Mechanisms of Protective!Immunity after Dengue Natural Infections and Vaccination OVERALL P01 SUMMARY The four dengue virus serotypes (DENV1-4) cause the most important mosquito-borne viral disease of humans, with 100 million cases annually. The mechanisms by which the host immune response to DENV provides either protection against or enhancement of a subsequent infection with a different DENV serotype are not fully understood, and this has been a major concern in vaccine development and implementation. The poor results of the first registered dengue live attenuated vaccine highlight the critical need to better understand the immune response to natural DENV infections and vaccine candidates and to identify robust correlates of protection. Our current Program Project has been very successful, generating >50 high-level publications in 3.5 years and producing key findings that are timely, topical, and impactful. Here, we propose to identify immune mechanisms responsible for outcomes of DENV infection and vaccination, comprehensively exploring both the antigenic specificity and Fc functionality of antibodies as well as the quality of T cell responses in the context of long-term ongoing clinical and epidemiological studies of natural DENV infections and vaccines. We integrate classical cutting-edge molecular genetic and systems serology approaches to systematically examine both antigen specificity and Fc characteristics and effector functions of antibodies, as well as T cell attributes, that predict protection or pathogenesis. We propose a coordinated P01 Program that includes four projects: 1) Quality of B Cell and Antibody Responses to Natural Dengue Virus Infections; 2) Dengue Vaccines: Linking Vaccine-Induced Antibody Responses to Protective or Disease-Enhancing Immunity; 3) Quality of T Cell Responses Following Dengue Virus Natural Infections and Live-Attenuated Dengue Virus Vaccination, and 4) Genetic and Structural Basis for Human Antibody Inhibition of Dengue Viruses. The P01 is highly synergistic in that samples from the same individuals, as well as specific assays, reagents and methodologies, are shared among the Projects, which are supported by an Administrative Core, Computational Biology and Statistical Modeling Core, and Clinical and Data Management Core. We will leverage unique sample sets from the longest continuous cohort study of dengue, in Nicaragua, as well as a cohort study following recipients of the Dengvaxia vaccine in the Philippines and human challenge studies of the NIH live attenuated vaccine. We have have expanded our existing P01 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 continued high-quality successful research program. All the partners have a long-standing record of collaboration and numerous joint publications (>225).
The Specific Aims are: 1) Define the antigenic repertoire and Fc characteristics of antibodies that predict outcome of subsequent DENV infection as well as the long-term humoral immune response; 2) Link vaccine-induced antibody responses to specific outcomes such as protection, vaccine failure and vaccine-primed severe disease; 3) Demonstrate that quality of T cell responses influences the clinical outcomes of infection and vaccination and modulates the quantity and quality of B cell responses; 4) Comprehensively define the protective antigenic landscape of DENV1-3 type-specific as well as DENV cross-reactive monoclonal and polyclonal antibodies. The overarching premise is that the accumulation of immunologic data from natural DENV infections, vaccine cohorts, and human challenge studies, coupled with state-of-the-art computational modeling and data integration, will enable identification of new immune correlates that predict protective immunity or immune enhancement, providing critical metrics for evaluating existing and second-generation DENV vaccines.

Public Health Relevance

(OVERALL P01) Dengue is a major public health problem worldwide and is complicated by four distinct yet cross-reactive sero- types, such that prior infection with one serotype can either protect or enhance a subsequent infection with a different serotype ? posing a major challenge for vaccine development. This Program Project addresses the critical need to improve understanding of the human antibody and B and T cell response to dengue virus infection and vaccination and to identify immune correlates of protection and pathogenesis. 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 as well as studies of vaccinated populations and human challenge models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI106695-06
Application #
9856088
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Morabito, Kaitlyn Melissa
Project Start
2015-07-29
Project End
2025-07-31
Budget Start
2020-08-21
Budget End
2021-07-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
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
94710
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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

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