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

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.

COVID-19 vaccine efficacy in people living with HIV (PLWH) and other immunosuppressive conditions such as B cell malignancies remains poorly evaluated. The objective of this study is to establish the quality and durability of responses to inform future recommendations/policy. Optimisation of vaccine responses will maximise protection against disease and new emerging variants in this vulnerable population. In this study we will use our combined expertise and well curated longitudinal cohorts of clinical samples to: 1. Perform an integrated analysis of innate and adaptive components of the immune responses and dynamic changes post vaccination to allow stratification of functional anti-SARS-CoV-2 responses regardless of clinical drivers. 2. Determine mechanistically why these inferior responses occur by testing the hypothesis that breadth is limited by inefficient B cell recall (assessed by BCR sequencing of spike-reactive B cells) due to sub-optimal T cell help and/or excessive NK cell regulation. To achieve these aims we have available samples pre and post vaccination from a well-characterised longitudinal cohort of HIV negative (n>100), PLWH) (n>100), and patients with B cell malignancies (n>70). In addition, we are uniquely placed to sample additional PLWH with suboptimal responses to vaccination through the current SARS-CoV-2 seroprevalance study (>1500 participants). Our approach is to investigate extreme ends of the immunosuppression spectrum by investigating mild to severe T cell impairment (PLWH) and major B cell dysfunction during malignancy. This will yield data to allow informed vaccination choices/boosters based on immunological phenotype rather than clinical presentation, facilitating translation of these results beyond the study populations.