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

Ellen Young; Robert H Carnahan; Daniela V Andrade; Nurgun Kose; Rachel S Nargi; Ethan J Fritch; Jennifer E Munt; Michael P Doyle; Laura White; Thomas J Baric; Mark Stoops; Aravinda DeSilva; Longping V Tse; David R Martinez; Deanna Zhu; Stefan Metz; Marcus P Wong; Diego A Espinosa; Magelda Montoya; Scott B Biering; Soila Sukulpolvi-Petty; Guillermina Kuan; Angel Balmaseda; Michael S Diamond; Eva Harris; James E Crowe Jr; Ralph S Baric

doi:10.1016/j.chom.2020.04.007

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

Cell Host Microbe. 2020 May 13;27(5):710-724.e7. doi: 10.1016/j.chom.2020.04.007.

Authors

Ellen Young¹, Robert H Carnahan², Daniela V Andrade³, Nurgun Kose⁴, Rachel S Nargi⁴, Ethan J Fritch⁵, Jennifer E Munt¹, Michael P Doyle⁶, Laura White⁵, Thomas J Baric¹, Mark Stoops⁵, Aravinda DeSilva⁵, Longping V Tse¹, David R Martinez¹, Deanna Zhu¹, Stefan Metz⁵, Marcus P Wong³, Diego A Espinosa³, Magelda Montoya³, Scott B Biering³, Soila Sukulpolvi-Petty⁷, Guillermina Kuan⁸, Angel Balmaseda⁹, Michael S Diamond¹⁰, Eva Harris¹¹, James E Crowe Jr¹², Ralph S Baric¹³

Affiliations

¹ Department of Epidemiology, Gillings School of Public Health, University of North Carolina, Chapel Hill, NC, USA.
² Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Division of Infectious Diseases and Vaccinology, School of Public Health, University of California Berkeley, Berkeley, CA, USA.
⁴ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵ Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
⁶ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷ Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
⁸ Health Center Sócrates Flores Vivas, Ministry of Health, Managua, Nicaragua.
⁹ National Virology Laboratory, National Center for Diagnosis and Reference, Ministry of Health, Managua, Nicaragua.
¹⁰ Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
¹¹ Division of Infectious Diseases and Vaccinology, School of Public Health, University of California Berkeley, Berkeley, CA, USA. Electronic address: eharris@berkeley.edu.
¹² Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: james.crowe@vumc.org.
¹³ Department of Epidemiology, Gillings School of Public Health, University of North Carolina, Chapel Hill, NC, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA. Electronic address: rbaric@email.unc.edu.

Abstract

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.

Keywords: DENV3; antigenic site; chimeric virus; dengue virus serotype 3; envelope protein; flavivirus; functional epitopes; in vivo protection; neutralizing monoclonal antibodies.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

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

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Dengue Vaccines
Epitopes
Viral Envelope Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding