Polio eradication in India: The way forward
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《美国医学杂志》
1 Department of Pediatrics, Max Hospital, Pitampura, India
2 Postgraduate Institute of Medical Education and Research, Chandigarh, India
Despite remarkable decline in the number of poliomyelitis cases, the dream of polio eradication in India remains elusive. This is despite considerable effort and expenditure for well over a decade. Various reasons have been cited for this and interventions implemented accordingly. None of these seem to have borne fruit. It is appropriate to have a relook at the polio eradication strategies in order to learn from past errors and determine a feasible solution to achieve the goal. This article examines important tissues that hamper the eradication effort and proposes a way forward.
Keywords: Poliomyelitis; Eradication; IPV; OPV
For the past several years, there have been expectations that India and therefore, the South Asian region and by extension the world itself stands very near to the stage of eradicating poliomyelitis. Against this mood of chest thumping and backslapping, dissenting views on important challenges that hamper this goal and make the achievement unlikely, have been ignored altogether. However, the situation today is not as rosy as one is led to believe. In fact, the authors are witnessing a replay of the events of 1999 and 2002. The year 2006 is again recording a "resurgence" of polio in India - 280 cases having been reported by mid-September,[1] most of them from chronically endemic areas of Moradabad district and adjoining areas of Uttar Pradesh. Meanwhile cases continue to occur in a sporadic manner in other states of India as they get exported from the endemic area. As of date there are eight states from where cases have been reported.
It is not as if efforts towards eradication have been deficient. In fact, since the year 2000 when the first target date for a polio free world was missed, an ever intensifying polio eradication drive has been carried out in India with a very large number of National and Sub-national Immunization Days (NIDs and SNIDs) and house to house campaigns. Lately pulse polio rounds have been carried out in the endemic areas almost every month and under-5 children have received more then 20-25 doses in these areas. Since April 2005, 6-8 rounds of SNIDs have been carried out with a monovalent vaccine (mOPV1) in the hope of rapidly achieving the goal of zero polio, but even this has been to no avail. A sense of panic nay despair has set in among policy planners and health ministry officials. Less and less people believe in the possibility of achieving the goal of zero polio. There are plans afoot to introduce Injectable Polio Vaccine (IPV) in the endemic areas, which may meet even greater community (communal) resistance than '2 drops' of oral polio vaccine.
It is apparent to all concerned that we are presently at a critical stage of polio eradication and a thorough reappraisal of the situation is called for, before bringing out any more policy changes on the ground. The present communication attempts to look at the Polio eradication drive in India in its entirety and suggests a possible way out of the present "messy situation"
What Has Been Achieved
Since the inception of the polio eradication (PE) initiative in India, there has been a dramatic decline in the number of paralytic poliomyelitis cases from an estimated 35,000 cases annually in 1994-1995, to less than 200 cases each year (barring the epidemic of 2002 and the current resurgence). P2 strain has been eradicated and P3 strain also appears to be on its last legs with just 5 cases reported so far in 2006. Even for P1, only 2 genotypes continue to circulate as compared to as many as 8 in 2004.[2] This encouraging trend is attributed to excellent Supplementary Immunization Activities (SIA); the quality (over 90% coverage) and quantity (22 NIDs and another 22 SNIDs, besides countless region specific rounds) which are at present apparently better than ever before. Another great gain of the polio eradication drive is that India now has an excellent surveillance system in place that can quickly detect areas of transmission of the wild virus. Surveillance quality reportedly far exceeds international standards for the same.[3]
Despite these tremendous gains, the goal of zero polio status appears to be as elusive as in 2000 and India continues to be a major problem area for the global polio eradication programme. It may be pointed out that very little progress has been made since the year 2000 (when the Intensified pulse polio campaign was launched) in the total number of wild polio virus (WPV) cases in the country.
What has gone wrong
It is worth mentioning that the strategy of strengthening routine polio immunization supplemented with 2 rounds of pulse polio has succeeded in eradicating poliomyelitis from most countries of the world. Naturally one is interested to know why it has not succeeded in India. Various reasons have been put forward for this apparent failure or delay in achieving zero polio status in some areas of UP and Bihar. These include.[4],[5] (1) Very low routine immunization, (2) High prevalence of non polio entero-viruses and abysmally poor environmental sanitation making OPV less effective thereby requiring at least 10 doses of OPV in these areas to achieve sero-positivity in 97% of individuals, (3) Resistance among Muslim Community (4) Lack of political and administrative will and (5) Pockets of un-immunized children allowing continued circulation of WPV. To this the authors may add increasing apathy and dishonesty among health workers who are being asked to reach every child every month, amidst increasing community resistance. It is obvious that one cannot win a race riding an unwilling /unmotivated horse. Also the rather heartless and ad hoc manner (every case of polio is met with a SIA), without any long-term perspective with which the PE is being carried out may also be responsible for the current situation.
