Takeda’s Dengue Vaccine is Promising, but Critics Still Have Concerns

Back in January 2019, Takeda Pharmaceutical announced that its vaccine for dengue fever hit its primary efficacy endpoint in its Phase III clinical trial. The company has provided new analysis for its TIDES clinical trial of 20,000 patients in dengue-endemic sites in Latin America and Asia, which was published in the New England Journal of Medicine.

Although the results look very promising, showing an overall protection rate of slightly over 80% in children age four to 16 who were evaluated 12 months after a two-dose treatment regiment, there are still concerns similar to those seen with Sanofi’s Dengvaxia. To be clear, the data presented does not show new safety concerns in the Takeda vaccine, but critics have expressed a need for more confirmation.

Dengue fever is marked by a sudden, high fever, severe headaches, pain behind the eyes, joint and muscle pain, fatigue, nausea, vomiting, skin rash and mild bleeding. It affects about 400 million people worldwide annually, with about 96 million resulting in illness. It is transmitted by mosquitoes.

In May 2019, the U.S. Food and Drug Administration (FDA) approved Sanofi’s Dengvaxia, a vaccine for all four serotypes of dengue. It was approved for dengue disease caused by serotypes 1-4 in people ages 9 through 16 who are living in areas of the U.S. who have had a laboratory-documented previous infection.

Dengue is endemic in the U.S. territories of Puerto Rico and the U.S. Virgin Islands. Puerto Rico had the largest outbreak in 2010, when more than 12,000 cases were confirmed. Incidence remained high in 2012 and 2013. People can get dengue up to four times and the second infection is generally worse than the first. An advisory committee voted 6 to 7 against Dengvaxia in people aged 9 to 45 with one panelist abstaining. The vote on safety was tied 7 to 7. A positive vote for the vaccine covered children and adolescents aged 9 to less than 18. The committee voted 13 to 1 on the vaccine’s efficacy for the 9 to 17-year-old group and on safety, voted 10 to 4 in favor.

Dengvaxia was pulled from the Philippine market in 2017 over safety issues. A pediatrician and medical researcher there, Rose Capeding, was indicted over the failed introduction of the vaccine. Dengvaxia has been linked to 10 deaths in the Philippines, but Sanofi strongly disagrees with those findings.

Takeda will need to show that its own vaccine doesn’t have the same problems as Dengvaxia—proving that it doesn’t make second infections more severe, particularly in children, according to several experts.

In the Takeda study, one strain, DENV-2, had an effectiveness rate of 97.7%. However, two other strains, DENV-1 and DENV-3, were lower, with 73.7% and 62.6%, respectively. And there isn’t enough data to determine how successful the DENV-4 strain was.

“We’re very encouraged by the results,” Derek Wallace, vice president and Global Dengue Program Head, told STAT. Although the DENV-1 and -3 strains results is moderate, the data “still represents a massive step forward in the reduction of the burden of the disease. We see it encouragingly when you consider the burden of dengue globally.”

Wallace added, “We’re looking very carefully at the safety of this vaccine candidate on the assumption it continues to have no important safety side effects. A vaccine which has partial efficacy against some serotypes would still have significant public health advantages.” He added that more data will be released later this month at a medical conference.

A retired dengue expert, Scott Halstead, formerly with the Uniformed Services University of the Health Sciences who recently served on a Takeda advisory board, points out that the Takeda vaccine shows some evidence that children who were not previously exposed to the virus seems to have some protection, but more data needs to be released. “We’ll have to wait to find out where that protection is going—will it stabilize or get worse? It’s very much a preliminary report. This suggests victory, but Takeda recognizes this is something they’re going to have to stick with, think about, work on, watch and be careful. … Let’s make sure nobody runs around claiming an early Pyrrhic victory.”

Another dengue expert, Anna Durbin, with Johns Hopkins, who is testing an experimental dengue vaccine developed at the National Institute of Allergy and Infectious Diseases, wants more long-term safety data, particularly in children.

Durbin told STAT, “The overall efficacy against the four different serotypes is higher than with Dengvaxia and may be more balanced. I am cautiously optimistic because of the better efficacy in (children who were not previously infected with Dengue) than was seen with Dengvaxia and the similar efficacy in the younger age groups. This suggests to me that if there is an unbalanced response, the problem will be smaller than was seen with Dengvaxia.”