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Driven to Extinction

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Driven to Extinction
de System Administrator - lunes, 6 de julio de 2015, 22:02
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Driven to Extinction

The eradication of smallpox set the standard for the global elimination of a devastating infectious disease. Will the ongoing polio and guinea worm campaigns be as successful?

By Jef Akst


EXTENDING THE REACH: A health worker administers polio vaccine to a child while her sisters watch, during a Polio National Immunization Day in Karachi, Pakistan. © END POLIO PAKISTAN/SAD SAIDI. WWW.ENDPOLIO.COM.PK

In the spring of 2000, Stephen Cochi, then-director of the Global Immunization Division at the US Centers for Disease Control and Prevention (CDC), stood in the town of Torkham on the border of Pakistan and Afghanistan, watching thousands of Afghans exit their country through the storied Khyber Pass. They were fleeing for their lives from the violence that had become a regular occurrence as Afghanistan entered its fifth year of civil war against the then-ruling Taliban. But Cochi and his colleagues from the World Health Organization (WHO) and Pakistan’s Federal Ministry of Health saw another opportunity to save lives. As the families crossed into Pakistan on their way to the city of Peshawar, public-health workers escorted any groups that included children who looked to be less than five years old to a tent set up to the side of the crowd and delivered two drops of an oral polio vaccine into the children’s mouths.

“There were people streaming across the border,” Cochi recalls. “I would guess that, over the course of a full day, they probably vaccinated in the thousands of children.” Cochi found it gratifying to see that so many children were being immunized against the potentially fatal disease that had once killed tens of thousands of people each year and paralyzed hundreds of thousands more. But the scene was also a stark reminder of how far those fighting for polio eradication had to go, he says. “[I could] see how the eradication of polio in Afghanistan is completely linked to the eradication of polio in Pakistan. This was a living, breathing, visible representation of that. We’re still dealing with that today.”

Epidemiologists, public-health workers, and researchers involved in eradication campaigns are confident that polio and guinea worm can meet the same fate as smallpox.

Indeed, while researchers and public-health officials have made great strides in ridding the world of the virus—the number of polio cases has dropped to just a few hundred from more than 350,000 in 1988, when the eradication campaign was launched—the final steps in extinguishing the disease have not been without setbacks. One major hurdle has been the migration of people into and out of polio-affected countries. “I think Afghanistan would be a polio-free country were there not so much back-and-forth movement to Pakistan,” Cochi says.

Even more threatening to the eradication campaign’s success, perhaps, are the challenges in immunizing all vulnerable children, many of whom reside in regions occupied by antigovernment forces such as the Taliban. And beyond the logistical hurdles, eradication efforts must overcome scientific challenges—such as the potential for the attenuated, noninfectious versions of the poliovirus used in the oral vaccine to mutate into an infectious agent.

A better understanding of pathogen transmission may be even more critical in supporting the world’s only other ongoing eradication campaign: the abolishment of guinea worm disease. Traditionally, humans have contracted the disease by ingesting water contaminated by parasite-infected copepods, and simply ensuring that affected regions have access to clean drinking water has succeeded in reducing cases of the disease from more than 3.5 million in 1986 to just 126 last year. But recent cases of guinea worm disease in dogs, which likely contract the parasite by eating the scraps of infected fish butchered on the shore by local fishermen, have researchers rethinking the final stages of eradication. “That’s a new wrinkle in what Mother Nature has to offer us,” says Ernesto Ruiz-Tiben, director of the Carter Center’s Guinea Worm Eradication Program.

Despite these setbacks, epidemiologists, public-health workers, and researchers involved in the two eradication campaigns are steadfast. They’ve done it once before—declaring the world free of smallpox in 1980—and experts are confident that polio and guinea worm can meet the same fate. And the lessons learned from these campaigns could set the stage for other infectious diseases on the chopping block.

“It starts with knowledge and then it carries on to medical practice and then it extends into medical research to get insights into what is going on,” says the University of Florida’s Grant McFadden. “If everything works right, all those things flow into new ideas for therapies, containment, and, ultimately, eradication.”


The number of polio cases has dropped from more than 350,000 in 1988 to just a few hundred last year.

The number of guinea worm disease cases has dropped from more than 3.5 million in 1986 to just 126 infections last year.

Putting polio in its place

Not every infectious disease is eradicable. In fact, even with all the resources in the world, most of the pathogens that currently plague humans would be extremely difficult, if not impossible, to banish from the planet. “When you look at the huge array of microorganisms out there, there really is a relatively small number of microbiological agents that would be considered to be good candidates for disease eradication,” says Cochi.