Adhocism in planning
The National Poliomyelitis Surveillance Project (NPSP) is currently the only body co-ordinating all strategies pertaining to polio eradication and their implementation in India. It not only plans and implements the strategies (right from detecting cases to SIA) but also evaluates and monitors the success or otherwise of the programme. Thus it serves as policeman, jury and judge. An India Expert Advisory Group (IEAG) has been constituted which meets every 4-6 months. At this meeting an overview of the current situation is presented (by NPSP), discussed and action to be taken during next 6 months is decided. A few weeks prior to the IEAG meetings the Adhoc Advisory Group of Polio Eradication (AAPGE) of WHO meets and actually decides about the plan of action for next 6 months which is then simply adopted by the IEAG as its 'own' decision. The WHO group takes a global view and suggests country specific action. But the IEAG hardly ever takes a countrywide view and merely dittoes the concerns and actions outlined by the AAGPE. The decisions are always taken for "next 4-6 months" and there has never been any long-term India-specific plan.[6],[7]
As the Polio eradication group of WHO is still pursuing the ever elusive goal of zero polio, the whole emphasis of the IEAG and NPSP is also towards combating continuing WPV circulation in the problem districts rather then taking a holistic view of the problem in the country, keeping the interest of polio free states as well as other health priorities of the country in mind.
Introduction of mOPV1 in the SNIDs
The manner of introduction of mOPV1 in the polio eradication program will serve to demonstrate the decision making process in the country. In September 2004, the AACPE (WHO) met in Geneva and recommended that mOPV1 be licensed, manufactured and used in the SNIDs in India.[8] IEAG group in its 12th meeting held in New Delhi in December 2004 endorsed the view.[9] Panacea Biotech, a pre-qualified United Nations manufacturer of polio vaccine, but till then only a bottler and distributor of OPV, was licensed to produce mOPV1 from stocks provided from various sources.[10] The company established Vero cell/monkey kidney cell culture for culturing and processing of mOPV1, and the vaccine so produced was tested for stability and licensed to be used in the national programme of India and other developing countries in March 2005, under the accelerated programme (italics authors). The whole process was accomplished in 3 months[11], a remarkable feat considering that WHO normally take a minimum of 3 years of good manufacturing practices (GMP) before licensing a vaccine.
To add insult to the injury, a phase IV clinical trial was built into the introduction of mOPV1 in the national PE programme in India. " Special permission of GOI and drug controller of India was taken (and given!) to introduce this vaccine ( as phase IV clinical trial) without parental consent". Also no special monitoring system was incorporated into the trial to assess its safety and efficacy with large volume use in Indian conditions. While the results (if any) of the trial are still awaited, the vaccine has failed to show any impact on the circulation of WPV. On the other hand, careful analysis of AFP surveillance data shows an abnormal increase in the number of P1 vaccine virus in non Polio AFP cases in the year 2005 and 2006, while the number of stool samples showing pure growth of P2 and P3 vaccine viruses have remained almost static over the years [Table - 1]. It is noteworthy that P1 virus cases among non-polio AFP have remained constant in all other countries of the WHO South East Asia Region [Table - 2].[12]
Heartless AFP Surveillance
The story of AFP surveillance is another poignant aspect of heartless and unscientific manner in which PE campaign is being carried out. Ever since AFP surveillance was launched in the country in 1997, non-polio AFP rate of 1/100,000 was taken as a benchmark of adequate and sensitive AFP surveillance.[3],[13] This was not revised despite suggestions that the actual baseline rate of AFP in India may be higher. In fact, based on data from states with zero polio reporting, the authors had proposed in 1999 that the baseline rate be revised upward to at least 1.5/100,000.[14],[15] Of course, this suggestion was ignored. It is noteworthy that for all the years from 1999 to 2003, the non-polio AFP rate remained constantly above 1.5, varying between 1.6 and 2.1. Then suddenly the number of AFP cases increased drastically from late 2004 onwards, with non polio AFP rates as high as 12.3/100,000 from polio endemic states of U.P and Bihar; which also influenced the all India rate going up to 5.5/100,000 in 2005. Similar high rates are continuing to be reported in 2006 [Figure - 1]. Again it is significant that these rates have not increased in any other country of the SEARO region during the same period [Table - 3].
