title: Dominant cross-reactive B cell response during secondary acute dengue virus infection in humans.
abstract: The four serotypes of dengue virus (DENV) cause dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Severe disease has been associated with heterotypic secondary DENV infection, mediated by cross-reactive antibodies (Abs) and/or cross-reactive T cells. The role of cross-reactive immunity in mediating enhanced disease versus cross-protection against secondary heterotypic DENV infection is not well defined. A better understanding of the cross-reactive immune response in natural infections is critical for development of safe and effective tetravalent vaccines. We studied the B cell phenotype of circulating B cells in the blood of pediatric patients suspected of dengue during the 2010-2011 dengue season in Managua, Nicaragua (n  =  216), which was dominated by the DENV-3 serotype. We found a markedly larger percentage of plasmablast/plasma cells (PB/PCs) circulating in DENV-positive patients as compared to patients with Other Febrile Illnesses (OFIs). The percentage of DENV-specific PB/PCs against DENV-3 represented 10% of the circulating antibody-producing cells (ASCs) in secondary DENV-3 infections. Importantly, the cross-reactive DENV-specific B cell response was higher against a heterotypic serotype, with 46% of circulating PB/PCs specific to DENV-2 and 10% specific to DENV-3 during acute infection. We also observed a higher cross-reactive DENV-specific IgG serum avidity directed against DENV-2 as compared to DENV-3 during acute infection. The neutralization capacity of the serum was broadly cross-reactive against the four DENV serotypes both during the acute phase and at 3 months post-onset of symptoms. Overall, the cross-reactive B cell immune response dominates during secondary DENV infections in humans. These results reflect our recent findings in a mouse model of DENV cross-protection. In addition, this study enabled the development of increased technical and research capacity of Nicaraguan scientists and the implementation of several new immunological assays in the field.
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, California, USA. simona.zompi@gmail.com
authors.forename: Simona
authors.initials: S
authors.lastname: Zompi
authors.forename: Magelda
authors.initials: M
authors.lastname: Montoya
authors.forename: Marie O
authors.initials: MO
authors.lastname: Pohl
authors.forename: Angel
authors.initials: A
authors.lastname: Balmaseda
authors.forename: Eva
authors.initials: E
authors.lastname: Harris
mesh_terms: D000293:Adolescent; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003429:Cross Reactions; D003715:Dengue / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D005260:Female; D006801:Humans; D007223:Infant; D008218:Lymphocytosis; D008297:Male; D009527:Nicaragua
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral