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  • Vaccine elicitation and structural basis for antibody protection against alphaviruses.

Vaccine elicitation and structural basis for antibody protection against alphaviruses.

Cell (2023-06-10)
Matthew S Sutton, Sergei Pletnev, Victoria Callahan, Sungyoul Ko, Yaroslav Tsybovsky, Tatsiana Bylund, Ryan G Casner, Gabriele Cerutti, Christina L Gardner, Veronica Guirguis, Raffaello Verardi, Baoshan Zhang, David Ambrozak, Margaret Beddall, Hong Lei, Eun Sung Yang, Tracy Liu, Amy R Henry, Reda Rawi, Arne Schön, Chaim A Schramm, Chen-Hsiang Shen, Wei Shi, Tyler Stephens, Yongping Yang, Maria Burgos Florez, Julie E Ledgerwood, Crystal W Burke, Lawrence Shapiro, Julie M Fox, Peter D Kwong, Mario Roederer
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Eastern Equine Encephalitis Antibody, Virus, clone 1A4B.6, clone 1A4B.6, Chemicon®, from mouse