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Background The tetravalent dengue vaccine (CYD-TDV, Dengvaxia, Sanofi Pasteur) demonstrated efficacy in 2 previous phase III trials conducted in endemic countries. Neutralizing antibodies (NAbs) elicited by 3 doses of this vaccine have been associated with efficacy. Long-term follow-up data has shown that NAb immune responses tend to wane over time, after the third dose. This study compared the immune response elicited by a booster (4th) dose of CYD-TDV with the immune responses from the same participants obtained post-dose 3 of the primary series administered 4-5 years earlier. Methods This multicenter, observer-blind, randomized, placebo-controlled, phase II noninferiority trial was conducted in healthy adolescents and adults in dengue endemic countries of Latin America (Colombia, Honduras, Brazil, Mexico and Puerto Rico). All participants had been immunized with 3 doses of CYD-TDV in phase II studies conducted 4-5 years earlier. NAb levels against each dengue virus serotype 28 days postbooster or placebo injection were reported. Results A total of 187 participants received CYD-TDV and 64 received placebo. Prospectively defined noninferiority criteria for dengue NAbs after the booster dose compared with postdose 3 were met for all 4 serotypes. Prospectively defined superiority criteria were met for 3 of the 4 serotypes. Conclusions Antidengue NAb levels can be boosted to levels at least as high as, or higher than those observed after completion of the primary 3-dose series, with an additional dose of CYD-TDV 4-5 years after the standard 3-dose vaccination schedule.

Background We previously described an increased immune response 28 days after a booster dose of the live, attenuated, tetravalent dengue vaccine (CYD-TDV) in healthy adolescents and adults in Latin America (CYD64, NCT02623725). This follow-up study evaluated immune response persistence and safety of a CYD-TDV booster dose up to Month (M) 24 post-booster. Methods This study included 250 participants who previously received 3 primary doses of CYD-TDV in the CYD13 (NCT00993447) and CYD30 (NCT01187433) studies, and who were randomized 4-5 years later to receive a CYD-TDV booster or placebo (3:1). Dengue neutralizing antibodies against the parental dengue virus strains were assessed using the plaque reduction neutralization test (PRNT50) at M6, M12, and M24 post-booster. Post-booster memory B-cell responses were assessed in a subset of participants using the FluoroSpot assay up to M12 post-booster. Results In the CYD-TDV group (n = 187), dengue neutralizing antibody geometric mean titers (GMTs) declined from the peak at day 28 through to M24 for all serotypes. GMTs at M24 were similar to those at pre-booster among baseline dengue seropositives. A similar trend was observed for baseline dengue seronegatives, albeit at a lower magnitude. Previous vaccination-induced detectable B-cell memory responses in seropositives and seronegatives that decreased to pre-booster levels at M12 post-booster. The CYD-TDV booster dose was well-tolerated. Conclusions In baseline dengue seropositives, following a CYD-TDV booster dose administered 4-5 years after primary immunization, dengue neutralizing antibody GMTs and B-cell memory responses peaked in the short-term before gradually decreasing over time. A CYD-TDV booster dose could improve protection against dengue during outbreak periods.

Our objective was to describe the risk of hospital admission for virologically confirmed dengue (VCD) and the risk of clinically severe hospitalized VCD occurring up to 4 years after the first dose (years 1 to 4) in three randomized clinical trials comparing tetravalent dengue vaccine with placebo.The relative risks (RR) for hospitalized VCD from first dose to year 4 were estimated by year and age-group in individual and combined studies.Overall, from Year 1 to Year 4, 233 and 228 participants had at least one episode of hospitalized VCD in the vaccinated (n = 22 603) and placebo (n = 11 301) groups, respectively (RR = 0.511, 95% CI 0.42-0.62). Among these, 48 and 47 cases, respectively, were classified as clinically severe. In children aged ≥9 years, 88 and 136 participants had at least one episode of hospitalized VCD in the vaccinated (n = 17 629) and placebo (n = 8821) groups, respectively (RR = 0.324; 95% CI 0.24-0.43). In vaccinated participants aged9 years, particularly in those aged 2-5 years, there were more hospitalized VCD cases compared with the control participants in Year 3 but not in Year 4. The overall RR in those aged9 years for Year 1 to Year 4 was 0.786 (95% CI 0.60-1.03), with a higher protective effect in the 6-8 year olds than in the 2-5 year olds.The overall benefit-risk remained positive in those aged ≥9 years up to year 4, although the protective effect was lower in years 3 and 4 than in years 1 and 2.

A tetravalent dengue vaccine (CYD-TDV) has recently been approved in 12 countries in southeast Asia and Latin America for individuals aged 9–45 years or 9–60 years (age indication approvals vary by country) living in endemic areas. Data on utilization of medical and nonmedical resources as well as time lost from school and work were collected during the active phase of two phase III efficacy studies performed in 10 countries in the Asia-Pacific region and Latin America (NCT01373281; NCT01374516). We compared dengue-related resource utilization and costs among vaccinated and nonvaccinated participants. Country-specific unit costs were derived from available literature. There were 901 virologically confirmed dengue episodes among participants aged ≥ 9 years (N = 25,826): corresponding to 373 episodes in the CYD-TDV group (N = 17,230) and 528 episodes in the control group (N = 8,596). Fewer episodes in the CYD-TDV group resulted in hospitalization than in the control group (7.0% versus 13.3%; P = 0.002), but both had a similar average length of stay of 4 days. Overall, a two-thirds reduction in resource consumption and missed school/work days was observed in the CYD-TDV group relative to the control group. The estimated direct and indirect cost (2014 I$) associated with dengue episodes per participant in the CYD-TDV group was 73% lower than in the control group (I$6.72 versus I$25.08); representing a saving of I$I8.36 (95% confidence interval [CI]:17.05–19.78) per participant with vaccination. This is the first study providing information on dengue costs among vaccinated individuals and direct confirmation that vaccination has the potential to reduce dengue illness costs.