Ebola – Small Market for Vaccines

From the 10/26/2022 PROMED Digest email, in an entry on the current Ugandan  Sudan Ebola outbreak, is this snippet from a longer release. It seems “a long, tortured history” is an apt description of the efforts for an ebola vaccine.

 

Small market
————
Ebola vaccines have a long, tortured history. The VSV platform used in
Merck’s shots was first developed nearly 20 years ago by virologists
Heinz Feldmann, then with the Public Health Agency of Canada (PHAC),
and Thomas Geisbert, then with the US Army Medical Research Institute
of Infectious Diseases. They showed that a single dose of a vaccine
protected 100% of monkeys against an otherwise lethal dose of Zaire
ebolavirus given 28 days later. Smaller animal studies showed a
vaccine against the Sudan ebolavirus based on the VSV platform had
promise as well. (In 2016, Science published a survey
[https://www.science.org/doi/full/10.1126/science.351.6268.16] of 50
leading vaccine researchers who ranked the Sudan ebolavirus vaccine as
the number one R&D priority based on feasibility and need.)

But pharmaceutical companies took little interest in Ebola vaccines
because the market is so small. For decades, outbreaks involved a few
hundred cases at most, usually in rural areas in Africa where the
virus spread slowly, so there was little incentive to invest in the
shots. In 2010, PHAC licensed the vaccines to NewLink Genetics, a
small biotech that did nothing with it.

Then came West Africa’s Zaire outbreak, which engulfed the capitals of
Guinea, Sierra Leone, and Liberia in 2014 and sickened tens of
thousands of people in a matter of months, including a handful in
Mali, Senegal, Nigeria, the United States, and Europe. Geisbert and
Feldmann were deeply dispirited because their vaccine had languished.
“It was really frustrating because we had vaccines that were developed
back in the early 2000s, and we knew that they would work, but we’re
just lab guys,” says Geisbert, who now has a lab at the University of
Texas Medical Branch.

In late September 2014, scientists at the US Centers for Disease
Control and Prevention projected that if control measures didn’t
improve, Sierra Leone and Liberia together could have between 550 000
and 1.4 million Ebola cases by January 2015. That’s when Merck decided
to license the vaccine from NewLink Genetics, Feinberg says. “Merck
knew from the very beginning, that it was not going to be a profitable
product,” he says. “They were moving it specifically for public health
reasons.”

Other major vaccine makers jumped in to develop their own candidates,
but by then public health measures and behavior changes began to put
the brakes on West Africa’s epidemic, causing cases to fall. (All
told, nearly 29 000 people fell ill and more than 11 000 died.)
Merck’s ring vaccination trial in Guinea, conducted with WHO and local
health officials, crossed the finish line in mid-2015, just before the
epidemic ended, but other candidates were too late. GSK later decided
to give away its vaccine to the Sabin Institute.

Merck’s Ervebo is now a standard part of the response during outbreaks
of Zaire ebolavirus. More than 300 000 people were vaccinated during
the world’s 2nd largest Ebola outbreak, for example, which caused 3470
reported cases in a conflict-riven area of the Democratic Republic of
the Congo between 2018 and 2020.

But Merck has no interest in developing the vaccine for Sudan
ebolavirus. In 2017, it gave the license for that vaccine back to
PHAC, which subsequently cut a licensing deal with IAVI. In 2021, the
US government’s Biomedical Advanced Research and Development Authority
(BARDA) awarded IAVI a grant worth up to USD 126 million to use
upgraded technology to develop VSV-based vaccines for both Sudan
ebolavirus and the related filovirus that causes Marburg disease,
another rare but often lethal infection. (BARDA awarded a similar
amount to Sabin to develop the same vaccines using its chimp
adenovirus platform.)

Those vaccines are still at early stages of development, and when the
Uganda outbreak began in September 2022, Geisbert was once again
beside himself. “I sent an email to my boss and said, Look, we are in
the same situation as in 2014,” he says. “The VSV vaccine we know
works in ring vaccination, and it would be perfect to stop this.”
Geisbert also now has unpublished data showing that the VSV Sudan
ebolavirus vaccine provides robust protection in the monkey model.

Conflicting emails
——————
Now, it has become clear that a big batch of Merck’s Sudan Ebola
vaccine is available and could soon be ready for clinical trials.

After Feinberg left Merck in 2015, virologist Richard Peluso, who then
ran vaccine bioprocessing for the company, says he told his boss,
senior vice president of R&D Joe Miletich, that if the Zaire Ebola
vaccine was safe and effective, the company had “an obligation to the
world” to use the VSV platform to also make a stock of Sudan Ebola
vaccine. Merck proceeded to make the vaccine under strict “good
manufacturing practices” and also produced a large batch of a
VSV-based Marburg vaccine.

When and how the company came to realize those stocks still exist
today is not entirely clear. Science asked Merck on 13 Oct 2022
whether the company had produced the Sudan Ebola vaccine and retained
stocks of it. A spokesperson emailed back that Merck had made
approximately 70 000 vials of it in 2015-16. “The vials of Sudan
ebolavirus (SUDV) vaccine candidate expired in 2021 and were
destroyed,” the email added. (The email also said Merck had destroyed
96 000 filled vials of its Marburg vaccine.)

In response to follow-up questions, Merck acknowledged on 20 Oct 2022
that the company did retain bulk quantities of the frozen Ebola
vaccine and arranged an interview with Coller. She says Merck
destroyed the fill-and-finished doses of the Sudan Ebola vaccine
because the vials had used rubber stoppers. “The stoppers become
brittle when they’re stored frozen,” she explains.

The bulk product Merck has now disclosed had reached “the end of its
shelf life,” she adds. The vaccine was destined for destruction as
well, but to the surprise of company scientists, it still was in the
freezer. “Frankly, fortuitously, it hadn’t yet been destroyed,” she
says. “We immediately looked at that and said, Oh, my goodness, we can
perhaps do something to help.” (Bulk Marburg vaccine, Coller says, was
destroyed.)

Coller says she initiated a search to see if any Sudan Ebola vaccine
remained after attending a WHO meeting that ended on 6 Oct 2022 in
which she learned Uganda’s outbreak was rapidly growing. Asked why the
company did not mention the find in response to Science’s 13 Oct 2022
email, she says Merck was still conducting tests to assess whether the
vaccine had remained free of contaminants. “We were not sure about
whether or not we would be able to use that bulk material and didn’t
want to speak out of turn until we knew that there was something that
we could actually do with it,” Coller says.

Merck never ran human studies with the Sudan Ebola vaccine. “That was
not something that was ever really put on the table,” said Coller,
noting that there has not been an outbreak of this virus anywhere
since Uganda’s last one in 2012. “With hindsight, perhaps it could
have been done better.”