The shadows lengthen in a guesthouse cafeteria on the sprawling campus of christian Medical College, Vellore, in India. Wrapped up as he is in an issue that has possessed him for years, T. Jacob John notices neither the dying light nor the gathering mosquitoes. He is talking about the oral polio vaccine.
A slight man who speaks and moves with a speed that belies his 76 years, John is one of India’s leading polio experts. Trained as a pediatrician, virologist and microbiologist, he is also a longtime critic of the continued reliance on the oral polio vaccine—OPV in polio speak—used by the nearly 25-year-old international campaign to rid the planet of the paralyzing and sometimes fatal disease. The vaccine is at once an excellent and an imperfect tool. Inexpensive and easy to administer (each dose consists of a few drops of serum on the tongue), it has brought the world to the point where polio eradication is visible on the horizon. Indeed, the World Health Organization announced this past January that there have been no cases of naturally occurring polio in India for a year. But if the distribution of the vaccine is not choreographed with exquisite care, its continued use—at least as it is currently formulated—could actually keep the world from eliminating polio.
Today John is talking with a reporter about a problem raised by a specific component of the oral vaccine, which uses weakened viruses to elicit immunity against the three strains of polio—known as types 1, 2 and 3. (An expensive, alternative vaccine, popular in wealthy nations, consists of an injected formulation that is made up of completely inactivated, or “killed,” viruses; it is known as IPV.) The issue: type 2 poliovirus no longer exists in nature; the last case stemming from naturally circulating virus was reported 13 years ago.
Ongoing vaccination against type 2 would not be worrisome if the viruses in the oral vaccine were perfectly benign. In rare cases, however, the weakened viruses from the vaccine can revert to disease-causing pathogens and provoke the very illness they are meant to prevent. In places where wild polioviruses are still a threat, the risk from natural infection is greater than the small hazard the vaccine poses. But if the only risk of paralysis from type 2 polio comes from the strain in the vaccine itself, then that strain’s continued usage could well be considered unproductive at best and quite possibly unethical. As long as the oral vaccine contains the type 2 virus, however, children in more than 100 countries around the globe must—paradoxically—be vaccinated against type 2 polio to protect them from the type 2 virus in the vaccine.
In 2004 John wrote a letter to the medical journal the Lancet, urging the international community to remove the type 2 component from the oral vaccine, thus making it a “bivalent” vaccine that would protect against types 1 and 3 polioviruses. Like other complaints John has made about the oral polio vaccine, however, the suggestion went nowhere—until now.
The Global Polio Eradication Initiative—a partnership of the WHO, UNICEF, Rotary International and the Centers for Disease Control and Prevention—is marshalling support for an initiative to drop the type 2 component from the oral vaccine. The proposal is part of a substantial overhaul of the plan to eventually phase out the oral polio vaccine altogether once all types of wild polioviruses are demonstrated to have been extinguished. The WHO’s governing council, the World Health Assembly, will be asked to approve the early withdrawal of the oral vaccine’s type 2 component at its annual meeting in May.
If the policy change passes—and the assembly is expected to vote in its favor—the move would eliminate an ethical problem that has been bedeviling the eradication effort for years. It could also speed the job of wiping out the remaining two strains of polio in the three countries where they remain endemic (Afghanistan, Pakistan and Nigeria); a 2010 Lancet study showed that the two-target vaccine is at least 30 percent more effective than the one that has to protect against three strains of polio. And yet the poliovirus has a nasty habit of eluding efforts to contain it. Last year, for example, China reported its first cases—genetic tests traced their origin to Pakistan—in more than a decade. Adjusting the oral polio vaccine, some fear, could have unintended consequences and thus disrupt an eradication campaign that is already 12 years past its original deadline and counting.
Countries have used the injected and oral vaccines to protect their citizens against polio for half a century. Jonas E. Salk developed the killed-virus vaccine, which was licensed by the U.S. in 1955, and Albert B. Sabin developed the oral vaccine, which was fully approved in the U.S. in 1962 [for newly available details about Sabin’s efforts, see “Birth of a Cold War Vaccine,” by William Swanson]. The greatest advantage of the oral vaccine—besides its low cost (about 15 cents a dose compared with $3 a dose for the injectable vaccine)—is its ability to trigger a low-level and generally safe infection that prompts the immune system to respond, thereby immunizing the recipient. An added bonus is that vaccinated children excrete vaccine viruses in their stool; in households, playgrounds and communities, those vaccine viruses spread from vaccinated to unvaccinated youngsters, eliciting a protective immune response in children who have not been inoculated. Health authorities had known from the early 1960s that Sabin’s live-virus vaccine would occasionally paralyze a child who received the drops (or even more rarely their immediate contacts), but they felt the millions protected justified that unfortunate cost. (The idea that vaccine viruses can also circulate on their own, causing problems in large groups of unvaccinated children, was not recognized until much later.) Eventually most countries adopted Sabin’s oral polio vaccine to protect their children—although some, such as the U.S., later switched back to Salk’s injected formulation.
