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. 2022 Nov 28;226(11):1959-1963.
doi: 10.1093/infdis/jiac272.

Specificity and Breadth of the Neutralizing Antibody Response to a Live-Attenuated Tetravalent Dengue Vaccine

Christina R DeMaso  1 , Lovkesh Karwal  1 , Melissa Zahralban-Steele  1 , David Dominguez  1 , Zhang-Li Springer  1 , Maima Kaiser  1 , Sunil Palani  1 , Tim Rindfleisch  1 , Kelly Bohning  1 , Greg Hather  1 , Subash Das  1 , Mayuri Sharma  1 , Hansi J Dean  1
Affiliations

Specificity and Breadth of the Neutralizing Antibody Response to a Live-Attenuated Tetravalent Dengue Vaccine

Christina R DeMaso et al. J Infect Dis. .

Abstract

Background: An effective dengue vaccine should ideally induce broadly neutralizing antibody (nAb) responses against all 4 dengue virus (DENV) serotypes.

Methods: We characterized the specificity and breadth of the nAb response to TAK-003, a live-attenuated tetravalent dengue vaccine, in serum samples from phase 2 and 3 clinical trials.

Results: Microneutralization tests using postvaccination serum showed comparable neutralization against diverse DENV-1-4 genotypes. Reporter virus particle neutralization assays after depletion of anti-DENV-2 nAbs demonstrated that the nAb response to DENV-1, -3, and -4 comprises both type-specific (TS) and cross-reactive (CR) nAbs.

Conclusions: Therefore, TAK-003 induces broad tetravalent TS and CR nAb responses.

Keywords: TAK-003; dengue vaccine; dengue virus; neutralizing antibody response; type-specific.

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Conflict of interest statement

Potential conflicts of interest. All authors are current employees of Takeda Vaccines, Inc. or were employees or contractors of Takeda Vaccines, Inc. at the time this study was conducted. HD was an employee of Takeda Vaccines, Inc at the time this work was conducted and then served as a paid consultant to Takeda Vaccines, Inc. Funding to pay the Open Access publication charges for this article was provided by Takeda Pharmaceuticals U.S.A. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Dengue virus (DENV)-2 antibody depletion and specificity of neutralizing antibody (nAb) response to TAK-003. (A) Schematic of DENV-2 antibody depletion, and log reporter virus particle (RVP) half-maximal effective concentration (EC50) titers for (B) DENV-1, (C) DENV-3, and (D) DENV-4 after DENV-2 antibody depletion. Sera from baseline-seronegative individuals vaccinated with TAK-003 (n = 71) collected 30 days after second vaccination from studies DEN-301 (red dots) and DEN-304 (blue dots) were depleted with mock antigen (x-axis) and DENV-2 antigen (y-axis) bound to magnetic beads, and their neutralization titers were measured by dengue RVP assay. Log10 EC50 represents the dilution factor required to neutralize 50% of RVPs. Samples where depletion of anti-DENV-2 antibodies leads to complete loss of detectable nAbs against DENV-1, 3 and/or 4 (seen as log10 EC50 < limit of detection (LOD) and represented by the open circles) contain a high proportion of cross-reactive antibodies. Samples where DENV-1, -3 and/or -4 titer remain > LOD postdepletion with DENV-2 (represented with closed circles) contain type-specific antibodies. HD, high dose.
Figure 2.
Figure 2.
TAK-003-Elicited neutralizing antibody (nAb) microneutralization test (MNT) titers against homologous tetravalent dengue vaccine (TDV) strains and diverse dengue virus (DENV)-1–4 genotypes in postvaccination serum. DEN-205 antisera from baseline-seronegative (n = 10) and seropositive (n = 10) individuals vaccinated with a single dose of high-dose TDV (n = 18; ● symbols) or TDV (n = 2; ◆ symbols) collected prevaccination and 30 days postvaccination were tested in a MNT against a panel of genetically diverse DENV strains representative of historical (1956–2007) genotypes isolated in Asia and Latin America (Supplementary Table 1). Titers were defined as the serum dilution resulting in a 50% reduction in plaque number compared with virus only control (NT50). Data were truncated at MNT limit of detection (log10 NT50 = 1.3). P values were calculated by ordinary one-way analysis of variance with Sidak’s method for multiple comparisons. Neutralizing titers against nonvaccine genotypes were compared with the homologous vaccine strain within each serum group (naive day 30, preimmune day 0, preimmune day 30) and between serum groups (naive day 30 vs preimmune day 30, preimmune day 0 vs preimmune day 30). No significant differences in NT50 were observed in any of the comparisons. *, Homologous (parental) TDV-1, -2, -3, or -4 strain.
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