Some hoped a new oral vaccine would solve all the polio campaign’s problems. Reality is settling in

When a new and hoped-to-be safer oral polio vaccine started to make its way into use in March 2021, there was huge optimism that this long-needed tool would help the polio eradication campaign quell a growing problem that was — and is still — complicating efforts to stamp out polio forever.

Two years later, expectations surrounding the new vaccine, known as novel oral polio vaccine type 2, or nOPV2 for short, are moderating a bit. It has since become clear it is a safe and effective tool, one that is much less likely to give rise to the aforementioned problem, in which live viruses used in an earlier type of oral vaccine overcame genetic changes made to weaken them, and in the process acquired the capacity to on rare occasions paralyze children.

But more than 600 million doses into nOPV2’s rollout, it has also become apparent that the polio program’s No. 1 problem — the failure to vaccinate a sufficient proportion of children against the disease — will not be magically solved by changing the tool in use, a number of experts say. In fact, this tool may raise the bar slightly for the people trying to stop outbreaks caused by those vaccine viruses, because it may require a higher percentage of children to be vaccinated in order to get the job done.

“Eradication, it was never about the vaccines. It’s all about coverage — getting the vaccine into the mouths of children,” said Roland Sutter, a consultant who has worked for decades on polio eradication. “And that’s still, I would say, the biggest problem for the [polio eradication] initiative, is to really get high coverage in … the most difficult areas.”

STAT spoke to a number of longtime polio campaign players in the wake of the publication in recent weeks and months of studies that pointed to some shortcomings of the new vaccine. They all said at this point there is overwhelming evidence that nOPV2 is much safer than the oral polio vaccine it replaced, though hints are emerging that it may not be quite as effective as the type 2 oral vaccine that polio vaccine legend Albert Sabin developed in the late 1950s.

But they also stressed nOPV2 is not a panacea, and suggested it is important for the polio program and the countries still struggling to stop the spread of wild polio or vaccine viruses to be realistic about what the new oral vaccine can do.

Mark Pallansch, who retired from the Centers for Disease Control and Prevention in August 2021, suggested a coming down to earth of expectations about nOPV2 would not be a bad thing, if it helps convey the message that efforts to vaccinate a higher percentage of kids in at-risk regions need to be stepped up.

“The ‘We’re now on the homestretch’ type of thinking led to, again, an expectation that the final success was right around the corner,” said Pallansch, who serves on a World Health Organization technical advisory group for polio eradication. “You don’t stop any of these outbreaks unless you can assure high [vaccination] coverage. And that to me is the dominant issue in the program in most of these geographies.”

In the late 1980s, when the world embarked on the ambitious plan to consign polioviruses to history’s trash bin, it was thought the job would have been done and dusted by now. The goal was to eradicate all three viruses that triggered the paralytic disease — types 1, 2, and 3 — by the dawn of the 21st century. Twenty-three years later, types 2 and 3 are eradicated and the campaign is tantalizingly close to snuffing out type 1. But all involved know the finish line has appeared tantalizingly close before.

Only three cases of paralytic polio caused by wild-type polio have been reported so far in 2023, from Afghanistan and Pakistan, the only two countries that have never managed to extinguish transmission of wild polio. Genetic sequencing of these viruses, and 28 others found in wastewater in the two countries, shows there are only two remaining lineages of wild viruses circulating, said Ananda Bandyopadhyay, deputy director of the polio team at the Bill and Melinda Gates Foundation.

That dwindling of the genetic diversity of the viruses has been seen in the past when polio was on the verge of being stopped in a country, or when type 2 and type 3 viruses were in their death throes, he said. “So this is the trend we see with viruses. It is promising. The virus is dying. It’s gasping.”

The Gates Foundation is one of the partners in the Global Polio Eradication Initiative. Other partners are: the CDC; the WHO; UNICEF, the U.N. Children’s Fund; and the service club Rotary International.

The program has set a goal of stopping transmission of wild-type polio by the end of this year, an objective that at this point appears as if it may be within reach. (It should be noted many previous target dates have come and gone.)

