Explore the vast range of titles available.

•CYD-TDV efficacy was maintained for up to 6 years in seropositives aged ≥9 years.•Persistent CYD-TDV efficacy was also observed in seropositives aged 6–8 years.•CYD-TDV efficacy estimates were lower in seropositives aged <9 years than ≥9 years.•CYD-TDV efficacy was null to modest in seronegatives aged ≥6 years. CYD-TDV is a live, attenuated, tetravalent dengue vaccine licensed in 21 countries. We undertook a post-hoc analysis of the long-term efficacy of CYD-TDV during the surveillance expansion phase (SEP) of two Phase III studies (CYD14 in the Asia-Pacific region; CYD15 in Latin America). The SEP included approximately Year 5 and the entire Year 6 of follow-up after the first study injection. Vaccine efficacy against symptomatic virologically-confirmed dengue (VCD) was assessed by participant age (any age, ≥9, <9, 2–5, and 6–8 years at the time of the first injection) and baseline dengue serostatus using a case-cohort framework. Baseline dengue serostatus was estimated by several methods including logistic regression-based multiple imputation (MI) to predict PRNT50 with key predictor being Month 13 (M13) anti-non-structural protein (NS1) titers; superlearner-based imputation by targeted minimum loss based estimation (TMLE); and M13 anti-NS1 titer threshold 9 EU/mL (NS1 M13). There were 436 symptomatic VCD cases (CYD14: n = 360; CYD15: n = 76) during the SEP. Vaccine efficacy in seropositive participants aged ≥9 years was assessed by MI (47.9% [95% CI 19.4; 66.3]), TMLE (53.0% [95% CI 23; 71]), and NS1 M13 (52.4% [95% CI 30.8; 67.3]). Vaccine efficacy estimates were lower in seropositive individuals aged <9 years compared with individuals ≥9 years. Among seropositive individuals aged 2–5 and 6–8 years, vaccine efficacy across the different approaches for assessing serostatus ranged from between −25.7 to 36.9% and 44.4 to 64.7% during the SEP, respectively. In the pooled CYD14/15 data of seronegatives, vaccine efficacy was null to modest. In conclusion, CYD-TDV was shown to maintain efficacy against symptomatic VCD in seropositive participants aged ≥9 years up to six years after the first dose. Persistence of efficacy was also observed in seropositive participants aged 6–8 years.

The tetravalent dengue vaccine (CYD-TDV) has been shown to provide protection against dengue disease over 5-year follow-up in participants with previous dengue infection, but increased the risk of dengue hospitalisation and severe dengue during long-term follow-up in those without previous dengue infection. WHO recommended pre-vaccination screening to identify those with previous dengue infection (ie, dengue seropositive) who would benefit from vaccination. We re-evaluated CYD-TDV efficacy in those identified as dengue seropositive using five commercially available immunoassays, and assessed immunoassay performance. We included participants in the immunogenicity subsets of the phase 3 CYD14 (NCT01373281) and CYD15 (NCT01374516) CYD-TDV efficacy trials, which enrolled children aged 2–16 years in 2011–12 in five countries in the Asia-Pacific region (CYD14) and five Latin American countries (CYD15). Participants assessed had received at least one injection of study drug (CYD-TDV or placebo) and had baseline samples available. We tested baseline samples by IgG-based immunoassays to classify baseline dengue serostatus, using two ELISAs (EUROIMMUN and Panbio) and three rapid diagnostic tests (RDTs; TELL ME FAST, SD BIOLINE, and OnSite). Vaccine efficacy in preventing symptomatic, hospitalised, and severe virologically confirmed dengue was determined for participants who tested positive by each immunoassay. The specificity and sensitivity of each immunoassay was determined as percentage negative and positive agreement compared with the reference algorithm, which used dengue plaque reduction neutralisation test with 50% and 90% cutoffs and non-structural protein 1 IgG ELISA results to assign baseline serostatus. Samples were available for 3967 participants, 2735 (69·0%) of whom were classified as seropositive by the reference algorithm. Vaccine efficacy against symptomatic virologically confirmed dengue in immunoassay-positive participants was high across all five immunoassays (EUROIMMUN ELISA 88·2% [95% CI 77·3 to 93·9], Panbio ELISA 87·6% [76·7 to 93·4], TELL ME FAST RDT 88·8% [67·0 to 96·2], SD BIOLINE RDT 82·8% [66·9 to 91·1], and OnSite RDT 89·7% [64·6 to 97·0]), as was vaccine efficacy against hospitalised virologically confirmed dengue (EUROIMMUN-ELISA 72·8% [38·9 to 87·9], Panbio ELISA 77·5% [52·8 to 89·3], TELL ME FAST RDT 92·4% [37·8 to 99·1], SD BIOLINE RDT 87·2% [54·5 to 96·4], and OnSite RDT 73·7% [–5·1 to 93·4]) and severe virologically confirmed dengue (EUROIMMUN ELISA 86·9% [–16·8 to 98·5], Panbio ELISA 91·3% [27·6 to 99·0], TELL ME FAST RDT 100·0% [not estimable to 100·0%], SD BIOLINE RDT 89·4% [9·6 to 98·8], and OnSite RDT 73·4% [–193·7 to 97·6]). The immunoassays exhibited high specificity (≥98·8% for all immunoassays apart from SD BIOLINE RDT) but variable sensitivities, with higher sensitivities observed for the ELISAs (EUROIMMUN 89·2% [87·9 to 90·3] and Panbio 92·5 [91·4 to 93·5]) than the RDTs (TELL ME FAST 52·5% [50·6 to 54·4], SD BIOLINE 71·1% [69·3 to 72·8], and OnSite 47·6% [45·7 to 49·5]). Our findings suggest that these immunoassays could be used for pre-vaccination screening for CYD-TDV as tools to assist risk stratification until more sensitive and convenient tests become available. Sanofi Pasteur.

