Humoral and cellular immunogenicity of sequential heterogeneous bivalent SARS-CoV-2 vaccinations in long-term care and retirement home residents

BACKGROUND: Older adults were administered sequential heterogenous bivalent Ancestral/Omicron BA.1 and Ancestral/Omicron BA.4/5 SARS-CoV-2 mRNA vaccines in 2022-2023 in Ontario, Canada. Immunogenicity of this unique vaccination schedule was evaluated within the COVID in Long-Term Care Study, a multisite observational cohort of long-term care and retirement home residents. METHODS: Humoral and cellular immunogenicity were evaluated 7-120 days after vaccinations with first bivalent (Ancestral/Omicron BA.1; BV1) and second bivalent (Ancestral/Omicron BA.4/5; BV2) vaccines. Hybrid immunity and biological sex were considered, with measurements of anti-spike and anti-RBD (receptor binding domain) IgG and IgA antibodies by ELISA, live SARS-CoV-2 ancestral and Omicron BA.1, BA.5 and XBB.1.5 neutralizing antibodies by microneutralization assays, and T cell responses to ancestral and Omicron BA.1, BA.4/5, and XBB.1.5 spike proteins by activation-induced marker assays. RESULTS: Bivalent vaccination induced cross-reactive antibody and T cell responses. Higher responses were observed against ancestral SARS-CoV-2 than Omicron-specific variants, but Omicron-specific neutralizing antibodies were enhanced after bivalent vaccination compared to monovalent vaccination. Humoral responses were increased by hybrid immunity. Neutralizing antibodies against Omicron BA.1 were initially increased after BV2 compared to BV1 (especially in males), but in infection-naïve individuals there was back-boosting of ancestral neutralizing antibodies within 4 months. Enhanced CD4⁺ T cell responses to the ancestral spike protein were observed after BV2 compared to BV1 (particularly in females). Omicron BA.4/5 and XBB.1.5 neutralizing antibody and T cell responses were similar after BV2 and BV1. Waning of anti-SARS-CoV-2 IgG was observed after BV1 and BV2 within 4 months, and after BV1 but not BV2 for neutralizing antibodies and CD4⁺ T cell responses. CONCLUSIONS: Humoral and cellular immune responses after two heterogenous bivalent vaccines were noninferior to those after a single bivalent vaccine within four months of vaccination. Continued surveillance of vaccine immunogenicity is essential to inform evidence-based decisions on vaccination of vulnerable older adults.