SCIENCES Mancn/Arsie 2000 THE END OF POLIO? The worthy campaign to eradicate the ancient scourge must confront hidden reserves of virus and a protean genetic foe. Many experts worry that the plan to end vaccinations could have lethal consequences BY WENDY ORENT MET JONAS SALK AT A four or five yearsago,” says William Lutz, a Ruc- gets University English pro- esor and a polio survivor, He was a very gracious gen nan. He asked me, "Why didn’t you di Good question, from a man who would know: who than Jonas E. Salk, the physi- lloped the first sale and effective polio vaccine, would understand Lutz's ordeal and hi hood case of one of the desc k's vac ie removed the shadow of polio; those of us who have zown up outside that darkness can hardly imagine its hor~ ror. In the 1940s and early 1950s, polio killed or crippled ds of children and young adults each year in the Unit ced Seates. Parents, beside children indoors and away from crowds, parks and other children all through the still heat of July and August, the dreaded “polio season.” No one knew then how polio spread, chough swimming pools were suspect; no one under stood why paralysis would strike one infected child and not another, The mystery of the disease added to its terror. In the summer of 1945, Lutz's parents agreed to let him outing. The five- ian who covery from a child- liest forms of polio thousa wemiselves with worry, kept old was allowed to Wisconsin State Fair. the stock-car drivers went,” he recalls. “There wou! crowd there. My parents thought | would be safe.” The disease that Lucz aught that day was bulbar polio, which invades the brain stem and can suppress bread ‘unace than Lurz had to endure th died, The episode left Lute with permanent weakness in his legs and chroat, and an abiding appreciation for the vaccine that began, in 1955, to hit the affliction from the earth. When hhe became a father, he was particularly grateful to be spared company a friend's family to th 0 the pit ate c les for= infamousiron lung: many ose Blser, The Tenth Examined Li the dread his own parents had “didn’t have to think he says, “because my suffered, about it By the mid-1960s, thanks t0 vaccines, polio had lost its hold in the United States and Wes cern Europe. Buc the disease has remained a problem. the less industrialized nations. In 1988 the World Health Onga- nization (WHO) embarked on a campaign to send polio the way of smallpox: into oblivion. The rarg the end of this year, ate tor that goal is (deni, 1991 che campaign be al number of new polio cases has dropped by more than 80 percent. “Days of ruces amanged beoween warring pi anti-polio vaccine « ‘Aighanistan, Ar ia and Sudan. But d 1¢ intensified immunization efforts, polio has not yet been eliminated. More than 6,000 cases were reported in 1998, and an outbreak in Angola in April 1999 took 89 lives. China, until recently chought to be polio~ free, has been struck again: this past October a sixteen month-old boy in Qinghai Provine lytic polio, and the government responded by vacc nating more than seven million people. Such outbreaks have made it far from certain that the target date for eradication will be met. Yet WHO officials are still preparing for life in a world without polio. When that time comes, all the samples of poliovirus being kept for research purposes in laboratories around the world are to be tracked down. consolidated and placed in high-secu- sty stor acess known as “containment. Those remaining stocks m: though there is no plan ‘Most problematically, the health officials who developed: the polio eradication program believe that once polio has been banished from nature and laboratory samples of the was diagnosed with facilities —a p y eventually be destroyed. do so now. ad Mersh/apul 2000 © THE SCIENCES 25,virus have been locked up, vaccinations ean safely . The eradication project, of course, if suc- cessl, would be 2 public-health triumph. And halt in polio vaccinations, in particular, would ako bean enormous fin cost the world $1.5 billion ay those g as easy to get rid of polio as officials once thought. And, once eradication has been achieved, we may ial boon, since the 3. But the road to soals runs through a minefield, Ie will not be find that the post-polio world has perils ofits own, HE ERADICATION OF SMALLPOX. which is usually held up as a mod- el and an inspiration for the anti- polio cam 1s actually a false analogy—and jonary tale. Although a worldwide effort drove smallpox from nature by 1980 and vaccinations hav virus has never been truly contained and has yet to be destroyed. The original plan was to consol- idate all che remaining laboratory stocks and con ‘hem to the autoclave in 1993. By 1991, how US. intell decades-long program that had run in the former