No satisfactory explanation is offered by NPSP for this abnormal increase, although it has been attributed to increased sensitivity of surveillance.[4] What is even worse is that no detailed analysis of these large number (over 27000 cases annually) of AFP cases has been undertaken to know the causes and outcomes (especially residual paralysis after 60 days) of these cases.
What about Vaccine Associated Paralytic Poliomyelitis (VAPP)
Despite extensive virological surveillance, no data is being provided of VAPP or cVDPV cases in India. In 1999, the authors had calculated that 83 cases of VAPP were expected for that year[15],[16] based on the number of OPV doses given and the incidence of VAPP as reported from the USA and other countries. NPSP analyzed the AFP surveillance data for the same year and estimated that 181 cases of VAPP would have occurred in that year in India and claimed that the incidence in India was much lower than seen in USA without giving any reasons for the same.[17] Since the year 1999, PE activities have been greatly intensified and if anything the number of VAPP cases is bound to be much more but no data is being provided for the same. Using the criterion that isolation of a single strain of the Vaccine virus (P1, P2 or P3 in pure form) from cases of AFP, in the absence of isolation of wild poliovirus is 'compatible with VAPP', then over 300-600 such cases of VAPP are occurring every year in India since 1999 [Table - 4].
Is polio eradicable
When in 1988, World Health Assembly adopted the goal of polio eradication and set the target date of 2000 for the same, it was fully hoped that polio would be eradicable. And that once polio had been eradicated, there would be no further need of polio vaccination and stoppage of the same (OPV) globally would ultimately eradicate both the wild and the vaccine virus resulting in savings of billions of dollars to the world. However, recent knowledge and events have belied these hopes. Some of these events are:
(a) Occurrence of cVDPV (circulating vaccine derived poliovirus) outbreaks [18] : Sabin (vaccine) polio virus is not only non-pathogenic but also does not have the ability to circulate. That is the very basis of using it to achieve eradication. However, some mutant strains have now been reported which have not only acquired abilities to cause paralysis but also to circulate via the oro-fecal route. These strains have been labeled as cVDPV. Several small outbreaks with cVDPV have been described with occurrence of more than 30 paralytic cases (Hispaniola 2000- 22 cases, Philippines 2001-3 cases, Madagascar 2002- 4 cases and China 2004-4 cases). Retrospective analysis in Egypt suggests another 32 cases during the period 1988-93. Although the outbreaks have largely occurred in areas with low immunization status, the threat posed by them to the goal of polio eradication cannot be taken lightly.
(b) Persistence of vaccine in immune-compromised individuals [19],[20] : Some mutant strains of vaccine virus have been described which are being continuously excreted by immune-compromised individuals over as long as 7 years period. These have been designated as iVDPV. At present at least 28 such individuals with 9 varieties of immunodeficiency have been identified all over the world, the majority being in developed countries. Although no paralytic case is reported to have occurred due to these strains, there is concern that they may have the potential to mutate back to the wild state and cause paralysis in the index case as well as others.
(c) Environmental persistence of wild polio virus : It was earlier believed that wild polio virus survives only for a very short period of time in the environment. This is the basis on which absence of polio cases over a period of time is taken to mean that the virus has been eradicated. However, recent environmental surveillance has revealed that wild poliovirus may survive in the environment even after these areas have not had any clinical case of polio for several months. This has been noted in India also from the only site where sewage samples are analyzed.[4] Thus zero polio status may no longer be consistent with eradication status.
(d) Persistence of wild polio virus in the guts of immunized individuals : Recent evidence that even immunized individuals can participate in continuing the orofeacal circulation of wild polio virus, has also raised doubts about the ability to completely eliminate the wild virus. If this alone were not enough, there is data suggesting that the vaccine virus can recombine with other entero-viruses causing AFP that cannot be differentiated from polio.[21]
In view of the above mentioned features, it appears that polio eradication in the true sense (i,e absence of both wild and vaccine virus) may never be possible. Many world renowned authorities who started as strong believers in the feasibility of polio eradication now concede otherwise and have started advocating effective polio control rather than polio eradication.[22],[23] Developed countries of the world have therefore, decided to continue routine immunization with IPV indefinitely even after achievement of global zero polio status to prevent cases of cVDPV or possible bioterrorism.
