Safety of CYD-TDV dengue vaccine
CYD-TDV is a tetravalent, live attenuated, chimeric dengue vaccine in a yellow fever 17D backbone developed by Sanofi Pasteur. The schedule that has been evaluated in Phase III clinical trials includes 3 doses of vaccine (at 0, 6 and 12 months). Results from 2 Phase III trials in Asia2 (CYD14; 10 275 children aged 2–14 years) and Latin America3 (CYD15; 20 869 children, aged 9–16 years) were published in 2014. Vaccine efficacy against symptomatic virologically confirmed dengue was estimated to be 56.5% and 60.8%, respectively. Vaccine efficacy varied by serotype, serostatus at the time of receiving the first dose (measured by presence of neutralizing antibody against dengue), and severity of disease in both studies, and by age in the Phase III study in Asia. The percentage of subjects with unsolicited non-serious adverse events, solicited systemic reactions, solicited injection site reactions, or solicited adverse reactions was slightly higher in the CYD vaccinated subjects compared to placebo recipients, but statistically not significant.
Sanofi Pasteur was asked to present the safety and the efficacy of the vaccine including data from the first year of long-term follow up (LTFU, starting one year post dose 3) as observed in these trials. During the first year of LTFU in CYD14 (Asian study), the risk of hospitalized dengue was significantly higher in the CYD vaccinated group compared to the control group in the 2–5 year age group (RR=7.45, 95% CI: 1.15, 313.80); the point estimate remained below 1 for the 6–11 and 12–14 year age groups (RR=0.627, 95% CI 0.22, 1.83 and RR=0.249, 95% CI: 0.02, 1.74, respectively). Given this signal of an imbalance of hospitalized and severe dengue cases in the youngest age groups (2–5 years) and the absence of identical risk in the group aged ≥ 9 years, the company decided, based on post hoc analysis, to set an age cut-off at ≥9 years for licensure request, as no such imbalance had been demonstrated over the currently available observation period in this age range. The relative risks of hospitalized dengue in subjects aged > 9 years in CYD14 and CYD15 during the first year of LTFU were 0.57 (95% CI: 0.18, 1.86) and 0.53 (0.25, 1.16), respectively.
Although there were relatively small numbers of hospitalized dengue cases in the first year of LTFU, GACVS acknowledged the increased relative risk in the 2-5 year old population. Despite the revised age indication based on the data presented, GACVS highlighted the importance of understanding the potential factors associated with this increased relative risk of hospitalization, and of severe dengue in particular, that may be in addition to, or instead of, age. Among other hypotheses, understanding the serostatus at the time of vaccination is critical given the lower vaccine efficacy in participants who were serologically naive and considering the potential risk of immune enhancement among previously infected subjects. Until this is better understood and characterized GACVS is unable to fully assess the risk in this age group. GACVS also considered the risk implications for all age groups under the proposed indication (9–60 years). Current data indicate that the risk of dengue has been lower among vaccine recipients in all other age groups studied up to 2 years post dose 3 (without distinguishing prior exposure to dengue virus). Additional data will be important in order to assess whether this effect is sustained over time. GACVS also emphasized the importance of further monitoring the risk of dengue requiring hospitalization (particularly severe dengue) in older individuals who are serologically naive at the time of vaccination. This will require, in particular, further examination of clinical trial data as the duration of observation after vaccination will increase.
The company also presented its proposed risk management plan. GACVS supports their commitment to long-term monitoring of trial participants to further characterize the signal in the youngest population. GACVS also supports their plans for post-licensure studies to mitigate potential risk of increase in the severity of dengue disease from the start of vaccination in the vaccinated population. The Committee emphasized the importance of further understanding the mechanism involved in the higher number of cases observed among the younger Asian children. This will be addressed in the context of continued follow-up of the controlled trials for each age group and both regions as proposed by the company. In addition, the Committee also acknowledged the need for additional information on co-administration with other age-appropriate vaccines, as well as vaccine safety among risk groups such as pregnant women and immune-compromised individuals, as proposed in the company’s risk management plan.
GACVS also noted that, as the company proposes to use the product in a broad age range, additional safety data should be generated for older age groups, (in particular among those aged ≥45 years) as currently the number of subjects evaluated is limited.
1 The main report was published in the Weekly Epidemiological Record on 17 July 2015 (No. 29, 2015, 365–372; available at http://www.who.int/wer/2015/wer9029.pdf?ua=1 ).
2 Capeding MR, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet. 2014 Oct 11;384(9951):1358–1365.
3 Villar L, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med. 2015 Jan 8;372(2):113–123.