Dengue vaccine breakthrough infections reveal properties of neutralizing antibodies linked to protection
Sandra Henein, … , Ralph Baric, Aravinda M. de Silva
Sandra Henein, … , Ralph Baric, Aravinda M. de Silva
Published May 18, 2021
Citation Information: J Clin Invest. 2021;131(13):e147066. https://doi.org/10.1172/JCI147066.
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Dengue vaccine breakthrough infections reveal properties of neutralizing antibodies linked to protection

Abstract

The 4 serotypes of dengue virus (DENV1–4) are mosquito-borne flaviviruses that infect humans. Live attenuated tetravalent DENV vaccines are at different phases of clinical testing. DENV vaccine developers have relied on neutralizing antibodies (NAbs) as a correlate of protection. A leading tetravalent vaccine (Dengvaxia) stimulated NAbs to the 4 DENV serotypes, yet overall vaccine efficacy was low in children who were DENV seronegative at baseline before vaccination. We compared the properties of (a) NAbs induced by WT DENV1 or DENV3 infections, which are strongly correlated with protection from repeat infections, and (b) NAbs induced by Dengvaxia in individuals who subsequently experienced DENV1 or DENV3 breakthrough infections. WT infections induced NAbs that recognized epitopes unique (type specific) to each serotype, whereas the vaccine stimulated qualitatively different NAbs that recognized epitopes conserved (crossreactive) between serotypes. Our results indicate that, among children who were DENV-seronegative at baseline, unbalanced replication of the DENV type 4 vaccine component in the tetravalent vaccine stimulates Abs capable of crossneutralizing DENV1 and DENV3 in vitro, but not protecting in vivo. In DENV-seronegative individuals who are vaccinated, we propose that type-specific NAbs are a better correlate of protection than total levels of NAbs.

Authors

Sandra Henein, Cameron Adams, Matthew Bonaparte, Janice M. Moser, Alina Munteanu, Ralph Baric, Aravinda M. de Silva

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Figure 2

Vaccine-induced Ab responses in children who experienced DENV1 breakthrough infections.

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Vaccine-induced Ab responses in children who experienced DENV1 breakthro...
Vaccine responses to DENV1 (A) and DENV4 (B) were analyzed in baseline seronegative children who received Dengvaxia and subsequently experienced DENV1 (n = 15) breakthrough infections. (A) DENV1 NAb responses after vaccination were measured without depleting any Ab (Control depleted), after removal of all DENV1-binding Abs (Complete Ab depleted with DENV1 antigen), and after removal of CR Ab (CR Ab depleted using a mix of DENV2 and DENV4 antigens). (B) DENV4 NAb responses after vaccination were measured without depleting any Ab (Control depleted), after removal of all DENV4-binding Ab (Complete Ab depleted with a mix of DENV2 and DENV4 antigens), and after removal of CR Ab (CR Ab depleted using DENV1 antigen). (C) The data were also analyzed to compare the percentages of DENV1 and DENV4 TS NAbs in the children after vaccination. Friedman’s 1-way ANOVA test (A and B) or Wilcoxon’s signed ranks test (C) was used to establish statistical significance.