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Seminar, March 2012 Lessons from the polio eradication campaign T. JACOB JOHN INDIA has just won a landmark victory in the long-drawn-out war on polio. Fourteen months have gone since 13 January 2011 without a single case of polio caused by wild poliovirus (WPV). But how sure are we that in this vast country, with about 125 million under-five children and a poorly performing health management system, there is no case of wild virus polio? Rest assured, India’s polio eradication project is a shining example of how India can pull itself together, even without a robust infrastructure, and solve ad hoc, specific problems. India has really eliminated WPVs. Poliomyelitis, polio for short, is a cruel disease. WPVs spread rapidly via saliva and stools of infected children. Infection is silent in the vast majority; one among some 200 suddenly develops paralysis, usually of the legs. As muscle groups around joints lose power, the limb becomes flaccid – polio is one of several causes of acute flaccid paralysis (AFP). The pathology is in the spinal cord nerve cells controlling muscle action – damaged or destroyed by polioviruses. Ordinarily polioviruses infect the mucous linings of throat and intestines. In some, viruses enter the blood stream; in a few they reach the spinal cord and cause polio. Unlike most other AFPs, polio paralysis is permanent in 80 per cent (because nerve cells are dead), but the lucky 20 per cent recover (if cells recover after damage). If muscles of respiration are paralysed children may die. In 2009, 76 children among 741 with polio died in India. In the decades of the 1970s and 1980s, about 200,000 to 400,000 children developed polio annually – a daily average of 500 to 1,000. Think of the great progress since then. Polio eradication is not only a humanitarian imperative, but also an economic investment. Formal certification of WPV elimination has to wait until after three years without a case, hopefully in 2014. India must continue all interventions as if we have WPVs lurking somewhere silently. India remains vulnerable to WPV importation across our western borders. Pakistan, Afghanistan and Nigeria continued with WPV transmission even in January 2012. In recent years several previously polio-free countries (such as China, Tajikistan, Angola, Chad, Congo) got reinfected by importations from endemic countries, needing much money and effort to regain polio-free status. Oral polio vaccine (OPV) contains live attenuated ‘vaccine polio-viruses’ or ‘Sabin viruses’, which may themselves cause ‘vaccine-associated paralytic polio’ (VAPP) on rare occasions. India’s government counts VAPP as adverse reaction to OPV instead of as polio – a stand of dubious validity, particularly in ethics. For the child with polio, paralysis caused by WPV or Sabin virus is identical. Children with VAPP are our unsung heroes, themselves suffering for the benefit of all other children; no one seems to spare a thought for them. They deserve recognition and ample compensation. Sabin viruses also spread occasionally between children; in the process they regain virulence through mutations. Such ‘vaccine derived polioviruses’ (VDPVs) are wild-like, able to cause polio sporadically and widely circulate (circulating or cVDPV) causing outbreaks. India had 21 VDPV polio cases in 2009, five in 2010 and seven in 2011 – suggesting that VDPVs may already be silently circulating in some places. The war on polio will be won only after VAPP and VDPVs are also eliminated – in other words, after eradication of Sabin viruses. That phase is ‘endgame’ in eradication parlance, ‘phase 2’ in Indian literature. OPV must be discontinued to stop VAPP, but then VDPVs, circulating silently but kept under check by OPV, will spread and cause outbreaks: Catch 22. Eradication means no poliovirus – WPV or Sabin – infecting humans, for which IPV will have to replace OPV. Polio used to occur in all countries, poor and rich alike. Hygiene, sanitation and safe water did not control it. WPVs spread efficiently child to child. Vaccination was the only solution. In the 1950s Jonas Salk created the ‘inactivated poliovirus vaccine’ (IPV), followed by Albert Sabin’s live ‘oral polio vaccine’ (OPV). WPVs exist as three distinct types, numbered 1, 2 and 3; the vaccine matches all. For IPV, the three WPV types are inactivated and mixed. For OPV, the three Sabin viruses are supplied as liquid drops. Till recently, a mixture of the three types – ‘trivalent’ OPV (tOPV) – was used exclusively. Currently monovalent OPVs (mOPV-1, mOPV-3) and bivalent OPV containing types 1 and 3 (bOPV) are used to fit specific needs. All rich countries wiped out polio in the 1960s and 1970s through routine immunization using IPV or OPV. Low and middle income (LMI) countries were slow to protect children. In 1974 the World Health Organization (WHO) popularized the Expanded Programme on Immunization (EPI) against childhood vaccine preventable diseases including polio. In 1984, Rotary International, established