Identification of Dengue Virus Serotype 3 Specific Antigenic Sites Targeted by Neutralizing Human Antibodies

The rational design of dengue virus (DENV) vaccines requires a detailed understanding of the molecular basis for antibody-mediated immunity. The durably protective antibody response to DENV after primary infection is serotype specific. However, there is an incomplete understanding of the antigenic d...

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Published inCell host & microbe Vol. 27; no. 5; pp. 710 - 724.e7
Main Authors Young, Ellen, Carnahan, Robert H, Andrade, Daniela V, Kose, Nurgun, Nargi, Rachel S, Fritch, Ethan J, Munt, Jennifer E, Doyle, Michael P, White, Laura, Baric, Thomas J, Stoops, Mark, DeSilva, Aravinda, Tse, Longping V, Martinez, David R, Zhu, Deanna, Metz, Stefan, Wong, Marcus P, Espinosa, Diego A, Montoya, Magelda, Biering, Scott B, Sukulpolvi-Petty, Soila, Kuan, Guillermina, Balmaseda, Angel, Diamond, Michael S, Harris, Eva, Crowe, Jr, James E, Baric, Ralph S
Format Journal Article
LanguageEnglish
Published United States 13.05.2020
Subjects
Adolescent
Animals
Antibodies, Monoclonal - immunology
Antibodies, Neutralizing - immunology
Antibodies, Viral - immunology
B-Lymphocytes - immunology
Child
Child, Preschool
Chlorocebus aethiops
Dengue - immunology
Dengue Vaccines
Dengue Virus - genetics
Dengue Virus - immunology
Epitope Mapping
Epitopes - immunology
Humans
Mice
Models, Molecular
Nicaragua
Sequence Alignment
Serogroup
Vero Cells
Viral Envelope Proteins - immunology
Virion
Nicaragua
functional epitopes
chimeric virus
DENV3
envelope protein
neutralizing monoclonal antibodies
dengue virus serotype 3
antigenic site
in vivo protection
flavivirus
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Summary:The rational design of dengue virus (DENV) vaccines requires a detailed understanding of the molecular basis for antibody-mediated immunity. The durably protective antibody response to DENV after primary infection is serotype specific. However, there is an incomplete understanding of the antigenic determinants for DENV type-specific (TS) antibodies, especially for DENV serotype 3, which has only one well-studied, strongly neutralizing human monoclonal antibody (mAb). Here, we investigated the human B cell response in children after natural DENV infection in the endemic area of Nicaragua and isolated 15 DENV3 TS mAbs recognizing the envelope (E) glycoprotein. Functional epitope mapping of these mAbs and small animal prophylaxis studies revealed a complex landscape with protective epitopes clustering in at least 6-7 antigenic sites. Potently neutralizing TS mAbs recognized sites principally in E glycoprotein domains I and II, and patterns suggest frequent recognition of quaternary structures on the surface of viral particles.
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These authors contributed equally.
AUTHOR CONTRIBUTIONS
A.d.S, M.S.D., E.H., J.E.C., and R.S.B. designed the study. E.H., G.K., A.B and E.H. directed the sample collection and preparation. D.V.A, E.H and M.M. directed the sample selection. N.K. S.M., R.C., M.S.D. and J.E.C. performed initial screening, isolation and purification of antibodies, and isolated hybridomas. N.K., R.C., D.V.A., S.S-P., and M.S.D. performed ELISA assays. E.Y., E.F., J.M., T.B., D.M., V.T, R.S.B. and D.Z. designed and recovered chimeric viruses and performed neutralization assays with recombinant and wildtype viruses. L.M., M. S., E.Y., J.M., T.B., D.M., and V.T tested and characterized recombinant viruses. D.V.A. and J.M. also conducted neutralization assays using wildtype viruses. D.V.A., M.P.W, D.E. and S.B.B. performed animal studies. Binding studies with E glycoprotein monomer and dimers were performed by S.M., L.W. and M.S.. A.d.S., M.S.D., E.H., J.E.C., and R.S.B. obtained funding. E.Y. and R.B. wrote the first draft of the manuscript, incorporating revisions as suggested by A.d.S., J.E.C., M.S.D., E.H, R.C., M.P.W., M.M., S.B.B., and D.V.A. All authors revised and approved the final version of the manuscript.
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2020.04.007