India seems to have arrived at the threshold of polio eradication, but should it lower its guard?
ON January 13, India achieved what had only two years ago seemed impossible in the immediate term. The country, which, given the epidemiological data in the new millennium, had come to be regarded by health experts around the world as one that would be the last to achieve freedom from polio (poliomyelitis), recorded no case of polio caused by the wild polio virus (WPV) over a period of one year beginning January 13, 2011. In 2009, the figure was 741 and then one saw a sharp decline to 42 in 2010. Even then no one expected this to happen because one has seen such low figures in the past, which proved to be illusory in the end. This happened in 2002 and then again in 2006 ( Frontline, January 2, 2004, and May 19, 2006).
India was named priority No. 1 country in the Global Polio Eradication Initiative (GPEI) of the World Health Organisation (WHO), which in 1988 set the target year for eradication as 2000. This was later pushed to 2005, but with India, Pakistan, Afghanistan and Nigeria witnessing continued transmission beyond 2005, such targets began to lose their meaning. The remarkable turnaround in India this time seems for real. The indicators: Uttar Pradesh and Bihar, the two holdout States that have been frustrating the national programme aimed at polio eradication all along with persistent transmission of the virus, have reported no cases of polio since April 2010 and September 2010 respectively. The last case of January 2011 was actually detected in a two-year-old girl in Howrah in West Bengal, where the transmission got reintroduced through the import of a strain that was traced to Bihar. The last positive detection of the WPV in the monthly sewage sampling conducted in Delhi, Mumbai and Patna, which is indicative of such importation through migrant and mobile communities, was in November 2010. The final assault could, therefore, be mounted around this solitary case in West Bengal before transmission could entrench itself in this hitherto zero-transmission region of the country.
The basic strategy that enabled us to achieve this is essentially fourfold, said Ajay Khera, Deputy Commissioner, Child Health and Immunisation, at the Ministry of Health and Family Welfare (MoH&FW). The first is the intensity, timing and high quality of [vaccine] coverage. The number of missed children in 2011 would be less than 2 per cent, he added. The second was the rapid response to any positive case recorded anywhere. When this particular case of transmission in West Bengal was detected on January 13, by February 7 the laboratory report, complete with the virological profile of the virus, was with us so that appropriate intensive emergency mop-up campaign [which includes a minimum of three large-scale, high-quality, house-to-house immunisation rounds covering over two million children around the particular case, with the first starting within two weeks of notification and the others occurring no more than two/four weeks apart] could be quickly mounted by mid-February, he said.
Besides the annual routine immunisation, in 2011 there were more intense pulse polio rounds or Supplementary Immunisation Activities (SIAs) in the form of two National Immunisation Days (NIDs) and seven smaller sub-National Immunisation Days (SNIDs) focussing on areas that had the highest risk of transmission and the most vulnerable populations, such as newborns (over 500,000 babies are born in Uttar Pradesh and Bihar each month) and migrants. While routine immunisation required 170 million doses of Oral Polio Vaccine (OPV), the NIDs required about 230 m doses per round and the SNIDs required 50-100 m doses each, according to Khera. In all, the total number of OPV doses administered in 2011 was over one billion (Figures 1 and 2).
The OPV is a vaccine containing the attenuated (and not killed) virus. There are three types of the virus, with Type 1 (WPV1) being the predominant causative agent. Traditionally, the OPV in use in immunisation programmes was the trivalent OPV (tOPV), carrying a cocktail of the three types. WPV2 was eradicated globally way back in 1999; the last WPV2 case was reported in October 1999 in Aligarh. The outbreaks in India in 2002 (1,600 cases, up from 265 and 268 in 2000 and 2001 respectively) and 2006 (676 cases, up from 225, 134 and 66 in 2003, 2004 and 2005 respectively) were mostly of WPV1. So, taking a cue from the eradication of WPV2, WPV1 was targeted with a monovalent Type 1 vaccine (mOPV-1), which is three times as efficacious as tOPV. In the latter, there is a competition among the three types to elicit immune response while inhabiting the gut in the host. The last case of WPV1 in Uttar Pradesh was reported in November 2009. While high-risk districts of central Bihar had been free of WPV1 since October 2009, it had only three cases of WPV1 in Champaran East on the border with Nepal (Figure 3) in 2010.
