Longitudinal Humoral and Cell-Mediated Immune Responses in a Population-Based Cohort in Zurich, Switzerland between March and June 2022 - Evidence for Protection against Omicron SARS-CoV-2 Infection by Neutralizing Antibodies and Spike-specific T cell responses (preprint)

Background: The correlate(s) of protection against SARS-CoV-2 remain incompletely de-fined. Additional information regarding the combinations of antibody and T cell-mediated immunity which can protect against (re)infection are needed. Methods: We conducted a population-based, longitudinal cohort study including 1044 individuals of varying SARS-CoV-2 vaccination and infection statuses. We assessed Spike (S)- and Nucleocapsid (N)-IgG and wildtype, delta, and omicron neutralizing antibodies. In a subset of 328 individuals, we evaluated S, Membrane (M) and N-specific T cells. 3 months later, we reassessed antibody (n=964) and T cell (n=141) responses and evaluated factors associated with protection from (re)infection. Results: At study start, >98% of participants were S-IgG seropositive. N-IgG and M/N-T cell responses increased over time, indicating viral (re)exposure, despite existing S-IgG. Com-pared to N-IgG, M/N-T cells were a more sensitive measure of viral exposure. N-IgG titers in the top 33% of participants, omicron neutralizing antibodies in the top 25%, and S-specific T cell responses were all associated with reduced likelihood of (re)infection over time. Conclusions: Population-level SARS-CoV-2 immunity is S-IgG-dominated, but heterogenous. M/N T cell responses can distinguish previous infection from vaccination, and monitoring a combination of N-IgG, omicron neutralizing antibodies and S-T cell responses may help estimate protection against SARS-CoV-2 (re)infection.

Distinct immune signatures discriminate SARS-CoV-2 vaccine combinations (preprint)

Several vaccines have been found effective against COVID-19, usually administered in homologous regimens, with the same vaccine used for the prime and boost doses. However, recent studies have demonstrated improved protection via heterologous mix-and-match COVID-19 vaccine combinations, and a direct comparison among these regimens is needed to identify the best employment strategies. Here, we show a single-cohort comparison of changes to the humoral and cellular immune compartments following five different COVID-19 vaccines spanning three technologies (adenoviral, mRNA and inactivated vaccines). These vaccines were administered in a combinatorial fashion, resulting in sixteen different homologous and heterologous regimens. SARS-CoV-2-targeting antibody titres were highest when the boost dose consisted of mRNA-1273, independent of the vaccine used for priming. Priming with BBIBP-CorV induced less class-switching among spike-binding memory B cells and the highest antigen-specific T cell responses in heterologous combinations. These were generally more immunogenic in terms of specific antibodies and cellular responses compared to homologous regimens. Finally, single-cell analysis of 754 samples revealed specific B and T cell signatures of the vaccination regimens, indicating distinctive differences in the immune responses. These data provide new insights on the immunological effects of COVID-19 vaccine combinations and a framework for the design of improved vaccination strategies for other pathogens and cancer.