Virus World

Experts have long understood that a new polio vaccine developed to try to minimize the risks associated with the oral polio vaccine made by Albert Sabin might also cause the problem it was created to sidestep. It’s now clear that theoretical risk is a real one. The Global Polio Eradication Initiative announced Thursday that six children in the Democratic Republic of the Congo and one in Burundi have been paralyzed by viruses from the new vaccine, which is referred to as novel oral polio vaccine, or nOPV2. (The “2” signals the vaccine targets type 2 polioviruses.) In addition, five environmental samples collected from Burundi contained the so-called type 2 circulating vaccine-derived polioviruses, or cVDPV2s. “We are disappointed,” said Ananda Bandyopadhyay, deputy director for technology, research, and analytics on the polio team of the Bill and Melinda Gates Foundation, a partner in the polio eradication effort. “Any such outbreak is disappointing.” The Gates Foundation is one of a half-dozen partners in the Global Polio Eradication Initiative. The others include the World Health Organization; UNICEF, the United Nations Children’s Fund; the Centers for Disease Control and Prevention; Gavi, the vaccine alliance; and the service club Rotary International.

Bandyopadhyay and the polio eradication initiative itself were quick to point out that this turn of events was not unexpected. The live polioviruses used in oral vaccines are manipulated to eliminate their ability to paralyze. Children who receive these vaccines shed live viruses in their stools. In settings where sanitation and hygiene are poor, the viruses can move from child to child, effectively indirectly vaccinating children whom vaccination teams haven’t reached — a feature that has made the Sabin vaccines the workhorse of polio eradication. But if the viruses spread long enough, they can regain the ability to paralyze — a problem that led the polio program to stop using type 2 oral vaccine in 2016, in a bold and ultimately failed effort, known as “the switch,” to stop spread of type 2 viruses from the Sabin vaccines. The injectable polio vaccine, designed by Jonas Salk and used in affluent countries like the United States, does not contain live viruses and therefore doesn’t trigger paralysis. But while it prevents paralysis, it cannot stop transmission of polioviruses — wild type or vaccine derived — which makes it less useful in countries where vaccine-derived viruses are spreading. In recent years, the nearly 35-year-old effort to rid the world of polio has managed to drive numbers of infections with wild viruses down to low levels. Last year, only three countries — Pakistan, Afghanistan, and Mozambique — reported 30 cases. So far this year, there has been only one case detected, in a child in Afghanistan. But as the battle against wild viruses has gained ground, use of the oral vaccine has seeded chains of transmission of the vaccine-derived viruses. In 2022, nearly 800 children or young adults in roughly two dozen countries developed paralytic polio after being infected with one of the vaccine viruses from the Sabin vaccines. Among them was an unvaccinated young man in New York State, this country’s first polio case in nearly a decade.

Of the three original strains of polio — types 2 and 3 have been eradicated, only type 1 remains — the portion of the Sabin vaccines targeting type 2 viruses triggers the vast majority of vaccine-derived polio cases. A few years ago, with support from the Gates Foundation, the novel oral vaccine targeting type 2 viruses was developed. It was put into use in mid-March of 2021 — two years ago. Since then 590 million doses of nOPV2 have been administered in 28 countries. The seven cases of paralytic polio, which stem from two chains of vaccine-derived viruses, are far fewer than would likely have occurred if those hundreds of millions of doses had been the Sabin vaccine, Bandyopadhyay said. An analysis from the Gates Foundation’s polio team suggested that there would have been 30 to 40 new chains of type 2 vaccine viruses over that period, rather than two, he said. Other experts agreed it is important to put the finding in context. “I’m not alarmed. It’s a much better tool than we used to have,” said Walter Orenstein, a polio expert at Emory University. “It’s not perfect,” he said of the new oral vaccine. “But given its rarity, it hopefully will be able to do the job. At least not generate lots of these kinds of outbreaks.” Kim Thompson, president of the nonprofit organization Kid Risk and a mathematical modeler who has worked on polio eradication for decades, said this event is only showing the world that what was assumed about the new oral vaccine is in fact true. “This possibility has always been out there in the cards. And really this is just the proof of concept that the nOPV2 can lose the attenuated mutations and behave like other live polioviruses, and particularly do so in populations where [vaccine] coverage is low,” she said. But Thompson is worried that given the low levels of immunity to type 2 polio, even less frequent outbreaks of vaccine-derived viruses will amplify a problem the polio program is struggling to contain. “The reality is that since we have transmission happening in these areas with low coverage and this immunity gap that exists … there’s more room for these viruses to go. That’s part of the challenge here, is to figure out what to do to stop type 2,” she said.

