Antigenic Variation of the Dengue Virus 2 Genotypes Impacts the Neutralization Activity of Human Antibodies in Vaccinees
David R. Martinez,
Boyd Yount,
Usha Nivarthi,
Jennifer E. Munt,
Matthew J. Delacruz,
Stephen S. Whitehead,
Anna P. Durbin,
Aravinda M. de Silva,
Ralph S. Baric
Affiliations
David R. Martinez
Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding author
Boyd Yount
Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Usha Nivarthi
Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
Jennifer E. Munt
Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Matthew J. Delacruz
Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
Stephen S. Whitehead
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Anna P. Durbin
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Aravinda M. de Silva
Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
Ralph S. Baric
Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Corresponding author
Summary: Dengue virus (DENV) infects an estimated 390 million people each year worldwide. As tetravalent DENV vaccines have variable efficacy against DENV serotype 2 (DENV2), we evaluated the role of genetic diversity within the pre-membrane (prM) and envelope (E) proteins of DENV2 on vaccine performance. We generated a recombinant DENV2 genotype variant panel with contemporary prM and E isolates that are representative of global genetic diversity. The DENV2 genotype variants differ in growth kinetics, morphology, and virion stability. Importantly, the DENV2 genotypic variants are differentially neutralized by monoclonal antibodies, polyclonal serum neutralizing antibodies from DENV2-infected human subjects, and vaccine-elicited antibody responses from the TV003 NIH DENV2 monovalent and DENV tetravalent vaccines. We conclude that DENV2 prM and E genetic diversity significantly modulates antibody neutralization activity. These findings have important implications for dengue vaccines, which are being developed under the assumption that intraserotype variation has minimal impact on neutralizing antibodies.
