Potent Plasmablast-Derived Antibodies Elicited by the National Institutes of Health Dengue Vaccine

• Type of Material: Article
• Authors: Diogo M. Magnani, University of Miami; Cassia G.T. Silveira, University of São Paulo; Michael J. Ricciardi, University of Miami; Lucas Gonzalez-Nieto, University of Miami; Nuria Pedreno-Lopez, University of Miami; Varian K. Bailey, University of Miami; Martin J. Gutman, University of Miami; Helen S. Maxwell, University of Miami; Aline Domingues, University of Miami; Priscilla R. Costa, University of São Paulo; Lilian Ferrari, University of São Paulo; Raphaella Goulart, University of São Paulo; Mauricio A. Martins, University of Miami; Jose M. Martinez-Navio, University of Miami; Sebastian P. Fuchs, University of Miami; Jorge Kalil, University of São Paulo; Maria do Carmo Timenetsky, Adolfo Lutz Institute; Jens Wrammert, Emory University; Stephen S. Whitehead, National Institutes of Health; Dennis R. Burton, Scripps Research Institute; Ronald C. Desrosiers, University of Miami; Esper G. Kallas, University of São Paulo; David I. Watkins, University of Miami
• Language: English
• Date: 2017-11-15
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2017 American Society for Microbiology.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.00867-17
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 91
• Issue: 22
• Start Page: e00867-17
• End Page: e00867-17
• Grant/Funding Information: This work was supported by funding from the Wallace H. Coulter Center for Translational Research, Miami, FL, the Brazilian Development Bank (BNDES), and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID, NIH).
• Keywords: MONOCLONAL-ANTIBODIES; monoclonal antibodies; TV003; vaccines; dengue; Life Sciences & Biomedicine; HUMANS; DISEASE SEVERITY; TRIAL; EFFICACY; MEMORY B-CELLS; NEUTRALIZING ANTIBODIES; Butantan-DV; Virology; VIRUS-INFECTION; Science & Technology; plasmablast; ENHANCEMENT; HIGHLY POTENT; B cell
• Research Categories: Biology, Virology; Biology, Microbiology; Health Sciences, Immunology

Abstract

Exposure to dengue virus (DENV) is thought to elicit lifelong immunity, mediated by DENV-neutralizing antibodies (nAbs). However, Abs generated by primary infections confer serotype-specific protection, and immunity against other serotypes develops only after subsequent infections. Accordingly, the induction of these nAb responses acquired after serial DENV infections has been a long-soughtafter goal for vaccination. Nonetheless, it is still unclear if tetravalent vaccines can elicit or recall nAbs. In this study, we have characterized the responses from a volunteer who had been previously exposed to DENV and was immunized with the live attenuated tetravalent vaccine Butantan-DV, developed by the NIH and Butantan Institute. Eleven days after vaccination, we observed an ~70-fold expansion of the plasmablast population. We generated 21 monoclonal Abs (MAbs) from singly sorted plasmablasts. These MAbs were the result of clonal expansions and had significant levels of somatic hypermutation (SHM). Nineteen MAbs (90.5%) neutralized at least one DENV serotype at concentrations of 1 μg/ml or less; 6 of the 21 MAbs neutralized three or more serotypes. Despite the tetravalent composition of the vaccine, we observed a neutralization bias in the induced repertoire: DENV3 was targeted by 18 of the 19 neutralizing MAbs (nMAbs). Furthermore, the P3D05 nMAb neutralized DENV3 with extraordinary potency (concentration to achieve half-maximal neutralization [Neut 50 ] = 0.03 μg/ml). Thus, the Butantan-DV vaccine engendered a mature, antigen-selected B cell repertoire. Our results suggest that preexisting responses elicited by a previous DENV3 infection were recalled by immunization.