Dengue viruses cluster antigenically but not as discrete serotypes

Abstract

The four genetically divergent dengue virus (DENV) types are traditionally classified as serotypes. Antigenic and genetic differences among the DENV types influence disease outcome, vaccine-induced protection, epidemic magnitude, and viral evolution. We characterized antigenic diversity in the DENV types by antigenic maps constructed from neutralizing antibody titers obtained from African green monkeys and after human vaccination and natural infections. Genetically, geographically, and temporally, diverse DENV isolates clustered loosely by type, but we found that many are as similar antigenically to a virus of a different type as to some viruses of the same type. Primary infection antisera did not neutralize all viruses of the same DENV type any better than other types did up to 2 years after infection and did not show improved neutralization to homologous type isolates. That the canonical DENV types are not antigenically homogeneous has implications for vaccination and research on the dynamics of immunity, disease, and the evolution of DENV.

Trial registration: ClinicalTrials.gov NCT00473135 NCT00831012 NCT00920517.

Copyright © 2015, American Association for the Advancement of Science.

Figures

Fig. 1

Genetic analyses of the DENV panel (n=47). (A) Phylogenetic tree showing the evolutionary relationships of DENV E gene sequences. Sequences were aligned with MAFFT, and a maximum likelihood tree (ML) was estimated using a general time reversible model, accounting for both among site rate variation and invariant sites (GTR+G4+I). Bootstrap support values of at least 75% are shown. (B) Amino acid map of dengue E protein sequences (493-495 amino acids in length). The total amino acid differences between pairs of E sequences correspond to distances between points on the geometric display.

Fig. 2

Antigenic map of the DENV panel (n=46) titrated against three-month post-infection African green monkey antisera (n=36). Each unit of antigenic distance (length of one grid-square side, measured in any direction) is equivalent to a two-fold dilution in the neutralization assay. Each antiserum (open shape) and virus (closed shape) is colored according to the infecting genetic type (). The size and shape of each point is the confidence area of its position.

Fig. 3

Human primary infection antigenic maps. (A) Antisera from individuals inoculated with each monovalent component of the NIH live vaccine (10 per group) were drawn 42 days post-infection and titrated against 36 viruses in the DENV panel. (B) Antisera from 20 Nicaraguan children drawn in the year after their first DENV infections were titrated against an antigenically diverse subset of the DENV panel (n=14).

Fig. 4

Antigenic maps of the DENV panel made with antisera drawn from NHPs one and five months post-infection. (A) An antigenic map of 47 DENV isolates titrated against 36 NHP antisera drawn one month post-infection. Colored arrows (DENV1=yellow, DENV2=blue, DENV3=green, DENV4=red) show the change in antiserum positions between one and three months. The black arrows show the average shift in serum position for each DENV type. The star denotes the antigenic center for each DENV type. (B) An antigenic map of 37 DENV isolates titrated against 16 NHP antisera drawn five months post-infection. Arrows point from positions of antisera at three months to the corresponding five-month positions.