mRNA Vaccine Binding Different RBDs Confirmed to Provide Cross-Protection Against Omicron Variants
Background
Although vaccination against COVID-19 has reduced the risk of severe disease, the continuous diversification of SARS-CoV-2 Omicron lineages has rapidly diminished the effectiveness of infection prevention. In particular, amino acid variations in the receptor-binding domain (RBD) have become a key mechanism for evading binding by existing neutralizing antibodies. Even if vaccines are updated based on the antigen of one variant, the protective range may narrow again when new lineages emerge.
Multivalent vaccines that mix antigens from multiple variants can address this issue, but differences in antigen expression levels and immunodominance may lead to responses skewed toward specific targets. The research team hypothesized that expressing two phylogenetically distant RBDs as a single immunogen could induce broader B cell and T cell responses. Based on this, they designed a heterodimeric mRNA vaccine 'SV' by serially linking an optimized monomeric RBD (BSCOV06) with the KP.3 variant RBD.
Key Findings
After two doses of SV in BALB/c mice, high-titer antibodies with neutralizing activity against BA.1, XBB.1.5, JN.1, KP.3, and the phylogenetically distant XDV variant were generated. Although the abstract did not provide absolute values for neutralizing titers per variant, the immunogenicity and cross-protective efficacy of SV were equal to or higher than those of three doses of BSCOV06, indicating a broader protective range with fewer doses.
The research team went beyond neutralization assays and conducted integrated analyses of B cell receptor (BCR) and T cell receptor (TCR) repertoires. In the SV-vaccinated group, class-switched B cells showed increased somatic hypermutation, and naive B cell participation was sustained. T cell populations composed of multiple clones also expanded broadly, and both BCR and TCR showed significant reprogramming of VJ gene usage. This suggests that the dual RBD did not merely increase antibody quantity but fundamentally altered the composition of the adaptive immune response.
Actual protective efficacy was evaluated in BALB/c and K18-hACE2 transgenic mice expressing human angiotensin-converting enzyme 2. When challenged with JN.1 or XDV virus, SV significantly reduced pulmonary viral loads and alleviated histopathological damage. The cross-reactivity of neutralizing antibodies and the expansion of lymphocyte repertoires translated into lung protection.
Implications and Outlook
These results suggest that placing two antigenically distinct RBDs into a single molecule could serve as a design strategy to counter the immune evasion of rapidly evolving viruses. Rather than simply mixing variant-specific vaccines, the concept involves using a single mRNA to co-express two antigens, enabling the immune system to recognize multiple epitopes simultaneously. This principle could also be evaluated for other viruses with frequent antigenic changes, such as influenza.
However, the study was conducted in a preclinical mouse model. It remains to be confirmed whether the two RBDs are expressed at equivalent levels in humans and whether pre-existing immunity from prior infection or vaccination might bias the response toward specific variants. Future evaluations should also address the duration of protection, mucosal immunity, safety, and consistency of quality at manufacturing scale. Since the abstract did not disclose absolute neutralizing titers or statistical effect sizes, detailed data from the full paper and primate and clinical results will be necessary to assess the superiority of the candidate.
The continued antigenic evolution of SARS-CoV-2 Omicron subvariants has progressively eroded vaccine-elicited protective immunity, driving demand for next-generation candidates that confer broad-spectrum protection against phylogenetically divergent strains. Here we report the design and preclinical evaluation of SV, an mRNA vaccine encoding a heterodimeric receptor-binding domain (RBD) antigen. In this construct, a previously optimized monomeric RBD (BSCOV06) is tandemly linked to the KP.3 RBD, presenting two antigenically distinct RBDs within a single immunogen. A two-dose SV regimen in BALB/c mice elicited high-titer neutralizing antibodies with potent cross-reactivity against BA.1, XBB.1.5, JN.1, KP.3, and the phylogenetically distant XDV variant. Integrated B cell receptor (BCR) and T cell receptor (TCR) repertoire profiling revealed that SV drives qualitatively distinct adaptive immune remodeling relative to BSCOV06. Key features included elevated class-switched somatic hypermutation, sustained naive B cell engagement, broad polyclonal T cell expansion, and extensive VJ gene-usage reprogramming across both lymphocyte compartments. In BALB/c and K18-hACE2 transgenic mice, SV conferred robust protection against JN.1 and XDV challenge, substantially reducing pulmonary viral loads and attenuating histopathological injury. Notably, SV achieved immunogenicity and cross-protective efficacy comparable to or exceeding those of the three-dose BSCOV06 schedule, supporting the potential of heterodimeric antigen design. These findings support SV as a promising broad-spectrum COVID-19 vaccine candidate. More broadly, they suggest that heterodimeric RBD architectures incorporating antigenically divergent variants may represent a generalizable platform for countering viral immune evasion, with implications for future SARS-CoV-2 variants and other rapidly evolving viral pathogens.
If SV demonstrates efficacy in humans, it could shift vaccine development from a strategy of replacing one antigen per season to a universal booster approach that precombines phylogenetically distant lineages. Pharmaceutical companies may be able to adjust the breadth of protection by incorporating the RBD sequences of two variants into a single mRNA cassette without significantly altering the production process.
Specifically, it may be worth exploring scenarios in which two doses provide immune protection equivalent to three doses in populations requiring repeated vaccinations, such as the elderly and immunocompromised individuals. However, to confirm this, clinical trials must compare infection and severe disease prevention rates, adverse reactions, immune durability, and response differences based on prior vaccination history.