It has also set the end of 2023 as a self-imposed deadline for having extinguished all outbreaks caused by the vaccine viruses, known in polio eradication parlance as cVDPVs, for circulating vaccine-derived polioviruses.

That latter goal, even program partners acknowledge, is probably out of reach at this point. “The current global epidemiology of poliovirus transmission makes the likelihood of meeting this target date unlikely,” CDC scientists wrote earlier this month in the agency’s online journal Morbidity and Mortality Weekly Report.

The original oral polio vaccine, known as OPV, was created by Sabin; it has been the workhorse of the global eradication effort. But one of its strengths turned out to be a double-edged sword. The live, weakened viruses contained in the vaccine, which is dripped into the mouths of children, are later shed in their stools. In places where hand hygiene and water quality are poor, these vaccine viruses transmit through communities, vaccinating kids who did not receive the oral vaccine.

When polio cases were common, that was a huge plus. But if these viruses spread long enough — which they can do if they are in environments where vaccination coverage is low — they can regain the power to paralyze. Last year 862 children in 26 countries were paralyzed by viruses from oral polio vaccine. By contrast, only 30 children were paralyzed by wild polioviruses in 2022.

(The United States stopped using oral polio vaccine in 2000 because of the risks associated with it. Children in the United States are vaccinated with inactivated polio vaccine, an injectable product that does not contain live viruses.)

The component of the Sabin vaccine that most frequently regained the power to paralyze was the part that targeted type 2 polio. With type 2 viruses long since gone — the last known case was in 1999 and the viruses were declared eradicated in 2015 — the polio eradication program decided to pull the type 2 component from the oral vaccine in a globally synchronized move in the spring of 2016. The hope was that by ceasing use of Sabin OPV2, the problem with the type 2 vaccine viruses would die out.

It has not. In the years since, there have been more than 2,600 type 2 vaccine virus cases, including one detected last summer in an unvaccinated young man in New York State.

At this point, “the switch,” as that process was called, is perceived to have been a failure — one that necessitated the development of nOPV2 to build up immunity to type 2 polio and stamp out transmission in places where the type 2 vaccine viruses are circulating. The vaccine viruses in nOPV2 were genetically altered in ways to make them much less likely to be able to regain the capacity to paralyze, though it was recently confirmed that on very rare occasions, this unfortunate development can occur.

Though fewer in number, there are also type 1 and type 3 vaccine virus outbreaks. Last year the Democratic Republic of the Congo recorded 143 cases of paralytic polio caused by type 1 vaccine viruses. Novel vaccines targeting types 1 and 3 are now in development, and a trivalent vaccine, including all three of the new oral vaccines, will follow, said Bandyopadhyay.

Since giving nOPV2 an emergency use listing — the equivalent of the emergency use authorizations the Food and Drug Administration gave Covid-19 vaccines — the WHO has stipulated that the new oral vaccine should not be given in conjunction with the Sabin oral polio vaccine, known as bivalent or bOPV (the current version targets only types 1 and 3 viruses). There should be at least a four-week window between outbreak response use of nOPV2 and mass vaccination efforts using bOPV, the global health agency says.

But as the number of vaccine virus outbreaks has increased, a further complication has arisen. Some places, like the DRC, have been battling outbreaks caused by more than one type of vaccine virus.

The nonprofit group Kid Risk did some mathematical modeling to try to determine how countries in this situation could best combat concurrent vaccine virus outbreaks caused by different virus types. Concomitant use of both nOPV2 and bOPV would be more effective than running separate vaccination campaigns targeting different viruses, the group concluded.

“Every time you go in with just one vaccine, it’s a missed opportunity to get kids who need the others,” Kimberly Thompson, the organization’s president, told STAT. Thompson has consulted for years with the polio eradication campaign.

In addition to requiring more workers and being more costly, vaccinating with different vaccines at different times creates a situation where no one has a clear picture of which children got what vaccine. Children who get oral polio doses have the nail on a pinky finger marked with purple marker; there are no electronic health records keeping track of what kind of vaccine led to the marked pinky.

