De novo design of a safe and potent respiratory syncytial virus immuno-focusing antigen

Kwon, Y.-C.; Hwang, W. Y.; Song, J.; Choe, J.; Ku, K. B.; Kim, H.-S.; Yoon, G. Y.; Kim, D. Y.; Choi, M.-R.; Kim, E.-J.; Lee, J. S.; Park, S.; Lee, S. K.; Ku, B.; Ahn, D.-G.; Kim, K.-D.; Kim, C.; Suh, H. N.; Lee, J.; Shin, H.-C.; Ko, J.

doi:10.64898/2026.01.28.702448

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bioRxiv · 10.64898/2026.01.28.702448

De novo design of a safe and potent respiratory syncytial virus immuno-focusing antigen

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Abstract

Respiratory syncytial virus (RSV) remains the leading cause of severe respiratory infections in infants, the elderly, and the immunocompromised. Although stabilized full-length pre-fusion (pre-F) protein vaccines are promising, enhanced respiratory disease (ERD) remains a critical safety concern. Here, we used artificial intelligence to design a de novo immuno-focused antigen that structurally preserves the RSV F head region containing critical neutralising epitopes-- site O, II and V-while replacing the non-neutralising stem with a computationally designed scaffold to minimise immunopathological risk. The lead candidate, aRF6, elicited robust protective immunity against RSV in mice and similar immunogenicity in non-human primates without detectable toxicity. Importantly, in stringent ERD-promoting models, aRF6 induced minimal pulmonary pathology and markedly attenuated Th2-biased cytokine responses, outperforming formalin-inactivated RSV and full-length-stabilized pre-F. The results of cryoelectron microscopy confirmed that the aRF6 structure precisely matched the computational predictions. These results demonstrated that computationally designed de novo immuno-focused antigens can yield safe and effective RSV vaccines, thereby providing a rational framework for next-generation vaccine development.

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Kwon, Y.-C., Hwang, W. Y., Song, J., Choe, J., Ku, K. B., Kim, H.-S., Yoon, G. Y., Kim, D. Y., Choi, M.-R., Kim, E.-J., Lee, J. S., Park, S., Lee, S. K., Ku, B., Ahn, D.-G., Kim, K.-D., Kim, C., Suh, H. N., Lee, J., Shin, H.-C., Ko, J.. 2026-01-29. De novo design of a safe and potent respiratory syncytial virus immuno-focusing antigen. https://doi.org/10.64898/2026.01.28.702448

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