Determining the immunological basis for weakened SARS-CoV-2 vaccination outcomes

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The goal of this study is to understand how effective post COVID-19 vaccine responses are and how long they last. Specifically, we will investigate this in people with compromised immune systems because early reports suggest they make very poor responses to COVID-19 vaccines. These people are often also the most at risk of severe disease if they develop COVID-19 so our work will inform future recommendations/policy on how to protect these vulnerable people. Beyond individual benefit, it is important to understand why some people make less effective vaccine responses to control the spread of the virus in the population. This is because, weak vaccine responses mean they may be more likely to catch and transmit the virus thus keeping it in circulation and potentially leading to emergence of additional variants. We will complete two aims by looking at individuals across a spectrum of immune function: healthy volunteers, people living with HIV (who have predominantly T cell deficiencies) and people with B cell malignancies (who have mainly had treatment that drastically reduces their B cell numbers). Firstly we will evaluate the vaccine responses in their blood and rank their effectiveness. We will then link this to data on how well their immune cells (B, T and NK cells in particular) are performing to understand what the immunological profile is of someone who makes a poor vaccine response. Secondly, we will attempt to understand whether some people's vaccine responses are less able to cope with variant viruses. We will do this by looking at diversity and resilience within their B cells, which make antibodies, and by examine how the T and NK cells respond to virus and cooperate to help B cells make antibody. Our findings will inform policy regarding the best frequency of variant boosters and whether a full course of vaccination or single boost is needed based on how severely a person's immune system has been compromised not based solely on their clinical diagnosis.