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

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-sought-after 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] = 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. 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 (Neut < 0.1 μg/ml) nAbs from a DENV-seropositive volunteer immunized with the tetravalent vaccine Butantan-DV, which is currently in phase III trials.

Induction of Transient Virus Replication Facilitates Antigen-Independent Isolation of SIV-Specific Monoclonal Antibodies

“…Similarly, our group isolated plasmablast-derived flavivirus-specific mAbs from a dengue vaccinee and a Zika virus-infected individual, where 90% of the mAbs neutralized the target virus. 43,58 Our current data, consequently, highlight the difficulty of isolating the infrequent neutralizing mAbs elicited during HIV and SIVmac239 infections.…”

“…40 Replication of acute viruses is usually followed by a surge of viral antigen-specific plasmablasts in the peripheral blood of infected individuals. [41][42][43] Abs produced by these antigen-specific plasmablasts are thought to be associated with the development of nAb titers for the cognate viruses. 41 Since SIV-infected ECs control viral replication after the acute phase of infection, we reasoned that the depletion of CD8 + T cells using the anti-CD8b mAb CD8b255R1 would increase viral replication and antigen exposure and, in turn, reactivate SIV-specific B cells.…”

Insights From Analysis of Human Antigen-Specific Memory B Cell Repertoires

“…That study emphasized the need to examine each B lineage compartment for a complete understanding of the humoral response. Recently, a DENV-exposed volunteer was vaccinated with a live attenuated tetravalent vaccine (Butantan-DV) and 15 days later plasmablasts were isolated to generate neutralizing Abs (147). The immunization resulted in neutralizing Abs to the previous exposure with DENV type 3 as well as six other mAbs that neutralized three or more serotypes.…”

Chikungunya, Dengue, and Zika in Immunocompromised Hosts

“…The other dengue vaccine undergoing phase III clinical trials is the Butantan-DV vaccine, a live-attenuated tetravalent vaccine produced by the NIH and Butantan Institute. The results of a safety and efficacy trial ( ClinicalTrials.gov identifier NCT01696422) in a DENV seropositive patient showed a robust expansion (~ 70-fold) of the plasmablast population post-vaccination, generating neutralizing titers for all serotypes by 91 days and amnestic response to DENV3 [ 84 ].…”