Vaccine elicitation and structural basis for broad antibody protection against alphaviruses

Alphaviruses are mosquito-transmitted RNA viruses that represent emerging public health threats. We immunized macaques with a trivalent mixture of western, eastern, and Venezuelan equine encephalitis virus (WEVEEV) virus-like particles (VLPs), an immunization that elicits protection in macaques against aerosol challenge with all three viruses. Single- and triple-virus specific antibodies were isolated, and competitive binding analysis identified 21 unique competition groups for all three VLPs. Cryo-EM structures revealed that broad VLP binding correlated with low sequence and conformational variability. One triple-specific antibody, SKT05, bound proximal to the fusion peptide and neutralized all three EEV pseudoviruses, yet utilized different symmetry elements for recognition across VLPs. Despite binding a less sequence-conserved region, SKT05 interacted with backbone atoms of sequence diverse-residues, enabling broad recognition. Accordingly, SKT05 protected mice against Venezuelan EEV, chikungunya virus, and Ross River virus challenge. Thus, a single vaccine-elicited antibody can protect against a broad range of encephalitic and arthritogenic alphaviruses.