With its dengue vaccine in the regulatory queue, Takeda outlines longterm followup data that it says keep it out of Dengvaxia's shadow
When Sanofi published longterm followup results from a trio of Phase III trials for its dengue vaccine in 2015, investigators flagged a concerning observation that they weren’t able to explain: In the third year post-vaccination, children younger than 9 who got the jabs were more likely to end up in the hospital than those in the control group.
The hospitalization imbalance didn’t stop Sanofi from clinching the approval to start the world’s first large-scale vaccination campaign in the Philippines with its vaccine, Dengvaxia. But even though public health officials tried to skirt it by limiting the inoculation drive to older children and adults, the issue — which Sanofi was later accused of playing down — would come back to haunt the effort. Kids and adults were developed with severe fever after vaccines, in some cases lethal, sparking nationwide panic and forcing the Phillippine government to shut down the program. Even though Dengvaxia eventually got adopted in other countries, the fiasco left its scars.
Takeda, which has been pushing its own dengue vaccine under that cloud for the past eight years, now has the three-year followup data to suggest it can steer clear of that wreckage — although some gaps remain before we get a complete profile of the shot.
With those results now in, the Japanese pharma has also completed the package it needs to file with regulators. Takeda submitted for a marketing approval with the EMA in March, and it’s plotting more in dengue-endemic countries like Argentina, Brazil, Colombia, Indonesia, Malaysia, Mexico, Singapore, Sri Lanka and Thailand. An FDA filing is expected to follow later this year.
Having followed 20,000 study participants for 36 months after their second dose of TAK-003, investigators reported that vaccine efficacy against hospitalized dengue is 83.6%.
“That’s really the component of the illness that has the most impact, at an individual level whether that’s on health or finances, it’s also the aspect of dengue that has the greatest impact on public health systems and our communities,” Derek Wallace, the dengue program leader at Takeda, told Endpoints News in a preview.
The efficacy numbers are similar regardless of whether the vaccine recipient has had a previous dengue infection — 86% for the seropositive group and 77.1% for the seronegative group — which is notable because a phenomenon known as antibody-dependent enhancement in virus-naïve patients had been blamed for Dengvaxia’s problems.
Overall vaccine efficacy, as measured by virologically-confirmed dengue, registered at 62.0%, with 65% in seropositive individuals and 54.3% in seronegative individuals.
The protection that the vaccine offers has waned across the board compared to the last cut of data at 18 months, when Takeda touted an overall efficacy rate of 73% and reduction of 90% in dengue-required hospitalization compared to placebo. But the waning focused on what Wallace calls “ambulatory dengue” and the drop was smaller in the group that mattered.
But Takeda didn’t provide an update on the breakdown of efficacy in each of four dengue serotypes, saying it will save those numbers for publication in a peer-reviewed journal later this year. At 18 months, while the efficacy for dengue 1 and dengue 2 looked promising, there were concerns about a lack of efficacy for dengue 3. (For dengue 4, the data were inconclusive.)
Sanofi scored approval for Dengvaxia with Phase III data that were presented in a slightly different way, suggesting pooled rates of efficacy for symptomatic dengue during the first 25 months of 60.3% — and pooled relative risks of hospitalization for dengue of 0.84.
Per the protocol, Takeda will monitor the participants for another year and a half. After 4.5 years, it plans to test whether a booster would offer more protection in the long run.
“The world we live in now with Covid-19 has really shown the potentially devastating impact that infectious diseases can have, and the value of careful vaccine developments and implementation of vaccine programs,” Wallace said. “In the background of all that, we have dengue. Dengue has been around for decades before Covid-19 and it will be around for decades to come. It’s a disease that is massive in its impact, affecting half of the world’s population and it’s not a disease that we’ve got a very good handle on in terms of management or prevention.”
They’ve come a long way to arrive at a stage where they are preparing to talk to regulators. Originally derived in the laboratories of Sutee Yoksan at Mahidol University in Thailand, the live-attenuated vaccine construct was muscled up at the US CDC and went through clinical studies at Inviragen before Takeda snapped the biotech up in 2013, while the dengue program was still in Phase II, according to a spokesperson.
Covid-19, of course, still figures prominently in the minds of any vaccine developer. Even as Takeda hammers out the arrangement for its German contract manufacturer IDT to make the initial doses of TAK-003 should it be approved (before eventually setting up its own production in Germany), it will be providing some manufacturing slots there to make J&J’s coronavirus vaccine while helping Moderna distribute its shots in Japan.