For years the global eradication strategy was pretty straightforward: use the oral vaccine in the countries that preferred it or could not afford the more expensive inactivated polio vaccine until wild polioviruses were declared gone. Then, at a prearranged time, all countries would simultaneously stop using the oral vaccine. Wealthy countries would undoubtedly continue to vaccinate with the killed-virus vaccine for a time as further protection against an unexpected reemergence, but if developing countries could not afford that option, then their children would go without vaccination—and the world would hold its breath waiting to see if polio was truly gone.
Over the past decade many polio experts have argued against that plan, calling it a high-stakes experiment that would put millions of children at risk. Now, it seems, the so-called cold turkey approach may finally be coming off the table. “Most people have moved away from cold turkey,” says Roland W. Sutter, the WHO scientist who heads research policy and product development efforts for the Global Polio Eradication Initiative. Promising research on the effectiveness of ultrasmall doses of inactivated polio vaccine is creating the hope that eventually a tiny, or “fractional,” dose of injectable polio vaccine could be bundled into a six-in-one childhood vaccine that would offer the world’s youngsters protection against diphtheria, tetanus, pertussis, hepatitis B, Hemophilus influenzae B and polio, Sutter says. But that objective would be considered sometime down the road.
For now the focus is on safely eliminating the type 2 virus from the oral polio vaccine. In addition to the ethical issues raised by retaining the type 2 component, the WHO and other health agencies are grappling with another concern: the component is standing in the way of completely eliminating polio. “The real driver of this is, How do you accelerate eradication?” says R. Bruce Aylward, the indefatigable Canadian who has long led the WHO’s polio effort. The answer to that question, he and his team have concluded, is to find a way to phase out the three-part (“trivalent”) oral vaccine using a formulation targeting types 1 and 3 instead. They expect to see immediate benefits, given that the two-strain version is more effective than the trivalent vaccine. Indeed, that is why India and Nigeria have been using a two-strain vaccine in some immunization rounds for the past couple of years. (Children in high-risk areas are often vaccinated many times to build their immunity.)
A Tricky Transition
Global officials are increasingly feeling the need to alter the trivalent vaccine because the cases of paralysis attributed to the type 2 vaccine component become harder to justify as the number of naturally occurring cases continues to decrease. Years of experience with the oral vaccine have shown that two to four out of every one million children born in the same year will develop polio from the oral vaccine, with roughly 40 percent of these cases caused by the type 2 viral component. (A child’s risk of contracting polio from the vaccine falls with each additional dose he or she gets.) All in all, the WHO estimates that about 120 children get polio every year as a result of the inoculation, although John thinks the true number is several times higher than that figure.
In addition, there are the rare indirect deleterious effects of polio vaccination. From 2000 to 2010 the secondary spread of vaccine viruses from vaccinated to unvaccinated children led to at least 538 cases of polio. The type 2 vaccine virus was responsible for 84 percent of those secondary cases.
When the vaccine itself causes polio, the resulting malady is called vaccine-associated paralytic poliomyelitis, or VAPP; when a nonvaccinated person contracts polio from vaccine viruses that are spreading from person to person, the virus is termed vaccine-derived poliovirus, or VDPV.
The biggest outbreak of vaccine-derived polio began in 2005 and is still under way in Nigeria, where the spread of the type 2 vaccine virus among unvaccinated children has crippled at least 376. Vaccine-derived viruses from that epidemic have also spread to nearby Niger and Guinea. The Nigerian outbreak will have to be halted before the world can safely drop the type 2 component from the oral polio vaccine, Aylward says. In a sad twist of fate, vaccination with a formulation that includes the type 2 strain has to continue despite its risks because for now it is the most feasible way to confer immunity to that strain.
Once the type 2 component can be safely removed, health officials foresee a transition period when first the injected and then the two-strain oral vaccines are used in successive waves. The killed-virus vaccine is needed to drive up immunity levels to the type 2 virus in case any residual viruses of this strain are still circulating. Health authorities hope to keep the price down below what a full-fledged injected vaccine campaign would cost by giving all children one or two fractional doses of the inactivated formula. Research suggests that under certain circumstances—and when done sequentially with the application of the oral vaccine in the same person—splitting doses of inactivated vaccine should be as effective as providing full-potency injections.
The cost of the injectable vaccine needed to prepare for the across-the-board move to the bivalent vaccine could be brought down to 35 or 40 cents a dose with bulk buying, local manufacture (in places such as India and China) and fractional dosing, the WHO’s Aylward says. Economic analyses suggest that if the price per injection can be reduced to 50 cents a dose, using the inactivated vaccine becomes feasible even in very poor countries. The bottom line is that a supercheap version of the injected vaccine—at least supercheap relative to the usual formulation—“all of a sudden changes the ball game,” Aylward says. “You’re taking cost away from the discussion, and you’re having a scientific discussion and a programmatic discussion about what is the safest way to manage the risk of polio these days.”