in 1905, chose polio prevention in LMI countries as its centenary project, culminating in 2005. I was privileged to be in the planning group representing polio vaccinologists and Indian Rotarians. The Rotary ‘PolioPlus’ programme was to focus on polio, while supporting the EPI. The fund raising was a resounding success. Its domino effect included WPV elimination programmes in the Americas (successful in 1991) and the 1988 World Health Assembly (WHA) resolution for polio eradication globally by 2000. WHO launched the Global Polio Eradication Initiative (GPEI) with four partners – WHO, UNICEF, Rotary and the United States Centres for Disease Control and Prevention. In 1988, some 125 LMI countries had polio; India had the highest burden. Today, only three countries continue with uninterrupted transmission of WPV 1 and 3. India’s success is a shot in the arm for GPEI. Polio is a visible disease, but only the tip of the iceberg of the magnitude of silent infections. One case represents 200 type 1 or 1,000 type 3 infections. Countrywide surveillance is necessary to detect all cases of AFP and stool samples from every child have to be collected for virology tests. Every detected poliovirus must be tested with sophisticated molecular virology to distinguish Sabin viruses from WPVs. Since voting in the 1988 WHA resolution to eradicate polio, no progress was made by India till 1995, when the National Polio Surveillance Project (NPSP) was established by WHO. Laboratories with virological capability were upgraded and networked with training of personnel and quality assurance. NPSP medical officers were placed in districts where the state healthcare management was very weak. Nationwide surveillance for AFP was established linking nearly all public and private sector hospitals. Surveillance and stool collection was closely supervised by NPSP. An India Expert Advisory Group (IEAG) with international and national experts was created to monitor progress, identify weaknesses, recommend corrective actions and prescribe the number of pulse campaigns in geographic regions after titrating the need and capacity. This polio- specific vertical project was essential for polio eradication in India, since India’s EPI was inadequate for the war on polio. The EPI coverage of tOPV was low in many states, especially in Uttar Pradesh and Bihar. Even where EPI coverage was good, many got polio in spite of three doses of OPV. Starting in 1996, nationwide pulse campaigns were organized, twice every year to begin with, aiming for 10 additional doses for every under-five child. This tactic succeeded partially by 1999, eliminating WPV 2 nationally and WPVs 1 and 3 also in all states except Uttar Pradesh and Bihar. India missed the 2000 time target of eradication – the only country in the South East Asia group that failed. Two problems bugged Uttar Pradesh and Bihar. First: extremely poor effectiveness of OPV – ‘failure of vaccine’ in other words. Children got polio in spite of seven or 10 or even 15 doses of tOPV. The high density of child population enhanced WPV transmission, while tOPV was no match against it. In 2005 mOPV-1 was licensed after Indian research showed three times higher efficacy against WPV 1. The number of pulse campaigns was increased to 10 each year. These measures effectively countered the failure of the vaccine factor. A second but less formidable problem was inadequate coverage of under-five children with OPV doses both under routine EPI schedule and in pulse campaigns – ‘failure to vaccinate’. Millions of migrant families are often out of home during pulse vaccination campaigns. After diagnosing this problem, children were vaccinated in trains, buses, brick kilns and sugarcane farms. The magnitude of work done by NPSP was colossal – especially for AFP surveillance. In the last 13 months alone stool samples from over 61,000 children with AFP were tested. From 97 per cent at least one stool sample, and from 84 per cent two samples – totalling over 110,000 samples – were collected within two weeks of the onset of paralysis. In nearly 15,000 children (>20%) a non-polio virus was detected, proving the quality of stool testing; globally, 10 per cent virus detection rate is accepted as satisfactory. In over 2,400 children vaccine polioviruses were detected, which is quite normal in recently vaccinated children. Disturbingly, there were seven children in whom VDPV were detected. Apart from the one WPV type 1 from a child in Howrah in West Bengal, with onset of paralysis on 13 January 2011, all other stool samples proved negative for WPVs type 1 or 3. No country has done as much, qualitatively or quantitatively, as India during the past decade. The vaccination drive in Howrah that followed was of unprecedented intensity. Sewage samples from selected spots in Mumbai and Delhi have been tested for WPVs over the years – and repeatedly tested positive as long as viruses circulated in Uttar Pradesh or Bihar. Migrants who travel in hordes in search of work carry wild polio- viruses in silent infection among