Single Dengvaxia dose cut severe dengue by 31% in Cebu

By Francis Allan L. Angelo

Children in Cebu who received only one dose of the dengue vaccine CYD-TDV before the Philippine government halted its mass immunization drive in 2017 were 31% less likely to develop more severe forms of dengue over the next five years, a University of the Philippines-led study found.

The protection, as reported in the journal Vaccine, held from the 2017 vaccination through February 2023 and covered both dengue with warning signs and severe dengue, with a 95 percent confidence interval of 6 to 49 percent and a p-value of less than 0.0001.

Against hospitalized virologically confirmed dengue overall, however, the single dose showed 21 percent effectiveness that did not reach statistical significance, with a confidence interval running from minus 7 percent to 41 percent and a p-value of 0.1129.

The study also found that whatever protection the dose conferred was concentrated early. Effectiveness against hospitalized confirmed dengue was 49 percent in the first year after the mass vaccination, from February 15, 2018 to February 14, 2019, with a confidence interval of 19 to 68 percent and a p-value of 0.0067. It appeared to decline after that first year.

Dengvaxia, the first dengue vaccine licensed for use, was introduced in the Philippines in 2016 for children aged nine to 14 years. The Department of Health was still rolling it out in Cebu province in 2017 when concerns about the vaccine’s safety in seronegative individuals prompted an abrupt halt, leaving many Cebu children with only the first of three scheduled doses.

Researchers ran a matched case-control study in Cebu province from February 15, 2018 to February 28, 2023. Cases were children born between 2003 and 2008, resident in Cebu since the 2017 mass vaccination, eligible for the vaccine, and admitted to one of four participating government hospitals with fever of less than five days.

Dengue was confirmed by real-time reverse transcription polymerase chain reaction, and illness was classified according to World Health Organization 2009 criteria as dengue, dengue with warning signs, or severe dengue. Two neighborhood controls of the same sex and age group were recruited for each case.

Of 71,223 acute febrile presentations screened at the study hospitals, 69,978, or 98.3 percent, were ineligible. Of the 1,245 eligible episodes, 333, or 26.7 percent, were excluded because of consent refusal, withdrawal, or refusal of blood collection within five days of fever onset.

The team enrolled 912 suspected dengue episodes, of which 620 tested positive by RT-PCR. Another 36 confirmed cases were dropped because matching controls could not be recruited, 13 of them because of mobility restrictions during the COVID-19 enhanced community quarantine. The final analysis covered 584 cases and 1,168 matched controls.

Among the 584 confirmed cases, 397, or 67.8 percent, presented as dengue with warning signs, eight, or 1.4 percent, had severe dengue, and one child, or 0.2 percent, died.

Beyond fever, the most common presumptive signs and symptoms were nausea or vomiting in 414 cases, or 70.9 percent, malaise in 373 cases, or 63.9 percent, and anorexia in 235 cases, or 40.2 percent. The most frequent warning sign was abdominal pain in 272 cases, or 46.6 percent, followed by lethargy in 158 cases, or 27.1 percent, and restlessness in 116 cases, or 19.9 percent.

All four dengue serotypes circulated among the cases. Serotype 3 was the most common at 287 cases, or 49.1 percent, followed by serotype 2 at 166, serotype 1 at 86, and serotype 4 at 37. The researchers said no conclusions could be drawn about effectiveness by serotype because of inadequate sample size.

Vaccination coverage differed between the two groups. Of the cases, 112, or 19.2 percent, had received a dose, compared with 270, or 23.1 percent, of the controls. The crude odds ratio was 0.74, and the adjusted odds ratio was 0.79 after controlling for dengue in the household, dengue in the neighborhood, concrete housing material, window screens, stagnant water, insect repellent use, and ownership of a bicycle and a computer.

The five-year figures are lower than the interim results the same team reported through February 2020, which showed 26 percent effectiveness against hospitalized confirmed dengue and 51 percent against dengue with warning signs. The authors attributed the drop to waning vaccine protection.

Both sets of estimates fall well below the 80 percent efficacy against hospitalized confirmed dengue recorded for the full three-dose regimen in this age group over two years. They are close, however, to the 26 percent single-dose effectiveness measured among people aged 19 to 27 within three years of a mass vaccination in Brazil.

The study could not determine whether participants had been infected with dengue before vaccination, which the authors identified as an important limitation because Phase 3 trials found three-dose efficacy of 76 percent among seropositive children aged nine to 16 and 39 percent among seronegative children. The researchers said a large majority of the Cebu cohort was likely seropositive.

The authors also flagged the COVID-19 pandemic as a source of bias, noting that lockdowns in 2020 and 2021 limited enrollment as hospitals prioritized COVID-19 cases and parents avoided bringing children in for care.

Public reaction to the Dengvaxia controversy, including criminal investigations against those involved in the campaign, likely introduced further selection bias toward the null, the authors wrote, because some vaccinated patients were urged to seek treatment for milder illness that would otherwise have gone unhospitalized.

The researchers concluded that the waning protection they measured underscores the need for the complete three-dose schedule to achieve sustained efficacy, and said policymakers should weigh the results when designing vaccination strategies in settings where baseline serostatus cannot be readily determined.

The study sponsor, the University of the Philippines Manila, received funding from Sanofi, the vaccine’s manufacturer, to undertake the effectiveness assessment. Sanofi took part in discussions of the study design and reviewed the initial manuscript draft, but the authors said they retained complete autonomy over data analysis, interpretation, and submission.

The study was led by Kristal An Agrupis and Maria Vinna Crisostomo as co-first authors, with Jedas Veronica Daag, March Helena Jane Lopez, Kiarah Louise Florendo, Clarissa de Guzman, Jacqueline Deen, and Michelle Ylade of the Institute of Child Health and Human Development, University of the Philippines–National Institutes of Health, Manila.

Also on the team were Jesus Sarol Jr. of the Interdisciplinary Health Sciences Institute at the University of Illinois at Urbana-Champaign, Ava Kristy Sy of the Department of Virology at the Research Institute for Tropical Medicine in Muntinlupa, Zoraida Yurango of Cebu Provincial Hospital–Bogo, Olivia Dandan of Cebu Provincial Hospital–Balamban, and Jean Balabat of Eversley Childs Sanitarium and General Hospital in Mandaue City.