Heterologous RBMRNA-405 mRNA booster enhances humoral immunity post-inactivated COVID-19 vaccination: a randomized clinical trial in adults and older through 12 months

To address the urgent need for effective immunization strategies against SARS-CoV-2 variants, particularly in older adults who are more vulnerable to severe disease, we evaluated the safety and immunogenicity of the bivalent COVID-19 mRNA vaccine RBMRNA-405 as a third-dose booster in adults aged 18 years and older previously vaccinated with two doses of inactivated vaccine. In a single-center, randomized, positive-controlled phase I study in China, 60 healthy participants were assigned (2:1) to receive either a heterologous booster (RBMRNA-405) or a homologous booster (CoronaVac). Primary endpoints assessed solicited local and systemic adverse events within 14 days post-vaccination, while secondary endpoints evaluated long-term safety and humoral immunogenicity via anti-Spike IgG ELISA and live-virus neutralization. Local pain at the injection site was the most common adverse event, primarily mild-to-moderate, with no serious vaccine-related adverse events reported. RBMRNA-405 induced 3.30-fold higher neutralizing antibodies against Omicron BA.1 and 17.66-fold higher anti-Spike IgG titers compared to CoronaVac on day 14 post-boost (P < 0.0001), with robust responses in older adults, where age-related immune decline necessitates tailored immunization strategies. Trial registration: Clinical Trial Main ID: NCT05897190. Date of Registration: 28/05/2023.