Zika virus (ZIKV) and the four-dengue virus (DENV) serotypes are emerging mosquito-borne flaviviruses that pose serious threats to human health. People exposed to primary DENV infections develop long-term serotype- specific neutralizing and protective antibodies (Abs). Individuals exposed to secondary DENV infections with a new serotype develop a novel class of cross neutralizing and protective Abs that are even effective against serotypes not previously encountered by the individual. While the molecular properties of type-specific human neutralizing Abs have been well-defined, little is known about the origin and properties of DENV cross- neutralizing Abs induced after secondary infection. In this project, we will use an established human challenge model of secondary DENV infection to test the hypothesis that secondary infections activate and expand memory B cells from primary infections to generate somatically mutated Abs that bind with high affinity to epitopes that are conserved between DENV serotypes (Specific Aim 1). We will also define the molecular specificity and functional properties of neutralizing Abs induced in US travelers with laboratory confirmed ZIKV infections. Building on our discoveries about primary Ab responses to DENVs, we propose that people exposed to ZIKV as a primary flavivirus infection develop type-specific neutralizing Abs that target quaternary structure envelope (E) protein epitopes displayed on the viral surface (Specific Aim 2). While repeat infections with different DENV serotypes induce durable cross DENV neutralizing Abs, it is unclear if this response can expand to neutralize ZIKV. By analyzing Ab responses in people exposed to secondary DENV infections and DENV immune individuals infected with ZIKV, we will determine the molecular mechanisms and structural features that promote or restrict the breadth of Ab cross-neutralization between the DENV sero-complex and ZIKV (Specific Aim 3). The importance of our studies is underscored by the disappointing results recently reported with tetravalent live attenuated DENV vaccines to induce balanced cross-protective immunity to the 4 DENV serotypes. Our studies are relevant to the successful design and evaluation of the next generation of safe and effective vaccines against emerging flaviviruses. Moreover, patterns of cross-neutralizing and protective immunity between dengue and Zika viruses may explain the explosive spread of ZIKVs in Latin America compared to Asia.

Public Health Relevance

Dengue and Zika are emerging flaviviruses and major threats to human health. Some people infected with dengue virus develop antibodies that are cross-protective against multiple dengue serotypes. In this application, we will determine the origin and properties of these useful cross protective antibodies. We will also study the properties of antibodies that neutralize Zika viruses. Our studies are relevant to the development of new vaccines within potential to cross protect people from different dengue serotypes and Zika virus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI107731-05A1
Application #
9687406
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Challberg, Mark D
Project Start
2013-08-05
Project End
2023-08-31
Budget Start
2018-09-24
Budget End
2019-08-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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de Silva, Aravinda M; Harris, Eva (2018) Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? The Path to a Dengue Vaccine: Learning from Human Natural Dengue Infection Studies and Vaccine Trials. Cold Spring Harb Perspect Biol 10:
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:
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Liu, Ping; Weinreb, Violetta; Ridilla, Marc et al. (2017) Rapid, directed transport of DC-SIGN clusters in the plasma membrane. Sci Adv 3:eaao1616

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