Soviet Union, in which smallpox was grown by on and sophisticated delivery systems for spray into the atmosphere were developed, mak ing the virus a potentially devastating biological weapon [sce “Escape from Moscow,” by Wendy Orent, May/June 1998]. In addition, it is now that Smallpox virus may have fallen into the hands of terronss or rogue states such as North Korea, Once it became clear that smallpox had not been contained, remaining labora- WHO's success in stopping the natural spread of smallpox, the wor The eradication of polio is more complex than that of smallpox, and it is only now, as the nears fulfillment, that those complenitiesare be ing clear. Smallpox spreads more lowly than polio, and it er have the ease, complete with obvious pustules, oryou don’t, Polio, ripples in water—silently and rapid- ly. Only one in a hundred people who are infected by it since ended, the nice had leamed about a secret, tory stocks made little sense, So, desp no means free of it al res unmistakable foo by contrast, moves lik suffer from paralysis, or worse. As a result, polio is much nore difficult than smallpox to track and e Polio is an enterovirus, a genus of viruses that colonize the lining of the digescive tract. Enteroviruses of the family Picornaviridae—small RNA viruses that mutace rapidly and cause a range of diseases, including the common ‘old and meningitis, as well as polio. You ean think ofa par tus asa perfect, ewenty-sided crystal, so small ght, invisible dust. Iedrifsalong the mucous ines ofthe intestines until it reaches a bump or members nile of polio thavitacts ikea memb et called the poliovirus receptor, om the surface of a cell Once the virus attaches itself to that receptor is os al steals inside the cell and begins to replicate That is not necessarily a problem. Most enteroviru including poliovirus, grow quietly in the intestinal tract, THE SCIENCES + Mant Apa 20 where they do no harm: the body's immune syseem gen- erally routs the infection before it can enter the bloodstream. But though they initially replicate in the intestines, some enteroviruses, including polio, also have a strong affinity the motor neurons ofthe spinal cord and the brain, And on occasion, perhaps as a result of an inadequate immune response, the virus breaks out ofthe intestinal t bloodstream. From there, iteither enters the brain or cs the nerves through muscle tissue, particulary ifthe infect= ed person suffers a The illness caused by poliovirus, poliomyelitis, is marked by fulike symptoms, ‘muscle spasms and paralysis that is sometimes permanent. THOUGH POLIO IS AN ANCIENT DISEASE (A stone tablet from ancient Egypt shows a priest swith what appears to be a withered leg typi- cal of pa human health until the nwentieth which usually spreads thro sach= tic polio), it did not surface as a major threat to entury. In the past, polio, zh contaminated water, infectIrom lungs, Los Augetes Counny Hospital, c. 1952 ced nearly every child shordy after birch. Babies acquired per- ly exposure, and only ¢ cvas at risk, improvement of the water supply early in the rnanent immunity through that e anforunate child tion in infaney—the Egyptian priest, With ch infunss were no longer auto matically exposed to polio, and so did not develop immu- nity. On poliovirus did get introduced into a modern water system, the rare occasions that fecal matter carrying therefore, the disease truck hard. One of the terrors of polio, was its unpredictability. Acthe hospital, Lute recalls, his ther once pointed out a litle girl whose father was one of the wwealdhies m n intown, She wore metal braces on both le “To polio it doesn't make any difference if you're rich ot rnd you don.” his fther poor—she has to wear those brace told him. “Iewas a very ln 1955, when Salk announced that clinical tess had proved that his vaccine actually worked, church bells rr nation. The modest, genial Salk, a relative unknown, was joctatic disease,” Luz says now across the thrust into the role of national hero. Vaceines tune tion by provoking an immune response in the recip- iene withour causing che disease, Salk’s vaccine ws made from dead poliovirus and administered by a m, Unfortunacely, che vaccine was to production too quickly: in that same year the Cutter Laboratories in Berkeley, Califor= nia, cultivated batches of vaccine but did not hem all thoroughly enough with formalin, the formaldehyde solution used to kill the virus. More han 200 children, inadvertently inject cd polio fom ‘was intended to prc The incident shook the public's fith in Salk’s vaccine Meanwhile, Salk’s archrival. Albert B. Sabin, had developed a different kind of polio vaccine fone made from live but weakened virus and 1y mouth, By the early 1960s Sabin’s oral vaccine, having proved sate