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The responsiveness/cross-binding of vaccine-induced memory B cells/MBCs to previous and emerging divergent SARS-CoV-2 variants (e.g., Omicron) is understudied. In this longitudinal study subjects receiving two or three doses of monovalent ancestral strain-containing COVID-19 mRNA vaccine were evaluated. In contrast to others, we observed significantly lower frequencies of MBCs reactive to the receptor-binding domain/RBD, the N-terminal domain/NTD, and the S1 of Omicron/BA.1, compared to Wuhan and Delta, even after a 3rd vaccine dose/booster. Our study is a proof of concept that MBC cross-reactivity to variants with greater sequence divergence from the vaccine strain may be overestimated and suggests that these variants may exhibit immune escape with reduced recognition by circulating pre-existing MBCs upon infection. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 and influenza pandemics have posed a devastating threat to global public health. The best strategy for preventing the further spread of these respiratory viruses worldwide is to administer a vaccine capable of targeting both viruses. Here, we show that a novel monoglycosylated vaccine designed based on the influenza virus H A stem conserved domain fused with the SARS-CoV-2 s pike- R BD domain (HSSR mg) can present proper antigenicity that elicits sufficient neutralization efficacy against various SARS-CoV-2 variants while simultaneously providing broad protection against H1N1 viruses in mice. Compared with the fully glycosylated HSSR (HSSR fg), HSSR mg induced higher ELISA titers targeting HA stem and spike-RBD and exhibited significantly enhanced neutralization activity against the Wuhan pseudovirus. The enhanced immune responses raised by JR300-adjuvanted HSSR mg compared to HSSR mg alone include more anti-HA stem and anti-spike-RBD antibodies that provide cross-protection against H1N1 challenges and cross-neutralization of SARS-CoV-2 pseudoviruses. Furthermore, the enhanced immune response raised by JR300-adjuvanted-HSSR mg skews toward a more balanced Th1/Th2 response than that raised by HSSR mg alone. Notably, HSSR mg elicited more plasma B cells and memory B cells, and higher IL-4 and IFN-γ cytokine immune responses than spike (S–2P) in mice with preexisting influenza-specific immunity, suggesting that B-cell activation most likely occurs through CD4+ T-cell stimulation. This study demonstrated that HSSR mg produced using a monoglycosylation process and combined with the JR300 adjuvant elicits superior cross-strain immune responses against SARS-CoV-2 and influenza viruses in mice compared with S–2P. JR300-adjuvanted HSSR mg has great potential as a coronavirus-influenza vaccine that provides dual protection against SARS-CoV-2 and influenza infections. • Platform for the production of a two-in-one bivalent protein vaccine targeting HA stem and spike-RBD. • HSSR mg induced broader immune responses against influenza and SARS-CoV-2 viruses. • Recall of HA stem immunity: HSSR mg elicited more B- and T-cell responses than spike in mice. • HSSR mg could serve as a coronavirus-influenza vaccine that provides dual protection against viruses. [ABSTRACT FROM AUTHOR]