Heterologous SARS-CoV-2 spike protein booster elicits durable and broad antibody responses against the receptor-binding domain

Takano et al. show that heterologous booster by SARS-CoV-2 recombinant spike protein vaccine recalls a more sustained and broader anti-spike receptor-binding domain antibody response compared to homologous booster by mRNA vaccine. The immunogenicity of mRNA vaccines has not been well studied when compared to different vaccine modalities in the context of additional boosters. Here we show that longitudinal analysis reveals more sustained SARS-CoV-2 spike receptor-binding domain (RBD)-binding IgG titers with the breadth to antigenically distinct variants by the S-268019-b spike protein booster compared to the BNT162b2 mRNA homologous booster. The durability and breadth of RBD-angiotensin-converting enzyme 2 (ACE2) binding inhibitory antibodies are pronounced in the group without systemic adverse events (AEs) after the S-268019-b booster, leading to the elevated neutralizing activities against Omicron BA.1 and BA.5 variants in the stratified group. In contrast, BNT162b2 homologous booster elicited antibodies to spike N-terminal domain in proportion to the AE scores. High-dimensional immune profiling identifies early CD16(+) natural killer cell dynamics with CCR3 upregulation, as one of the correlates for the distinct anti-RBD antibody responses by the S-268019-b booster. Our results illustrate the combinational effects of heterologous booster on the immune dynamics and the durability and breadth of recalled anti-RBD antibody responses against emerging virus variants.

Automated summary

Takano et al. demonstrate that a heterologous booster using a SARS-CoV-2 recombinant spike protein vaccine induces a more sustained and broader anti-spike receptor-binding domain antibody response compared to a homologous booster using an mRNA vaccine. The study shows that the S-268019-b spike protein booster generates higher and longer-lasting IgG titers specific to the SARS-CoV-2 spike receptor-binding domain, with the ability to bind to antigenically distinct variants, while the BNT162b2 mRNA homologous booster has a weaker effect. Additionally, the S-268019-b booster enhances the production of RBD-angiotensin-converting enzyme 2 (ACE2) binding inhibitory antibodies, resulting in increased neutralizing activities against Omicron BA.1 and BA.5 variants.