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

Vaccination has been highly successful in helping to control the current COVID-19 pandemic. However some individuals have less protection from vaccination as their immune system fails to generate a strong response to the vaccine. This occurs more commonly in older people, when you have other illnesses or a weakened immune system for other reasons. However our knowledge of why this happens is incomplete and we urgently need to gain this understanding to better target use of booster vaccinations to those who will most benefit. To address this, researchers at the University of Oxford, the Office for National Statistics, Public Health England, The Pirbright Institute and the University of Edinburgh are investigating whether inherited factors are involved in determining an individual's response, and studying the nature of our immune response to vaccination in poor responder individuals. This programme of work brings together geneticists, immunologists, virologists, epidemiologists, public health experts and clinical trialists in a collaborative team. The researchers will be inviting participants in the National COVID-19 Infection Survey to take part in the research as well as those who have had the Oxford-AstraZeneca vaccine in clinical trials. The genetic analysis will include looking at single letter differences in the DNA as well as the chemical modifications that can occur to the DNA sequence following infection or other environmental exposures. The immunological analysis will focus on our antibody response to the virus, ability to kill the virus and we will test if a booster vaccination helps these individual's response. The research design and delivery will involve patient and participant representatives, and findings will be communicated to lay audiences and the public. The results of the study will be used to inform vaccine policy and rollout.

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.