children and possibly even adolescents and adults. The detection rate in sewage dwindled steadily in 2010 in parallel with the dramatic decline of cases in Uttar Pradesh and Bihar. There were anxious weeks when WPV type 1 was found in Delhi sewage in July 2010, while preparing for the Commonwealth Games. Intensive vaccination campaigns were organized and there was no more WPV. It was this Delhi lineage of virus that showed up in Howrah five months later. Wild poliovirus type 1 is indeed a tricky enemy, moving surreptitiously in communities. The good news is that all through 2011 children in Uttar Pradesh and Bihar as well as sewage in Mumbai and Delhi remained without any WPV. In 2000 and 2001 there were 265 and 268 cases due to WPV 1 and 3. Then the government unilaterally declared 2005 as the target year in its National Health Policy. Yet, 2002 saw an outbreak with 1,600 cases, mostly of type 1 and largely in Uttar Pradesh and Bihar. Numbers again played hide and seek, with 225, 134 and 66 respectively in 2003, 2004 and 2005 – and viruses strayed into other states, as far as Kerala and Tamil Nadu. There was another outbreak in 2006, with 648 cases of type 1 and 28 of type 3, again most cases occurring in Uttar Pradesh and Bihar. The government’s optimism was shaken, but not IEAG’s. IEAG guided research that confirmed the high efficacy of mOPV-1 and NPSP continued with multiple campaigns using mOPV-1. WPV type 1 came under control, but immunity gaps remained for type 3, since routine immunization was not reaching a majority of infants and vaccination campaigns used mOPV-1. That led to type 3 outbreaks in 2007-08 in Bihar and in 2008-09 in Uttar Pradesh, adding up to totals of 874 cases in 2007, 559 in 2008 and 741 in 2009. In 2009 bOPV was licensed and put to use – after finding its efficacy non-inferior to that of mOPV-1 and mOPV-3. While IEAG remained steadfast to the goal and plan, and understood the epidemiology of these outbreaks, serious fault lines appeared between the government and IEAG. Obviously in high quarters in the government despondency was leading to despair and loss of hope. In December 2009, top officers of two departments under the Ministry of Health and Family Welfare co-chaired a special meeting of EPI officers and exclusively Indian experts. The government’s second thoughts on polio eradication were announced to a shocked audience. The eradication goal was described as not an Indian agenda but that of international agencies. The project was consuming huge amounts of funds for OPV campaigns in Uttar Pradesh and Bihar. The government wanted to accept the level of polio control achieved so far, and discontinue the pulse polio vaccination campaigns. While a few experts endorsed the government’s choice, it was strongly opposed by the IEAG chairman, who emphasized eradication was an international commitment made by India. The government then replaced the chairman in the hope that the truncated IEAG might be forced to toe its line. But that very step forewarned everyone and the next IEAG meeting rejected the government’s line of thinking. Then, as luck would have it, but clearly due to carefully crafted tactics of IEAG and its implementation in totality by NPSP, state health leaderships and grassroots workers, the number of cases dropped drastically to an all-time low of 42 in 2010. Uttar Pradesh became polio-free by April and Bihar by September 2010. Had success not blessed us so fast, I shudder to imagine what earthquakes these fault lines would have led to. Rich tributes are due to all the workers, families who allowed children to be repeatedly vaccinated, NPSP, IEAG, the GPEI partnership and to the Government of India for unstinting budget support. While rich countries preferred IPV for its safety, WHO and GPEI chose OPV for its low cost and ease of administration by mouth. Since 1984, a second generation IPV of enhanced potency had replaced the original 1954 vintage Salk vaccine. IPV is highly effective against polio in both rich and LMI countries. Indeed, globally, no child has developed polio after receiving three doses of the modern IPV. But OPV shows differential effectiveness. In many LMI countries, children were not protected with the usual three doses, a problem repeatedly raised in India since 1972. Additional doses were needed to induce immune response, but that would take time. Delay in protection meant that WPVs infected children before they became immune. The speed of protection by OPV had to surpass the speed of WPV spread – not possible in Uttar Pradesh/Bihar while depending exclusively on tOPV. The tide was turned when mOPVs and bOPV were used in pulse campaigns. One wonders if we could have achieved eradication faster and cheaper had we used IPV in EPI and strengthened EPI for sufficient coverage. If necessary, OPV could have been reserved for pulse campaigns for the final push against WPVs. Both IPV and OPV were American gifts to the world. So also was the IPV-OPV controversy, which spilled over into WHO. Though the two vaccines have different