Helen Branswell

Senior Writer, Infectious Diseases

Helen Branswell covers issues broadly related to infectious diseases, including outbreaks, preparedness, research, and vaccine development. Follow her on Mastodon and Post News.

The vaccine, designed to prevent harmful mutations, is seen as key to eradicating polio. A vaccine against a type of polio that is spreading in the Southern Hemisphere is expected to receive emergency approval before the end of the year. If it does, it will be the first time the World Health Organization has steered an unlicensed vaccine or drug through its emergency listing process. Wild polio has been almost eradicated. Only two countries — Afghanistan and Pakistan — still report cases. But a version of the virus that arose naturally from the weakened polio virus used in vaccination is increasing. What is called circulating vaccine-derived poliovirus (cVDPV) is increasing in both Afghanistan and Pakistan, as well as in the Philippines, Malaysia, Yemen and 19 African countries — with Chad, the Democratic Republic of the Congo and Côte d’Ivoire the worst affected in Africa.

So far in 2020, there have been more than 460 cases of vaccine-derived polio worldwide. This is more than 4 times the number detected by this time in 2019, which is a major problem for the 32-year, US$17-billion global campaign to wipe out the disease. Researchers who model polio infections say that for every known case, there are about 2,000 infections in the population. “Millions of people potentially have no immunity to the vaccine-derived virus, and that’s why we’re very concerned,” says Kathleen O’Reilly, an epidemiologist at the London School of Hygiene and Tropical Medicine who models polio infections. Independent scientific advisers to the World Health Organization (WHO) have been assessing a vaccine that is designed specifically to protect against cVDPV. This vaccine, a decade in the making, has been tested for safety and efficacy, but is not yet licensed and still has to undergo further trials. The WHO is in the last stages of considering whether to approve it more quickly, under what is called an emergency-use listing — a procedure that was created during the 2014–16 Ebola outbreak in West Africa, and which the agency is also preparing to use for coronavirus vaccines...

Published in Nature (Oct. 29, 2020):

https://doi.org/10.1038/d41586-020-03045-2

With six confirmed and two suspected cases, health officials are ramping up a vaccination push amid fears of a wider outbreak.  A polio outbreak centered in Jerusalem has prompted Israel’s return to the World Health Organization’s list of polio “outbreak countries.” Israel now appears along with 28 other countries on the WHO’s Global Polio Eradication Initiative’s list of countries with polio outbreaks, after being declared polio-free in 1988. Nations including Egypt, Iran, Ethiopia and Ukraine are also on the list of outbreak countries — places where the virus was halted but has resurfaced — while Afghanistan and Pakistan are considered endemic countries. Last month, the first case of polio in more than 30 years was confirmed in Jerusalem, spurring deep concerns and a renewed vaccination drive.  According to the latest Health Ministry figures, released last week, there have been six confirmed polio cases, all among unvaccinated patients. In addition, there is a high likelihood of another case in an unvaccinated child, and an eighth potential case that is being investigated. Traces of the disease have also been found in the sewage system in Jerusalem, Beit Shemesh, Tiberias and Modiin Illit.

Over the past month, more than 18,000 children in the Jerusalem area have received a polio vaccine dose as part of the ministry’s push to reach those who were unvaccinated or partially vaccinated. Like much of the world, Israel administers polio vaccines — spread out in multiple doses — to children as part of its standard vaccine regimen. Polio spreads mostly from person to person or through contaminated water. It attacks the nervous system and can sometimes paralyze people within hours. The disease mostly affects children under 5 and has been largely wiped out in wealthy countries. Dr. Sharon Alroy-Preis, the Health Ministry’s public health director, explained last week that during the years 2005-2013, polio vaccinations were scaled back as the disease was vanquished in the country and many babies did not get all the necessary doses. “We are definitely seeing an outbreak of polio in Israel,” Alroy-Preis said. “It reaches unvaccinated pockets and is spreading.” One Jerusalem child who was recently diagnosed with polio has weakness and paralysis on one side, she reported. “That is just the tip of the iceberg, under which there are many other infected children,” she assessed. Disease experts have warned of the real prospect of a resurgence of polio cases — in manageable numbers but enough to leave some children with long-term damage. Traces of the virus have occasionally been found in sewage samples in Israel, but have not resulted in any clinical cases for several decades.