One criterion that makes a pathogen a good target for eradication is the lack of an animal reservoir. Even though outbreaks of SARS and Ebola have been controlled a number of times, for example, the causative pathogens can continue to jump from their animal hosts to kindle new epidemics. Another important feature of an eradicable disease is, tipically, that there be an effective treatment or vaccine.


A health worker vaccinates a child against polio during an immunization campaign in Quetta, Pakistan. © END POLIO PAKISTAN/2013/ASAD ZAIDI

A polio vaccination team wades through flood water in the Sindh province in Pakistan. © END POLIO PAKISTAN/2012/ASAD ZAIDI.

Cheshire Home for Handicapped Children in Freetown, Sierra Leone WORLD HEALTH ORGANIZATION

Smallpox fit the bill on both counts, and in 1966, the World Health Assembly, WHO's highest governing body, voted to initiate a worldwide smallpox-eradication campaign. It started out as a mass vaccination program, then converted to a search-and-containment strategy, in which all contacts of smallpox patients and nearby households—depending on the country, sometimes entire apartment buildings—were vaccinated to prevent further transmission of the pathogen. In less than 15 years, case numbers dropped from more than 15 million to zero. "The strategy for eradication was very straightforward and successful in the end," says David Heymann, a medical epidemiologist at the London School of Hygiene and Tropical Medicine who worked for two years on the smallpox-eradication program in India.

But smallpox eradication held some other advantages over the polio campaign. For example, "every infection was clinically expressed in the same way," Heymann says. "There weren't, as is the case with polio, people without symptoms." Indeed, fewer than 1 in 200 cases of polio results in paralysis, making most infections invisible to public-health workers. For this reason, a search-and-containment strategy wouldn't work, as it would often miss infected but asymptomatic individuals who could continue to spread the virus. Instead, the polio campaign must continue to vaccinate every child, and therein lies the principal challenge to clinching the virus's eradication. In Afghanistan and Pakistan, the Taliban has repeatedly interfered with the eradication campaign, prohibiting vaccination and even killing health workers delivering immunizations. "I think there's general agreement that the biggest obstacle is access to children in Pakistan," says John Modlin, deputy director of the polio arm of the Bill & Melinda Gates Foundation.

But the campaign has faced, and overcome, such challenges before. In 2009, the northern states of Nigeria—the headquarters of the violent extremist group Boko Haram, which, like the Taliban in Pakistan, has prohibited vaccinations and even killed to enforce this ban—was the scene of a polio outbreak that resulted in more than 350 cases over a period that had seen fewer than 65 infections the year before. Then, in 2013, polio jumped from Nigeria to Somalia, causing an outbreak of 194 infections in a country that had not recorded a case of nonvaccine-related poliovirus since 2007.

In response to the spike in cases, the Nigerian government and partners set up an emergency operations center and enacted a national emergency-action plan, including “hit-and-run” immunizations in which security forces protected mobile units of health-care workers who would rush into the war-torn northern regions of the country to vaccinate as many children as possible in just a few hours. In the end, the efforts paid off, with the last case of polio reported in Nigeria in late July 2014. The last case in Somalia was recorded less than a month later. Although it will be another couple of years before polio can be declared eradicated from the continent, “we are hopeful that we now have a polio-free Africa,” says Cochi.

Similar emergency actions are now being put into place in Pakistan, including several new emergency operation centers in high-risk areas. “This is a strategy that worked very well in Nigeria and now is being replicated in Pakistan,” says Modlin. In addition, the Pakistan Army intervened in Taliban-occupied regions last summer, giving public-health workers access to some half a million children who were previously unvaccinated, Cochi notes.

“To me, that’s the story of infectious-disease elimination and eradication attempts as a whole,” says the University of East Anglia’s Sebastian Taylor, a member of WHO’s Technical Advisory Groups for Polio Eradication in Afghanistan and Pakistan. “Biotechnology and finance will only get you so far.”

“If polio [eradication] fails it won’t be because of technical reasons, it will be lack of political will,” agrees Oliver Rosenbauer, a spokesperson for the WHO’s Global Polio Eradication Initiative.

Improved targeting

That’s not to say that science doesn’t have a role to play in finalizing the eradication of polio. Another main challenge is that multiple vaccinations are necessary to ensure complete protection against poliovirus. One reason for this is that the original oral polio vaccine—made from live, attenuated viruses—targets all three serotypes of poliovirus, and type 2 replicates most robustly in the intestinal tract, actually interfering with the replication of types 1 and 3. The type 2 virus is thus the most immunogenic, spurring the production of the most antibodies by immune cells in the gut lining—the primary site for poliovirus replication—as well as in the blood after the first dose of the vaccine. But such antibodies don’t do today’s children much good, as the last case of polio caused by naturally occurring type 2 virus occurred more than 15 years ago.


