The WHO Global Advisory Committee on Vaccine Safety has been following the development of a tetravalent recombinant live dengue virus vaccine for the past 5 years 1,2,3,4. The most advanced product, CYD-TDV by Sano?-Pasteur (Dengvaxia®) is a yellow fever vaccine virus backbone vector that expresses envelope proteins of dengue viruses type 1 to 4 yellow fever vaccine virus genetic backbones. During early clinical trials no serious vaccine-related events had been documented among the recipients, and no excess cases of dengue fever or severe dengue attributable to the vaccine had been observed. Subsequent large scale phase 3 trials, CYD14 in Asia (among subjects aged 2 to 14 years) and CYD15 in Latin America (among subjects aged 9 to 16 years) were conducted in over 20,000 vaccine recipients and 10,000 control subjects and demonstrated partial efficacy of the vaccine.
WHO
Dengvaxia has received its first marketing authorizations in late 2015 and is currently available in several Asian and Latin American countries. This statement briefly reviews the experience presented to GACVS during clinical trial development (with now over 5 years of follow up), and discusses new evidence presented to WHO during the December 2017 GACVS meeting. This new data is based on re-analysis of clinical trial data using a new test that retrospectively distinguished subjects with and without prior exposure to wild dengue virus.
Background
Dengue is an increasingly important disease worldwide. As outlined in the WHO position paper on dengue vaccines published in July 20165, the number of cases reported annually to WHO has increased from 0.4 to 1.3 million in the decade 1996-2005, reaching 2.2 million in 2010 and 3.2 million in 2015. Based on mathematical modelling, the global annual incidence has been estimated at about 50-100 million symptomatic cases, predominantly in Asia, followed by Latin America and Africa. However clinical cases are likely to represent only about 25% of all dengue virus infections. In 2013 dengue was estimated to be responsible for approximately 3.2 million severe cases and 9,000 deaths, the majority occurring in lower middle income countries. GACVS recognized several challenges for the evaluation of the safety of dengue vaccines, particularly the follow-up time needed to monitor the theoretical risk of increased severe dengue following vaccination. Severe dengue cases represent a small percentage of all dengue infections and are more common on second exposure to wild dengue viruses.
In 2015, the committee was presented with results from the third year of follow up in the CYD14 trial conducted in Asia. The trial found that the risk of hospitalized dengue was signi?cantly higher in the vaccinated group compared to the control group in the 2 to 5 year age group (RR=7.45, 95% CI: 1.15, 313.80). This risk was not found to be elevated in older age groups. GACVS at the time highlighted the importance of understanding potential factors other than age that may be associated with this increased relative risk of hospitalization and of severe dengue. Among them, understanding if a subject and been exposed to wild dengue virus prior to vaccination was deemed critical given the lower vaccine ef?cacy in participants who were serologically naïve, and the potential risk of immune enhancement among previously infected subjects.
Based on those results GACVS noted that the excess cases of hospitalized dengue (in the age group 2-5 years) could be related to age, serostatus or both. The plausible hypothesis proposed was that vaccination primes the immune system similarly to natural infection and after a period of protection following vaccination, immunity wanes. According to this hypothesis among seronegative individuals, the response to the first natural infection following vaccination (and waning immunity) may act as a second infection, which has typically been associated with a higher risk of serious disease. In seropositive individuals, the response to the first natural infection following vaccination is as if it was a third or later infection and not associated with a higher risk of serious disease. As a result of available evidence, licensure was sought for children and adults aged 9 years and older. SAGE issued recommendations in April 2016 to introduce DENGVAXIA® only in geographical settings (national or subnational) with high endemicity, as indicated by seroprevalence of >70% in the age group targeted for vaccination.
In June 2016 [4], GACVS was presented with the longer-term 4-year follow-up of hospitalized dengue among CYD14 and CYD15 clinical trial participants. While no consistent increase was observed in the risk of hospitalization or severe dengue in vaccinated individuals aged 9–16 years, in the younger age group of 2–8 years an increased relative risk (not reaching signi?cance) was observed in year 3 of follow up that persisted during year 4 but was declining. GACVS recommended that existing and planned clinical ef?cacy trials should be evaluated in depth and include careful assessment of pre-immunization seropositivity in selected cohorts. These data would contribute to a greater understanding of the potential risk factors and underlying immunology of dengue infection and severe dengue post-vaccination.
Current status and new data
To date, the vaccine has been licensed in 19 countries and introduced in public immunization programs in the Philippines and Brazil. Immunization began in the Philippines in April 2016 and GACVS was presented with the program’s early post-market surveillance experience [4]. The country had seen dramatic increases in cases since 2010 with over 150,000 dengue episodes and about 1,000 deaths annually. By the time of the meeting in June 2016 [4], almost 250,000 children age 9 years and older had been vaccinated.