However, while this strategy brought down the incidence of WPV1, it led to gaps in immunity against WPV3 and resulted in WPV3 outbreaks in both Bihar and Uttar Pradesh in 2007-2009. So, since January 2010, while bivalent OPV (bOPV) carrying Types 1 & 3 has been used for pulse polio campaigns in the endemic States of Uttar Pradesh and Bihar, reinfected States such as West Bengal and Jharkhand (owing to importation) and the high-risk areas of Delhi and Mumbai, tOPV was used for routine immunisation across the country. In 2010, there were 24 cases of WPV3 in Bihar and Uttar Pradesh, but in 2011 there was none. The last polio cases in U.P. and Bihar (in April and September 2010 respectively) were both of WPV3.
Another strategy adopted since 2010 was the 107 Block Plan targeting the highest risk areas in western Uttar Pradesh (66) and Bihar (41) with persistent transmission, which is an integrated approach that aims at ensuring high-quality polio vaccination campaigns to reach even the most vulnerable groups consistently in every round, and also includes routine immunisation and prevention and control of diarrhoea through sanitation, availability of clean water and hygiene practices.
The Indian Expert Advisory Group (IEAG) for Polio Eradication noted in its November 2010 meeting: [T]he 107 Block Plan, which although not yet uniformly implemented in all its elements, shows improvements in some routine immunisation indicators in some of these blocks. Evidence from seroprevalence surveys in western U.P. and central Bihar shows that even in very young children of 6-7 months of age an extremely high proportion has immunity against Type 1, and there is evidence of that immunity against Type 3 has risen significantly. The introduction of bOPV appears to have maintained the high levels of immunity against Type 1 achieved in 2009, while increasing immunity to Type 2 (emphasis added).
With the decline of endemic circulation of WPV, the IEAG noted, the relative importance of circulation in migrant and mobile communities has risen significantly. In some endemic States, including Delhi, Maharashtra, West Bengal and Punjab, there is a strong possibility that concentrations of migrant and mobile populations are creating a mixing bowl' effect, allowing the movement of virus from one mobile group to another. Evidence for this includes not only WPV cases but also WPV [1 & 3] in sewage samples in Delhi related to recent circulation in Bihar, West Bengal and Jharkhand. Noting that the situation in 2010 was significantly different from the same period in 2007, 2008 or 2009, the IEAG said, The very low levels of transmission of both WPV1 and WPV3, the evidence of very high immunity to WPV1 and rising immunity to WPV3 in the highest risk areas, the intensification of efforts to reach the underserved, mobile and migrant groups, all indicate that India is in the final phase of polio eradication.
The fact that the country has had no recorded case in the last 12 months suggests that this final push was effectively and successfully implemented. For instance, according to Khera, following the call by the IEAG, the 107 Block Plan was fully implemented in 2011. To reach people on the move, mobile vaccination teams were deployed to immunise children at railway stations, on running trains, at bus stands, market places, brick kilns, construction sites, and so on. Around five million children were vaccinated by transit ad mobile teams during every round in Uttar Pradesh, Bihar, West Bengal and Maharashtra. The non-detection of WPV from sewage samples in 2011 indicates that targeting migrant and mobile populations too has been successful.
But despite all the immunisation strategies, even in the middle of 2011 it was not at all obvious, even to the experts, that the 12-month period would pass without a case. With no additional case after the Howrah case (of WPV1) in January and no WPV in environmental samples, the IEAG in its July meeting cautioned: [T]he impressive reduction in transmission has occurred during low transmission season. Only continuation of this trend through the high transmission season will bring confidence that WPV transmission may truly be interrupted. Analysis of previous very low transmission years (2005, 2008) shows that despite very restricted low transmission, there was considerable WPV1 activity in the subsequent high transmission seasons of 2005 and 2008. Low transmission season epidemiology is not necessarily predictive of high transmission season epidemiology.
