A third vaccine dose equalises the levels of effectiveness and immunogenicity of heterologous or homologous COVID-19 vaccine regimens, Lyon, France, December 2021 to March 2022

Background: To cope with the persistence of the COVID-19 epidemic and the decrease in antibody levels following vaccination, a third dose of vaccine has been recommended in the general population. However, several vaccine regimens had been used ini-tially for the primary vaccination course, and the het-erologous Vaxzevria/Comirnaty regimen had shown better efficacy and immunogenicity than the homolo-gous Comirnaty/Comirnaty regimen. Aim: We wanted to determine if this benefit was retained after a third dose of an mRNA vaccine. Methods: We combined an observational epidemiolog-ical study of SARS-CoV-2 infections among vaccinated healthcare workers at the University Hospital of Lyon, France, with a prospective cohort study to analyse immunological parameters before and after the third mRNA vaccine dose. Results: Following the second vaccine dose, heterologous vaccination regimens were more protective against infection than homologous regimens (adjusted hazard ratio (HR) = 1.88; 95% con-fidence interval (CI): 1.18-3.00; p = 0.008), but this was no longer the case after the third dose (adjusted HR = 0.86; 95% CI: 0.72-1.02; p = 0.082). Receptor -binding domain-specific IgG levels and serum neutral-isation capacity against different SARS-CoV-2 variants were higher after the third dose than after the second dose in the homologous regimen group, but not in the heterologous group. Conclusion: The advantage conferred by heterologous vaccination was lost after the third dose in terms of both protection and immu-nogenicity. Immunological measurements 1 month after vaccination suggest that heterologous vaccina-tion induces maximal immunity after the second dose, whereas the third dose is required to reach the same level in individuals with a homologous regimen.