and extremely di with liv hot chat ing wild vieus, conta st chen administer ive, lad all but replaced Salk’s injected vac~ cine—delightful news for those who preferred sugar cubes to different principles, and lead to different kin immunity. Salk’s injection of dead viru: bodies against polio to develop in the blood, result what's called humoral immuniey. The inject- ed vaccine protects the individual and prepared according to Salk’s specifications, extremely safe. Bur it does ofpoliovirus fom son, Salk-vaecina to prevent colonies wing in che gue, For thaceea- ople exposed to poliovirus sient carriers, capable of infecting others for a Few weeks, alter which the virus naturally clears itself Like the Salk va ine, the Sabin oral vaccine nst polio to develop in th blood, thus conierring humoral immunity. But the oral vac odies a cine also induces colonies of live, weakened virus to take up residence fora while in the gus, creating what is known, is mucos] immunity, a localized immune response by cells n the intestine, which from then on will be inhospitable to poliovirus. Asa result, che oral vaccine not only protects, people from coming down with polio, bue also prevents, them from becoming cartiers of the disease. Furthermore person who has received che oral vaccine ean bring health benefits to an entire community. People infected with wild it for bees eight weeks i poliovirus exc their stool. Likewise, people who get ine « the weakened form of the virus for a similar pe ood of time. If Sabin-vaccinated people happen to “infec others during that period, they are in effect passing on the vaccine, thereby enabling the unimmunized people around them to develop th The oral vaccine has other advantages as wel. I is much ibute than the injected vaccine, since there is March/Apnl 2000 © THE SCIENCES 27nno need for sterile needles or trained nurses. The oral vac~ cine is aso less dangerous than the injected vaceine to pro duce, because, unlike the injected vaccine, its manufactut does not requir that huge amounts of live wild poliovirus bbe grown in the lhboratory. In addition, the oral vaccine is cheaper to make, in part because it does not require carefial treatment with formalin. Oral vaccine does have one disad- vantage (which it shares with the injected vaccine): i spoils when it is exposed to heat; in fact, ‘cold chain" —that is, k ing the vaccine re journey from manufac- turing to administra on—has been one of the principal hurdles for she eradication effort in tropical countries. Given iss many ad- vantages—reduced of discribu- 14. community and mucosal p tion—oral polio. vac~ cine has b weapon of c or eliminating polio epidemics. Although Salk’s was the first fect not the one that erad icated polio from the Western Hemisphere; that_honor Sabin, But 0 vaceine is not without its troubling aspects Indeed, nothing nal. deadly crystal that is poliovirus is simple—least of 10a world free of polio, tire issue becomes, ILD POLIOVIRUS MUTATES EXTREMELY apidly. The problem with the oral polio vaccine is thar it mutates as well, and in ‘ous fashion. A single nucleotide change in the so- noncoding region of the viral genom virus in the oral vaccine to become newrovit ‘or, in other words, capable of causing paralysis. And the mutation occurs frequently—at least half the time, within about a week of vaccination, according to the vac cine specialist Philip D, Minor of the National Institute for Biological Standards and Control (NIBSC) in South Mimms, England, The mutated virus from the oral vaccine is sill far less harmful and less contagious than wild poliovirus. In the vast majority of cases it causes no harm, But it can cripple and Kall In hy who have received the oral polio vaccine, and some caretakers, have died or become permanently par- bout causes the United States, for instance, a small number of Al Fean, Sal vane, 19 alyzed. The phenomenon, knownas vaccine-associated par- alytic polio (VAPP), is rare, given the vaccine’s strong ten- dency to revert to neurovirulence: th paralysis for every 2.4 million people vaccinated, That low rate does not reflect the true p cine to cause harm in an unprotected population, howev- -cause practically everyone nowadays who comes ini contact with a Sabin-vaccinated person has been immunized, Why do a few people have such trag spite of what many American parents who is one case of sal of the mutated vac~ Jc reactions to the polio vaccine? In oppose oral vaccina- tion seem to think, it is not a question of ‘bad lots” of vaccine. The vaccine is always the same,” says Vin- R, Racani virologist at ca loa polio Columbia University Instead, the problem is likely to be a sare and previously um patient. And Racaniello thinks that in some cases, nized im another enterovirus— such