Determinants of early antibody responses to COVID-19 mRNA vaccines in exposed and naive healthcare workers

Background Two doses of mRNA vaccination have shown >94% efficacy at preventing COVID-19 mostly in naive adults, but it is not clear if the second dose is needed to maximize effectiveness in those previously exposed to SARS-CoV-2 and what other factors affect responsiveness. Methods We measured IgA, IgG and IgM levels against SARS-CoV-2 spike (S) and nucleocapsid (N) antigens from the wild-type and S from the Alpha, Beta and Gamma variants of concern, after BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna) vaccination in a cohort of health care workers (N=578). Neutralizing capacity and antibody avidity were evaluated. Data were analyzed in relation to COVID-19 history, comorbidities, vaccine doses, brand and adverse events. Findings Vaccination induced robust IgA and IgG levels against all S antigens. Neutralization capacity and S IgA and IgG levels were higher in mRNA-1273 vaccinees, previously SARS-CoV-2 exposed, particularly if symptomatic, and in those experiencing systemic adverse effects. A second dose in pre-exposed did not increase antibody levels. Smoking and comorbidities were associated with lower neutralization and antibody levels. Among fully vaccinated, 6.3% breakthroughs were detected up to 189 days post-vaccination. Among pre-exposed non-vaccinated, 90% were IgG seropositive more than 300 days post-infection. Interpretation Our data support administering a single-dose in pre-exposed healthy individuals. However, heterogeneity of responses suggests that personalized recommendations may be necessary depending on COVID-19 history and life-style. Higher mRNA-1273 immunogenicity would be beneficial for those expected to respond worse to vaccination. Persistence of antibody levels in pre-exposed unvaccinated indicates maintenance of immunity up to one year.