Dominant cross-reactive B cell response during secondary acute dengue virus infection in humans

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. © 2012 zompi et al.