The development of a type of Zika vaccine that authorities had hoped to usher to the market has proven more challenging than some scientists and pharmaceutical companies had expected, people involved in the research have told STAT, posing a setback for efforts to avoid future outbreaks of the disease.
Although vaccines typically take years to produce, test, and license, U.S. health officials had voiced confidence that Zika would not be a difficult target, and some predicted that a vaccine could be made and fully tested, ready for Food and Drug Administration assessment, within two to three years. Others predicted a licensed Zika vaccine could be available sometime in 2020.
Even the more cautious forecast now seems optimistic.
Early this month, the vaccine maker Sanofi (SNY) Pasteur quietly pulled the plug on its Zika vaccine efforts, a reflection of some complications in the development of the vaccine as well as of evaporating market prospects and limited U.S. government funding.
The company said the latter factor — word that the government would not fully fund the vaccine work — was the key. Without full government funding of the program “we could not continue development of a Zika vaccine,” said Jon Heinrichs, the Sanofi executive who led the effort. “We still don’t see that this would be a profitable vaccine for Sanofi Pasteur.”
Testing delays that stemmed from adjustments needed for the vaccine may have affected Sanofi’s ability to gain more funding for the project. Both Sanofi and a competitor working on a similar style of Zika vaccine found they had to lengthen their projected development timelines.
The Biomedical Advanced Research and Development Authority, the division of the Department of Health and Human Services that is funding Zika vaccine development, met over the summer with all the companies receiving Zika funding to assess where each project stood. It decided that Takeda (TAK) Pharmaceuticals, which is working on the same type of vaccine, was further along in its effort than Sanofi.
“We have only been provided limited funds and we want to be able to take at least one vaccine candidate as far as we can with the funding and support that we have available to support Zika vaccines,” said BARDA Director Rick Bright. “And so it’s important that we have a portfolio approach.”
Takeda reported that its first human testing would begin this fall. But Sanofi expected that it would take the company more time to be ready to get to that phase, Bright said.
“We learned that we needed to do some additional work to really understand our product before we were comfortable moving quickly into clinical studies,” Heinrichs told STAT.
Creating a new vaccine is a bit like inventing a new cake recipe from scratch. You have to figure out how to make it, test it to make sure the recipe works, then build and equip a production facility that can pump out identical versions of the cake batch after batch. And before the cakes can be sold, the FDA must assess the product and inspect and certify the bakery.
Sanofi and Takeda were both working on what might have been considered the standard white cake version of a vaccine — using an inactivated or killed Zika virus to generate antibodies, with a simple adjuvant added to boost the immune response.
Inactivated whole virus vaccines have been made for decades, to protect against a range of diseases. They have a clear safety record and the FDA knows a lot about how these types of vaccines work. A vaccine made using this recipe would likely sail through the licensure process. That’s why Sanofi opted for this approach, and why BARDA was funding it.
But this white cake of a vaccine hasn’t been quite as simple to make as people expected when the race to develop a Zika vaccine was launched by the Obama administration last year.
“Two years ago — basically early February 2016 — people thought it would be easy and straightforward to make a Zika vaccine based on all the years of knowledge we had in making other vaccines for other flaviviruses such as dengue, etc.,” Bright told STAT. “We did learn a lot from those other experiences, but no vaccine is easy to make.”
Rajeev Venkayya, president of Takeda’s vaccine business unit, agreed.
“The Sanofi news was news to us,” said Venkayya. “It’s a reminder of how challenging vaccine development can be.”
The Sanofi project — a collaboration with the Walter Reed Army Institute of Research — was the second Zika vaccine project the company had shelved. Last year it stopped work on a Zika vaccine it was funding from its own coffers.
In the early days, it looked as if the Sanofi project had a head start over the Takeda effort to make an inactivated whole virus vaccine. U.S. Army scientists at the Walter Reed Institute had completed the first stage in the vaccine creation — they had invented the prototype. They were even conducting the first stage of human testing, in conjunction with the National Institute of Allergy and Infectious Diseases.
Sanofi licensed the vaccine from them, leaving it up to the company to do the second phase of testing and to learn to make the recipe consistently and on a larger scale.
That’s the part that seems to have taken longer than expected. The initial development timelines had been set when Zika was a global health emergency. But the World Health Organization downgraded that status in November 2016. As the Zika outbreak seemed to sputter out, some of the urgency went with it.
“I would say that we started out with very, very aggressive timelines to try and respond to an emergency situation,” Heinrichs said. “And as that emergency lessened, we readjusted our timelines to really understand the product and to be able to develop a robust system of manufacturing. And because of that, timelines were adjusted.”
At the same time, Sanofi came under fire from some lawmakers who were angry its contract with Walter Reed did not include a guarantee the vaccine would be sold at an affordable price. A company that felt it had stepped up in answer to a call for help felt stung by the criticism.
“I would say that that’s not the major driving force of us getting out. … But it certainly didn’t help,” Heinrichs said.
Venkayya said Takeda feels added responsibility to get its vaccine through testing and development. It isn’t thinking, he said, about the market prospects — surprising given that at the moment they seem tenuous. But he admitted that without BARDA funding, Takeda would also be out of the Zika vaccine race.
“The fact that BARDA has come in and de-risked this program by funding a substantial portion of the cost — not all the cost, but a substantial portion of the cost — makes this a viable program for us,” he said.
Meanwhile, there are other companies still working on a Zika vaccine.
BARDA is also funding research by Moderna (MRNA) Therapeutics, which is already doing initial safety and dose-setting testing of a novel vaccine using what is called messenger RNA to induce an immune response to the Zika virus.
Mike Watson, who is president of Valera — Moderna’s infectious diseases unit — said the company should have some immunological data from the trial toward the end of the year.
Inovio Pharmaceuticals has partnered with GeneOne Life Science on a DNA vaccine. That vaccine was the first to be tested in people. Results of early trials are promising, said Inovio CEO Joseph Kim, who added the company hopes to publish the results in a journal soon. The company is currently looking for funding to conduct larger studies.
The National Institute of Allergy and Infectious Diseases has developed and is testing a DNA vaccine as well; it’s already in the second phase of human trials, one of the few vaccines to date to get that far.
But DNA and mRNA vaccines are more sophisticated confections than inactivated whole virus vaccines. And while both types are further along than the whole virus vaccines at this point, they will face challenges further along in the process.
These are newer approaches. To date there have not been any mRNA or DNA vaccines approved for use in people, so the FDA does not have the same level of experience with them. If they proceed, the licensure process would likely take longer.
And all the Zika vaccine projects — even the inactivated whole virus product — face a huge hurdle at this point. In order to persuade vaccine regulators to license a vaccine, manufactures normally have to provide evidence that the product works — that vaccinated people are protected from the target illness.
With the collapse of the Zika epidemic, it’s not practical at this point to stage the type of trial that would be needed to show a vaccine works. These trials are expensive as it is, and with low levels of disease, it would take years to generate the proof.
Viruses like Zika typically flare and subside, so time may solve that problem. Or the FDA may be willing to consider an emergency use request based on other kinds of data.
Bright remains insistent that at least one Zika vaccine needs to be made.
“We do not want to leave Zika vaccines in the same freezer where we left SARS years ago or we left Ebola years ago and be caught off guard,” he said. “We want to continue development.”