https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32525-5/fulltext
Vaccine-attributable severe dengue in the Philippines
Published:December 14, 2019DOI:https://doi.org/10.1016/S0140-6736(19)32525-5
In 2016, WHO recommended that the dengue vaccine CYD-TDV (Dengvaxia; Pasteur, Lyon, France), the first dengue vaccine, licensed for use in adults and children aged 9 years or older, be considered for use in highly endemic regions where at least 70% of 9-year-old children had previously been infected with dengue. The Philippines was the first country to introduce Dengvaxia on a large scale in selected highly endemic regions, targeting about 1 million children aged 9–10 years. In November, 2017, an excess risk of hospitalisation for dengue and severe dengue in vaccinees who had not had a previous dengue infection at the time of vaccination was reported, on the basis of retrospective analyses of data from the Dengvaxia phase 3 trials, using a novel non-structural protein 1 (NS1) based antibody assay. Following a reanalysis of these data, the Philippine Dengvaxia programme was suspended. However, by the time the programme had been suspended, more than 830 000 children had received at least one of the three recommended Dengvaxia doses. The news about the safety concerns in dengue-naive vaccinees led to major public outcry, with loss in vaccine confidence that extended to routine childhood vaccines.
Parents whose children had received Dengvaxia were understandably alarmed by the reported adverse effect of the vaccine, especially because most parents will not have known whether their child had been infected by the dengue virus previously, and any cases of severe dengue in vaccinees might have been attributed to the disease-enhancing properties of the vaccine in seronegative children. Similarly, clinicians looking after vaccinated children admitted with severe dengue were also tempted to attribute every episode to vaccine-enhanced disease. However, in reality a minority of cases are likely to be attributed to vaccine-enhanced disease.
No vaccine is 100% efficacious and cases of breakthrough disease arise through vaccine failure. For the first licensed dengue vaccine, the issues of efficacy and safety are complex because both are driven by serostatus. Serostatus refers to whether a person has had a previous dengue infection; a seropositive person will have had at least one dengue infection in the past, whereas a seronegative person is dengue-naive. The efficacy of Dengvaxia against severe dengue in seropositive vaccinees in the phase 3 trials was 84% (95% CI 63–93). Most vaccinees in the Philippine programme, possibly around 85%, were likely seropositive. Hence, we would expect to see breakthrough disease in seropositive vaccinees when exposed to natural infection, especially in light of the current outbreak of dengue in the Philippines. Cases of severe dengue would be a mixture of breakthrough cases and of enhanced disease in seronegative children.
The risks associated with Dengvaxia must be put into perspective. First, many cases of hospitalisation and severe dengue following vaccination are likely to be attributable to vaccine breakthrough cases in seropositive vaccinees because a high proportion of vaccinees are dengue seropositive, in whom the vaccine protects but does not give total protection. Second, in all children vaccinated, the overall incidence of hospitalised dengue is likely to be substantially lower in the 5 years following vaccination than would have been the case had no one been vaccinated. On a population level, in highly endemic regions, like the selected regions of the Philippines, the number of dengue cases averted by Dengvaxia is likely to substantially outweigh the number of vaccine-induced cases, and vaccination with Dengvaxia has an overall net benefit to the population. Vaccinating only those testing seropositive would be the preferred strategy for future use of the vaccine, but this depends on the development of sensitive and specific rapid point-of-care tests to identify this group.
AW-S serves as a consultant to WHO. PGS reports personal fees from Sanofi Pasteur and Takeda. SF and PGS were members of the WHO SAGE Working Group on dengue vaccines. The views expressed in this Correspondence are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the agencies or organisations with which the authors are affiliated.
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Published: 14 December 2019
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