Investigation of proven vaccine breakthrough by SARS-CoV-2 variants in established UK healthcare worker cohorts: SIREN consortium & PITCH Plus Pathway

The SIREN Consortium aims to investigate the correlates of immunity against SARS-CoV-2 post-vaccination, including the durability of the immune response in healthcare workers (HCW). The study uses the strengths of the largest global cohort study (N~45,000) with regular serological and alternate weekly SARS-CoV-2 PCR testing. This additional funding enables detailed immunological nested case-control studies where cases are infections post-vaccination and compared to appropriately matched controls. 75 proven vaccine breakthrough cases have already been identified and daily alerts for new infections are in place. It will assess host and pathogen factors related to infections post-vaccination with the PITCH Plus pathway 1. Anti-S and anti-N neutralising antibodies against the current SARS-CoV-2 variants of concern, using validated pseudovirus microneutralisation (pMN) assay and live virus MN & Tcell memory responses, by IFNG Elispot and T cell proliferation assay 2. The durability of binding and quantification S and N antibody, neutralising antibody and T-cell responses in recipients of different vaccines and vaccination schedules 3. Genotype to phenotype mapping including centralised genomic surveillance for all cases, analysis and exploratory assessment to better define the correlates of humoral and cellular immunity for novel mutations/ emerging variants. 4. Clinical immunology consultation: individuals with post-vaccine infections will be invited to a telephone consultation to review their medical history, have bloods undertaken to assess underlying health conditions, associated immunodeficiency and the humoral and cellular immune system. 5. Human genotyping with consent we will obtain and store genetic material from vaccine breakthrough cases to enable future assessment of known single nucleotide polymorphisms and where necessary whole genome sequencing for associations with suboptimal vaccine response and immunodeficiency.