WHO, preparing for the worst, makes plans for reduced doses of Ebola vaccine

The World Health Organization is drawing up plans to use reduced doses of Ebola vaccine in the Democratic Republic of the Congo in the event that supplies in the long-running outbreak run short, according to the head of the WHO’s health emergencies programs.

There is currently no shortage of the vaccine — half a million doses are available, Dr. Mike Ryan said in an interview with STAT. If the outbreak continues at the current pace, he said, that will be enough to see the effort through to early next year, when the manufacturer, Merck, will have new stock available.

But if the outbreak were to deteriorate substantially, it’s conceivable supplies of the experimental vaccine would be tapped out later this year, Ryan said, stressing the WHO has to plan for that possibility: “We have to be responsible.”

“There are some epidemiologic models that could see us running out of vaccine, should the situation worsen,” Ryan said. “And it would have to worsen fairly significantly; it’s not just a small worsening.”

In late May, the amount of vaccine given to each person in the DRC was already halved. The decision was made, with the approval of government officials, after the Food and Drug Administration informed the WHO it was using a little more than twice as much vaccine per person as was used in the clinical trial that proved the vaccine was protective. (That trial was conducted in Guinea during the West African Ebola outbreak.)

That has eased the pressure somewhat on the management of supplies, but it remains important for health officials and Merck to plan for contingencies. It takes about a year to make a batch of this vaccine and fresh stock from the company will not be available until January.

Ryan said the WHO has asked several groups of mathematical modelers to help it identify a Goldilocks-type scenario for making a shift to a lower dose — not too early and not too late.

“Obviously if you let your vaccine supplies run too low before you further adjust the dose, then you don’t get the multiplication,” said Ryan. “But if you do it too early, before you need them, then you end up unnecessarily adjusting the dose and [facing] all the associated issues.”

“We don’t want to go there unless we have to. But if we have to, we will go there,” he said.

Ryan said the supply management planning has to take into account a number of factors, including the possibility that another Ebola outbreak in a different location could erupt before this one is contained. There have been five in the past five years, including the mammoth West African outbreak of 2014-2016, where more than 28,000 people were infected and more than 11,000 died.

“We’re not just looking at vaccine supply and availability for now. We’re looking at vaccine availability for next year, for the next outbreak, for wherever we will end up with,” he said.

The current outbreak in North Kivu and Ituri is the second largest on record, with more than 2,600 people having been infected; the death toll has already topped 1,700. Last week WHO Director-General Tedros Adhanom Ghebreyesus declared it a public health emergency of international concern.

The epidemic, which will hit the one-year mark next week, is the first in which Ebola vaccine has been used from the start of the outbreak to try to contain it. The vaccine is being deployed in what’s called a ring vaccination approach, where people who have been in contact with a confirmed case are offered vaccine, as are their contacts. The intent is to block the virus’ ability to spread by throwing up a wall of immunity in its path.

As of this week, just over 170,000 people have been vaccinated.

While the clinical trial that confirmed the Merck vaccine’s effectiveness did not study a lower dose, some of the earlier clinical trials in people did. Those trials looked only at safety and immunogenicity — checking the blood of recipients to see if the vaccine activated an immune response. The evidence suggests a dose that is a fraction of the current one would be protective, but that the immune response might take a little longer to develop. With the current dose, most people are protected within 10 days, which is quick for a vaccine.

Dr. Heinz Feldmann, who led the project to design the vaccine at Canada’s National Microbiology Laboratory, has tested far smaller doses in macaque monkeys.

“We think, based on these non-human primate studies, that they can most likely reduce the vaccine much more than they have done so far,” said Feldmann, who is now heads the National Institute of Allergy and Infectious Diseases’ virology laboratory in Hamilton, Mont. “But it is hard to say how much because a non-human primate is not a human. I think the next step has to be a clinical trial.’’

Because the vaccine is currently unlicensed, it is being given in the context of a clinical trial, with recipients going through an informed consent process. Any further lowering of the dose would be studied to see if people were still protected.

Fractional dosing of live-virus vaccines has been done before, including during a large yellow fever outbreak in Angola and eastern DRC in 2016.

A study published after the outbreak showed the people who received the fractional dose still generated a strong immune response to the virus.

Another option under discussion is introducing a second Ebola vaccine into the response, one made by Johnson & Johnson. The J&J vaccine, which like the Merck one is not yet licensed, has been shown in multiple studies to be safe and to trigger an immune response, but as yet the type of clinical trial that would prove that that response translates into protection in humans has not been done.

J&J has said it is maintaining a stockpile of enough vaccine for 1.5 million people that could be used “in public health emergencies.” In a statement last week, the company’s chief scientific officer, Dr. Paul Stoffels, said: “We remain ready to mobilize our resources if we are called on to help with outbreak response efforts.”

A consortium of global health entities — the Coalition for Epidemic Preparedness Innovations, the Wellcome Trust, the London School of Hygiene and Tropical Medicine, among others — has been pushing for months to use the J&J vaccine in the outbreak. The goal is twofold: to take advantage of the rare opportunity to test an Ebola vaccine, which can only be done during an outbreak, and, if the vaccine is effective, to help speed the end of the epidemic.

But there are real concerns among some partners in the Ebola outbreak response about the communications challenges that deploying a second vaccine would entail, according to a recently published report from a group of experts who traveled to DRC in late April to assess the Ebola response for the WHO.

The Merck vaccine is given in a single dose. The J&J vaccine has to be given in two doses, at least 56 days apart.

“Certainly the closer you bring the [J&J] vaccine to the epidemic zone the more likely it is that people misinterpret the two-vaccine solution,” Ryan said. “We don’t want ‘the good vaccine’ story and ‘bad vaccine’ story. There are a lot of issues there.”

Dr. Oly Ilunga, who until Monday was DRC’s health minister, shared those concerns. He had said he would allow the consortium to test the vaccine outside the outbreak zone, but later closed the door to any use of other vaccines after learning planning was still underway to use the J&J vaccine near the transmission zone to act as a sort of firewall.

DRC’s president, Félix Tshisekedi, announced Saturday that Ilunga would no longer be responsible for the Ebola response. On Monday, Ilunga resigned.

Members of the consortium and the WHO — which is also keen to test the J&J vaccine — have been urging the country to reconsider. Ryan said the ultimate decision rests with the DRC authorities, but he believes there will be a way forward.

“Bringing it very close into the epidemic zone may present us with difficulties,” Ryan said. “But I do think there’s a way of finding a solution that can satisfy both sides of that equation. And we’ll hope to be having a discussion with the appropriate authorities in the coming days.”