•CYD-TDV was efficacious in dengue seropositives aged ≥ 9 years from dose 1 to M25.•Inter-dose efficacy was similar to that post-dose 3 in seropositives aged ≥ 9 years.•Immunogenicity data are in line with CYD-TDV efficacy results in dengue seropositives.•CYD-TDV inter-dose efficacy was null to modest in dengue seronegatives of any age. A simplified dose regimen of the live, attenuated, tetravalent dengue vaccine (CYD-TDV) could have the potential to facilitate easier implementation of immunization programs against symptomatic virologically-confirmed dengue (VCD) in dengue seropositive individuals aged ≥ 9 years. This post-hoc analysis of two Phase III studies (CYD14 [NCT01373281] and CYD15 [NCT01374516]) in dengue endemic areas assessed the efficacy of CYD-TDV by dengue serostatus between dose 1 and 2 (at Month [M] 6), between dose 2 and 3 (at M12), and from dose 3 to M25. Baseline dengue serostatus (seropositive or seronegative) was determined based on measured dengue neutralizing antibody titers with the 50% plaque reduction neutralization test (PRNT50) or ascertained by logistic regression-based multiple imputation (MI) to predict PRNT50. Vaccine efficacy against symptomatic VCD was assessed by age and baseline dengue serostatus using a case-cohort framework. Dengue neutralizing antibody geometric mean titers (GMTs) were measured with the PRNT50 at 28 days post-dose 2 and 3. Vaccine efficacy estimates in seropositive participants aged ≥ 9 years at post-dose 1, 2, and 3 were 80.5% (95% CI, 66.2, 88.7), 82.0% (95% CI, 70.5, 89.0), and 75.2% (95% CI, 65.9, 81.9), respectively. In seropositive participants aged < 9 years, vaccine efficacy estimates were 48.5% (95% CI, –24.3, 78.6), 68.3% (95% CI, 34.5, 84.7), and 65.3% (95% CI, 40.2, 79.9), respectively. CYD-TDV efficacy was null to modest after any dose in seronegative participants, regardless of age group. Seropositive participants aged ≥ 9 years in the CYD-TDV group had GMTs post-dose 3 that did not exceed those observed post-dose 2. In conclusion, CYD-TDV has high efficacy against VCD from the first dose through to M25, with estimates at post-dose 1 and 2 similar to or higher than those at post-dose 3 in seropositive participants aged ≥ 9 years, consistent with immunogenicity data.

Background. Sanofi Pasteur has developed a tetravalent dengue vaccine (TDV) against the world's most common arbovirus infection. Methods. We assessed the safety and immunogenicity of the TDV in healthy adults randomized into 2 groups. Group 1 received 3 TDV injections at months 0, 4, and 12–15; group 2 received saline placebo at month 0 and then 2 TDV injections at months 4 and 12–15. Adverse events were recorded, and biological parameters and viremia levels were measured. Neutralizing antibodies against 4 World Health Organization (WHO) reference strains were measured before and after vaccinations. Results. A total of 33 participants were enrolled in each group. Demographic characteristics were comparable. No vaccine-related serious adverse event was reported. The most common systemic reactions were headache, malaise, and myalgia. Low viremia levels were detected, mainly of serotype 4. Immune response increased with successive vaccine doses. All participants seroconverted against all 4 serotypes after receiving 3 doses at 0, 4, and 12–15-months, and almost all seroconverted after 2 doses given 8–11 months apart. Conclusions. Sanofi Pasteur's TDV was well tolerated and induced full seroconversion against all WHO reference strain serotypes after 3 doses.

