Vaccine elicitation and structural basis for antibody protection against alphaviruses

Cell. 2023 Jun 8;186(12):2672-2689.e25. doi: 10.1016/j.cell.2023.05.019. Epub 2023 Jun 8.

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.

Keywords: alphavirus; broadly neutralizing antibody; cryo-EM; in vivo challenge; vaccine.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alphavirus*
  • Animals
  • Antibodies, Viral
  • Encephalitis Virus, Venezuelan Equine* / genetics
  • Macaca
  • Mice
  • Viral Vaccines*

Substances

  • Antibodies, Viral
  • Viral Vaccines