Immunogenicity and safety of a tetravalent dengue vaccine during a five-year follow-up period

Self Cite

Dengue is prevalent in the Asia-Pacific region. Participants of two immunogenicity and safety phase II studies conducted in Singapore and Vietnam (NCT0088089 and NCT00875524, respectively) were followed for up to four years after third vaccine dose of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV). Participants (2–45 years) received three doses of CYD-TDV or control at 0, 6, and 12 months. Dengue plaque reduction neutralization test (PRNT50) antibody titers were measured in both studies. Cytokine-producing antigen-specific CD4+ and CD8+ T-cells were quantified to assess cell-mediated immunity (CMI) in Singapore. Post-hoc analyses were carried out for participants aged <9 and ≥9 years old. Related and fatal serious adverse events (SAEs) were collected during long-term follow-up. Of participants who received ≥1 CYD-TDV injection in Singapore (n = 1198) and Vietnam (n = 180), 87% and 92% participants completed long-term follow-up, respectively. At four years, geometric mean titers (GMTs) in participants who received CYD-TDV ranged from 30.2 1/dil (95% CI 23.9–38.3) to 73.7 (49.3–110) 1/dil in Vietnam and 9.73 1/dil (95% CI 8.28–11.4) to 21.8 (18.9–25.1) 1/dil in Singapore. Interferon and interleukin-13 levels were lower at four years than one year post-vaccination but were still present. Tumor necrosis factor-α levels at four years were similar to those after the third vaccine dose. Seropositivity rates were higher at year four in participants who were seropositive vs. seronegative at baseline in both studies. No safety concerns were identified. CYD-TDV demonstrated long-term immunogenicity and was well-tolerated for four years after the third vaccine dose.

Section: Discussionmentioning

confidence: 95%

Long-term immunogenicity and safety of tetravalent dengue vaccine (CYD-TDV) in healthy populations in Singapore and Vietnam: 4-year follow-up of randomized, controlled, phase II trials

Tran

Chansinghakul²,

Chong

et al. 2019

Self Cite

“…Indeed, in dengue-endemic areas, GMTs tend to decline in the first year after the last injection, but thereafter remain relatively stable up to 5 years after the three-dose schedule with annual fluctuations due to natural exposure to wild-type dengue, or other flaviviruses, contributing to antibody persistence in this setting. 17 For children living in endemic countries, including participants from the CYD64 study, the annual incidence of asymptomatic dengue infection was shown to be over four-times higher than for symptomatic dengue, with the incidence 14.8% and 3.4% for asymptomatic and symptomatic infection, respectively. 18 The present study had some limitations.…”

Section: Discussionmentioning

confidence: 97%

Immunogenicity and safety of a dengue vaccine given as a booster in Singapore: a randomized Phase II, placebo-controlled trial evaluating its effects 5–6 years after completion of the primary series

Park¹,

Archuleta

et al. 2019

The tetravalent dengue vaccine (CYD-TDV; Dengvaxia®) is administered on a three-dose schedule, 6 months apart in those aged ≥9 years in a number of dengue-endemic countries in Asia and Latin America. In this study, CYD63 (NCT02824198), participants aged 9-45 years at first vaccination, and who had received three doses of CYD-TDV in the CYD28 study more than 5 years previously, were randomized 3:1 to receive a booster CYD-TDV dose (Group 1) or placebo (Group 2). Dengue neutralizing antibody geometric mean titres (PRNT 50 GMTs) for each of the four dengue serotypes were assessed in sera collected before and 28 days after booster injections. Non-inferiority of the booster immune response versus that induced after the third dose was demonstrated for each serotype if the lower limit of the two-sided 95% confidence interval (CI) was >0.5 for the GMT ratios (GMTRs) between post-booster CYD-TDV dose and post-dose 3 in Group 1. Overall, 118 participants received CYD-TDV booster or placebo and 116 (98.3%) completed the study; two participants were withdrawn because of noncompliance. GMTs in the booster CYD-TDV group increased across all serotypes post-booster injection by 1.74-(serotype 1) to 3.58-fold (serotype 4). No discernible increases were observed in the placebo group. Non-inferiority was demonstrated for serotypes 1, 3, and 4, but not for serotype 2 (GMTR; 0.603 [95% CI, 0.439-0.829]). No safety issues were observed. These data show that the CYD-TDV booster given 5 or more years later tended to restore GMTs back to levels observed post-dose 3.

“…[2][3][4][5] While the efficacy of the vaccine is now established, few data are available on the longterm immune memory generated by this vaccine. 6 Such data are essential to decide if and when re-vaccination might be required. Because the vaccine is more efficacious in individuals with preexisting DENV immunity (plaque reduction neutralizing titers (PRNT50) of > 10) from previous DENV or related flavivirus infections, it can be assumed that protection relies on the expansion of pre-existing cross-reactive immune memory.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to this large observation-based follow-up study, a longitudinal study by Capeding et al monitored neutralizing titers in children and adults vaccinated with CYD-TDV over a 5-year period following the last immunization. 6 A marked decline in neutralizing titers was observed over time in vaccinees that did not experience a natural dengue or flavivirus infection within the followup period. While neutralizing titers measured in the blood are a useful readout of DENV immunity, the correlation between neutralizing titers and protection is still not clear.…”

Section: Introductionmentioning

confidence: 95%

Low antibody titers 5 years after vaccination with the CYD-TDV dengue vaccine in both pre-immune and naïve vaccinees

Velumani

Toh

Balasingam

et al. 2016

Globally, dengue virus (DENV) is one of the most widespread vector-borne viruses. Dengue disease affects populations in endemic areas and, increasingly, tourists who travel to these countries, but there is currently no approved vaccine for dengue. A phase 3 efficacy trial with Sanofi-Pasteur's recombinant, liveattenuated, tetravalent dengue vaccine (CYD-TDV) conducted in South East Asia showed an overall efficacy of 56% against virologically confirmed dengue infections of any severity and any of the 4 serotypes, but the long-term protection of the vaccine has yet to be demonstrated. To address longevity of antibody titers and B cell memory, we recalled study participants from an earlier CYD immunogenicity study (Phase 2) conducted in Singapore that enrolled healthy volunteers in the year 2009. Depending on the age group, 57-84% of the participants initially generated a neutralizing antibody titer 10 to all 4 DENV serotypes 28 d after the third and final dose. We observed very low antibody titers in blood samples collected from 23 vaccinees 5 y after the first dose, particularly titers of antibodies binding to virus particles compared with those binding to recombinant E protein. The in vivo efficacy of plasma antibodies against DENV-2 challenge was also tested in a mouse model, which found that only 2 out of 23 samples were able to reduce viremia. Although the sample size is too small for general conclusions, dengue immune memory after vaccination with CYD-TDV appears relatively low.