qualities, on safety IPV scored better. Many rich countries used it exclusively, and others switched to IPV in the 1980s and 1990s. None of those countries had outbreaks due to importation of WPVs from endemic countries. Nor have they faced VDPV problems. Therefore, completion and conclusion of polio eradication avoiding the risks of VDPVs seems inevitably to require switching to IPV – in India as well as in all OPV-using countries. Indeed, much research and planning had been done in India on IPV but not to fruition. In 1977, Jonas Salk came to India to receive the Jawaharlal Nehru Award and met Prime Minister Indira Gandhi and discussed polio vaccines. In 1982, the WHO Bulletin announced the safety problems of OPV and advised countries using OPV to carefully monitor the number of VAPP. In 1983, Jonas Salk visited India again to advise the prime minister on the advantages of using IPV. He visited the Serum Institute of India in Pune, which began IPV production in 1985 under the Maharashtra drug license. In 1986, Pune released the ideal combination vaccine – the Diphtheria-Pertussis-Tetanus vaccine (DPT) with IPV. The Government of India stepped in and stopped production of IPV. Indira Gandhi was assassinated in October 1984; had she been alive in 1986, India would have been routinely using the combination vaccine. In 1986, Salk mentioned to India’s San Francisco Consul General, Kishan S. Rana, that he had declined to visit India again for meetings of the jury of the Indira Gandhi Award in protest of the negative attitude of the government regarding IPV and the consequent heavy burden of polio due to low OPV efficacy and VAPP. Prime Minister Rajiv Gandhi established a Technology Mission, headed by Sam Pitroda. The mission made its own assessment, in 1988, independent of the prevailing Ministry of Health policy of the exclusive use of OPV. It determined that India must have ready access to IPV in order to gain experience with it and to evaluate the pros and cons of both vaccines. It was decided to construct a vaccine manufacturing facility in Gurgaon, with technical and financial assistance from the French industry and government. Since the Ministry of Health opposed the idea, the public sector Indian Vaccine Company Ltd (IVCOL) was put under the Ministry of Chemicals and Petroleum, supported by the Department of Biotechnology. Land was purchased, buildings constructed, equipment bought and staff trained in France. Rajiv Gandhi was assassinated in May 1991 and within a year IVCOL was closed. Had he been alive we would have been using IPV on a large scale, but that was not to be. The trump card was licensure of IPV. The National Regulatory Agency for drugs and vaccines was controlled by the Ministry of Health and it declined to license IPV, except for purposes of investigation. All Indian investigations showed the remarkable effectiveness of IPV. As all rich countries had abandoned OPV and as the endgame loomed large on the horizon, IPV was licensed in India in 2006. By then all damage had been done. IPV is the vaccine of the future, but WHO has a new policy – no developing country, including India, will be allowed to manufacture IPV. The raw material is WPVs, maintained in laboratories and grown in biological systems. In a world with no human transmission of WPVs, there is a risk of leakage with unthinkable consequences. WHO is right, but we could have been exporting IPV today had Rajiv Gandhi lived longer. Today WHO prefers IPV made from Sabin viruses, the ultimate vindication of the stand taken by Jonas Salk. We hope that the rest of the world will become free of WPVs one day soon. After that, using OPV will be banned as unethical, as any polio will be exclusively vaccine-caused. Today global numbers of VAPP could be as many as 500-800 cases annually. VAPP will stop once OPV stops. But the greater risk, putting polio eradication itself in jeopardy, is from VDPVs. The day OPV is stopped some silent spread of VDPVs would still be going on, somewhere, possibly several places, only to flourish if children are not immunized. VDPVs show up as polio cases after one to three years of silent transmission. The day OPV is stopped many children will be shedding Sabin viruses and they will continue to do so for many more weeks. At the same time, every baby born from then on would be completely non-immune to polio viruses. The juxtaposition of these two groups may act as donor and recipient leading to the evolution of fresh lineages of VDPV, to show up one to three years later. By then all under-three children would be non-immune and the magnitude of consequent polio outbreaks could be unimaginably large. We may return to square one, with cVDPVs capturing the niche left vacant by eradicating WPVs. We must pre-empt the development of VDPVs and be ready to intercept if they are detected. The only tool we will have is IPV, and we must have it in plenty. Let India not be caught unprepared yet again. Learn from history to avoid repetition.
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