as enteroviris 71 or ane ofthe coxsack- es, which car aralysis—i probably at fault, Thy difficulty is that, in ven clinical case, itis often impossib know for sur virus caused an infection, Nerve tissue cannot be exam- ined unless the patient dies, At any rate, in a population risk that even a few people will ge of wild poliovirus, the paralytic polio because of a vaccine is too high. This past January 1, ehe United States officially switched to a new Salk’ originl injected vaccine. The move will prevent fur ther cases of VAPP, because, unlike the oral vaccine, the dead Salk virus cannot revere to a disease-causing form. But il also spell an end to the many ben cal vaccine. For example, as | mentioned eat into contact with someone who has recently rece cssome immunity to polio—an efit holds for everyone except few immunocompromised people, even if the virus has mutated and become n rovirulent. And because vaccination cover absolute, losing the benefits of comm poses a risk—particularly during what is, in Racanielo's wor i For example, someone fom a developing country whe was infected with polio could come to the United States The chances are small that such a person would have direct nore potent version of its ofthe the switch wi oral vaccine cres thatben-ccontaet with an unimmunized person, Buc remember, the injected vaccine permits poliovirus to grow in the gut. even though the recipient of the vaccine is personally protect ed. Hence one foreign visitor could initiate an ever-widen- ing network of infection in the intestines of ummunized people. a “silent” spread in which no one exhibited the symptoms of polio or even realized that exposure had eak= en place. It would then be possible for polio to reach the rare unimmunized pers theoretical, Racaniello thinks i¢ would have been wiser to have wwitched to che injected vaccine only afier polio had been eradicated worldwide. HE ERADICATION CAMPAIGN HAS COME under sniper fire fron: polio virologist. all of whom applaud its goals bue many of whom quescion the wisdom of carrying it outs it has been designed Part of che problem may be the fuse analogy wih smallpox, ‘How Smallpox Showed the Way.” urscle by the public-health expert Donald A. Henderson of ins University in Baltimore, Margland, But what The three-step program for smallpox —eradica- tion, containmentand destruetion—has not worked. and the prospects for vanquishing polio are more doubsfilstill, Wip The isk issmall, but more than dechares the ttle of an cussisshor that children already receive. His ers pone out hat sophisticated! manuificturing methods in industrialized countries allow for sucl an addition bur thae #2 bee available co children in ocher part of the world. "What ischis,” Chumakov ask in response. “Equal misery tor all? HAT WORIES CHUMAKOV AND OTHER polio virologists about ending imma- nization isthe difficulry of ensuring that poliovirus has vanished from nature and that laboratory held stocks have been safely contained. There are many ways in which che virus could linger unobreusively, Civil onrest, for instance=-in Afghanistan, Angola, che Democratic Republic of the Congo (D.A.C)—is the rest problem still ficing the eradieation campaign, "Can you vaccinace every final outpost?” asks the virologit Bert L. Semler of the University of California, levine. In other words, if the vaccine does not get to every mountain vil- nistan, to every child in the fturi officials be certain that eradica- Forest. D.R.C.. how & tion has been achieved? Furthermore, whereas WHO plansto lock research stocks known to include poliovirus in specially designated high containment ficilities some virologists argue chat other OnE * ‘PERSON INFECTED WITH POLIO could start a “silent” epidemic + in a population protected only with the injected vaccine. ing polio out oF nacure will nor be exy. Deciding when and how to end vaccination will be even more diticult. And ensuring that che earth is ru tree of polio, so chat destruc tion makes sense, will be all but impossible Asche campaign isplanned aow. vaccination against polio will cease worldwide somedime atter WHO declares che world to be five of the virus. And why not? Supporters of the pln are adamant: Whe needs an extra shot—oe four we fixe—onee poliovitus has been driven ftom the « Why nor save che money for, sav, the eradication of eases, which stil takes the lives of more than a million children each year? "Do you wane the world to spend a billion and sul dollars a year to vaccinate against something chat does not exist?” asks Stephen L, Coch of the National Imm nization Program at the Centers tor Disease Control and Prevention (CDC) in Athnta, Georgia, “We're entering 3 world where polio may be one of thousinds of perceived threats. You can't