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

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.