ABSTRACT
The recent Zika virus (ZIKV) epidemic in the Americas has revealed rare but serious manifestations of infection. ZIKV has emerged in regions endemic for dengue virus (DENV), a closely related mosquito-borne flavivirus. Cross-reactive antibodies confound studies of ZIKV epidemiology and pathogenesis. The immune responses to ZIKV may be different in people, depending on their DENV immune status. Here, we focus on the human B cell and antibody response to ZIKV as a primary flavivirus infection to define the properties of neutralizing and protective antibodies generated in the absence of preexisting immunity to DENV. The plasma antibody and memory B cell response is highly ZIKV type-specific, and ZIKV-neutralizing antibodies mainly target quaternary structure epitopes on the viral envelope. To map viral epitopes targeted by protective antibodies, we isolated 2 type-specific monoclonal antibodies (mAbs) from a ZIKV case. Both mAbs were strongly neutralizing in vitro and protective in vivo. The mAbs recognize distinct epitopes centered on domains I and II of the envelope protein. We also demonstrate that the epitopes of these mAbs define antigenic regions commonly targeted by plasma antibodies in individuals from endemic and nonendemic regions who have recovered from ZIKV infections.
Subject(s)
Antibodies, Viral/immunology , Antigens, Viral/chemistry , Epitopes, B-Lymphocyte/chemistry , Zika Virus Infection/immunology , Zika Virus/immunology , Animals , Antibodies, Monoclonal/blood , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/isolation & purification , Antigens, Viral/immunology , Cross Protection/immunology , Cross Reactions/immunology , Dengue/epidemiology , Dengue/immunology , Dengue/prevention & control , Dengue/virology , Dengue Virus/immunology , Disease Models, Animal , Endemic Diseases/prevention & control , Epidemics/prevention & control , Epitopes, B-Lymphocyte/immunology , Female , Host-Pathogen Interactions/immunology , Humans , Immunologic Memory , Male , Mice , Protein Structure, Quaternary , Viral Vaccines/therapeutic use , Zika Virus Infection/epidemiology , Zika Virus Infection/prevention & control , Zika Virus Infection/virologyABSTRACT
Little is known about enduring memory B cell (MBC) responses to Zika virus (ZIKV) and their relationship with circulating antibodies. Here we comprehensively assess MBC frequency and specificity alongside serum binding and neutralizing antibody responses to ZIKV ~2 weeks and ~8 months postinfection in 31 pediatric subjects with 0, 1 or >1 prior infections with the related dengue virus (DENV). ZIKV infection elicits a robust type-specific MBC response, and the majority of late convalescent anti-ZIKV serum neutralizing activity is attributable to ZIKV-specific antibodies. The number of prior DENV infections does not influence type-specific or cross-reactive MBC responses, although ZIKV has the highest cross-reactivity with DENV3. DENV cross-reactive MBCs expanded by ZIKV infection decline in number and proportion by late convalescence. Finally, ZIKV induces greater cross-reactivity in the MBC pool than in serum antibodies. Our data suggest immunity to DENV only modestly shapes breadth and magnitude of enduring ZIKV antibody responses.