Vaccine elicitation and structural basis for antibody protection against alphaviruses.
Sutton, M.S., Pletnev, S., Callahan, V., Ko, S., Tsybovsky, Y., Bylund, T., Casner, R.G., Cerutti, G., Gardner, C.L., Guirguis, V., Verardi, R., Zhang, B., Ambrozak, D., Beddall, M., Lei, H., Yang, E.S., Liu, T., Henry, A.R., Rawi, R., Schon, A., Schramm, C.A., Shen, C.H., Shi, W., Stephens, T., Yang, Y., Florez, M.B., Ledgerwood, J.E., Burke, C.W., Shapiro, L., Fox, J.M., Kwong, P.D., Roederer, M.(2023) Cell 186: 2672-2689.e25
- PubMed: 37295404
- DOI: https://doi.org/10.1016/j.cell.2023.05.019
- Primary Citation of Related Structures:
8DEC, 8DED, 8DEE, 8DEF, 8DEQ, 8DER, 8DUL, 8DUN, 8DWO, 8EEU, 8EEV - PubMed Abstract:
Alphaviruses are RNA viruses that represent emerging public health threats. To identify protective antibodies, we immunized macaques with a mixture of western, eastern, and Venezuelan equine encephalitis virus-like particles (VLPs), a regimen that protects against aerosol challenge with all three viruses. Single- and triple-virus-specific antibodies were isolated, and we identified 21 unique binding groups. Cryo-EM structures revealed that broad VLP binding inversely correlated with sequence and conformational variability. One triple-specific antibody, SKT05, bound proximal to the fusion peptide and neutralized all three Env-pseudotyped encephalitic alphaviruses by using different symmetry elements for recognition across VLPs. Neutralization in other assays (e.g., chimeric Sindbis virus) yielded variable results. SKT05 bound backbone atoms of sequence-diverse residues, enabling broad recognition despite sequence variability; accordingly, SKT05 protected mice against Venezuelan equine encephalitis virus, chikungunya virus, and Ross River virus challenges. Thus, a single vaccine-elicited antibody can protect in vivo against a broad range of alphaviruses.
Organizational Affiliation:
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.