Protective pan-betacoronavirus neutralizing antibodies by vaccination

Zhou, P.; Feng, Z.; He, W.-t.; Zhu, Y.; Yuan, M.; Li, X.; Zhang, Y.; Vo, L.; Capozzola, T.; Callaghan, S.; Mishra, N.; Avillion, G.; Dueker, K.; Liang, B.; Roy Chowdhury, R.; Nedellec, R.; Lee, W.-H.; Allen, J. D.; Walsh, A.; Melo, M.; McAnarney, E. T.; Kumar, N. A.; Rinaldi, W.; Ferguson, M.; Crispin, M. M.; Ward, A. B.; Irvine, D. J.; Alameh, M.-G.; Weissman, D.; Baric, R.; Gralinski, L. E.; Wilson, I.; Burton, D. R.; Andrabi, R.

doi:10.64898/2026.08.06.743418

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bioRxiv · 10.64898/2026.08.06.743418

Protective pan-betacoronavirus neutralizing antibodies by vaccination

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Abstract

The continued emergence of betacoronaviruses underscores the urgent need for vaccines that provide broadly protective immunity. Here, we present an epitope-focused vaccine strategy targeting the conserved S2 stem-helix region of the spike fusion machinery, a broadly neutralizing antibody-(bnAb) epitope shared across betacoronaviruses yet partially occluded on the native spike. Immunization of non-human primates with engineered S2 stem-helix nanoparticle immunogens, alone or followed by a SARS-CoV-2 BA.1 spike mRNA boost, elicited broadly cross-reactive antibody responses against sarbecoviruses, merbecoviruses, and embecoviruses and neutralized SARS-CoV-2, multiple variants, other sarbecoviruses, and MERS-CoV. Vaccine-elicited monoclonal antibodies displayed broad in-vitro neutralizing activity and protected against both SARS-CoV-2 and MERS-CoV in-vivo. Structural analyses revealed conserved features between rhesus and human stem-helix bnAbs, supporting the translational potential. Overall, our findings provide proof-of-concept that epitope-focused nanoparticle immunogens can target partially occluded, immunoquiescent bnAb epitopes, laying the groundwork for pan-betacoronavirus vaccines that provide broad protection and strengthen pandemic preparedness. ONE SENTENCE SUMMARYEpitope-focused S2 stem-helix nanoparticle immunogens elicit protective broadly neutralizing antibodies (bnAbs) against diverse betacoronaviruses in non-human primates, establishing a framework for development of pan-betacoronavirus vaccines.

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Zhou, P., Feng, Z., He, W.-t., Zhu, Y., Yuan, M., Li, X., Zhang, Y., Vo, L., Capozzola, T., Callaghan, S., Mishra, N., Avillion, G., Dueker, K., Liang, B., Roy Chowdhury, R., Nedellec, R., Lee, W.-H., Allen, J. D., Walsh, A., Melo, M., McAnarney, E. T., Kumar, N. A., Rinaldi, W., Ferguson, M., Crispin, M. M., Ward, A. B., Irvine, D. J., Alameh, M.-G., Weissman, D., Baric, R., Gralinski, L. E., Wilson, I., Burton, D. R., Andrabi, R.. 2026-08-07. Protective pan-betacoronavirus neutralizing antibodies by vaccination. https://doi.org/10.64898/2026.08.06.743418

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