T

he world appears to be on the verge of finally putting an end to polio. But the endgame could get complicated.

For more than a year there has been a severe shortage of the injectable polio vaccine known as IPV. Manufacturers have been racing to overcome production problems and hope to be back to full output early next year. But the shortage could be repeated in a few years, and at a more critical time, public health officials acknowledge.

“We may not have enough IPV for the whole world to use,” Michel Zaffran, the World Health Organization’s director of polio eradication, told STAT in an interview.

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The WHO recommends children vaccinated with the injectable product get two doses, and initially there may not be enough to give all children two full doses, he said.

In the US and other developed countries, injectable polio vaccine is actually given in a combination shot with other childhood vaccines; the current shortage has not affected those supplies.

But in the developing world, where the risk of polio is greater, most children are protected with a much cheaper oral polio vaccine. That vaccine has some risks, however, and will need to be withdrawn from use at a point. For at least a decade after that, countries will be urged to use injectable vaccine — a need that could not be met with existing manufacturing capacity.

Before the polio eradication effort began in 1988, an estimated 350,000 children a year were paralyzed by polioviruses. So far in 2017 there have only been five polio cases detected, in Pakistan and Afghanistan.

Never in history has the polio burden been so low; never have so few polioviruses circulated.

But if polioviruses stop spreading sometime in 2017 or early 2018 — a development that now seems possible — the threat of the disease will not yet be relegated to the history books. Polioviruses might have gone undetected in hard-to-reach conflict zones. Or an accident at a vaccine plant — like one in Belgium in 2014 that pumped polioviruses into a river and the North Sea — could release the viruses back into the world.

The vaccine will still be critical.

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Zaffran and others in the Global Polio Eradication Initiative — a partnership that includes the WHO, the Bill and Melinda Gates Foundation, and other institutions — insist supply problems with the injectable vaccine will not get in the way of stopping polio transmission or declaring the viruses eradicated.

“The IPV shortage is bad news. It’s absolutely not good news. But it’s not coming in the way of interrupting transmission,” Zaffran said.

Still, adequate supplies of injectable vaccine will be needed to prevent backsliding after transmission stops.

The current supply problems stem from sharply increased global demand.

Last year, in an unprecedented synchronized campaign, developing countries switched from the oral vaccine that had been in use for more than half a century to a newly formulated version.

The component of the oral vaccine that protected against now eradicated type 2 polioviruses was removed. The rationale: The live-but-weakened viruses in the vaccine would occasionally spread from child to child, becoming more dangerous as they did. On rare occasions, these viruses would paralyze children.

Because those vaccine viruses may still be spreading in some parts of the world, countries using oral vaccine were told to give children at least one dose of the injectable vaccine, which protects against all three polioviruses. The problem was that vaccine was in short supply.

“To a certain extent we were over-optimistic in [manufacturers’] capacity to produce. And they were over-optimistic,” Zaffran said. “But perhaps we also did not expect countries to come on board so fast in demanding [the injectable] vaccine.”

As a result of the shortage, 35 countries have been limited or had no access to injectable vaccine for their children in the lead-up to and in the year after the so-called “switch,” which occurred over a two-week stretch last spring. Zaffran said many are angry they’ve been put in this situation.

“We’re in a tough situation, a constrained situation,” agreed Apoorva Mallya, a senior program officer for polio eradication at the Gates Foundation. Mallya said supply has been directed on a prioritized basis to countries whose children are at high or moderate risk of being exposed to type 2 vaccine viruses.

Zaffran suggested that, in hindsight, the polio program didn’t give manufacturers enough time to ramp up production to meet the increased demand generated by the switch.

A lot of effort — and Gates Foundation funding — is now being directed to try to meet the next surge in need, when the oral vaccine is withdrawn entirely. That is expected to occur about a year after a WHO committee certifies that polio has been eradicated. There will be at least a three-year verification period after the last case before the committee concludes polio has been wiped out.

If transmission stops in 2017, that means as early as 2021 the world will need more injectable polio vaccine than it can currently make. That’s not a long lead time in the world of vaccine production.

It typically takes years to develop and test a new vaccine, persuade regulatory agencies to license it, build and get regulatory certification of production facilities, and actually make batches of vaccine. A vaccine production run takes between nine and 12 months.

A couple of companies are working to bring new injectable products to market, including Takeda Vaccines, which received a $38 million grant from the Gates Foundation for the work. The company has committed to produce 50 million doses a year, though how quickly it can reach that level of output isn’t clear.

“We’re in a tough situation, a constrained situation.”

Apoorva Mallya, a senior program officer for polio eradication at the Gates Foundation

Studies are testing whether pairing the vaccine with an adjuvant — a performance booster — works, said Dr. John Modlin, deputy director of the Gates Foundation’s polio research and development team. Using an adjuvant would allow for dose stretching — a child could be protected with less vaccine in each injection.

And companies are exploring whether there are different ways to grow the viruses used in vaccine production to increase the yield — in effect, to make bigger batches with each production run.

Another option is one that countries are currently being encouraged to try — using smaller doses of the injectable vaccine. Research has shown that two small doses — each the equivalent of one-fifth of a standard shot — are as effective as a full shot, if injected in the skin rather than into a muscle as the vaccine is currently given.

But intradermal vaccination, as that process is called, requires special needles, and medical staff need to be trained on how to vaccinate this way. Some countries are adopting this approach to stretch vaccines supplies in the current shortage, but it may not be workable in all settings and will take time to implement.

In addition to exploring alum and fractional dosing, the Gates Foundation and other partners in the polio program have been encouraging the development of newer and better polio vaccines for the post-eradication era.

For years, there was little incentive for other manufacturers to consider getting into polio vaccine production. The thinking was that with polio disappearing from the globe, sooner or later countries would stop buying polio vaccine. Polio was the vaccine market equivalent of Latin.

But a recent recommendation from a WHO expert panel suggests a robust market for polio vaccines should exist for more than a decade after eradication. The Strategic Advisory Committee of Experts on Immunization recommended that countries continue to vaccinate against polio for at least 10 years after the viruses are declared gone.

And countries that have research institutions work on or store polioviruses or production facilities that make vaccine from polioviruses are urged to continue to vaccine indefinitely.

This advice helps countries and companies plan, said veteran polio hand Dr. Walter Orenstein, associate director of the Emory Vaccine Center at Emory University in Atlanta.

“There’s a lot of work going on. How long that will take and whether it will be successful is too early to say,” Orenstein said. “But at least people are recognizing that there is a need for having a safe supply, an adequate supply. And ideally, a supply at minimal cost, particularly to developing countries.”

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