Abstract
There are challenges in selecting SARS-CoV-2 vaccine compositions, primarily due to divergent infection or vaccination history and immunological biases toward previous strains. In this study, we evaluated humoral immune responses induced by variant-based monovalent vaccines as booster shots in mice previously vaccinated with an ancestral strain-based vaccine with or without Omicron BA.5 exposure. Our data suggest that immunological biases toward earlier variants attenuated the potency of variant-based vaccines as a booster dose against subsequent variants, whereas a second booster dose mitigated this effect. Furthermore, in the context of vaccine-induced immunity, prior exposure to Omicron sublineages (e.g., BA.5) attenuated the effect of immunological biases toward earlier variants on the neutralizing potency against Omicron subvariants. In addition, the interval between vaccine doses should also be considered, as an immunologic plateau might occur after repeated vaccination. Furthermore, the XBB.1 monovalent vaccine and a tetravalent vaccine (SCTV01E-2) composed of pre-Omicron variant (Beta) and Omicron subvariants (BA.1, BQ.1.1, and XBB.1) showed comparable neutralizing potency against several Omicron sublineages (BA.1, BA.5, BQ.1.1, XBB.1, XBB.1.5, XBB.1.16, and EG.5) under divergent vaccination history, implicating that multivalent platforms could be explored as a flexible strategy if future strains diverge significantly from current variants.IMPORTANCEContinuous evolution of SARS-CoV-2 variants has raised the need to optimize immunization regimens and update vaccine compositions to protect against the newly emerging variants in the context of repeated vaccination. The significance of this research is briefly summarized as follows:1) Immunological biases toward earlier variants attenuated the potency of variant-based vaccines as a booster dose against subsequent variants, which can be mitigated by a second booster dose.2) In the context of vaccine-induced immunity, a previous exposure to Omicron sublineages, such as BA.5, attenuated the influence of immunological biases toward earlier variants on the neutralizing potency against Omicron subvariants.3) The interval between vaccine doses should be taken into account since an immunologic plateau might occur after repeated vaccination.4) Multivalent vaccines, with epitope diversity, may theoretically enhance the magnitude and breadth of cross-neutralization responses, thereby providing a buffer for unpredictable future variants.