麻豆传媒

There was more bad news for the beleaguered dengue vaccine CYD-TDV (Dengvaxia) -- a reanalysis of efficacy data by the manufacturer found a higher risk of hospitalization for dengue virus among seronegative children who received the vaccine.

Cumulative 5-year incidence of hospitalization of children, ages 2-16 years, due to virologically confirmed dengue was 3.06% among dengue-seronegative vaccine recipients compared with 1.87% of controls (HR 1.75, 95% CI 1.14-2.70), reported Saranya Sridhar, MD, of Sanofi Pasteur in France, and colleagues.

However, the rates were much lower for dengue-seropositive participants of the same age (0.75% for cases versus 2.47% for controls, HR 0.32, 95% CI 0.23-0.45), the authors wrote in an early release of the .

Dengvaxia has been under fire even before of the vaccine in young children prompted the Philippines to stop using the vaccine, and launch an investigation into its effects. The World Health Organization (WHO) recently recommended that dengue vaccination should only be given once a patient receives a diagnostic test that confirms they have been exposed to dengue.

But there were hints of problems with this type of vaccine long before last year, when investigators noted that the CYD vaccine appeared to increase the risk of hospitalization in children age <9.

Sridhar's group acknowledged that in the third year of the phase III trial in Asia, they observed "an excess in hospitalizations" for children who had been vaccinated at ages 2-5. They added that efficacy trials assessed baseline serostatus of participants in a way that "did not allow for precise estimates of the risk of hospitalization for dengue or the risk of severe dengue in seronegative vaccine recipients."

So they went back and reexamined blood samples that were collected after the third vaccination, and then used a newly developed assay to tell the difference between antibodies that were developed as a result of the vaccine or as a result of exposure to infection.

The primary endpoint of the study was actually to measure the risk of hospitalization for virologically confirmed dengue in seronegative vaccine recipients ages ≥9, the authors said, with similar results in children ages 2-8 and 2-16 as prespecified secondary objectives.

Risk of hospitalization for seronegative children ages 9-16 through month 60 was 1.57% (95% CI 1.13-2.19) in the vaccine group and 1.09% (95% CI 0.53-2.27) in the control group (HR 1.41, 95% CI 0.74-2.68).

For seronegative children ages 2-8, the hazard ratio for hospitalization for dengue was 1.95 (95% CI 1.19-3.19), whereas it was 0.50 (95% CI 0.33-0.77) for seropositive children.

Another safety endpoint was the risk of severe dengue, where the results were slightly worse. The HR for severe dengue among seronegative children ages 9-16 was 2.44 (95% CI 0.47-12.56), albeit with a wide confidence interval, and was similar for children ages 2-16 (HR 2.87, 95% CI 1.09-7.61). This was even higher among seronegative children ages 2-8 (HR 3.31, 95% CI 0.87-12.54), with similar wide confidence intervals.

The news was much better for seropositive children, with the authors writing "the rates of severe [virologically confirmed dengue] and hospitalization for VCD over a 5-year period for all ages considered ... were approximately 70% lower in the vaccine group than in the control group, and among those 9 years of age or older at vaccination ... were approximately 80% lower."

They authors acknowledged that their findings could have an impact on dengue vaccination programs, given the WHO recommendations, and that while a diagnostic test to determine previous dengue exposure "would be ideal, no such test has been widely registered ... and prevaccination screening in large programs could be challenging to implement."