Immunogenicity of the CYD tetravalent dengue vaccine using an accelerated schedule: randomised phase II study in US adults

Abstract Background The live attenuated tetravalent dengue vaccine (CYD-TDV) is licensed using a 0-, 6- and 12-month schedule in dengue-endemic areas. An effective shorter schedule may provide more rapid, optimal protection of targeted populations during vaccine campaigns in dengue-endemic countries. We compared immune responses to two schedules of CYD-TDV in a non-endemic population. We also evaluated the impact of yellow fever (YF) co-administration. Methods This phase II, open-label, multicentre study enrolled 390 healthy 18–45-year-olds in the USA with no prior exposure to dengue. Participants were randomised (4:4:4:1) to four treatment groups stratified by prior YF vaccine status: Group 1, CYD-TDV standard 0–6–12 months schedule; Group 2, CYD-TDV accelerated 0–2–6 months schedule; Group 3, CYD-TDV accelerated schedule with YF co-administered (dose 1); Group 4, YF vaccination only. Neutralising antibody geometric mean titres (GMTs) and percentages of seropositive participants (antibody titres ≥10 [1/dil]) were measured against each dengue serotype using a 50% plaque reduction neutralisation test. Results On D28 post-CYD-TDV dose 3, there were no marked differences in seropositivity rates and GMTs between Groups 1 and 2. In Groups 1 and 2 respectively, 73.4 and 82.4% were dengue seropositive for ≥3 serotypes, with 50.0 and 42.6% seropositive against all four serotypes. Flavivirus status (FV+ or FV−) at baseline did not markedly affect GMTs and seropositivity rates with either schedule. In Groups 1 and 2, GMTs measured 6 months after the third dose decreased against all serotypes, except for a small increase in GMT for serotype 4 in Group 1. In addition, dengue seropositivity remained above 70% for serotypes 2, 3 and 4 in Groups 1 and 2. Co-administration with YF did not affect antibody responses against dengue and YF or impact vaccine safety following completion of the compressed schedule, compared to dengue or YF vaccination alone. Conclusions The live attenuated CYD-TDV vaccine given in a compressed schedule in a non-endemic setting can elicit similar antibody responses to the licensed CYD-TDV schedule. Trial registration This trial was registered on cinicaltrials.gov, NCT01488890 (December 8, 2011)

A recombinant live attenuated tetravalent vaccine for the prevention of dengue

Introduction: Dengue is an important and still growing public health problem associated with substantial morbidity, as well as significant social and economic impact. The present review describes the main features and development of the first dengue vaccine (CYD-TDV, Dengvaxia®), which has been licensed by several dengue-endemic countries in Asia and Latin America for use in populations above 9 years of age. Areas covered: The review focuses on the large clinical development of CYD-TDV, which includes in particular two pivotal phase III efficacy trials conducted in Asia and Latin America and supported vaccine licensure. Based on these clinical data, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization recommended considering introduction of the vaccine in geographic settings (national or subnational) with high burden of disease. Long-term safety follow-up studies of the efficacy trials are currently ongoing, and post-licensure studies will evaluate the vaccine effectiveness and safety in ‘real-life’ following vaccine introduction. Expert commentary: During vaccine development, a number of complexities were tackled, innovation pursued, and risk managed. These aspects, as well as the potential impact of CYD-TDV on public health are also discussed

Summary of the characteristics of clinical trials included in the analysis.

<p>Summary of the characteristics of clinical trials included in the analysis.</p

Relative risk (solid line) and 95% confidence interval (dotted lines) against hospitalized or severe dengue due to any serotype by age at enrollment.

<p>The Epanechnikov kernel method (with h = 2.0) was used to provide a smooth curve. Data were combined from post-dose 1 up to year 3 in the phase III trial in Latin America and up to year 4 in the phase IIb and phase III trial in Asia.</p

SAEs within 28 days after any dose of CYD-TDV vaccine or placebo in participants aged 9–60 years.

<p>None of the preferred term events affected ≥0.1% of the participants; n = number of participants with ≥1 of each SAE.</p

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

10.1080/21645515.2019.1578595Human Vaccines & Immunotherapeutics15102315-232

Number of CYD-TDV (final formulation) injections received overall and by age group in main trials (CYD-TDV at D0 M6 and M12), and all trials (including those who received three doses of CYD-TDV at D0 M3.5/4 and M12) and number of placebo and active control injections.

<p>Number of CYD-TDV (final formulation) injections received overall and by age group in main trials (CYD-TDV at D0 M6 and M12), and all trials (including those who received three doses of CYD-TDV at D0 M3.5/4 and M12) and number of placebo and active control injections.</p

Overall safety profile of CYD-TDV and placebo.

<p>Percentages and 95% confidence intervals for participants those who received at least one dose of CYD-TDV (left) or placebo (right) reporting solicited injection-site reactions within 7 days of any dose, solicited systemic reactions within 14 days of any dose, unsolicited AEs and SAEs within 28 days of any dose, by age group.</p

Unsolicited non-serious adverse reactions affecting ≥0.1% of participants aged 9–60 years in the CYD-TDV and placebo groups.

<p>n = number of participants with ≥1 of each SAE.</p

Definitions and severity scales for solicited injection site and systemic reactions.

<p>Definitions and severity scales for solicited injection site and systemic reactions.</p