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The Penn approach to tackling Zika virus

August 23, 2016

The first confirmed Zika virus (ZIKV) infections in Brazil were promulgated by the Pan American Health Organization in May 2015. By the start of 2016, the World Health Organization had declared the outbreak a Public Health Emergency of International Concern as evidence for a causal relationship between primary ZIKV infection during pregnancy and microcephaly amassed. Epidemiologic and pathogenic uncertainties hinder efforts to treat ZIKV. If a pregnant woman is exposed to ZIKV, how likely is she to contract the virus? What are the chances ZIKV will be transmitted to her fetus? Does sexual transmission of ZIKV pose a different risk of birth defects than mosquito-borne transmission?  Fortunately, numerous labs at Penn are well-poised to search for answers to some of these outstanding questions.

 

One such lab is that of Dr. Sara Cherry. Her group studies several mosquito-borne RNA viruses to identify cellular factors that impact infection as novel targets for therapeutics. ZIKV belongs to the Flaviviridae viral family along with dengue and West Nile virus, both of which Cherry’s lab researches. “When it became clear that ZIKV was running rampant through South and Central America, we decided to include it in the experiments we were already doing. We had all the reagents to study it because we’d been studying very related viruses,” said Cherry. Additionally, her group screens small molecule libraries for their ability to block ZIKV infection in relevant cell types, including placental trophoblasts and blood-brain barrier endothelial cells. These compounds are FDA approved and could be rapidly repurposed to treat ZIKV. While these drugs may be useful to prevent Guillain-Barré syndrome, a nervous system disorder that can cause paralysis, and sexual transmission of ZIKV, it is unlikely that any of these drugs would be given to the truly negatively affected demographic: pregnant women. “ZIKV is a women’s health issue as much as it is a global health issue,” mused Cherry. “The current recommendation for women of child-bearing age is to not get pregnant. Unfortunately, there are many women worldwide that aren’t afforded the luxury of choosing when they become pregnant, especially in the countries affected by this current outbreak.”

 

If pregnant women were to be treated, it would most likely be with neutralizing antibodies. However, the similarity between ZIKV and dengue virus (DENV) heightens the risk of antibody-dependent enhancement (ADE). The extent of the similarity between the two viruses is reflected by the humoral immune system, where monoclonal antibodies (mAbs) generated from DENV-infected subjects exhibit cross-reactivity with ZIKV. The mAbs fail to neutralize the virus, instead potently enhancing its infectivity. Observing ADE of ZIKV infection is worrisome because the mechanism is preferentially associated with the development of severe dengue hemorrhagic fever. Cross-reactive, non-neutralizing antibodies generated for one of four DENV serotypes facilitate viral uptake by macrophages and other Fc-receptor bearing cells upon secondary infection with an another serotype, increasing viremia and pathogenicity.

 

Research conducted by MVP students in Dr. Scott Hensley’s lab may be useful for solving this problem. The group studies the effect of prior DENV exposure on the immune response to ZIKV. Rising second year Shannon Barbour screens hybridomas for mAbs that can differentiation between ZIKV, DENV, and other arboviruses. The results of her research could identify antibodies that can be safely administered to pregnant women infected with ZIKV without risk of cross-reactivity with DENV. Such antibodies could additionally be used to rapidly test pathogen exposure and risk of severe disease development. Conversely, rotation student Nawar Naseer focuses on determining whether the repertoire of antibodies obtained upon ZIKV infection alone is different from that obtained with DENV pre-exposure, which would help identify antibodies that can neutralize both DENV and ZIKV.

 

This past June marked an exciting time for Dr. Dave Weiner when the FDA approved the first human clinical trials for a ZIKV vaccine developed in part by his lab. The speed at which the DNA vaccine was developed is remarkable considering Weiner and his collaborators – Inovio Pharmaceuticals, GeneOne Life Science, and Dr. Gary Kobinger, the head of Special Pathogens at the Public Health Agency of Canada – only began their work last fall. “There weren’t any reagents or models when we started working on ZIKV,” recalled Weiner. “You learn a lot by focusing on new things because you’re forced to stretch your imagination. You have to apply things that you know about other pathogens, which is a great exercise for students and postdocs.” Although the nature of a protective immune response against ZIKV is unknown, both Weiner’s group and the Vaccine Center at the Wistar Institute are well experienced with indicators of consistent levels of immunity. Beginning with Dr. Stanley Plotkin’s rubella vaccine, the Wistar Institute has been developing life-saving vaccines for over half a century and Weiner’s novel synthetic DNA platform serves to advance this prestige. The trial participants are scheduled to receive the ZIKV vaccine within the next few weeks.  

 

Penn fosters an environment conducive for cutting-edge research. This is particularly important when studying emerging infectious diseases like ZIKV, where time is a precious resource. 

 

 

                   

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