“The logistics are a nightmare. At least if you’re giving them both at the same time, you have some sense of every kid we got got two things,” Thompson said.

But a recently published study showed that when the two vaccines are given at the same time, the effectiveness of nOPV2 is lessened.

It’s a phenomenon called interference, where one vaccine dampens the immune response to another when two or more are given together. It was an issue with the vaccine Sabin created; the type 2 component worked better, and to the detriment of the types 1 and 3 components when they were delivered in a trivalent (three-in-one) formulation. The problem was eventually resolved by increasing the potency of the types 1 and 3 components.

In the new study, published in the Lancet, healthy 6-week-old babies were randomized to get two doses each of nOPV2, nOPV2 plus the bivalent Sabin type 1 plus 3 vaccine, or the Sabin bivalent vaccine alone, after which their immune responses were measured. The responses were as expected for the types 1 and 3 components in the Sabin vaccine, but the response to nOPV2 given with the Sabin vaccine was substantially lower than what is seen if nOPV2 is given alone, dropping from 86% to 65%.

“It is a big drop. It was larger than expected,” said Steven Wassilak, associate chief for science for CDC’s polio eradication branch and one of the authors of the paper.

“We had hoped that this could be an opportunity for battling against circulation of type 1 and type 2 at the same time in the populations that are having those two outbreaks together, whether it be wild or vaccine-derived cVDPV type 1,” Wassilak said in an interview. “It would be best, in terms of resources and efforts, if it could be given together. … But it appears that it doesn’t have the full effect given together as if you’re giving it separately.”

For Wassilak, there is a takeaway that goes beyond the issue of whether nOPV2 should be given at the same time as the Sabin bivalent vaccine. “The novel OPV2 is less effective per dose than Sabin. That’s my takeaway.”

There have been other signals this may be the case. A study published in late December looked at how well nOPV2 did at eliciting immune responses in children during a vaccine virus outbreak in Tajikistan in 2021. There were still cases after two rounds of nOPV2 administration, prompting a decision to conduct a third round of vaccination. In a commentary that accompanied the study, Thompson suggested the results “might hint at lower population immunity effectiveness for nOPV2” than had been seen with the Sabin oral vaccine component targeting type 2 viruses.

She made a similar observation in a commentary that was published with the study showing interference when nOPV2 is given at the same time as the Sabin bivalent. “These results hint at the probable need to achieve higher coverage (or to perform more campaign rounds) using nOPV2 … to induce the same level of population immunity, and imply that nOPV2 use comes with real trade-offs that increase the complexity of an already complicated polio endgame,” she wrote.

Sutter, who has worked on polio eradication since 1987, first at the CDC and then at the WHO before retiring from the latter, agreed that the new oral vaccine may not be as immunogenic — it isn’t as good at inducing an immune response — as the older oral vaccine.

“It’s important that we keep this in mind when we plan campaigns,” he said. “Maybe with this vaccine we need to add one more campaign for outbreaks than we would usually do, or things like that.”

That said, Sutter was quick to point out that even if the vaccine is less effective than the Sabin oral vaccine, it is still a highly useful vaccine, one that is far less likely to cause vaccine virus cases.

Pallansch agreed. “There is the possibility that is becoming a little more seriously considered that indeed per-dose efficacy is not as good as” the Sabin type 2 oral vaccine, he said. “And whether that difference matters compared to coverage is not clear.”

A little less effective still could be good enough to get the job done, both Pallansch and Sutter said, but only if enough children get the vaccine.

“Coverage is still the number one issue for either vaccine,” Pallansch said. “In the end, stopping the outbreaks is the requirement. And the requirement is identical in that you have to achieve high coverage.”

Correction: An earlier version of this article incorrectly stated there should be a four-week window between outbreak response use of nOPV2 and routine vaccination with bOPV. The gap is required outbreak responses with nOPV2 and mass vaccination efforts using bOPV.