Humoral and cellular immunogenicity and safety following a booster dose of a tetravalent dengue vaccine 5+ years after completion of the primary series in Singapore: 2-year follow-up of a randomized phase II, placebo-controlled trial

Abstract

The tetravalent dengue vaccine (CYD-TDV) is approved for use as a 3-dose series for the prevention of dengue in seropositive individuals ≥9 years. A randomized, placebo-controlled, phase II study of a booster dose of CYD-TDV in individuals who completed the 3-dose schedule >5 years previously (NCT02824198), demonstrated that a booster restored neutralizing antibody titers to post-dose 3 levels. We present additional immunogenicity assessments up to 24 months post-booster, and B- and T-cell responses in a participant subset. Participants aged 9-45 years that had received all three doses of CYD-TDV were randomized 3:1 to receive a booster dose of CYD-TDV (n = 89) or placebo (n = 29). Neutralizing antibody levels at Months 1, 6, 12, and 24 post-booster were assessed by plaque reduction neutralization test. In a subset, B-cell responses were assessed by a fluorescent immunospot assay, and T-cells analyzed by flow cytometry at Days 0, 7, 12, Months 1 and 12. We observed an increase of antibody titers Month 1 post-booster, then a gradual decline to Month 24. In the CYD-TDV booster group, an increase in plasmablasts was seen at Day 7 declining by Day 14, an increase in memory B-cells was observed at Day 28 with no persistence at Month 12. CYD-TDV booster recalled a CD8+ T-cell response, dominated by IFN-γ secretion, which decreased 12 months post-booster. This study showed a short-term increase in antibody titers and then gradual decrease following CYD-TDV booster injection >5 years after primary immunization, and the presence of memory B-cells activated following the booster, but with low persistence.

Keywords: B-cell response; CYD-TDV; T-cell response; booster vaccine; dengue vaccine; long-term follow-up.

Figures

Figure 1.

GMTs of neutralizing antibodies against (a) serotype 1, (b) serotype 2, (c) serotype 3 and (d) serotype 4 during the 24-month follow-up in all participants by baseline dengue serostatus before the first dose of CYD-TDV in CYD28 (PPAS)

Figure 2.

Geometric means of the number of IgG secreting plasmablasts per million PBMCs specific to (a) CYD1, (b) CYD2, (c) CYD3, and (d) CYD4 by FluoroSpot (AIT subset)

Figure 3.

Percentage of IgG secreting memory B-cells specific to (a) CYD1, (b) CYD2, (c) CYD3, and (d) CYD4 out of total IgG secreting memory B-cells by FluoroSpot (AIT subset)

Figure 4.

Geometric means of percentage of CD8+ T-cells positive for (a) IFN-γ, (b) TNF-α, (c) IL2, (d) MIP-1 β, and (e) CD107a by intracellular cytokine staining after YF 17D NS3 stimulation (AIT subset)

Figure 5.

Proportion of simple, double, triple and >triple positive CD8+ T-cells stimulated by YF 17D NS3 peptide pool at Day 0, Day 28 and Month 12, shown as the proportion of the geometric means (AIT subset)

Figure 6.

Memory subpopulations of activated CD8+ T-cells* stimulated by YF 17D NS3 at Day 0, Day 28 and Month 12, shown as the proportion of the geometric means (AIT subset)