Does previous dengue fever infection have an effect on Zika virus outcome?

Photo of a pregnant woman standing in a field by Kathy West
Photo by Kathy West

By Jordana Lenon
Sept. 1, 2021                                    

Understanding whether the severity of maternal and fetal Zika virus infection increases in pregnant women who previously had dengue fever should be a public health priority, according to researchers from multiple universities studying rhesus macaques at the Wisconsin National Primate Research Center.

A new study by these researchers is the first to examine the impact of pre-existing dengue immunity on Zika pathogenesis during pregnancy in a translational nonhuman primate model. The research was published July 30 in the journal PLoS Neglected Tropical Diseases.

Concerns have arisen that pre-existing immunity to dengue fever virus could enhance Zika virus disease due to the similarity between the two viruses and the possibility of antibody-dependent viral enhancement of infection, the researchers shared. The concern would be that dengue antibodies may not only be unable to prevent Zika infection, but may even act like a Trojan horse to allow more Zika particles into cells, leading to more viral replication and an overactive and potentially dangerous immune system response.

The researchers found that Zika-infected pregnant rhesus macaques with prior dengue exposure had more Zika viral RNA in their maternal-fetal interface tissues (e.g., placenta and uterus) when compared with Zika-infected monkeys with no previous dengue exposure. However, pre-existing dengue immunity had no measurable impact on Zika virus replication in maternal plasma, which is one way to detect enhanced infection.

Furthermore, all animal pregnancies progressed to term without adverse outcomes such as fetal growth restriction, microcephaly, missing limbs or hydrops fetalis, as has been reported in 5-10 percent of infants born to pregnant women infected with Zika. All eight healthy infant monkeys were placed with their mothers following delivery by cesarean section at term. The infants will also be studied for long-term behavioral analysis as part of a separate study, the researchers stated.

Matthew Aliota in his lab at the University of Minnesota, Department of Veterinary and Biomedical Sciences
Matthew Aliota in his lab at the University of Minnesota, Department of Veterinary and Biomedical Sciences

Four pregnant saline-inoculated animals served as a control group and underwent the same experimental regimen as the Zika virus infected cohort, including sedation for all blood draws and ultrasounds.

Rhesus macaque development, including placental development, resembles that of humans more closely than does development in other animals, making these monkeys particularly relevant for understanding viral infections in pregnancy in controlled settings.

Continuing to study and understand the risks of antibody-dependent enhancement to pregnant women worldwide is critical as vaccines against dengue and Zika are developed and licensed – and as dengue and Zika continue to circulate in the global tropical population.

This work was supported by a Research Project Grant from the National Institute of Allergy and Infectious Disease to Matthew Aliota, assistant professor of veterinary and biomedical sciences at the University of Minnesota and Thomas Friedrich, professor of pathobiological sciences at University of Wisconsin–Madison; by the NIH Office of Research Infrastructure Programs base grant to the Wisconsin National Primate Research Center; and by an Institutional Research Training Grant to Chelsea Crooks from the National Institute of Allergy and Infectious Disease.

David O’Connor, left, and Thomas Friedrich of the WNPRC's Global Infectious Disease Scientific Group are pictured in their lab at the University of Wisconsin–Madison in 2020. Photo: Jeff Miller, UW-Madison
David O’Connor, left, and Thomas Friedrich of the WNPRC’s Global Infectious Disease Scientific Group are pictured in their lab at the University of Wisconsin–Madison in 2020. Photo: Jeff Miller, UW-Madison