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Primary infection with dengue or Zika virus does not affect the severity of heterologous secondary infection in macaques

View ORCID ProfileMeghan E. Breitbach, Christina M. Newman, View ORCID ProfileDawn M. Dudley, Laurel M. Stewart, View ORCID ProfileMatthew T. Aliota, View ORCID ProfileMichelle R. Koenig, Phoenix M. Shepherd, Keisuke Yamamoto, View ORCID ProfileChelsea M. Crooks, Ginger Young, Matthew R. Semler, Andrea M. Weiler, Gabrielle L. Barry, Holly Heimsath, Emma L. Mohr, Jens Eichkoff, View ORCID ProfileWendy Newton, Eric Peterson, View ORCID ProfileNancy Schultz-Darken, Sallie R. Permar, Hansi Dean, Saverio Capuano 3rd, Jorge E. Osorio, View ORCID ProfileThomas C. Friedrich, View ORCID ProfileDavid H. O’Connor
doi: https://doi.org/10.1101/613802
Meghan E. Breitbach
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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  • ORCID record for Meghan E. Breitbach
Christina M. Newman
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Dawn M. Dudley
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Laurel M. Stewart
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Matthew T. Aliota
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
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Michelle R. Koenig
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Phoenix M. Shepherd
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Keisuke Yamamoto
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Chelsea M. Crooks
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Ginger Young
Takeda Vaccines, Inc., Madison, Wisconsin, United States of America
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Matthew R. Semler
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Andrea M. Weiler
Wisconsin National Primate Research Center, Madison, Wisconsin, United States of America
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Gabrielle L. Barry
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Holly Heimsath
Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina, United States of America
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Emma L. Mohr
Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Jens Eichkoff
Department of Biostatistics & Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Wendy Newton
Wisconsin National Primate Research Center, Madison, Wisconsin, United States of America
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Eric Peterson
Wisconsin National Primate Research Center, Madison, Wisconsin, United States of America
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Nancy Schultz-Darken
Wisconsin National Primate Research Center, Madison, Wisconsin, United States of America
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Sallie R. Permar
Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina, United States of America
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Hansi Dean
Takeda Vaccines, Inc., Madison, Wisconsin, United States of America
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Saverio Capuano
Wisconsin National Primate Research Center, Madison, Wisconsin, United States of America
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Jorge E. Osorio
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Thomas C. Friedrich
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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David H. O’Connor
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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  • For correspondence: dhoconno@wisc.edu
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Abstract

Zika virus (ZIKV) and dengue virus (DENV) are genetically and antigenically related flaviviruses that now co-circulate in much of the tropical and subtropical world. The rapid emergence of ZIKV in the Americas in 2015 and 2016, and its recent associations with Guillain-Barré syndrome, birth defects, and fetal loss have led to the hypothesis that DENV infection induces cross-reactive antibodies that influence the severity of secondary ZIKV infections. It has also been proposed that pre-existing ZIKV immunity could affect DENV pathogenesis. We examined outcomes of secondary ZIKV infections in three rhesus and fifteen cynomolgus macaques, as well as secondary DENV-2 infections in three additional rhesus macaques up to a year post-primary ZIKV infection. Although cross-binding antibodies were detected prior to secondary infection for all animals and cross-neutralizing antibodies were detected for some animals, previous DENV or ZIKV infection had no apparent effect on the clinical course of heterotypic secondary infections in these animals. All animals had asymptomatic infections and, when compared to controls, did not have significantly perturbed hematological parameters. Rhesus macaques infected with DENV-2 approximately one year after primary ZIKV infection had higher vRNA loads in plasma when compared with serum vRNA loads from ZIKV-naive animals infected with DENV-2, but a differential effect of sample type could not be ruled out. In cynomolgus macaques, the serotype of primary DENV infection did not affect the outcome of secondary ZIKV infection.

Author summary Pre-existing immunity to one of the four DENV serotypes is known to increase the risk of severe disease upon secondary infection with a different serotype. Due to the antigenic similarities between ZIKV and DENV, it has been proposed that these viruses could interact in a similar fashion. Data from in vitro experiments and murine models suggests 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 for understanding the role of cross-reactive antibodies in flavivirus pathogenesis. We examined secondary ZIKV or DENV infections in rhesus and cynomolgus macaques that had previously been infected with the other virus. We assessed the outcomes of secondary ZIKV or DENV infections by quantifying vRNA 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 a year of primary infection, secondary infections with either ZIKV or DENV were similar to primary infections and were not associated with enhancement or reduction in severity of disease based on the outcomes that we assessed.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 18, 2019.
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Primary infection with dengue or Zika virus does not affect the severity of heterologous secondary infection in macaques
Meghan E. Breitbach, Christina M. Newman, Dawn M. Dudley, Laurel M. Stewart, Matthew T. Aliota, Michelle R. Koenig, Phoenix M. Shepherd, Keisuke Yamamoto, Chelsea M. Crooks, Ginger Young, Matthew R. Semler, Andrea M. Weiler, Gabrielle L. Barry, Holly Heimsath, Emma L. Mohr, Jens Eichkoff, Wendy Newton, Eric Peterson, Nancy Schultz-Darken, Sallie R. Permar, Hansi Dean, Saverio Capuano 3rd, Jorge E. Osorio, Thomas C. Friedrich, David H. O’Connor
bioRxiv 613802; doi: https://doi.org/10.1101/613802
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Primary infection with dengue or Zika virus does not affect the severity of heterologous secondary infection in macaques
Meghan E. Breitbach, Christina M. Newman, Dawn M. Dudley, Laurel M. Stewart, Matthew T. Aliota, Michelle R. Koenig, Phoenix M. Shepherd, Keisuke Yamamoto, Chelsea M. Crooks, Ginger Young, Matthew R. Semler, Andrea M. Weiler, Gabrielle L. Barry, Holly Heimsath, Emma L. Mohr, Jens Eichkoff, Wendy Newton, Eric Peterson, Nancy Schultz-Darken, Sallie R. Permar, Hansi Dean, Saverio Capuano 3rd, Jorge E. Osorio, Thomas C. Friedrich, David H. O’Connor
bioRxiv 613802; doi: https://doi.org/10.1101/613802

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