TY - JOUR
T1 - Potent plasmablast-derived antibodies elicited by the National Institutes of Health dengue vaccine
AU - Magnani, Diogo M.
AU - Silveira, Cassia G.T.
AU - Ricciardi, Michael J.
AU - Gonzalez-Nieto, Lucas
AU - Pedreño-Lopez, Núria
AU - Bailey, Varian K.
AU - Gutman, Martin J.
AU - Maxwell, Helen S.
AU - Domingues, Aline
AU - Costa, Priscilla R.
AU - Ferrari, Lilian
AU - Goulart, Raphaella
AU - Martins, Mauricio A.
AU - Martinez-Navio, José M.
AU - Fuchs, Sebastian P.
AU - Kalil, Jorge
AU - Timenetsky, Maria do Carmo
AU - Wrammert, Jens
AU - Whitehead, Stephen S.
AU - Burton, Dennis R.
AU - Desrosiers, Ronald C.
AU - Kallas, Esper G.
AU - Watkins, David I.
N1 - Funding Information:
We thank Ana Carolina Soares, Carla Sant'Anna Corr?a, Ovini Senelka, and Meagan Read for help provided in different stages of this study. We also thank Beatriz Thome, Ricardo Palacios, and Alexander Precioso for support at the Butantan Institute. 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). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© 2017 American Society for Microbiology.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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 [Neut50] = 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.
AB - 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 [Neut50] = 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.
KW - B cell
KW - Butantan-DV
KW - Dengue
KW - Monoclonal antibodies
KW - Plasmablast
KW - TV003
KW - Vaccines
UR - http://www.scopus.com/inward/record.url?scp=85032272521&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85032272521&partnerID=8YFLogxK
U2 - 10.1128/JVI.00867-17
DO - 10.1128/JVI.00867-17
M3 - Article
C2 - 28878078
AN - SCOPUS:85032272521
VL - 91
JO - Journal of Virology
JF - Journal of Virology
SN - 0022-538X
IS - 22
M1 - e00867-17
ER -