An immunogenetic approach to guide the need for booster shots and combat immune failure in SARS-CoV-2 vaccine response

Vaccination has been hugely impactful in control of the current COVID-19 pandemic. However, in a significant proportion of individuals, the immune response to vaccination is insufficient to control SARS-CoV-2 and this may be exacerbated with viral variants of concern. To establish the optimal strategy for booster vaccination, we propose a programme of work that will advance our ability to identify individuals who have, or are at risk of mounting, a low response to COVID-19 vaccination; to understand the underlying heritable, molecular and immunological mechanisms for this response; and whether booster dose vaccination can mitigate a dampened immune response. To deliver this, we propose a collaborative, multi-disciplinary and multi-centre approach. We will work with the National COVID-19 Infection Survey to contact individuals in the general UK population with extremes of antibody responsiveness to vaccination and map genetic associations with response. This will deliver specific predictive genetic biomarkers that can help identify at risk individuals and populations and reveal novel insights into mechanism of poor vaccine response. Complementing this genetic analysis, we will investigate the role of clonal hematopoiesis of indeterminate potential and of epigenetics. We will determine the effect of booster vaccination in poor responders to facilitate multivariate analysis of the immune response and help identify associated immune correlates. The project deliverables will directly impact and inform vaccine policy and rollout.