vaccinate against paranoia Bucothes,inclading Konstantin M. Chumakov, a vieol- gist at the Center for Biologics Evaluation and Research of the US. Food and Drug Administration. say it would be irresponsible co stop vaveinating, “We are creating with our own handsan entire population ofsuscepubles.” Chumakov says, Chumakov is well acquainted with the polio of ol his tither. the Emous Russian virologise Mikhail P. makov, a friend of Sabin’, inteodsced the S. cine «0 the Soviet Union and stopped an epidemic in the Bultic states. Today the younger Chumakov endorses the inclusion ofthe polio vaecine in the diphtheria-tetanus-per- coral va polio samples could easily he overlooked. For one thing, Freezer samples of tool and cerebrospinal Hud could ear a. Once nple could ry live poliovirus without anyone's knowin immunization has ceased. the disposal ofsuch cause an outbreak of poli, In addition, some samples once known © cary polio muy have been shoved co the back of someone's lborato- ry freezer and forgotten. In 196 the physicist and nologist Alan P. Zeticoff of Sandia National Laboratories in Albugnerque, New Mexico, asked investigators at sev etal laboratories whether they were storing any phgue or chrax bacteria, They allstid no. Then Zelicotf lid asearch. Sample after sample of both plague and anthrax: emerged om the relfigeritors. The scientists themselves. were dumbfounded. Polio, which Chumakov cals “the crown, Jewel of molecular biology.” has been studied more than any other virus; the number of samples that have been stowed away could be immense, Another drawback to ending vaceinations i the danger posed by poliovirus that may live on in human hoss. Cem #9 mmunocompromised people who are infected with er wild poliovirus or the mutated, neurovirulent virus tiom the oral vaccine may continue to exerete it for years. instead ofthe usual sito eight weeks. Throughout that peri- ixisuch people remain potentially infectious chose round shen, One patient, whom Racaniello call tee Typhi Mary of polio, excreted poliovirus for nearly ten years before he died. And polio, unlike the smallpox virus, can survive for months in sewage. According fo Racaniello, 2 recent Marsh/jpnt 2000 + THE SCIENCES 29Israeli study recovered live poliovirus that, on the basis of genetic analyses of the degree of n circulating in sewers for months. Yet current polio surveil: lance programs generally monitor only cases of paralysis, and WHO has no plans co begin monitoring water systems, Even if poliovirus itself disappeared tomorrow of poliomyelitis could remain, A recent paper by Eckard Wimmer, 2 prominent poliovirus investigator at the Sta University of New York at Stony Brook, and by th Russian virologs Alesan: der E. Gorbalenya of the Advanced Biomedical Computing Ce Frederick, Mary made a staring sugges” tion: in the absence of cir- culating poliovirus anti- entero: viruses might evolve the bodies, other xx to the poliovirus receptor. Recall that some that are closely related to polio are aso high- Itmay take one ora thousand years,” says W mer. But its 2 risk that he is not willing to discount. Worrsome, 00, isthe manufacture of vaccine once polio has been eradicated. No one is optimistic enough—or fool hardy enowgh—to suggest that maintaining emergency stockpiles of fresh vaccine will be unnecessary. But which vaccine? And how can waccine workers themselves be pro: tected, yet prevented from becoming dangerous poliovinis carrier? If vacc vaccine, they could bring mutated, neuroviralent virus into an unprotected community. Ifworkers were protected wich the injected vaccine but were making the oral vaccine, they could still shed mutated oral virus; if they were making the injected vaecine, they could shed wild polioviras chat « hhad acquired before the virus was killed in the manu turing process. And how could large quantities of vaccine bbe manufactured under the stringent biosafety conditions biohazard containment levels of three oF three and a half ut of four—that would be required after eradication? ND, FINALLY, THERE IS ANOTHER PROBLEM that the eradication campaign must confront, pethaps the most serious problem of all: Could poliovirus serve as a biological weapon? Polio is a clatively small and simple virus. It is made up of about 7,500 nucleotides (smallpox, by contrast, is a DNA virus fe up of 186,000 pairs of nucleotides). The nucleotide sequence for poliovirus has been publicly available since 1981. With today’s technology, making. infectious poliovirus would require nothing more than "a graduate scudent,a synthesizer and three months’ time,” Chumakov says. In twenty years, or fifty, who knows? A high school student with a grudge might be able to do it. What kind of biological weapon would polio make? Smallpox, anthrax, plague