Burton DR, Timenetsky MDC, Wrammert J, Bailey VK, Pedreño-Lopez N, Ricciardi MJ, Desrosiers RC, Goulart R, Maxwell HS, Whitehead SS, Costa PR, Gutman MJ, Magnani DM, Kallas EG, Martinez-Navio JM, Ferrari L, Domingues A, Waktins DI, Fuchs SP, Martins MA, Kalil J, Silveira CGT, Gonzalez-Nieto L
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 only develops after subsequent infections. Accordingly, the induction of these nAb responses acquired after serial DENV infections has been a long sought-after goal for vaccination. Nonetheless, it is still unclear if tetravalent vaccines can elicit or recall nAbs. Here, 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. Eleven days after vaccination, we observed a ∼70-fold expansion of the plasmablast population. We generated 21 monoclonal (m)Abs 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; six 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 (n)mAbs. Furthermore, the P3D05 nmAb neutralized DENV3 with extraordinary potency (Neut50 0.03 μg/ml). Thus, the Butantan-DV vaccine engendered a mature, antigen-selected B cell repertoire. Our results suggest that pre-existing responses elicited by a previous DENV3 infection were recalled by immunization.IMPORTANCE The dengue epidemic presents a global public health challenge that causes widespread economic burden and remains largely unchecked by existing control strategies. Successful control of the dengue epidemic will require effective prophylactic and therapeutic interventions. Several vaccine clinical efficacy trials are approaching completion, and the chances that one or more live attenuated tetravalent vaccines (LATVs) will be introduced worldwide is higher than ever. While it is widely accepted that dengue virus (DENV)-neutralizing antibody (nAb) titers are associated with protection, the Ab repertoire induced by LATVs remain uncharacterized. Here, we describe the isolation of potent (Neut50 < 0.1 μg/ml) nAbs from a DENV-seropositive volunteer immunized with the tetravalent vaccine Butantan-DV, which is currently in Phase III trials.
