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Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants. [Display omitted] • A chimeric RBD-dimer immunogenic approach can be used to rapidly adapt SARS-CoV-2 variants • Chimeric RBD-dimers elicit broader responses to variants compared with homodimers • Prototype-Beta chimeric vaccine is protective in both mice and macaques • Delta-Omicron chimeric vaccine protects mice from either Delta or Omicron challenge Vaccine immunogens designed as chimeras of the spike protein receptor-binding domain of two distinct SARS-CoV-2 variants elicit broad serum neutralization and protection from infection by the Beta, Delta, and Omicron variants in mice and macaques. The chimeric approach is applicable for rapid updating of immunogens against both circulating and emerging variants. [ABSTRACT FROM AUTHOR]

Vaccines are urgently needed to control the ongoing pandemic COVID-19 and previously emerging MERS/SARS caused by coronavirus (CoV) infections. The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. We describe a dimeric form of MERS-CoV RBD that overcomes this limitation. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. Crystal structure showed RBD-dimer fully exposed dual receptor-binding motifs, the major target for NAbs. Structure-guided design further yielded a stable version of RBD-dimer as a tandem repeat single-chain (RBD-sc-dimer) which retained the vaccine potency. We generalized this strategy to design vaccines against COVID-19 and SARS, achieving 10- to 100-fold enhancement of NAb titers. RBD-sc-dimers in pilot scale production yielded high yields, supporting their scalability for further clinical development. The framework of immunogen design can be universally applied to other beta-CoV vaccines to counter emerging threats. • A dimeric form of MERS-CoV RBD is highly immunogenic and protective in mice • RBD-dimer structure guides further design of a homogeneous dimer by tandem repeat • The strategy is generalizable to design beta-CoV vaccines against COVID-19 and SARS • CoV RBD-dimer immunogens can be produced at high yields in pilot scale production Gao et al. present the structure-guided design of a coronavirus immunogen comprised of two protein subunits each containing the virus spike receptor binding domain fused together via a disulfide link or tandem repeat. The immunogen elicits strong immunogenicity in mice and protects them against viral challenge. The vaccine design strategy can be universally applied to SARS, MERS, COVID-19, and other CoV vaccines to counter emerging threats. [ABSTRACT FROM AUTHOR]