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Front Immunol. 2017 Oct 13;8:1309. doi: 10.3389/fimmu.2017.01309. eCollection 2017.

Global Assessment of Dengue Virus-Specific CD4+ T Cell Responses in Dengue-Endemic Areas.

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Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States.
Laboratorio Nacional de Virología, Centro Nacional de Diagnóstico y Referencia, Ministerio de Salud, Managua, Nicaragua.
Division of Clinical Immunology and Allergy, School of Medicine, University of São Paulo, São Paulo, Brazil.
Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States.
Vaccine Testing Center, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, United States.
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia.
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
Genetech Research Institute, Colombo, Sri Lanka.
Chantal BIYA International Reference Centre for Research on the Prevention and Management of HIV/AIDS CIRCB, Yaoundé, Cameroon.
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC, United States.
Emerging Infectious Disease Programme, Duke-NUS Medical School, Singapore, Singapore.
Immunology Programme, Department of Microbiology and Immunology, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
National Institute for Health Research, Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, United Kingdom.
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
Neurovirology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, United States.



Dengue is a major public health problem worldwide. Assessment of adaptive immunity is important to understanding immunopathology and to define correlates of protection against dengue virus (DENV). To enable global assessment of CD4+ T cell responses, we mapped HLA-DRB1-restricted DENV-specific CD4+ T cell epitopes in individuals previously exposed to DENV in the general population of the dengue-endemic region of Managua, Nicaragua.


HLA class II epitopes in the population of Managua were identified by an in vitro IFNγ ELISPOT assay. CD4+ T cells purified by magnetic bead negative selection were stimulated with HLA-matched epitope pools in the presence of autologous antigen-presenting cells, followed by pool deconvolution to identify specific epitopes. The epitopes identified in this study were combined with those previously identified in the DENV endemic region of Sri Lanka, to generate a "megapool" (MP) consisting of 180 peptides specifically designed to achieve balanced HLA and DENV serotype coverage. The DENV CD4MP180 was validated by intracellular cytokine staining assays.


We detected responses directed against a total of 431 epitopes, representing all 4 DENV serotypes, restricted by 15 different HLA-DRB1 alleles. The responses were associated with a similar pattern of protein immunodominance, overall higher magnitude of responses, as compared to what was observed previously in the Sri Lanka region. Based on these epitope mapping studies, we designed a DENV CD4 MP180 with higher and more consistent coverage, which allowed the detection of CD4+ T cell DENV responses ex vivo in various cohorts of DENV exposed donors worldwide, including donors from Nicaragua, Brazil, Singapore, Sri Lanka, and U.S. domestic flavivirus-naïve subjects immunized with Tetravalent Dengue Live-Attenuated Vaccine (TV005). This broad reactivity reflects that the 21 HLA-DRB1 alleles analyzed in this and previous studies account for more than 80% of alleles present with a phenotypic frequency ≥5% worldwide, corresponding to 92% phenotypic coverage of the general population (i.e., 92% of individuals express at least one of these alleles).


The DENV CD4 MP180 can be utilized to measure ex vivo responses to DENV irrespective of geographical location.


CD4+ T cells; HLA; adaptive immunity; dengue virus; epitope

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