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Dengue Vaccine –Philippines / GACVS
Safety of dengue vaccine in the Philippines
Extract from report of GACVS meeting of 6-7 June 2018, published in the WHO Weekly Epidemiological Record of 20 July 2018
GACVS last reviewed the CYD-TDV dengue vaccine at its meeting on 6–7 December 2017.5 The Committee noted that long-term follow-up in clinical efficacy trials indicated that, overall, vaccinated trial participants had a reduced risk of virologically confirmed severe dengue and hospitalization; however, a subset of trial participants who had not been infected with dengue virus before vaccination (i.e. dengue-naïve, seronegative according to the NS1 assay) had a higher risk of severe dengue and hospitalization. The new evidence presented at that meeting was based on a reanalysis of the clinical trial data by the manufacturer, with a new test that distinguishes individuals with and without previous exposure to wild dengue virus retrospectively.6 The WHO Strategic Advisory Group of Experts (SAGE) on immunization previously identified research on vaccine safety in this seronegative population as a priority.7
Following the December 6–7 meeting in 2017, GACVS recommended that CYD-TDV not be administered to individuals who have not been previously infected with wild dengue virus. GACVS also noted that no data are currently available to allow an analysis of risk according to the number of vaccine doses received by people who are seronegative at baseline.
At its meeting on 17–18 April 2018, SAGE advised countries considering CYD-TDV vaccination as part of their dengue control programme to include pre-vaccination screening, so that only dengue-seropositive persons are vaccinated; the limitations of such screening should be clearly communicated to those offered vaccination.8
WHO will release a revised position paper on dengue vaccine in September 2018. The purposes of an update of the GACVS statement on dengue vaccine are: (i) to review the reports on vaccine safety received by the Philippines Ministry of Health after announcement of the risk for severe dengue of vaccine recipients who were dengue-naïve at the time of vaccination; (ii) to review difficulties in determining whether, apart from vaccine failure, the cases of severe dengue in vaccine recipients who were dengue-naive at the time of CYD-TDV vaccination were due to vaccine-related immune enhancement; and (iii) to review the updated safety profile of CYD-TDV.
The Philippines Food and Drug Administration approved use of CYD-TDV in December 2015, and the Disease Prevention and Control Bureau proposed its introduction as part of the National Dengue Prevention and Control Program. Vaccine administration began in 2016, first as part of a school programme in highly endemic regions and then extended to community programmes in Octo¬ber 2016. Surveillance of the safety of all vaccines is well established in the country, as a part of integrated disease surveillance and response. Should a serious AEFI or cluster be detected, the epidemiology bureau of the Department of Health is notified within 24–48 h. Serious cases are investigated, and the results of the investigations are compiled and sent to the regional and national AEFI committees. Before the programme was suspended, over 875 000 children had received at least 1 dose, almost 350 000 had received all 3 doses, and about 400 000 had received 2 doses.
Post-marketing data were presented to GACVS by the manufacturer. CYD-TDV is registered in 20 countries, and most doses are distributed in Brazil (where it is used in a public programme in Parana State) and the Philippines. In Brazil, dengue cases are reported through a national reportable disease information system, and data on AEFI are collected through passive surveillance in a national immunization programme. Guidelines for enhanced reporting and training of vaccine centre workers were provided by local authorities in Parana State.
The 14 fatal case reports in the Philippines were first reviewed by the national AEFI committees and the Dengue Investigative Task Force (DITF). The reports included 3 cases of dengue shock syndrome and 6 cases with other clinical diagnoses and no clear causal link other than a temporal association. The other cases were coincidental (3) or unclassifiable (2). A further review of 12 cases (8 fatal and 4 non-fatal) was undertaken by the DITF after training in AEFI methodology by international specialists. Although the DITF found that most cases were indeterminate, coincidental or unclassifiable, it recognized several cases of dengue disease. GACVS maintained its earlier recommendation that CTD-TDV should not be administered to people who have not previously been infected with wild dengue virus. It concluded that, in the absence of criteria for distinguishing vaccine failure from vaccine-related immune enhancement, individual cases cannot be attributed to one or the other. As a result, such cases should be classified as indeterminate, irrespective of the time since vaccination.
Between December 2015 and March 2018, 1876 adverse events were reported to the manufacturer, mainly from Brazil and the Philippines; reporting was consistent with the pattern of dose distribution in both countries. The most frequently reported adverse events were fever, headache, dizziness, vomiting and rash. Of the 211 serious AEFI reported, most were consistent with an underlying infectious disease, including dengue fever. By 20 March 2018, 87 cases of dengue infection had been reported after vaccination with CYD-TDV; 23 were serologically confirmed, 61 suspected with no virological confirmation and 3 with negative virological tests. Of the 87 dengue cases, 14 were fatal. Of the 14 cases, 6 had completed the vaccination schedule, 3 had received 2 doses and 5 had received only 1 dose. All 9 cases for which the interval between vaccination and disease onset was known occurred within 6 months of the last vaccination.
Progress was reported in cohort event monitoring, sponsored by the manufacturer to obtain information on selected AEFI and serious adverse events in people vaccinated with CYD-TDV over 5 years in Brazil, Mexico and the Philippines. The target for enrolment in the study of post-authorization safety is 30 000 vaccinated participants. As of 5 April 2018, 12 573 participants had been enrolled and had received at least 1 dose of CYD-TDV.
One of the challenges in conducting post-market surveillance after vaccination with CYD-TDV is determining whether the vaccine gives rise to vaccine-related immune enhancement. An increasing number of AEFI were reported after suspension of the vaccination programme in the Philippines and media coverage. A task force was established by the Department of Health to review all fatal cases, and guidelines on AEFI reporting and response to vaccine recipients were issued by the Department of Health. In addition, the National AEFI Committee, established in 2012, was charged with reviewing all non-fatal AEFI.
GACVS also examined the possible risk of viscerotropic or neurotropic disease associated with the yellow fever backbone of the CYD-TDV vaccine. Although this remains a theoretical possibility, non-clinical and clinical evaluations do not provide evidence of an association. Viscerotropic and neurotropic diseases are rare serious reactions to yellow fever vaccination and occur only in close temporal association with vaccination. As severe dengue may also be accompanied by haemorrhagic systemic phenomena, a differential diagnosis can be made only if the vaccine strain is isolated from affected organs and if such syndromes occur within the accepted interval between vaccination and symptom onset (8 days).
5 See No. 3, 2018, pp. 21–25.
6 Sridhar S et al. Effect of dengue serostatus on dengue vaccine efficacy. N Engl J Med 2018. doi: 10.1056/NEJMoa1800820.
7 See No. 21, 2016, pp. 282–284.
8 See No. 23, 2018, pp. 337–340.