Examining the association of live virus neutralisation activity of capillary microsamples and risk of SARS-CoV-2 infections: a nested case control study within the Virus Watch community cohort (preprint)

Due to the proliferation of new SARS-CoV-2 variants, most COVID-19 cases are now caused by post-vaccine infections and a substantial proportion are reinfections. While prior research on correlates of protection has focused on the role of anti-spike antibodies, the results of the corresponding antibody assays may not accurately predict the risk of infection with new SARS-CoV-2 variants. In this study, we investigated the association between live virus neutralising antibody activity and SARS-CoV-2 infection risk using self-administered capillary microsample blood tests from VirusWatch participants. The study was conducted during the transition between the dominance of the B.1.617.2 (Delta) and B.1.1.529 (Omicron BA.1) SARS-CoV-2 variants, enabling us to investigate the association between variant-specific virus inhibition and subsequent infections within each dominance period. Greater inhibition of Omicron BA.1 live virus was associated with a reduction in infection risk during both the Delta and Omicron BA.1 dominance periods. Delta virus inhibition was associated with infection risk reduction during the Delta dominance period, but we found no association between Delta inhibition and protection against infection during the Omicron BA.1 dominance period. Our results are consistent with earlier findings and suggest that variant-specific serosurveillance of immunity and protection against SARS-CoV-2 infection at the population level could inform public health policy in near-real time using inexpensive and accessible home-based testing.

Dichotomy of neutralizing antibody, B cell and T cell responses to SARS-CoV-2 vaccination and protection in healthy adults (preprint)

Heterogeneity in SARS-CoV-2 vaccine responses is not understood. Here, we identify four patterns of live-virus neutralizing antibody responses: individuals with hybrid immunity (with confirmed prior infection); rare individuals with low responses (paucity of S1-binding antibodies); and surprisingly, two further groups with distinct serological repertoires. One group - broad responders - neutralize a range of SARS-CoV-2 variants, whereas the other - narrow responders - neutralize fewer, less divergent variants. This heterogeneity does not correlate with Ancestral S1-binding antibody, rather the quality of the serological response. Furthermore, IgDlowCD27-CD137+ B cells and CCR6+ CD4+ T cells are enriched in broad responders before dose 3. Notably, broad responders have significantly longer infection-free time after their third dose. Understanding the control and persistence of these serological profiles could allow personalized approaches to enhance serological breadth after vaccination.

CD4+ and CD8+ T cell and antibody correlates of protection against Delta vaccine breakthrough infection: A nested case-control study within the PITCH study (preprint)

T cell correlates of protection against SARS-CoV-2 infection after vaccination ('vaccine breakthrough') are incompletely defined, especially the specific contributions of CD4+ and CD8+ T cells. We studied 279 volunteers in the Protective Immunity from T Cells in Healthcare Workers (PITCH) UK study, including 32 cases (with SARS-CoV-2 positive testing after two vaccine doses during the Delta-dominant era) and 247 controls (no positive test nor anti-nucleocapsid seroconversion during this period). 28 days after second vaccination, before all breakthroughs occurred, cases had lower ancestral S- and RBD-specific immunoglobulin G titres and S1- and S2-specific T cell interferon gamma (IFN{gamma}) responses compared with controls. In a subset of matched cases and controls, cases had lower CD4+ and CD8+ IFN{gamma} and tumour necrosis factor responses to Delta S peptides with reduced CD8+ responses to Delta versus ancestral peptides compared with controls. Our findings support a protective role for T cells against Delta breakthrough infection.