Health officials are rushing a genetically engineered product into the field to counter uncontained outbreaks of vaccine-derived polio. To stem a growing polio crisis, health officials are accelerating the development of a new oral vaccine with plans for emergency approval and deployment in regions with active polio transmission as early as June 2020. The new vaccine, called nOPV2, might conclusively end the outbreaks, caused by the live virus in the vaccine reverting to a virulent form. But expedited approval means skipping the real-world testing of large clinical trials. Instead, key questions about the vaccine’s effectiveness will be answered in the field. “The nOPV strains have been tested in a small number of volunteers and we do not see reversion to neurovirulence,” says Vincent Racaniello, a virologist at Columbia University, “but when they are used for mass immunization of millions of individuals, rare events can become evident.”

Oral polio vaccine strains, originally developed by Albert Sabin in the 1950s, can in rare instances revert to virulence, spread, and paralyze children just like polio itself, a phenomenon first recognized in 2000. Because the Sabin vaccine had successfully eradicated wild type 2 poliovirus in 2015, health officials across the world quit administering it the following year. However, herd immunity had not been achieved before the cessation of the type 2 vaccine, which gave an opportunity for un-immunized people to later become infected by the virus that had begun reverting to virulence in people who had gotten the vaccine. With successive transmission through the unvaccinated, the vaccine strain can regain the virulence of wild polio. Nowadays, cases of polio caused by vaccine-derived strains outnumber those caused by the wild virus–and they continue to spread unchecked, most recently from the Phillipines to Malaysia. Vaccine-derived polio threatens as many as 210 million children globally, according to the World Health Organization. Using the reversion-prone Sabin type 2 vaccine to fight outbreaks caused more new outbreaks than it stopped, a virologist at the Centers for Disease Control and Prevention (CDC) told Science earlier this year. 

nOPV2, the new type 2 oral polio vaccine, has been genetically engineered to avoid the pitfalls of Sabin’s vaccine. The project is funded by the Gates Foundation and coordinated by PATH, a nonprofit developer of public health innovations, with scientific work taking place at the National Institute for Biological Standards and Control (NIBSC) in the UK, the University of California, San Francisco, the CDC, and the Food and Drug Administration. Poliovirus “evolves readily to any situation it finds,” says Andrew Macadam, a principal scientist at NIBSC and a designer of nOPV2. As RNA viruses, polio and polio vaccine strains evolve using mutation and recombination. Polio “has a polymerase that is not very accurate,” says Macadam, so mutations occur frequently during replication. More importantly for rapid adaptation, recombination allows the virus to incorporate RNA strands from other C type enteroviruses in human hosts that enable gains in virulence. These partners include all the Sabin strains and Coxsackievirus, for example. nOPV2 obstructs some key genetic routes to pathogenicity, believed to be controlled by “gatekeeper” mutations. In particular, a single point mutation at nucleotide 481 increases neurovirulence and actually occurs in most people soon after immunization. The pivotal change at 481 makes a return to virulence possible, according to Macadam. “The gatekeeper idea,” he explains, “is that it needs to revert at 481 before it can do anything else and then you can incorporate these other mutations” that cause the vaccine to become pathogenic. So nOPV2 developers modified 18 nucleotides near 481 in the poliovirus genome so that the well-known single substitution no longer opens the gate to virulence. This safeguard in turn is protected from wholesale replacement via recombination by relocating a gene necessary for replication to another part of the genome so that if the modifications near 481 are lost through recombination, the gene needed for replication will also be lost. As a result, reversion “requires two recombination events instead of one,” according to Macadam, one being the acquisition of a second copy of the replication gene and the other being the loss of the 481-related modifications. “Therefore, it’s less likely,” says Macadam. In addition, Macadam’s team outfitted nOPV2 with a higher-fidelity polymerase that introduces fewer errors during replication while another gene received alterations to decrease the virus’ propensity for recombination....