Building on Experience
Transitioning between polio vaccines is a complex undertaking even in countries, such as the U.S., with substantial resources. Many officials were staunchly opposed when the U.S. first started considering a switch back to Salk’s inactivated vaccine in the early to mid-1990s. They feared the move would backfire badly.
Relying strictly on the inactivated vaccine would mean that some nonvaccinated individuals who previously would have gained protection from the spread of the vaccine virus would no longer be afforded that passive protection. They would be vulnerable to infection from either travelers who harbored the poliovirus or from vaccine viruses from people who had been immunized with the live-type vaccine. “It took a good bit of time to convince people that in a nation like this, where we were so successful in our immunization program, that we could switch to IPV,” says Samuel L. Katz, an emeritus professor of pediatrics at the Duke University School of Medicine, a co-developer of the measles vaccine and, until about a year ago, chair of the WHO’s Polio Research Committee.
Walter Orenstein, a polio specialist now at Emory University who has worked with the CDC and the Bill & Melinda Gates Foundation, was an ardent supporter of the oral polio vaccine. He was convinced the U.S. had only managed to rid itself of the scourge of polio because of the secondary spread of Sabin’s vaccine. “I was scared that if we switched to IPV only that we would still have this risk of new polio outbreaks,” Orenstein explains. He knew the vaccine paralyzed a few children every year but worried that if a switch to inactivated polio vaccine left an immunity gap through which polioviruses could slip, many times more children would be hurt.
At one of many meetings held to debate whether the U.S. should switch back to the inactivated polio vaccine, Orenstein had a religious-style conversion. The year was 1996; it had been 17 years since polio had spread within U.S. borders. People who had been crippled by polio vaccine viruses attended the meeting to press for the change. “When I looked at those people and recognized that had they gotten IPV, they would never have gotten paralyzed and would have likely been protected from polio, it was hard to continue,” Orenstein admits. “It was a defining moment. I became an IPV advocate.” The U.S. began a gradual phasing out of the oral vaccine in 1997 (it inoculated children with both vaccines in tandem through 1999 to guarantee that an adequate level of public protection was maintained).
Orenstein vividly recalls the uncertainty of the time. “Had we been wrong, had these fears been played out and we had a big polio outbreak in the U.S., people would have said, ‘Why in the world did you switch?’ It’s a lot easier to be a historian than it is to be making policy. Because there were a lot of unknowns.”
Experience soon proved the U.S. had made the right decision. Within months of switching to inactivated polio vaccine, the number of vaccine-associated cases of polio dropped to zero. Currently 56 countries use the inactivated vaccine exclusively. (Some countries, such as Sweden, always opted for the safer but more expensive, injectable vaccine.) Sixteen countries immunize with both vaccines, and 121 countries use the oral vaccine alone.
The switch from trivalent to bivalent oral vaccine could come sometime between April 2013 and April 2014, says Sutter of the Global Polio Eradication Initiative. A number of things have to fall into place before the move can be made, including ensuring that countries that make their own oral polio vaccine—such as Mexico, China and Brazil—quickly move to license a two-strain oral vaccine. If they require manufacturers to conduct additional safety and efficacy trials of the newer vaccine rather than relying on a WHO-led clinical trial that has already been completed, the changeover could be delayed.
Major questions remain. Would fractional doses of inactivated vaccine be introduced everywhere, just in high-risk countries, or perhaps in high-risk countries and their neighbors? Unlike the oral vaccine, the injected formulation must be given by a health care professional, and many of the countries on the polio front line also have shortages of trained personnel—hence, the need to marshal resources wisely. Orenstein, who is involved in the discussions, says the details are still being worked out. For now the WHO’s member countries are only being asked to approve the withdrawal of oral vaccine virus components in phases beginning with what WHO documents describe as “the particularly problematic Sabin type 2 poliovirus.”
Will development of a two-strain oral vaccine satisfy John, who pushed for this change eight years ago? Ironically, he is now one of the people concerned about the plan. Having seen how readily vaccine-derived polioviruses spread from person to person, he now believes that leaving children without protection to the type 2 virus in the next few years would be unsafe because some of the vaccine-derived virus may yet linger undetected in the environment. John says he would feel comfortable making the switch only after there is solid evidence that the preparatory campaign with inactivated vaccines has resulted in very high, widespread levels of immunity against type 2 poliovirus. Otherwise, he fears, even the painfully slow progress of the past few years will vanish, and polio will continue crippling children for years to come.
This article was published in print as "Polio's Last Act."