But, more pertinently, the IEAG noted that there were several instances of detection of orphan viruses viruses with significant genetic differences from their nearest known relatives during 2008-10, which indicated long periods (more than 12 months) of undetected transmission. Therefore, the IEAG said, the absence of cases in the period February to May does not definitively mean that transmission has stopped the programme should put in place a plan of action to manage one or more cases during the peak period of risk from June to November. The progress towards interrupting poliovirus transmission is real. The opportunity to eradicate polio from India has never been better (emphasis original). Clearly, the National Polio Surveillance Project (NPSP) for polio eradication of the Health Ministry, which is carried out in association with the WHO and the United Nations Children's Fund (UNICEF), seized the opportunity and succeeded in achieving zero transmission up to January 2012.
India's success is arguably the greatest public health achievement and has provided a global opportunity to push for the end of polio. Stopping polio in India required creativity, perseverance and professionalism. The lessons from India must now be adapted and implemented through emergency actions to finish polio everywhere, said WHO Director-General Margaret Chan.
India's achievement, remarked Anthony Lake, UNICEF Executive Director, is proof positive that we can eradicate polio even in the most challenging environments of high poverty, high population density and poor sanitation and infrastructure, conditions in which diseases like polio can thrive.
If all testing for WPV through January, including laboratory analysis of all acute flaccid paralysis (AFP) the predominant manifestation of polio but which could also arise because of other infections and causes and environmental sampling, returns negative, India will officially be deemed to have stopped indigenous WPV transmission and will be removed from the WHO's list of polio-endemic countries by mid-February. That would leave only Pakistan, Afghanistan and Nigeria. But India will be certified polio-free by the WHO only if the following three conditions are met:There must be three years of zero WPV cases.
Disease surveillance efforts must meet international standards.
The country must illustrate the capacity to detect, report and respond to polio cases caused by importation of the virus from overseas.
The endgame is now clearly upon the national polio eradication programme. The crucial issue now is what measures and strategies India must put in place for sustaining zero transmission. The key challenge is to ensure that any residual or imported WPV is rapidly detected and eliminated. This requires very high levels of vigil, surveillance and emergency preparedness and response.
Identifying the risks involved in the completion of the polio eradication drive in India, the IEAG said in its July 2011 report that although immunity levels in the historic reservoir areas of western Uttar Pradesh and central Bihar remained high, it would be dangerous to consider them as anything other than extremely high risk and turn complacent. It pointed to the detection of an orphan virus in 2009, which subsequently circulated throughout the high season, and to the sustained outbreak for over 18 months following the reintroduction of WPV1 in 2008.
Echoing the draft resolution for global eradication that the WHO made in November 2010, the IEAG said any WPV detected, regardless of source, anywhere in the country should be considered a public health emergency and responded to by multiple high-quality mop-up campaigns. In this context, commending the speed and scale of response to the 2011 WPV1 case reported from Howrah, the IEAG said that it should be used as a model for any future detection of the WPV, and the lessons learned from this experience should guide future emergency preparedness and response plans. Citing the instances of WPV outbreaks in Maharashtra and West Bengal in 2010, it said that undetected circulation in migrant, mobile and undeserved communities posed a double risk from both virus persistence and further virus spread. Most transmission of WPV in 2010, it noted, was the result of movement of virus from an infected area to polio-free areas, and genetic record had several examples of long chain of virus transmission appearing in migrant or underserved communities in high-risk areas.
Orphan virus isolates, as pointed out earlier, are indicators of surveillance gaps. The districts detecting these multiple times, as happened during 2008-10, the IEAG noted, represented areas that missed transmission. Many of the districts with orphan isolates, it said, were destinations for populations supporting transmission that were missed by other districts or States. Stating that both instances represented high risk, it called for highly sensitive surveillance in such areas and populations. In addition to all the above, there is always the risk of international importation of the WPV. There have been several instances of WPV exportations from India to other polio-free areas, the most recent being the WPV1 outbreak in Tajikistan. In 2011, China had a WPV outbreak due to importation from some polio-infected country. Similar risks exist for India. The WPV could get reintroduced through people carrying the WPV outside India returning to the country or new movements of people from another polio-infected country into India.
