Previous infection with either Zika virus or dengue virus has no apparent effect on the clinical course of subsequent infection with the other virus, according to a study published August 1 in the open-access journal PLOS Pathogens by David O'Connor of the University of Wisconsin-Madison, and colleagues. This work is timely, given recent efforts to develop an effective vaccine for Zika virus, as well as the introduction of dengue virus vaccines in areas where both viruses are now co-endemic.
Zika and dengue viruses are related flaviviruses that now co-circulate in much of the tropical and subtropical world. The rapid emergence of Zika virus in the Americas in 2015 and 2016, and its recent associations with a neurological disorder called Guillain-Barré syndrome, birth defects, and fetal loss have led to the hypothesis that dengue virus infection induces cross-reactive antibodies that influence the severity of secondary Zika virus infections. It has also been proposed that pre-existing Zika virus immunity could affect the severity of secondary dengue virus infections. Data from in vitro experiments and mouse models suggest that pre-existing immunity to one virus could either enhance or protect against infection with the other. These somewhat contradictory findings highlight the need for immune-competent animal models to understand the role of cross-reactive antibodies in flavivirus infections.
In the new study, O'Connor and colleagues examined secondary Zika virus or dengue virus infections in rhesus and cynomolgus macaques that had previously been infected with the other virus. They assessed the outcomes of secondary Zika virus or dengue virus infections by quantifying viral RNA loads, clinical and laboratory parameters, body temperature, and weight for each cohort of animals and compared them with control animals. These comparisons demonstrated that within one year of primary infection, secondary infections with either Zika virus or dengue virus were similar to primary infections and were not associated with enhanced or reduced disease severity. All animals had asymptomatic infections and, when compared to controls, did not have significantly perturbed blood parameters. Although additional studies are needed, the findings suggest that vaccination against either dengue virus or Zika virus may not influence the severity of disease upon secondary infection with the other virus.
"Within a year of primary DENV or ZIKV infection, we did not observe any significant enhancement of, nor protection from, secondary infection with the opposite virus in non-pregnant macaques," the authors add. "Our results differ from those shown in tissue culture and immunocompromised mouse models and aligns more closely with current human epidemiological data where enhanced secondary Zika infection has not been reported after primary dengue infections."
Funding: This research was funded by grants from the United States National Institutes of Health - National Institute of Allergy and Infectious Diseases (NIH/NIAID) https://www.niaid.nih.gov/: principally award number R01 AI116382 (to D.H.O.), secondarily, R21 AI131454 (to M.T.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: G. Young and H. Dean are employees of Takeda Vaccines, Inc. All other authors declare no conflicts of financial or personal interests.
Citation: Breitbach ME, Newman CM, Dudley DM, Stewart LM, Aliota MT, Koenig MR, et al. (2019) Primary infection with dengue or Zika virus does not affect the severity of heterologous secondary infection in macaques. PLoS Pathog 15(8): e1007766. https://doi.org/10.1371/journal.ppat.1007766
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
Takeda Vaccines, Inc., Madison, Wisconsin, United States of America
Wisconsin National Primate Research Center, Madison, Wisconsin, United States of America
Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina, United States of America
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