To Finish Off Polio

FLICKR, JULIEN HARNEISThe international spread of polio from Pakistan, Syria, and Cameroon to Afghanistan, Iraq, and Equatorial Guinea, respectively, which last month caused World Health Organization (WHO) officials to declare a public health emergency, serves as a devastating reminder that, although vaccination campaigns have squelched polio in most of the world, eradication is not complete. As of June 11, the virus has sickened 79 people in those three polio-exporting countries and 94 individuals worldwide this year alone. That’s up from 55 cases worldwide through June last year. Vaccination campaigns and global public health initiatives have caused worldwide cases of polio infection to drop from more than 350,000 reported in 1988, giving researchers reason to hope the infectious disease was near defeat. But as the WHO points out on its website, “as long as a single child remains infected with poliovirus, children in all countries are at risk of contracting the disease.” In addition to the formidable challenge of vaccinating every child to halt disease transmission, another problem threatens to keep complete eradication out of reach. After immunization with the live oral polio vaccine, which is used in most of the developing world, children with impaired antibody production fail to clear the infection. These immune-deficient patients can continue to excrete poliovirus in their stool for years. Although rare, such “prolonged excreters” pose a potential public health threat, because the longer the virus replicates, the greater the opportunity that—through mutation—these vaccine-derived polio strains could become neurovirulent, endangering both the immunocompromised person and those who have not been vaccinated. “We’re concerned about [prolonged excreters] because they might be the source of new outbreaks after eradication of the wild-type viruses has been accomplished,” said Neal Halsey, a global disease epidemiologist from the Johns Hopkins Bloomberg School of Public Health. “There can be no true eradication of polio with the continued presence of prolonged poliovirus excreters,” explained Mark McKinlay, head of the Polio Antivirals Initiative within The Task Force for Global Health, in an e-mail to The Scientist. The only way to stop excretion, researchers say, is to use an antiviral drug, or combination of drugs. There are two such therapies now in development. Vaccine as source of poliovirus Live oral polio vaccines contain attenuated strains of up to three types of poliovirus. After vaccination, healthy individuals excrete viral particles in their stool for six to eight weeks, until they develop targeted antibodies and clear the virus. During this time, the vaccine strains can spread by the fecal-oral route to unvaccinated individuals. In this way, vaccine viruses can circulate and, through mutation, become paralytic. Circulating vaccine-derived polioviruses, explained John Modlin, deputy director of the polio eradication branch of the Bill & Melinda Gates Foundation, in an e-mail, “are [oral poliovirus strains] that have gained neurovirulence through genetic reversion as a result of continuous, long-term circulation in an under-immunized population.” Scientists first documented circulating vaccine-derived polio outbreaks in 2000. The ability of the vaccine virus to become neurovirulent with continued replication is accentuated in prolonged excreters, of whom there were 65 recorded worldwide by 2012, according to a US Centers for Disease Control and Prevention report. Beyond continuing to excrete virus, people with such immune deficiencies can also be infected with and excrete circulating vaccine-derived poliovirus throughout their lives. The live oral polio vaccine is used in the developing world because, taken by mouth, it does not require a trained medical professional to administer, McKinlay said. The alternative, the inactivated vaccine, is given by an intramuscular injection. In the U.S., the inactivated vaccine has been used since 2000 because of the risk of genetic reversion posed by the live oral polio vaccine. With one in 2.7 million total vaccinations, live oral polio vaccine reverts quickly to a neurovirulent form, called vaccine-associated paralytic polio, paralyzing the recipient. Still, the risks of the oral polio vaccine are far smaller than the risks of remaining unvaccinated. “The live polio vaccine has been given to billions and billions of people and has been responsible for controlling polio over much of the globe,” Modlin said. “It’s very inexpensive, and it’s been very effective, so if you had to take your risk between getting polio and getting the polio vaccine, there’s not much of a choice.” Toward reducing excretion In 2006, a committee of polio experts convened by the US National Academies recommended the development of one or two antiviral drugs against polio to enhance vaccination-based eradication efforts. “An effective antiviral would have the potential to stop excretion of virus—and would benefit both the patient and the surrounding susceptible population,” said McKinlay. Antiviral drugs could also be used to both reduce polio transmission during an outbreak and as a prophylactic after accidental exposure, he added. If public health initiatives “are successful at eradicating polio within the next several years, that’s a wonderful thing,” said Modlin—whose employer, the Gates Foundation, supports the Task Force for Global Health. “But it could all be lost if there [is even one] person out there sometime in the future who continues to excrete virus. . . . The only way of addressing and managing [the problem] is to treat [prolonged excreters] with antiviral drugs. There’s no other way to get rid of the virus.” Unfortunately, there are still no polio antivirals approved for marketing by any agency, and there are only two drugs in development. Pocapavir and the viral protease inhibitor, V-7404, both under study by the Rockville, Maryland-based biotech firm ViroDefense, have both been found effective against vaccine-derived and wild-type poliovirus isolates. Pocapavir has also been shown to reduce animal mortality in a mouse model of lethal polio infection and has been administered in a compassionate use program with infants who have other “serious enterovirus infections,” where it has had no adverse effects, said ViroDefense President Marc Collett. With support from the Polio Antivirals Initiative, the company is now progressing pocapavir through early-stage clinical trials. The absolute soonest that either drug could reach the market is “several years for pocapavir, and several more for V-7404,” Collett told The Scientist in an e-mail. Pocapavir binds to a pocket in the virus’s protein coat, preventing the pathogen from unloading its RNA into the host cell. The drug has been shown to reduce the duration of polio excretion among vaccinated patients in Sweden. Study participants, who had already been immunized against polio by the inactivated polio vaccine, were given the monovalent oral polio vaccine type 1 followed by two weeks of daily treatment with pocapavir or placebo. Monitoring virus titer as well as the shedding of virus in patients’ stool over six weeks, the researchers found that the drug reduced the overall median time of virus excretion from 13 days to 10 days, a statistically significant change. “[Pocapavir] shows promise as having an effect at reducing excretion of the virus,” said Halsey, who was not involved in the work. “That is what we’re looking for. It would be nice if it were a more dramatic effect, but nevertheless, there is some effect, and right now, we don’t have any drugs . . . available that would do that.” The results were mixed, however, with 41 percent of treated subjects ceasing to shed the virus within just five days, while the other 59 percent continued to shed virus as long as those receiving the placebo. Moreover, pocapavir-resistant polio, as confirmed by laboratory tests, emerged in some subjects and circulated in the clinic, Collett said. ViroDefense is now gearing up for a pilot study to test pocapavir on prolonged excreters of polio. The hope is to stamp out the lingering vaccine virus in these prolonged excreters so that it does not continue to replicate and mutate, potentially to a paralytic form that could cause outbreaks. “How [pocapavir] will behave with real disease remains to be seen,” Richard Whitley, a professor of pediatrics in the University of Alabama, Birmingham, School of Medicine who was part of the National Academies committee that recommended polio antiviral development, told The Scientist in an e-mail. “But it is the only game in town.”