Another important issue with regard to future immunisation strategies concerns the choice of polio vaccine. In India there has been a long-standing debate among medical scientists and policymakers on the choice of appropriate vaccine for the eradication of the disease. Besides the live-attenuated OPV discovered by Albert Sabin in 1960, there is the inactivated (killed) polio vaccine (IPV), an injectable vaccine, discovered by Jonas Salk in the 1950s. For mass vaccination, OPV is the preferred vaccine in India, as it has been in most countries in the pre-eradication phases of their polio programmes. This is the vaccine recommended by the WHO as well.
There are pros and cons for both the vaccines. From the perspective of a developing country like India, the main factors have been the cost and mode of delivery. OPV is much cheaper than IPV. With about 25 million babies born every year, this consideration becomes very important in mass immunisation programmes. Delivery of OPV, which is administered as drops, is easy and safe as against IPV, which can lead to various other infections because of unsafe injection practices. Over one-third of injections given in India are unsafe, according to the Health Ministry. Another factor in favour of OPV is the mucosal immunity that it is believed to confer. That is, mucosal surfaces like the gastrointestinal tract and pharynx develop immunity against infection when exposed to WPV. IPV does not confer mucosal immunity.
The flip side to the replication of the live oral vaccine virus in the gut is what is known as vaccine associated paralytic poliomyelitis (VAPP). It is a rare adverse event of OPV caused by the reversion of its neurovirulence resulting in AFP to vaccinated children. The transmissibility of such reverted vaccine virus when shed is extremely low and its infectivity dies out quickly, particularly if there is environmental pressure of high OPV coverage. So it is not of any serious public health concern. The rationale of using OPV is that this is an acceptable risk when weighed against its obvious advantages.
However, those in favour of IPV would find even a low-risk burden ethically unacceptable, especially when there is a safer vaccine available that does not lead to VAPP. Practically all developed countries switched to IPV because of the unacceptable burden of VAPP incidence once low transmission was achieved. According to scientists, the WHO has underestimated OPV's negative aspects and overestimated its positive aspects. Critics of the Indian polio eradication programme have always maintained that the number of VAPP cases in India constituted an unacceptably high burden, morally and ethically, and have argued for years for a switch-over to IPV in a phased manner in the Indian programme.
Repeated passages of the vaccine virus can also result in mutations of the vaccine virus and make it neurovirulent. This is called Vaccine-Derived Polio Virus (VDPV). But, besides its neurovirulence, the shed mutated vaccine virus can also acquire efficient transmissibility. When this happens then it is virtually wild-like and is called circulating VDPV, or cVDPV. But under high OPV coverage and with circulating WPV, the circulation and transmissibility of the mutated VDPV gets rapidly interrupted. However, there have been four instances globally where cVDPV has caused small or large polio outbreaks, but none so far in India.
While these facts indicate the inherent risk of OPV, as long as immunity levels in the population are maintained at high levels through high coverage, the risk of infection by VDPV will remain low. However, if the coverage drops, VDPV transmission can increase and acquire circulation in the environment. In India, since the coverage with OPV has been very high especially in recent years, no cVDPV strain has so far been seen. But once there is zero transmission of WPV and eradication appears imminent, as Jacob John, the eminent virologist from Vellore, says, We cannot afford to drop guard at this juncture and allow cVDPV to grow.
In the post-polio resurgence phase, the AFP and laboratory surveillance system under the NPSP has begun to function at high levels of sensitivity and speed. Since 2000, the classification of AFP cases which include AFP due to any cause in a child under 15 years of age or any case of paralytic illness in a person of any age when polio is suspected have been on virological examinations of stool specimens (which contain the virus shed by infected people) of AFP cases rather than on clinical basis. An Expert Review Committee (ERC) provides the necessary advice on the final classification of AFP cases from which adequate stool specimens could not be obtained, resulting in a lack of virological evidence, to classify a case as polio or polio-compatible or a case of VDPV or non-polio AFP. Given the increased sensitivity of surveillance, the AFP rates have been very high in recent years. In particular, the non-polio AFP rates have been high. While the target for non-AFP cases is set at >1/100,000, the rates achieved have been over 12 in the last couple of years. A rate less than 1/100,000 implies that the surveillance is missing cases of AFP.
