W

ith dangerous yellow fever outbreaks smoldering in a number of African countries and elsewhere, the World Health Organization is set to propose the use of smaller doses of a vaccine to stretch the limited global supply.

Experts at the global health agency are working on a plan that would advise member states to use one-fifth of the normal dose per person, if the current outbreaks cannot be brought under control, a top WHO official told STAT. The proposal comes amid a debate over whether a lower dose would be sufficient to provide protection to children.

Concern about the limited global supply of yellow fever vaccine has been mounting over the past few months as a large and still-spreading outbreak in Angola has seeded cases into Kenya, China, and the Democratic Republic of Congo.

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Unrelated outbreaks in Uganda and Peru are putting further pressure on the vaccine supplies.

Alejandro Costa, the WHO team leader for emergency vaccination and stockpiles, said in an interview that an outbreak in the megacity of Kinshasa, capital of the Democratic Republic of Congo, could trigger a plan to use smaller doses of the vaccine. Kinshasa has a population of 12 million to 14 million people; the WHO has only 6 million doses of yellow fever vaccine stockpiled.

“If we have to vaccinate Kinshasa,” where there is already evidence the virus is being transmitted locally, “we don’t have enough vaccine today,” Costa said.

Brazzaville, the capital of the Republic of Congo, sits across the Congo River. Yellow fever spreading in Kinshasa would likely mean Brazzaville’s estimated 1.8 million inhabitants would also need to be vaccinated.

“If it goes to Brazzaville, the situation would be even worse,” Costa said.

Yellow fever is a disease caused by a virus that infects monkeys and people. It is transmitted by Aedes mosquitoes — the same mosquitoes that transmit the Zika virus — and normally spreads among primates in the Amazon and forested parts of Africa, only occasionally infecting humans. From time to time, however, the virus starts to spread among people.

People who contract the virus experience fever, headache, backache, muscle pain, loss of appetite, and nausea or vomiting. For most people, symptoms last three or four days, the WHO says.

About 15 percent of people go on to suffer from a second, more severe phase of the illness, when jaundice develops — hence the name yellow fever. Roughly half of people who develop a toxic phase die.

Experts have been calling on the WHO to recommend countries use fractional doses of the scarce vaccine for some time. In mid-April, some leading yellow fever experts argued for the approach in the journal The Lancet.

It would not be the first time the WHO has recommended using fractional doses of vaccine to stretch supplies. It’s currently doing so with injectable polio vaccine as a stopgap measure to deal with a global shortage.

With yellow fever vaccine, studies, mainly done in Brazil, have suggested that far smaller doses than normally used can protect against the disease.

But the studies were conducted in adults only, leaving questions about whether smaller doses would protect children, who generally require higher doses.

“If we make a mistake and children die, that would be terrible,” said Alan Barrett, director of the Sealy Center for Vaccine Development at the University of Texas Medical Branch in Galveston.

“We’ve got to be careful.”

Here's what you should know about the yellow fever outbreak happening in Angola right now. Hyacinth Empinado/STAT

So far this year the WHO — and the partners with which it maintains a yellow fever vaccine stockpile — have sent 13 million doses to Angola. But spread there continues, Costa said.

Under the WHO proposal, the standard dose would be reduced and recipients would be revaccinated later, when supplies are available, Costa said. It’s not known if giving a smaller dose will provide the lifelong immunity a standard dose of yellow fever vaccine confers.

The plan will be submitted, potentially as early as next week, to the WHO’s vaccine advisers, the Strategic Advisory Group of Experts on Immunization. The group is known as the SAGE.

If the SAGE accepts the proposal, it would advise countries using the vaccine to lower the per-person dose.

The next meeting of the group isn’t scheduled until October, but an emergency session would be called to debate the proposal if the need arises, Costa said.

The idea is to approve the dose-sparing regimen on an emergency-use basis. That would not permanently change the amount of vaccine used in yellow fever vaccine.

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But over the longer term, fractional doses and other approaches could provide solutions to the yellow fever vaccine supply problem, Barrett suggested in a perspective article published Wednesday in the New England Journal of Medicine.

He noted, for instance, that while there is a set minimum for the number of vaccine viruses — yellow fever vaccine is made with live but weakened viruses — per dose, there is no maximum.

Some manufacturers’ vaccine contains 1,000 times more viruses per dose than needed, Barrett wrote. If their production processes were modernized and the amount of virus per dose lowered, that would fix the shortage.

But both he and Costa noted it’s not as simple as that. Any changes, other than those approved for an emergency, require vaccine manufacturers to conduct studies to show that the new formulation is as protective and long-lasting as existing vaccines.

Studies cost money. And with a $1 a dose price tag, there’s little incentive for manufacturers to spend much on yellow fever, Barrett said.

Still, he suggested, the current spotlight on the rising threat of yellow fever and the inadequacy of the vaccine supply provides the world with an opportunity to think about changes.

“In the short term, there will be difficulties in ensuring that sufficient vaccine is available to fight this major public health problem, but we have the opportunity to avoid vaccine shortfalls in the future,” Barrett wrote.

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