Key result
Heteromultimeric sarbecovirus RBD immunogens fail to elicit antibodies capable of neutralizing divergent viruses.
Why the study?
It was postulated that heteromultimeric sarbecovirus receptor binding domain immunogens positioning different antigens in close proximity might selectively engage cross-reactive B cell receptors and elicit antibodies neutralizing a broad range of viral species.
Do heteromultimeric sarbecovirus RBD immunogens elicit broadly cross-reactive neutralizing antibodies compared to homomultimeric or monomeric immunogens in mouse models?
Do heteromultimeric sarbecovirus RBD immunogens elicit broadly cross-reactive neutralizing antibodies compared to homomultimeric or monomeric immunogens in mouse models?
Combining divergent RBDs in a single immunogen primarily generates variant-specific neutralizing antibodies rather than broadly cross-reactive ones.
Answers are grounded in this paper and cite their sources.
Heteromultimeric RBD immunogens may not elicit broad cross-neutralization in mice; leaves open optimal designs for sarbecovirus vaccines.
Vaccination will likely be a key component of strategies to curtail or prevent future sarbecovirus pandemics and to reduce the prevalence of infection and disease by future SARS-CoV-2 variants. A "pan-sarbecovirus" vaccine, that provides maximum possible mitigation of human disease, should elicit neutralizing antibodies with maximum possible breadth. By positioning multiple different receptor binding domain (RBD) antigens in close proximity on a single immunogen, it is postulated that cross-reactive B cell receptors might be selectively engaged. Heteromultimeric vaccines could therefore elicit individual antibodies that neutralize a broad range of viral species. Here, we use model systems to investigate the ability of multimeric sarbecovirus RBD immunogens to expand cross-reactive B cells and elicit broadly reactive antibodies. Homomultimeric RBD immunogens generated higher serum neutralizing antibody titers than the equivalent monomeric immunogens, while heteromultimeric RBD immunogens generated neutralizing antibodies recognizing each RBD component. Moreover, RBD heterodimers elicited a greater fraction of cross-reactive germinal center B cells and cross-reactive RBD binding antibodies than did homodimers. However, when serum antibodies from RBD heterodimer-immunized mice were depleted using one RBD component, neutralization activity against the homologous viral pseudotype was removed, but neutralization activity against pseudotypes corresponding to the other RBD component was unaffected. Overall, simply combining divergent RBDs in a single immunogen generates largely separate sets of individual RBD-specific neutralizing serum antibodies that are mostly incapable of neutralizing viruses that diverge from the immunogen components.
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Zang et al. (2023) studied Sarbecovirus/SARS-CoV-2 vaccination. Heteromultimeric sarbecovirus RBD immunogens vs. Homomultimeric and monomeric RBD immunogens was evaluated on Neutralizing antibody titers and cross-reactivity. Heteromultimeric sarbecovirus RBD immunogens generated largely separate sets of individual RBD-specific neutralizing antibodies that were mostly incapable of neutralizing divergent viruses.
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