Four-year safety follow-up of the tetravalent dengue vaccine efficacy randomised controlled trials in Asia and Latin America.

Objective; Our objective was to describe the risk of hospital admission for virologically-confirmed dengue (VCD) and the risk of clinically-severe hospitalised VCD occurring up to four years post-first dose (Years 1 to 4) in three randomised clinical trials comparing tetravalent dengue vaccine to placebo. Methods; The RRs (relative risks) for hospitalised VCD from first dose to Year-4 were estimated by year and age-group in individual and combined studies. Results; Overall, from Year-1 to Year-4, 233 and 228 participants had ≥1 episode of hospitalised VCD in the vaccinated (N=22,603) and placebo groups (N=11,301), 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 ≥1 episode of hospitalised VCD in the vaccinated (N=17,629) and placebo groups (N=8,821), respectively (RR=0.324 (95% CI: 0.24; 0.43). In vaccinated participants aged <9 years, particularly in those aged 2-5 years, there were more hospitalised VCD cases compared with the control participants in Year-3 but not in Year-4. The overall RR in those aged <9 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. Conclusions; The overall benefit-risk remained positive in those aged ≥9 years up to Year-4, although the protective effect was lower in Years-3 & 4 than in Years-1 & 2.