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Evolution of Dengue Virus Antigens Reflected in Outbreaks in Thailand


NEW YORK – New research from investigators at the National Institute of Allergy and Infectious Diseases, the University of Florida, and international centers has revealed the dynamic immune-dodging methods used by dengue viruses (DENV) from four serotypes that show distinct interactions with human antibodies.

"Over the course of 20 years, the Thailand DENV serotypes gradually evolved away from one another. However, for brief periods, the serotypes increased in similarity, with corresponding changes in epidemic magnitude," University of Florida researcher Derek Cummings, Henrik Salje of the University of Florida and the University of Cambridge, and NIAID's Stephen Whitehead, the study's co-corresponding authors, and their colleagues reported in a paper appearing in Science Advances on Thursday.

For its study, the team sequenced 1,944 DENV isolates from serotypes 1 to 4 (DENV1-4) collected at the Queen Sirikit National Institute of Child Health, a tertiary children's hospital, in Bangkok from 1994 to 2014. They compared the viral genomes to one another and to dozens more international isolates to track the evolution of corresponding DENV antigens that are recognized by the host immune system.

"[W]e tested whether DENV1-4 circulating in Bangkok, Thailand, changed antigenically over two decades in relation to each other and a selection of globally representative DENV1-4 strains," the authors explained.

The team noted that one genotype predominated within each of the serotypes over the time frame considered, although past research suggests that a given serotype can encompass as many as seven genotypes.

"Antibodies from naturally infected and vaccinated individuals differentially neutralize distinct genotypes and even distinct clinical isolates (strains) of each serotype," the authors noted. "Homotypic immunity is generally protective, although protection against clinical disease is not always complete against viruses of different genotype; this could also potentially reduce vaccine efficacy."

Using a subset of 348 sequenced strains from Thailand and 64 DENV isolates collected in 20 other countries from 1944 to 2012, the team went on to profile serological immunity, antigenic relationships, and other antigenic features with plaque assays and other approaches in mosquito cells exposed to blood serum from DENV-infected African green monkeys.

Based on these and other analyses, the researchers determined that a range of selective effects — from immune evasion and local DENV rates to protein structure constraints within the viruses themselves — can impact the evolution of the DENV antigens recognized by infected hosts.

For example, they found that distinct DENV serotypes tended to become more antigenically distant from one another over time, consistent with the notion that enhanced host or population immunity against the predominant strain at a given time can selectively push viruses toward antigenic changes that may help evade such immunity. But these changes also tended to oscillate, with serotypes from earlier time points sometimes reappearing.

These shifts corresponded with distinct epidemic features in the region, the team reported, noting that the most pronounced epidemic events tended to coincide with the presence of strains and serotypes with antigens that were similar to one another, but distinct from those found in serotypes circulating earlier.

At the genotype level, meanwhile, the researchers saw several types of antigen evolution dynamics for genotypes that came from the same serotype, genotypes across serotypes, and genotypes arising from replacement events involving antigen features distinct from those in circulating serotypes.

"This work constitutes the most comprehensive dataset to date that has been used to explore hypothesized evolutionary trade-offs for DENV and more broadly among antigenically interacting serotypes, with potentially valuable insights for identifying the determinants of viral antigenic evolution and informing virus surveillance and vaccine evaluation," the authors concluded.

In a related Science Advances perspectives article, University of Georgia researchers Pejman Rohani and John Drake noted that the new findings may have implications for future studies on everything from features influencing viral fitness and outbreak dynamics to vaccine developments and updates.

"Given the propensity of DENVs to evolve, it is important to know when it is time for an updated vaccine that uses new antigens," Rohani and Drake wrote. "Accordingly, a more complete understanding of the processes involved in antigenic evolution could be of great public health benefit."