Immunological responses to pan-CoV vaccines

Summary The pan-coronavirus vaccine (PanCoVac) consortium will develop novel coronavirus vaccines that can provide protection against a range of coronaviruses. Research Project 1 (RP1, 'Design and evaluation of pan- CoV vaccines') will develop novel coronavirus antigens and test them in pre-clinical animal models. Research Project, RP2, will test the 'Immunological Responses to pan-CoV vaccines', including a detailed analysis of B and T cell responses in mice immunized with antigens developed in RP1 and formulated into a vaccine platform. In Aim 1 ('Provide a panel of well-characterized antibodies cross-reacting or specific to various coronavirus strains'), human monoclonal antibodies (mAbs) cloned from the B cells from COVID-19 patients will be generated and characterized for activity against various coronaviruses. The functional and structural characterization will be carried out in collaboration with investigators in RP1. The characterized mAbs will be provided to RP1 to test novel antigens. The goal is to identify novel antigens that maintain key cross-reactive epitopes while strain-specific immunodominant epitopes are lost. In Aim 2 ('Analysis of B cell immunity cross- reactive to SARS-CoV-2 and other coronavirus strains'), "Ig-omics", i.e., single-cell technologies allowing high-throughput analysis of B cell responses, phenotypes, immunoglobulin (Ig) repertoires and mAbs that react to various coronaviruses (developed by one of the RP2 investigators) will be utilized for characterizing B cell- mediated immunity and mAb specificity induced by the candidate vaccine antigens. These data will be compared with results from a human cohort study (funded through a different mechanism) to identify vaccine candidates that generate a broad B cell response and stimulate affinity maturation in germinal centers and the generation of long-term memory B cells and plasma cells. In Aim 3 ('Analysis of T cell immunity cross-reactive to SARS- CoV-2 and other coronavirus strains'), we will test the ability of novel vaccine candidates to elicit responses to cross-reactive CD4 and CD8 epitopes. In particular, novel methods based on T cell repertoire sequencing will be used to characterize epitope-specific responses that are cross-reactive between SARS-CoV-2 and other human coronaviruses, and those responses that are SARS-CoV-2 specific. Using data from ongoing longitudinal cohort study of SARS-CoV-2-infected people (funded through a different mechanism), we will be able to identify naïve and baseline cross-reactive T cell responses that expand after SARS-CoV-2 infection. These data will be compared with the T cell responses in mice vaccinated with the novel vaccine candidates. Overall, these data will allow an in-depth comparison of B and T cell responses between vaccinated animals and human COVID- 19 samples in order to refine vaccine candidates to be more cross-reactive.