A recombinant live attenuated tetravalent dengue vaccine (TDV) is safe and immunogenic in adults and children in dengue-naïve populations. Data are needed in dengue endemic populations. In a phase I, randomized, controlled, blind-observer study in the Philippines, groups of participants aged 2–5, 6–11, 12–17, and 18–45 years received either three TDV vaccinations at months 0, 3.5, and 12 (TDV–TDV–TDV group) or licensed typhoid vaccination at month 0 and TDV at months 3.5 and 12 (TyVi–TDV–TDV group) and were followed for safety (including biological safety and vaccine virus viremia) and immunogenicity. No serious adverse vaccine related events and no significant trends in biological safety parameters were reported. Injection site pain, headache, malaise, myalgia, fever, and asthenia were reported most frequently, as mild to moderate in most cases and transient. Reactogenicity did not increase with successive vaccinations and was no higher in children than in adults and adolescents. Low levels of vaccinal viremia were detected in both groups after each TDV vaccination. After three TDV vaccinations, the seropositivity rates against serotypes 1–4 were: 91%, 100%, 96%, 100%, respectively, in 2–5 year-olds; 88%, 96% 96%, 92% in 6–11 year-olds; 88%, 83%, 92%, 96% in adolescents; and 100% for all serotypes in adults. A similar response was observed after two doses for the TyVi–TDV–TDV group. The safety profile of TDV in a flavivirus endemic population was consistent with previous reports from flavivirus naïve populations. A vaccine regimen of either three TDV vaccinations administered over a year or two TDV vaccinations given more than 8 months apart resulted in a balanced antibody response to all four dengue serotypes in this flavivirus-exposed population, including children.

Three independent, phase 1 clinical trials were conducted in Australia and in USA to assess the safety and immunogenicity of sanofi pasteur dengue vaccine candidates. In this context, Dengue 1–4 and Yellow Fever 17D-204 (YF 17D)-specific CD4 and CD8 cellular responses induced by tetravalent chimeric dengue vaccines (CYD) were analyzed in flavivirus-naive or flavivirus-immune patients. Tetravalent CYD vaccine did not trigger detectable changes in serum pro-inflammatory cytokines, whatever the vaccinees immune status, while inducing significant YF 17D NS3-specific CD8 responses and dengue serotype-specific T helper responses. These responses were dominated by serotype 4 in naive individuals, but a booster vaccination (dose #2) performed 4 months following dose #1 broadened serotype-specific responses. A similar, broader response was seen after primary tetravalent immunization in subjects with pre-existing dengue 1 or 2 immunity caused by prior monovalent live-attenuated dengue vaccination. In all three trials, the profile of induced response was similar, whatever the subjects’ immune status, i.e. an absence of Th2 response, and an IFN-γ/TNF-α ratio dominated by IFN-γ, for both CD4 and CD8 responses. Our results also showed an absence of cross-reactivity between YF 17D or Dengue NS3-specific CD8 responses, and allowed the identification of 3 new CD8 epitopes in the YF 17D NS3 antigen. These data are consistent with the previously demonstrated excellent safety of these dengue vaccines in flavivirus-naive and primed individuals.

We conducted a Phase 1b study to evaluate the immunogenicity and safety of two live attenuated tetravalent dengue vaccines in healthy adult volunteers. After one injection, all subjects reported systemic reactions consistent with a mild dengue-like syndrome. Seven volunteers developed dengue 3 viraemia after vaccination. All subjects developed a neutralizing antibody response against serotype 3 with partial response against other serotypes. The trial was stopped early (after 10 subjects enrolled) due to formulation issues, which were related to the dengue 3 vaccine component. Managing viral interference and balancing attenuation to produce acceptable tetravalent immunogenicity with minimal reactogenicity may be a recurring problem for future multivalent live vaccines.

VDV3, a clonal derivative of the Mahidol live-attenuated dengue 3 vaccine was prepared in Vero cells. Despite satisfactory preclinical evaluation, VDV3 was reactogenic in humans. We explored whether immunological mechanisms contributed to this outcome by monitoring innate and adaptive cellular immune responses for 28 days after vaccination. While no variations were seen in serum IL12 or TNFα levels, a high IFNγ secretion was detected from Day 8, concomitant to IFNα, followed by IL10. Specific Th1 and CD8 responses were detected on Day 28, with high IFNγ/TNFα ratios. Vaccinees exhibited very homogeneous class I HLA profiles, and a new HLA B60-restricted CD8 epitope was identified in NS3. We propose that, among other factors, adaptive immunity may have contributed to reactogenicity, even after this primary vaccination. In addition, the unexpected discordance observed between preclinical results and clinical outcome in humans led us to reconsider some of our preclinical acceptance criteria. Lessons learned from these results will help us to pursue the development of safe and immunogenic vaccines.

Development of a vaccine to prevent dengue infection is an unmet global need. In this report, further data on the safety and efficacy from two phase 3 trials of a tetravalent dengue vaccine are presented. A recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) has been assessed in two phase 3 randomized efficacy trials involving more than 31,000 children between the ages of 2 and 14 years in the Asian–Pacific region (CYD14 trial) and between the ages of 9 and 16 years in Latin America (CYD15 trial). 1 , 2 The vaccine was administered in three doses: at baseline, at 6 months, and at 12 months. Vaccine efficacy against virologically confirmed dengue and safety were assessed during a 25-month efficacy surveillance phase (i.e., until 13 months after the third dose was administered). Reactogenicity and immunogenicity were also assessed . . .