The solution is to remove type 2, going from a trivalent to a bivalent oral vaccine. “As a result, the immune response against types 1 and 3 [is] enhanced, dose for dose,” Cochi says. The bivalent vaccine has already been introduced into the polio-eradication campaign across the Middle East, Africa, and India. “It is the vaccine of choice for vaccination campaigns in polio-infected countries and those countries which are considered at high risk of reinfection,” Rosenbauer says. Public-health officials are now gearing up to transition from the trivalent to the bivalent form for routine immunization programs. Countries are currently in the process of securing licensing for the bivalent oral vaccine, with the goal of adopting it into routine care by the end of the year.

Although naturally occurring type 2 poliovirus hasn’t been seen since before the turn of the century, the type 2 virus isn’t completely gone. That’s because the live viruses used to make the trivalent oral vaccine can be shed in the stool of vaccinated individuals and, on rare occasion, can mutate to become infectious again. While all three virus types can mutate in this way, the type 2 form is responsible for the vast majority of vaccine-derived polio outbreaks. Last year saw a total of 55 cases of such vaccine-derived polio infections, for example, only one of which was not type 2. By eliminating type 2 poliovirus from the oral vaccine, “the idea is to have all type 2 viruses disappear from the world forever, including the vaccine virus,” says Cochi. But until then, vaccinated individuals will still harbor attenuated versions of the virus that could revert to an infectious form, and health officials need a way to continue to protect children against these vaccine-derived type 2 viruses as they make the switch to a bivalent oral vaccine.

The role of bridging that gap falls to the inactivated polio vaccine (IPV), which has been the exclusive vaccine used in the United States since 2000. IPV is administered via intramuscular injection and provokes an immune response only in the blood, in contrast to gut-based immunity triggered by the oral vaccine. The IPV thus provides personal protection and prevents the virus from reaching the spinal cord where it can cause paralysis, but it doesn’t stop naturally occurring polioviruses from entering and replicating in the gut—and spreading the virus. For this reason, as well as the fact that IPV is more expensive and requires a trained professional to administer, this vaccine is not practical for the eradication campaign efforts still ongoing in high-risk countries. But because it affords protection against all three serotypes of the virus, it could serve as the perfect supplement as these regions of the world transition to the bivalent oral vaccine. IPV has been introduced into polio campaigns in affected areas, and “the goal is to have all countries using IPV in [routine immunization programs] by the time of the switch,” Modlin says. (See “For Polio, Two Vaccines Work Better Than One,” The Scientist, August 21, 2014.)

Eventually, health-care officials hope to transition all countries to exclusive use of IPV, eliminating the risk of vaccine-derived viral infections. But IPV’s injection mode of delivery remains a challenge.  As a possible alternative, researchers are now exploring the use of microneedle patches, as simple to administer as putting on a Band-Aid. An added bonus is that the microneedle vaccines would not require cold storage. Cochi speculates that a microneedle version of IPV, which is currently undergoing testing in early Phase 1 trials, could be available within the next five years, easing the transition from the oral forms of the vaccine.

Even longer-term, if the polio eradication campaign is successful, there is the possibility that polio vaccinations could be stopped altogether, as happened with smallpox. “Speaking for myself, [I] consider the Holy Grail to give up using all polio vaccines altogether,” says Modlin. “We’d like to take those dollars and apply them to other public-health priorities, if we can.”

Worldwide deworming

Guinea worm—the only other pathogen currently targeted for eradication—differs dramatically from smallpox and polio in that there is no vaccine. In fact, there isn’t even a treatment. Instead, elimination of the disease may be achievable thanks to the extremely predictable life cycle of the parasitic nematode Dracunculus medinensis. Guinea worm larvae hiding in infected copepods are ingested by humans, where they mature and mate. Females grow into meter-long worms, migrate to the foot or ankle, and escape via burning blisters, which their human hosts often plunge into water to relieve the pain. Upon sensing the water, the female worms discharge new larvae, starting the cycle over again. Thus, to halt guinea worm disease, the primary focus of the eradication campaign has simply been to provide clean drinking water to affected villages. This strategy has succeeded in reducing cases of guinea worm in Africa and Asia from more than 3.5 million in 1986, when the World Health Assembly passed a resolution to eliminate guinea worm, to just 126 infections last year.

“[There’s] no drug, no vaccine, and no real diagnostic,” says David Molyneux, an infectious-disease expert at the Liverpool School of Tropical Medicine. “And yet you can still [eradicate] it by implementing public-health measures.”

