A hierarchical activation threshold shapes RSV F antibody repertoires from toddler vulnerability to adult protection

Deng, J.; Li, Y.; Lei, S.; Xu, K.; Nie, J.; Zhai, H.; Wang, J.; Xu, L.; Jian, F.; Feng, R.; Lv, Z.; Yu, W.; Ma, M.; Zhang, Y.; Zhang, C.; Wang, L.; Hu, Y.; Xu, X.; Huang, W. J.; Liu, E.; Cao, Y. R.; Wang, X.

doi:10.64898/2026.07.28.735825

bioRxiv · 10.64898/2026.07.28.735825

A hierarchical activation threshold shapes RSV F antibody repertoires from toddler vulnerability to adult protection

Deng, J.·Li, Y.·Lei, S.·Xu, K.·Nie, J.·Zhai, H.·Wang, J.·Xu, L.·Jian, F.·Feng, R.·Lv, Z.·Yu, W.·Ma, M.·Zhang, Y.·Zhang, C.·Wang, L.·Hu, Y.·Xu, X.·Huang, W. J.·Liu, E.·Cao, Y. R.·Wang, X.

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Abstract

Respiratory syncytial virus (RSV) causes severe infant morbidity, yet the mechanisms underlying their suboptimal immunity and the failure of prefusion F-stabilized adult vaccines in infants remain unclear. Here we integrate deep mutational scanning of 761 preF-binding antibodies, repertoire profiling of 102 repeatedly exposed pediatricians and 61 RSV-experienced toddlers, structural analysis, and >40,000 viral genomes to decode RSV F immunity. We resolved 12 immunologically distinct functional antibody subclasses and uncovered a hierarchical activation threshold: apical epitope-targeting antibodies with superior neutralizing potency demand extensive somatic hypermutation and cooperative CDR networks, whereas central-to-basal epitope-directed, marginal or non-neutralizing antibodies engage germline-encoded antibodies through minimal mutations (e.g., S31G). Toddler repertoires are confined to low-threshold, non-productive sites; adult repertoires enrich for apical elite neutralizers whose immune pressure drives contemporary RSV-B evolution. These reframe pediatric RSV vulnerability as a threshold-gated repertoire deficit and prescribe vaccine strategies that actively redirect immunodominance from permissive epitopes toward high-barrier apical targets.

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Deng, J., Li, Y., Lei, S., Xu, K., Nie, J., Zhai, H., Wang, J., Xu, L., Jian, F., Feng, R., Lv, Z., Yu, W., Ma, M., Zhang, Y., Zhang, C., Wang, L., Hu, Y., Xu, X., Huang, W. J., Liu, E., Cao, Y. R., Wang, X.. 2026-07-29. A hierarchical activation threshold shapes RSV F antibody repertoires from toddler vulnerability to adult protection. https://doi.org/10.64898/2026.07.28.735825

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