But critics of the national polio programme and the NPSP have always held that the AFP data do not give the real picture. It can hide a lot of true polio cases because of ineffective follow-up of the AFP cases to identify cases of residual paralysis (RP) after a 60-day period. Moreover, complete surveillance data, including RP cases, are not made public. These cases, critics argue, discarded as non-polio, carry twice the risks associated with WPV or VAPP cases.
Data for 2005 obtained through the Right to Information Act in 2007 showed that of 10,879 cases of AFP, only 2,043 were followed up and of these 989 had RP and there were 244 deaths. With a much higher number of AFP cases now, because of increased sensitivity of AFP identification and WPV detection, RP numbers could be much higher unless follow-up strategy has also correspondingly increased in its effectiveness.
However, data made public now are much more than what they used to be some years ago and include Intra-Typic Differentiation (ITD) information from genetic analysis of the isolated virus in the AFP cases. In 2011, of the total 60,466 AFP cases identified, besides one confirmed WPV1 of Howrah, there were 43 polio-compatible cases, seven VDPV cases (six Type 2 and one Type 3) and 3,163 vaccine virus cases (978 of Type 1, 452 of Type 2, 1,035 of Type 3, and 698 of mixed type). The last figure would be the number of VAPP cases, which is about 5 per cent. Proponents of IPV would consider this ethically untenable.Polio-compatible cases
According to Jacob John, who has been IEAG Chair earlier, the number of polio-compatible cases has consistently come down over the years. Last year it was 190. This, according to him, is an indication that the number of true polio cases hidden in these figures would also have correspondingly come down. The VDPV cases are all isolated and, given the absence of any cluster of cases, they are not in circulation. But there is an interesting fact about these VDPV cases.
The areas in which these six cases of this mutant Type 2 virus have been found include those where Type 2 OPV was stopped in 2005 itself. WPV2 is an effective infection agent and it is less weakened in the vaccine. So the mutant can cause child-to-child transmission over a period, which may have manifested only now, says Jacob John as a plausible explanation. Now that India has probably achieved true zero-transmission status, how and when the transition to IPV should be made is the question . We now need to brainstorm on the issue of IPV and we have to also consider global guidance, particularly from the WHO, based on the experience of other countries, says Khera. We will soon have a discussion of experts on what the endgame strategy should be, he adds.
Jacob John has always advocated concurrent use of OPV and IPV and a phased withdrawal of OPV. In fact, he believes that if the country had prepared itself for IPV in terms of production capacity and necessary infrastructure and had also evolved a strategy for its introduction in a planned manner 10 years ago, polio would have been eradicated. It has been a choice between public health ethics and individual health ethics all along. This argument can no longer hold in the present context, he says.
The mandate of the IEAG has been only to devise the endgame strategy and so it has never discussed the IPV issue, points out Jacob John. It is supposed to be the domain of the National Technical Advisory Group on Immunisation (NTAGI). But when the issue was referred to the NTAGI, it said it was the job of IEAG and its task only related to Universal Immunisation Programme (UIP). In 2006 it was decided that NTAGI would request the IEAG to discuss the issue and give its recommendations, but this request never came. It is time the IEAG and the NTAGI sat together and evolved a strategy. It may be already too late, he adds.
As a fallout of the bid by the IEAG to raise the IPV issue, IPV was licensed to the private sector, and some companies had begun to undertake trials. Also, the French company Aventis-Pasteur, which has taken over the Indian company Shantha Biotech and has the IPV technology, could begin its manufacture in India. But given the proprietary nature of the technology and the cost of the seed for Indian private players, IPV will be costly. The failure of the government to pursue and get the French government to honour the Indo-French Agreement under which the IPV technology was to be transferred to the Indian public sector company that had been formed for the purpose ( even a manufacturing unit had been set up in Gurgaon) is likely to impact our endgame strategy quite severely.
In recent years Jacob John had been advocating R&D on what he calls Salkified Sabin Vaccine' in the country and technology to produce a Sabin virus-based IPV by inactivating the OPV virus like the Japanese and Chinese have done in recent years. But with no concerted thinking on this issue all these years, in the words of Jacob John, as the endgame nears, we are without a war room and a war general to take decisions.