and cularemia are the usual suspects when one thinks of biological weapons. No ane mentions polio, and for good reasor point in launching a weapon that is not going to hurt any fone. But in five or ten years, if vaccinations have ceased workers were protected with the oral there is nor much people will be living in a different, susceptible world. Experis differ on the viability of polio as a biological weapon. “I would say that itis not an efficient weapon,” says the medical epidemiologist Harry F. Hull of WHO. Racaniello does not agree: the rapid infectivity and slle spread of poliovirus, he thinks, could make ita serious threat in the future. Poliovirus would be easy to release into a public water supply. In a city such as New York, even if only onc out ofa hundred people developed paralytic polio, the consequences are appalling to contemplate, The virologist Olen M. Kew of the CDC, one of the principal forcesbehind the eradication campaign, acknowledges that the potential for exists. But such a x would be so horrend use it, “Polio wouldn't he says. "You would people mad at you. apo da make a very good terror weapon n't want sis and a half billion LTHOUGH THEY DISAGREE ABOUT THE Wis- dom of stopping vaccinations, most polio virologists concede thatit will happen even- -mostly for pragmatic and financial reasons. Yer few expect polio to go down quietly. Both Semlerand the virol- ogist James M. Hogle of Harvard Medical School predict that even after eradication appears to be complete, the dis- ase may flare up again. What then? The injected vaccine not suitable for stopping such epidemics, because i allows wild virus to spread silently. But the oral vaccine is pro! lem: rovirulent virus into the environment. In today's world, which almost everyone is vaccin: ‘mal. Bur once vaccinations have ceased, that r neurovirulence could prove much more dangerous. ‘There may be an alternative. The potential problems with the existing polio vaccines suggest that it makes sense -k new vaccines—though five or six years ago, heady c eatly successes ofthe eradication campaign, WHO discouraged such work. This past January, however, WHO sponsor 1g in Geneva to discuss how ¢o control outbreaks of polio in the post-vaccination era, Among the topics covered was the potential usefulness of alter native vaccines. Coming so close to the agency's own, deadline for eradication, such willingness to explore new vaccines suggests a new pragmatism, and perhaps a cer- tain failure of nerve. ‘One of the most promising new vaccines is being devel: oped by Philip Minor and two associates, Andrew: J, Macadam, a colleague of Minor’s at NIBSC, and Jefftey W Almond, of the University of Reading in England, Their vaccine shows no propensity to mutate back to neuroviru- ence. Minor’s team began with a weakened viral the oral vaccine, then replaced several nucleotides in the noncoding region wich other nucleotides, The result is a sequence that has the same number of hydrogen bonds as its counterpart in the Sabin virus, but that is crippled in a he asserts, that no one would tually too, because sple who receive it e the imAled Eisen way that prevents dangerous mutations. Test-tube and ani- mal tess have demonstrated the vaccine’s probable safety though to prove that it would be safer than the Sabin vac- track record of one case of paralytic disease for every 2.4 million vaccines administered, Minor and his associates would have to test it on six nsillion children. In a Europe ‘hat is virally free of polio, that is not going to happen. ted after eradication, the nations of If vaccination is, the world stand to save a great deal of money and human effort, which can then be directed toward other public- health issues—measles, tuberculosis and malaria, among oth- ers. But Kew, who has dedicated years of his life co the eradication campaign, points out that its real achievement is the saving of human lives. There are, afterall, 550,000 at, Polio epidemic, Hithory, North Carlin, c. 1950 children each year who are spared crippling disease because of the worldwide effort to vaccinate against polio, That in itself is an incalculable savings, and an incalculable good. Kew recognizes the problems with halting immunization, and is not so naive as to believe that eradication automat ically means an end to the financial burden of making, dis- ‘ributing and administering vaccines. For his part, Chumakov says, “Don't expect chat the fact that we eradicated polio means we can forget about it, Polio will aways be with us. Ie will always be Wenpy Onexr is a writer living in Ailanta, Georgia, Her my biolegical warfare, communicable diseases ad related topics ve dppered in THE SCIENCES, THE LOS ANGELES TIMES, THE AMERICAN PROSCECT and DISCOVER.