responses to mediate protection. Since its emergence in late 2019 the SARS-CoV-2 virus has undergone significant evolutionary change and the spike protein is a hotspot for mutations. Successive waves of new variants have dominated infections and then been replaced by new strains. Mutations in spike occur in regions crucial for the binding of antibodies, induced by vaccination and infection, rendering them less able to neutralise the virus and prevent infection. There is thus a huge selective pressure for the SARS-CoV-2 virus to continue to evolve and escape immune responses in order to maintain infectious cycles in the human population, many of whom have received multiple vaccines and natural infections.
It is now clear that SARS-CoV-2 is established in humans and will be present for the long term. This programme of work aims to study the continued evolution of the virus and its ability to escape the immune response. Our findings will aid the assessment of the risk that newly emerging variants pose, the choice of future vaccines for vulnerable populations and may lead to the development of monoclonal antibody theraies.

Since its emergence in Wuhan in late 2019 there has been considerable mutational change in the SARS-CoV-2 spike sequence. A particular hotspot is in the receptor binding domain, responsible for binding to the cellular receptor ACE2. Some of these changes can increase ACE2 affinity perhaps increasing viral transmissibility, but many are likely selected because they mutate the binding sites for potent neutralising antibodies. In the case of Omicron the accrual of around 30 mutations in spike led to large reductions in the neutralisation titres of serum obtained from vaccinated or naturally immune individuals. Since the arrival of Omicron the evolution of SARS-CoV-2 has continued at pace and seems driven by the need to escape preexisting antibody responses to maintain infectious cycles in the human population, while maintaining affinity to ACE2, a prerequisite to initiate the infectious cycle. In this programme we propose to continue monitoring the emergence of new variants, assess their potential to escape the immune response and to interrogate the antibody response induced by infection and vaccination in detail through the generation of monoclonal antibodies.