As SAGE had identified vaccine safety in the seronegative population as a research priority [6], Sanofi Pasteur has undertaken a case-cohort study using a dengue anti-NS1 IgG ELISA assay (NS1) on blood samples available from clinical trial participants at 13 months after the first dose (one month following the third and last dose of vaccine administered during the clinical trials). The research assay is designed to differentiate between prior natural infection and vaccination. Based on these results, the company reanalysed the safety and efficacy according to this surrogate of serostatus as well as age at the time of vaccination.
Overall, vaccinated trial participants had a reduced risk of virologically-confirmed severe dengue and hospitalizations. The subset of trial participants who had not been exposed to dengue virus infection prior to vaccination (i.e., dengue-naïve, seronegative according to the NS1 assay) had a twice higher risk of more severe dengue and hospitalizations compared to unvaccinated participants, regardless of age. In contrast, those trial subjects, at any age, with evidence of a previous dengue infection (as determined by NS1 assay) experienced a reduced risk of severe dengue for the duration of the observation period.
Based on this new analysis Sanofi Pasteur estimated actual risks in the study population. In study subjects of (2-16 years of age) without prior dengue infection, data suggest modest efficacy (15%-32%) of vaccine against symptomatic dengue until the second year of follow up. Subsequently, starting during year 3, the risk of hospitalized and severe illness becomes higher than among controls. In practical terms, and within the population studied, these data suggest that during a 5-year follow-up, about 5 additional hospitalized dengue cases or 2 additional severe dengue cases per 1000 vaccinees with no previous dengue infection (i.e. dengue naïve subjects) could occur following vaccination compared to unvaccinated seronegative children. Importantly, in the clinical trial population, all cases recovered and no deaths were observed. On the other hand, among children who have had a prior dengue infection (i.e. seropositive) there is a reduction of 15 cases of hospitalized dengue and 4 cases of severe dengue per 1,000 who are vaccinated for the same duration of follow-up.
Implications and assessment by GACVS
The GACVS considered these new results as well as the clinical trial data and early post-market data submitted. Key issues included the validity of these findings, to which subgroups they mostly apply, the magnitude of the risk, and implications both, for those subjects already vaccinated and those who have not yet been vaccinated. GACVS acknowledged that the vaccine is safe and efficacious in individuals who have had a primary infection with wild dengue preceding immunization, thus preventing a “second” and therefore more severe episode of dengue. GACVS noted that the increased risk of severe dengue among vaccinated individuals who are seronegative to dengue at time of vaccination became apparent during the third year after receipt of the first vaccine dose irrespective of the age. Thus, as post-licensure use started in the second quarter of 2016, an increase in the number of severe dengue cases among seronegative subjects would not occur before 2018 in Brazil and the Philippines, the two countries that introduced the vaccine early.
The new data indicate that the increased risk of hospitalization (and severe disease) from dengue affects vaccinated subjects who are naive to wild dengue infection prior to vaccination. This provides strong indication that previously identified excess risk among younger vaccine recipients in the Asian study reflected a confounding association between age and exposure to wild dengue virus. In other words, it appears that history of exposure to wild dengue predicts the risk of severe disease among vaccine recipients rather than their age. This also corroborates prior hypotheses suggesting that immune priming from natural or other stimulation such as immunization with the dengue vaccine can lead to a higher risk of severe dengue disease on secondary exposure to wild dengue viruses.
GACVS recognizes that the vaccine has, to date, been administered to a large majority of subjects among populations where exposure to dengue virus is high and therefore the majority of vaccine recipients are seropositive to wild dengue. Of note, the clinical data presented by Sanofi Pasteur also showed that, even among seronegative population, the number that would experience untoward severe dengue is likely to be lower than one percent and that with proper clinical care, more serious consequences can be prevented in most instances.
As a result, GACVS recommends that Dengvaxia should not be administered to individuals who have not been previously infected with wild dengue virus. Data are not currently available to allow an analysis of the risk according to the number of vaccine doses received by subjects seronegative at baseline. It is therefore not possible to determine if incomplete vaccination would lead seronegative subjects to a higher or lower risk of severe dengue as compared to seronegative subjects who have received the full 3-dose course.
In order to minimize untoward consequences for dengue-naive vaccinated subjects, GACVS recommends ensuring that measures that reduce exposure to dengue infection among populations where the vaccine has already been administered be enhanced. For vaccine recipients who present with clinical symptoms compatible with dengue virus infection, access to medical care should be expedited to allow for proper evaluation, identification, and management of severe forms of the disease.…
