Professor Duane Gubler is one of the world’s leading experts on dengue vaccines. He has supported the development of all three of today’s leading vaccines: Sanofi’s Dengvaxia, the Takeda dengue vaccine and the NIH (US National Institutes of Health) dengue vaccine, both currently in clinical trials. We caught up with him to learn about the history and complexity of developing a vaccine to protect against a virus with four serotypes.  

The Takeda dengue vaccine has a long history. Where did it all begin?

Back in the 1970s, dengue haemorrhagic fever was increasing dramatically in Southeast Asia, and dengue had started to appear in the American region as well. Dr Scott Halstead at the University of Hawaii had begun researching dengue vaccines and was using dog kidney cells to attenuate (weaken) the four serotypes of the dengue virus.

In 1977, SEARO (the Southeast Asia Regional Office of the World Health Organization) agreed to support the development of a dengue vaccine at a WHO meeting in Singapore. SEARO then awarded a grant to Professor Natth Bhamarapravati at Mahidol University in Thailand to develop the first tetravalent dengue vaccine in early the 1980s.

Dr Scott Halstead shared his work with Professor Natth. By the early 1990s, Professor Natth had what he considered to be four attenuated monovalent (for only one serotype) dengue vaccines – one for each of the dengue serotypes. He had based the vaccines for the first three serotypes on Thai viruses and used an Indonesian virus for the fourth.

I was a member of the WHO peer review that reviewed Professor Natth’s work every year and made recommendations. By 1993, we were confident that Professor Natth had a tetravalent (for all four serotypes) vaccine that was ready for further clinical trials.

Professor Natth then signed a licensing contract with Pasteur Mérieux, now Sanofi Pasteur, handing over all four monovalent vaccine candidates. Professor Natth kept the right to use those vaccine candidates to develop second-generation vaccines.

What happened next?

The four monovalent vaccines were then combined to create a tetravalent dengue vaccine. Sanofi ran their first clinical trial in 1995 in collaboration with the US Army programme at the Walter Reed Institute of Research in Washington DC, inoculating volunteer dengue naïve US soldiers. It did not go well; DENV-3 overgrew the other three serotypes.

A new attenuated DENV-3 monovalent vaccine was then derived by CDC under contract from Sanofi and trialled in medical students in Hong Kong. That did not progress either as the virus was not attenuated.

Sanofi Pasteur decided to shelve Professor Natth’s vaccine and pursued a vaccine based on the yellow fever 17D vaccine backbone. That was the origin of the Dengvaxia vaccine.

What are the origins of the Takeda dengue vaccine?

During the mid-1990s, Professor Natth gave me his four monovalent vaccines to take back to Fort Collins with the agreement that we would work with him to develop second-generation dengue vaccines. My molecular virologists, Rich Kinney and Claire Wong, constructed a clone of the best of the four monovalent vaccines: the DENV-2 vaccine, also known as PDK 53. They inserted the structural genes from the DENV-1, DENV-3 and DENV-4 viruses into the clone to create a tetravalent vaccine. We called it the CDC Mahidol vaccine, and myself, Rich Kinney, Claire Wong and Professor Natth in Thailand filed a patent on it.

We licensed it to a small biotech vaccine company in Fort Collins called Inviragen. We continued to collaborate with Inviragen to develop the vaccine. First trials were on mice and primates were followed by Phase 1 trials in 2010 and Phase 2 trials in 2011.

Takeda bought Inviragen in 2013, and that’s how Takeda’s Tetravalent Dengue Vaccine (TDV) came into existence. Takeda then repeated Inviragen’s trials, following the Phase 1 and 2 trials more recently with Phase 3 trials.

What were some of the key challenges you faced along the way?

It takes a lot of time and effort and money to bring the vaccines to a stage where you’re confident that they’re going to work in humans. The pre-clinical trials take several years; then there is a period of getting the results you need to go on to the next step. You can only move onto human clinical trials once the results from these laboratory trials were good. The initial safety trials were primarily in the US but were then moved to dengue endemic countries for the Phase 2 and Phase 3 trials.

There were a lot of ups and downs, particularly in the early days when we were trying to get the right formulations. But we were persistent because we had a strong belief that we desperately needed vaccines for dengue.

The four different dengue serotypes made developing this vaccine particularly challenging; we still don’t fully understand their interactions. We know the vaccines induce antibodies for all four dengue serotypes, but we don’t know whether they’re enhancing antibodies (antibodies that help the dengue virus) or protecting antibodies (antibodies that fight the dengue virus).

But a lack of funding was one of the main challenges that delayed this whole process. In the early days, the funding agencies never really thought that dengue was a high priority for funding, and so a lot of the development work was done on a shoestring. We developed the Takeda vaccine at CDC out of my own budget and a small grant from the Rockefeller Foundation to Mahidol University. There was no major funding from CDC – or any other funding agency – earmarked for dengue vaccine development.

We should also mention the dengue vaccine being developed by the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, out of their own budget. It’s following right behind Takeda. The NIH vaccine was developed independently by Steve Whitehead and Brian Murphy. I gave them a lot of my viruses and some of those are used in the NIH vaccine.

What are the next steps for the Takeda vaccine?

Takeda will be looking at the data that comes in over the next year or two as well as acquiring longer-term data. If the data are consistent, then the Takeda vaccine is going to make a big impact. And the preliminary data suggests it can be used as a single dose. The NIH vaccine will also be probably used as a single dose.

I am concerned that it may be difficult for us to get a perfect tetravalent dengue vaccine that provides equal protection against all four dengue serotypes. If a vaccine doesn’t protect people against all four serotypes, we need to decide how, where and when we use it. That’s the next big challenge. We desperately need dengue vaccines, and I think we can use them effectively even if they are not perfect– if we do it properly.

I don’t see a vaccine that we can confidently use in a national immunisation programme for at least another three or four years.

While the Takeda story has taken a while to unfold, successes from recent trials regardless of previous exposure to dengue are bringing hope.