This proposal focuses on the rational design of antigens for serodiagnosis of Zika virus (ZIKV) with minimal cross-reactivity to other human pathogenic flaviviruses. Zika virus (ZIKV) infection can cause miscarriage, microcephaly, and Guillain-Barr syndrome. A specific serodiagnosis of ZIKV infection is urgently needed to track the spread of ZIKV infection and to diagnose individuals exposed to ZIKV in scenarios such as prenatal diagnosis and neonatal monitoring, blood donor screening, screening of travelers returning from Zika-endemic regions. ZIKV serodiagnosis is highly challenging because of extensive cross-reactivity with dengue and other flaviviruses that co-circulate with ZIKV. Our previous and ongoing work defining the human serotype specific antibody responses to dengue envelope (E) protein place us in a unique position to define similar regions in ZIKV E and produce candidate diagnostic antigens for serodiagnostics. Fortified with detailed structural information, we will rationally design and produce substructures of Zika E protein bearing unique antigenic sites for specific and sensitive serological detection of ZIKV infections in flavivirus nave, flavivirus pre-immune or flavivirus-vaccinated populations.
For aim 1, we will produce ZIKV candidate antigens and measure their antibody binding response across a reference panel of immune sera from people exposed to primary or secondary flavivirus infections, including ZIKV and DENV.
In Aim 2, we will use protein engineering approaches to redesign most efficacious candidate antigens to change cross-reactive antigenic sites, while preserving Zika specific sites, to improve the diagnostic potential of antigens for differential serodiagnosis of Zika infection. We will compare and contrast one or a combination of surface redesigned Zika antigens for serological detection of recent and prior exposure to ZIKV. In follow up studies, we will partner with reference laboratories and commercial partners to use recombinant protein antigens to develop simple assays for use at the point of care and in surveillance programs.

Public Health Relevance

Zika virus causes dangerous neurologic conditions and birth defects making it a major public health concern. Available blood tests for diagnosing Zika can be inaccurate if a person has previously been infected by a related virus, which is the case for millions of people at risk for Zika infection. We are using cutting edge molecular biology methods to develop antigens for blood diagnostic test that will accurately detect Zika virus exposure regardless of prior virus exposure history ? a reagent that has broad application in the public health response to the Zika epidemic and to understand its severe pathogenesis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZAI1)
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Challberg, Mark D
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Premkumar, Lakshmanane; Collins, Matthew; Graham, Stephen et al. (2018) Development of Envelope Protein Antigens To Serologically Differentiate Zika Virus Infection from Dengue Virus Infection. J Clin Microbiol 56: