Live attenuated dengue vaccines
GACVS reviewed progress with the development of tetravalent recombinant live dengue virus vaccines, of which at least one chimeric candidate with a yellow fever virus genetic backbone is undergoing phase III studies. The objective was to appraise the safety assessment plans proactively in order to determine the data critical to safety should the vaccine attain authorization for use in populations where the burden of dengue is significant.
To date, no serious vaccine-related events have been documented in the 41 700 subjects who have participated in different phases of the dengue vaccine trials. In addition, among vaccine recipients, no excess cases of dengue fever or severe dengue attributable to the vaccine virus have been demonstrated compared with control groups. Published results from a phase 2b study conducted among school-age children in Thailand indicated an overall efficacy of 30% but there was evidence of greater protection against 3 of the 4 serotypes.5 GACVS agreed that the safety profile observed up to date is encouraging but efficacy to protect against dengue remains a critical factor to be confirmed.
GACVS recognized that several issues will remain challenges for the evaluation of the safety of dengue vaccines if phase III studies indicate efficacy against clinical disease, in particular the lack of harmonization of dengue case classifications and the lack of consensus on the follow-up time or exposures to different dengue virus types needed to monitor the theorical risk of vaccine-mediated enhanced severe disease outcomes. Safety evaluation of dengue vaccines is also complicated by the rarity of suspected adverse events that could be readily attributable to the vaccine, i.e. neurotropic or viscerotropic disease from the yellow fever vaccine virus backbone, and severe dengue from natural infection potentially induced by incomplete vaccine protection.
In 2008, WHO issued technical recommendations to guide the development of dengue vaccines. GACVS concurs that long-term follow-up of vaccinated and unvaccinated cohorts, including those in randomized double-blind controlled trials, should be sought to help determine the safety of dengue vaccines when exposed to several natural infection cycles. In addition, storage of adequate samples of sera and peripheral blood mononuclear cells will be important for future studies on the immune mechanisms of protection or of sensitization conferred by dengue vaccines. Post-licensure studies will also provide estimates of the long-term effectiveness of immunization against multiple dengue virus serotypes in large populations; assess the risk of vaccine virus escape and any herd effects of vaccination; help establish whether booster immunization is needed; and indicate any potential age shifts in dengue presentations. GACVS identified several approaches that should be considered in designing those studies: collection of background dengue surveillance data; use of phased introduction (e.g. stepped wedge designs); use of case-control and case-only methods (to detect rare early adverse events); and epidemiological exploration of signals as the most appropriate way to establish causality for potentially related adverse events following immunization.
5Sabchareon A et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet, 2012, 380:1559–1567.