PROJECT 1: Quality of B Cell and Antibody Responses to Natural Dengue Virus Infections (University of California, Berkeley) SUMMARY The four dengue virus serotypes (DENV1-4) cause the most important mosquito-borne viral disease of humans, with ~390 million infections annually and over 3 billion people worldwide at risk of infection. Yet, no treatment is currently approved for use in humans, and the only registered vaccine is problematic. The overall approach of Project 1 is to take advantage of unique Nicaraguan sample sets to address complex questions about DENV antibody and B cell immunology in a relevant clinical and epidemiological context. The Project is designed to analyze the antibody/B cell immune profile in relation to infection outcome, disease severity, and antibody dynamics.
Each aim also addresses specific fundamental questions in dengue immunology. The overall hypothesis of this project is that the quality of B cell and antibody responses, as detemined by the repertoire and characteristics of the antibodies and B cells, impacts outcome of subsequent DENV infection as well as the long-term antibody response. The focus is on characterizing the repertoire and dynamics of the antibody response before and after primary and secondary infections in more detail as new state-of-the-art tools become available in our P01 program.
Each aim derives from findings and reagents arising from the current P01. Importantly, we integrate classical state-of-the-art molecular genetics and systems serology approaches to comprehensively examine both antigen-specific and Fc characteristics and effector functions that predict protection or pathogenesis with unprecedented resolution. The proposed research is possible due to the ongoing Pediatric Dengue Cohort Study (2004-present), a community-based prospective cohort study in Managua, Nicaragua, following ~3,700 children, now in its 15th year, and the Dengue Hospital-based Study (2005-present) in Managua, which together enable investigation of pre-infection samples, documented repeat DENV infections, and long-term B cell/antibody responses. This project is highly synergistic with the other Projects in this P01 by sharing similar samples (Projects 3 & 4) and methods and reagents (Project 2) and integrating computational biological analyses and statistical models (Core B) of the B cell/antibody response during DENV natural infections with the T cell response to DENV (Project 3) and with the immune response obtained after live attenuated DENV vaccination (Project 2). Project 1 Aim 1 will define the complete repertoire of type-specific antibodies in dengue-endemic populations in Asia and the Americas, define the footprint of major antigenic sites, and investigate the effect of genotype on epitope recognition in polyclonal sera.
Aim 2 will determine predictors of clinical outcome in terms of antibody repertoire and Fc effector function, in relation to inapparent vs. symptomatic infection as well as mild vs. severe dengue disease.
Aim 3 will examine epidemiological, antigen-specific, and Fc effector-driven predictors of antibody magnitude and kinetics after primary and secondary DENV infection and will compare the two. This discovery approach willl yield mechanistic insights into immune function. Overall, this project will identify antibody/B cell correlates of protection and pathogenesis, as well as of magnitude and durability of the antibody response, which should be useful for development and evaluation of dengue vaccines.

Public Health Relevance

(PROJECT 1) Dengue is a major public health problem worldwide and is complicated by the existence of four antigenically distinct yet immunologically cross-reactive serotypes. It is critical for development and evaluation of dengue vaccines, treatments and diagnostics to improve our understanding of the human immune response to dengue virus infection and identify what elements of the antibody/B cell response are associated with protection from or enhancement of disease. This project uses state-of-the-art immunological methods in the clinical and epidemiological context of our long-term studies in Nicaragua and synergizes extensively with the other Projects and Cores in the P01.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI106695-06
Application #
9856092
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2015-07-29
Project End
2025-07-31
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Type
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94710
Patil, Veena S; Madrigal, Ariel; Schmiedel, Benjamin J et al. (2018) Precursors of human CD4+ cytotoxic T lymphocytes identified by single-cell transcriptome analysis. Sci Immunol 3:
Oldfield, Lauren M; Fedorova, Nadia; Puri, Vinita et al. (2018) Sequences of Zika Virus Genomes from a Pediatric Cohort in Nicaragua. Genome Announc 6:
Vannice, Kirsten S; Wilder-Smith, Annelies; Barrett, Alan D T et al. (2018) Clinical development and regulatory points for consideration for second-generation live attenuated dengue vaccines. Vaccine 36:3411-3417
Rojas, Alejandra; Diagne, Cheikh T; Stittleburg, Victoria D et al. (2018) Internally Controlled, Multiplex Real-Time Reverse Transcription PCR for Dengue Virus and Yellow Fever Virus Detection. Am J Trop Med Hyg 98:1833-1836
Dhanda, Sandeep K; Vaughan, Kerrie; Schulten, Veronique et al. (2018) Development of a novel clustering tool for linear peptide sequences. Immunology 155:331-345
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

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