The four dengue virus serotypes (DENV1-4) cause the most important mosquito-borne viral disease of humans, with ~400 million infections annually. The mechanisms by which the host immune response to DENV provides either protection or enhancement in a subsequent infection with a different DENV serotype are poorly understood, and this has been a major hindrance in vaccine development. The suboptimal results from the first proof-of-concept dengue vaccine efficacy trial highlight the critical need t better understand the immune response to natural DENV infections and vaccine candidates and to identify robust correlates of protection. This P01 Program applies state-of-the-art immunological methods in the context of long-term ongoing clinical and epidemiological studies of natural DENV infections in Nicaragua as well as Phase 2 and 3 vaccine trials of the Takeda tetravalent live-attenuated dengue vaccine (TV-LAV). We propose to study qualitative and quantitative features of B and T cell immune responses in humans under a coordinated P01 Program including three projects: 1) B cell and antibody responses to natural dengue virus infections; 2) B cell and antibody responses following live attenuated dengue virus vaccination; 3) T cell responses following DENV natural infections and live-attenuated dengue virus vaccination. The overall hypothesis is that DENV-nave and DENV-exposed individuals develop fundamentally different protective B and T cell responses upon exposure to a new DENV infection or live vaccine. Moreover, we posit that it is the quality as well as the quantity of neutralizing antibodies that determines protective efficacy. The P01 is highly synergistic in that samples from the same individuals and/or sample sets, as well as specific assays and methodologies, are being shared among the Projects, which are supported by an Administrative Core, Immunology Core, and Clinical & Data Management Core. The P01 also leverages a number of existing grants and contracts supporting dengue studies, vaccine trials, and epitope mapping programs. We have formed a Consortium of world-renowned investigators with extensive experience and on-going programs in dengue clinical, immunological, and virological research and vaccine development - thus ensuring a high-quality successful research program, especially since the investigators have a long history of productive collaboration (>190 joint publications). The P01 should result in: 1) Improved understanding of what constitutes protective adaptive immunity in 1 and 2 DENV infections and in nave and previously DENV-exposed recipients of a dengue TVLAV, which can inform future vaccine formulations; 2) Identification of natural and vaccine-induced B cell/antibody and CD4+/CD8+ T cell correlates of protection that can be used to assess existing and future vaccines; 3) Identification of potential therapeutic monoclonal antibodies and T cell peptide vaccines; and 4) Mapping of novel epitopes and generation of recombinant viruses that can serve as new epitope-specific diagnostic tools.

Public Health Relevance

Dengue is a major public health problem worldwide and is complicated by four distinct yet cross-reactive serotypes. This P01 addresses the critical need to improve understanding of the human B and T cell response to dengue virus infection and vaccination and to identify immune correlates of protection from disease. To this end, our consortium of world-renowned investigators is applying state-of-the-art immunological methods in the context of long-term ongoing clinical and epidemiological studies of dengue and Phase 2 and 3 trials of dengue vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI106695-01A1
Application #
8854816
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Program Officer
Cassetti, Cristina
Project Start
2015-07-29
Project End
2020-06-30
Budget Start
2015-07-29
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$2,106,690
Indirect Cost
$295,771
Name
University of California Berkeley
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Scott, Jason M; Lebratti, Tania J; Richner, Justin M et al. (2018) Cellular and Humoral Immunity Protect against Vaginal Zika Virus Infection in Mice. J Virol :
Andrade, Paulina; Coloma, Josefina; Harris, Eva (2018) ELISPOT-Based ""Multi-Color FluoroSpot"" to Study Type-Specific and Cross-Reactive Responses in Memory B Cells after Dengue and Zika Virus Infections. Methods Mol Biol 1808:151-163
Zambrana, José Victor; Bustos Carrillo, Fausto; Burger-Calderon, Raquel et al. (2018) Seroprevalence, risk factor, and spatial analyses of Zika virus infection after the 2016 epidemic in Managua, Nicaragua. Proc Natl Acad Sci U S A 115:9294-9299
Regla-Nava, Jose Angel; Elong Ngono, Annie; Viramontes, Karla M et al. (2018) Cross-reactive Dengue virus-specific CD8+ T cells protect against Zika virus during pregnancy. Nat Commun 9:3042
Montoya, Magelda; Collins, Matthew; Dejnirattisai, Wanwisa et al. (2018) Longitudinal Analysis of Antibody Cross-neutralization Following Zika Virus and Dengue Virus Infection in Asia and the Americas. J Infect Dis 218:536-545
Fowler, Angela M; Tang, William W; Young, Matthew P et al. (2018) Maternally Acquired Zika Antibodies Enhance Dengue Disease Severity in Mice. Cell Host Microbe 24:743-750.e5
Burger-Calderon, Raquel; Gonzalez, Karla; Ojeda, Sergio et al. (2018) Zika virus infection in Nicaraguan households. PLoS Negl Trop Dis 12:e0006518
Tsai, Wen-Yang; Youn, Han Ha; Tyson, Jasmine et al. (2018) Use of Urea Wash ELISA to Distinguish Zika and Dengue Virus Infections. Emerg Infect Dis 24:1355-1359
Gallichotte, Emily N; Baric, Thomas J; Yount Jr, Boyd L et al. (2018) Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes. PLoS Pathog 14:e1006934
Katzelnick, Leah C; Harris, Eva (2018) The use of longitudinal cohorts for studies of dengue viral pathogenesis and protection. Curr Opin Virol 29:51-61

Showing the most recent 10 out of 54 publications