Implications of a highly divergent dengue virus strain for cross-neutralization, protection, and vaccine immunity

• Published in: Cell host & microbe 2021-11, Vol.29 (11), p.1634-1648.e5
• Main Authors: Chen, Rita E., Smith, Brittany K., Errico, John M., Gordon, David N., Winkler, Emma S., VanBlargan, Laura A., Desai, Chandni, Handley, Scott A., Dowd, Kimberly A., Amaro-Carambot, Emerito, Cardosa, M. Jane, Sariol, Carlos A., Kallas, Esper G., Sékaly, Rafick-Pierre, Vasilakis, Nikos, Fremont, Daved H., Whitehead, Stephen S., Pierson, Theodore C., Diamond, Michael S.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Viral - blood; Antibodies, Viral - immunology; antibody; Antigens, Viral - immunology; Broadly Neutralizing Antibodies - blood; Broadly Neutralizing Antibodies - immunology; Cross Protection; Cross Reactions; dengue; Dengue - immunology; Dengue - prevention & control; Dengue - virology; Dengue Vaccines - immunology; Dengue Virus - genetics; Dengue Virus - immunology; divergent; Female; Genotype; Humans; Immunization, Passive; Immunogenicity, Vaccine; Macaca mulatta; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; neutralization; pathogenesis; protection; Serogroup; serotype; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - immunology
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2021.09.006

Although divergent dengue viruses (DENVs) have been isolated in insects, nonhuman primates, and humans, their relationships to the four canonical serotypes (DENV 1–4) are poorly understood. One virus isolated from a dengue patient, DKE-121, falls between genotype and serotype levels of sequence divergence to DENV-4. To examine its antigenic relationship to DENV-4, we assessed serum neutralizing and protective activity. Whereas DENV-4-immune mouse sera neutralize DKE-121 infection, DKE-121-immune sera inhibit DENV-4 less efficiently. Passive transfer of DENV-4 or DKE-121-immune sera protects mice against homologous, but not heterologous, DENV-4 or DKE-121 challenge. Antigenic cartography suggests that DENV-4 and DKE-121 are related but antigenically distinct. However, DENV-4 vaccination confers protection against DKE-121 in nonhuman primates, and serum from humans immunized with a tetravalent vaccine neutralize DENV-4 and DKE-121 infection equivalently. As divergent DENV strains, such as DKE-121, may meet criteria for serotype distinction, monitoring their capacity to impact dengue disease and vaccine efficacy appears warranted. [Display omitted] •DKE-121 immune sera neutralize DENV-4 infection poorly•DENV-4 or DKE-121 immune sera do not protect against DKE-121 or DENV-4 infection•DENV-4 vaccination protects against DKE-121 infection•DKE-121 falls between genotype and serotype levels of sequence divergence Chen et al. describe antigenic relationships between a highly variant dengue virus (DENV) strain, DKE-121, and its closest serotype relative, DENV-4. A lack of serum antibody cross-neutralization and protection between DENV-4 and DKE-121 highlight limitations in existing definitions of dengue serotypes and flavivirus taxonomy.