Primary And Secondary Dengue Virus Infections Elicit Similar Memory B-Cell Responses, But Breadth To Other Serotypes And Cross-Reactivity To Zika Virus Is Higher In Secondary Dengue

Background. The 4 antigenically distinct serotypes of dengue virus (DENV) share extensive homology with each other and with the closely related Zika flavivirus (ZIKV). The development of polyclonal memory B cells (MBCs) to the 4 DENV serotypes and ZIKV during DENV infection is not fully understood.Methods. In this study, we analyzed polyclonal MBCs at the single-cell level from peripheral blood mononuclear cells collected similar to 2 weeks or 6-7 months postprimary or postsecondary DENV infection from a pediatric hospital-based study in Nicaragua using a Multi-Color FluoroSpot assay.Results. Dengue virus elicits robust type-specific and cross-reactive MBC responses after primary and secondary DENV infection, with a significantly higher cross-reactive response in both. Reactivity to the infecting serotype dominated the total MBC response. Although the frequency and proportion of type-specific and cross-reactive MBCs were comparable between primary and secondary DENV infections, within the cross-reactive response, the breadth of MBC responses against different serotypes was greater after secondary DENV infection. Dengue virus infection also induced cross-reactive MBC responses recognizing ZIKV, particularly after secondary DENV infection.Conclusions. Overall, our study sheds light on the polyclonal MBC response to DENV and ZIKV in naive and DENV-preimmune subjects, with important implications for natural infections and vaccine development.