But in the past couple of years, the parasite has thrown officials a curveball: it began infecting dogs in Chad, one of four remaining countries (all in Africa) where guinea worm is endemic. “This is an entirely new phenomenon as far as human guinea worm—one that is quite concerning,” says Molyneux, especially given that lack of an animal reservoir is a commonly cited prerequisite for eradicability. While Chad had only 13 cases of guinea worm disease reported in humans last year, 113 dogs were infected. A similar pattern was observed the year before. A handful of dog infections have also been reported in Ethiopia.

The canine cases suggest that guinea worm may be infecting mammalian hosts, possibly including humans, via a different route than the classic path of contaminated drinking water. The Logone and Chari Rivers that feed Lake Chad support a thriving fishing industry, in which fish are caught by hand and with baskets in the dry season, when the water levels drop and the rivers become more like large lagoons of stagnant water. “It’s quite significant and unique to Africa,” Ruiz-Tiben says. “I’ve never seen this intensity and dependency on fish products for food.” While the fishing industry supports the local economy, all signs seem to point to infected fish, which prey on copepods, as a new source of guinea worm infections. As the fishermen bring in their catch, they clean the fish on the river bank, dropping the guts on the ground. The local dogs, of course, are all too happy to clean up the mess. In all likelihood, these fishy meals are the source of the outbreaks of guinea worm in Chad’s dogs. And if people do not fully cook the fish themselves, they, too, may become infected.


That only sporadic human cases of guinea worm have been seen in Chad suggests that this is exactly what’s going on. Rather than mini-outbreaks, in which one or a couple of infected individuals leads to bouts of dozens of cases in the following year after the worm has completed its cycle and contaminated the village’s water source, there have been just a handful of cases in Chad villages, and often no repeat cases the following year. “That was one clue that transmission is not occurring via drinking water,” says Ruiz-Tiben. Public-health workers are now striving to educate affected villages about this presumed new mode of guinea worm transmission, encouraging people to cook their fish thoroughly; dispose of the fish entrails in a sanitary way; and keep infected dogs out of the water.

“The change in the number of new [guinea worm] cases in the last 20 years has been spectacular; it’s a remarkable public-health achievement,” says Molyneux. “But as always, the last few cases are the most expensive and the most difficult.”

Next on the chopping block

When polio was selected to be the object of a worldwide eradication campaign in the late-1980s, it wasn’t the only pathogen that officials considered. Another potential candidate that made the shortlist was measles, says Cochi. Like polio, it has an effective vaccine—the combination measles, mumps, and rubella (MMR) vaccine—and no animal reservoir. The World Health Assembly’s decision to target polio may simply have been a matter of circumstance.

“Beginning around 1980, first Brazil and then an increasing number of countries in Latin America began nationwide polio campaigns,” Cochi says, which “knocked polio disease burden way down to low levels. . . . That was one big factor—there was demonstration of success in a large geographic area. The other big factor was [that] Rotary International became interested in polio eradication in the mid-1980s and signed on as the largest private-sector [participant] in the polio eradication effort.”

But as polio eradication approaches what may soon be a realistic near-term goal, some epidemiologists are starting to turn their sights back to measles, which, like polio in the 1980s, is now the target of numerous regional campaigns. In fact, each of the WHO’s six regions now has an ongoing measles elimination effort. As a result, “there’s been a real acceleration in reduction of measles worldwide,” Cochi says, with deaths from the disease dropping by 75 percent since 2000.

Despite such progress, measles still kills about 140,000 children each year. And that number means that even regions of the world that were once measles-free, such as the United States, are still at risk, a fact highlighted by the recent outbreak that originated at a Disney theme park in California in late 2014. “This is just a reminder that there’s still a lot of measles elsewhere in the world,” Cochi says. “These organisms don’t respect borders.”

Measles eradication does face a few challenges that the polio campaign has largely avoided, however, most notably the fact that the MMR vaccine must be administered by a trained professional. “Because measles is an injectable vaccine, we can’t go house-to-house,” Cochi says. “[It requires] more of a facility-based measles mass campaign.” But, he added, the MMR vaccine does have one advantage over the polio immunization: it needs to be given only twice, instead of the four times recommended for the oral polio vaccine. “The measles campaigns are far less frequent and therefore less disruptive to the health-care system,” he says.

For now, however, there is no official talk of a worldwide measles-eradication effort. With polio still circulating, most say it’s too soon to think about diverting resources away from the ongoing campaign. “Measles is the next disease that people talk about for eradication,” says Heymann. “[But] no one is willing to talk about measles eradication until polio is finished.”

Clarification (July 2, 2015): This story has been updated to correctly reflect David Molyneux’s affiliation as the Liverpool School of Tropical Medicine. He is also an emeritus professor at the University of Liverpool. The Scientist regrets the oversight.