Can India achieve zero polio status
Despite intensive, house-to-house efforts several times in a year, over last several years, India continues to have cases of paralytic polio due to wild poliovirus. This year India seems to be in the midst of a possible epidemic albeit in limited number of districts. Various reasons for failure of even intensified strategies in some areas have been given, as described above. The latest explanation being offered is that because of particularly heavy load of NPEV in the affected areas, OPV is even less effective and as many as 10 doses of the same may be required to achieve 97% seroconversion in these areas.[24] As administration of 10 doses may occur over as long as 2 year period, a large number of infants would remain susceptible in the community at all times and catch the virus before effective vaccination. They would continue to participate in the circulation of the wild virus in the community. Although an attractive possibility, this theory does not explain why children in Bihar (living in similarly abysmal conditions) have done so much better; the improvement coinciding with a change of political leadership.
The authors strongly feel that the major reason of failure in UP is essentially a failure of system rather than of the strategy. In fact overenthusiastic strategy seems to be counterproductive and zero or near zero polio status is probably still possible with continued use of OPV in both routine and pulse immunization (vide infra).
Will introduction of IPV in hyper endemic areas be beneficial
This question is relevant because some experts have suggested use of 2 doses of IPV in the endemic areas in a one off manner to achieve the zero polio status. Introduction of IPV singly or in a combination with DPT in hyper-endemic area will definitely help in boosting immunity. However, this may prove to be a double-edged sword - as the community resistance to an injectable vaccine (of the same agent which was allegedly being given only to make their children sterile) may be much greater. Besides, the logistics of giving injections to lakhs of children over one to two days with the requirement of trained vaccinators as well as other aspects (precautions against possible reactions to injections) forbid this attractive option. Further, injections may increase the incidence of provoked paralysis in areas where WPV continues to circulate. In any case overall acceptance of an injectable vaccine is going to be much less and a large number of children may remain unvaccinated in which case the entire exercise may turn out to be fruitless or even counter productive. And what if even after giving two doses of IPV, the WPV continues to circulate What will we do next Thus introduction of IPV in the hyper-endemic areas, in a pulse manner, will not only not be beneficial but may be counter productive and reach a point of no return in the efforts to control/eradicate polio.
What then is to be done What is the way forward
It is clear that polio eradication drive in India is at the crossroads and no one can be sure of the path to be taken in future. However, the intensified efforts till now have not helped the cause, but in many ways might have contributed to the present messy situation by increasing apathy, dishonesty and even outright antagonism among both the health workers and the community. It is clear that fatigue has set in the system and unless corrective measures are taken immediately, polio eradication program may go the same way as the erstwhile National Malaria Eradication Programme (NMEP). It is therefore, necessary that a level-headed re-appraisal of the whole situation is urgently undertaken with a view to consolidate the already achieved success rather than to continue panic response to every case of wild polio with a round of supplementary immunization activities (SIA).
Firstly, it should be remembered that almost all countries of the world and large parts of India became polio free with just 2 rounds of pulse polio coupled with decent levels of routine OPV coverage. Even in the so-called difficult areas, the situation has only marginally improved since 2000 when all the intensified drives were initiated. Thus it appears that intensification of polio eradication drive with multiple rounds of NIDs, SNIDs and SIA etc, has not achieved much. Instead it has only helped to increase the panic and sense of despondency and defeat. It has certainly adversely affected the routine immunization and other child health services. In any case gains if any, are not commensurate with thousands of crores spent on these intensifications in last few years. What therefore may be of help is to cool down the PE drive to just 2 good rounds of NIDs all over the country and step up efforts to increase routine immunization with OPV in the difficult areas. This strategy will help to rebuild the confidence among health workers and the public at large and help to regain the confidence of opposing communities. With stepped up efforts at routine immunization, it may even help to achieve zero or near zero polio status in 2-3 years. In any case it will help to maintain effective polio control. What is most important is that the PE drive would be carried out within reasonable resources without disrupting or neglecting the other health services.
Long-term policy
A long- term policy is needed for the whole country. Most of the states have been Polio free for more than 3-6 years. They deserve a plan for the so-called "post eradication" stage. As per current WHO guidelines[25], after global polio eradication, tOPV will no longer be available. Each country will be free to decide its own strategy. WHO has suggested that developed countries continue to use IPV in routine immunization to prevent possibilities of import of cVDPV or WPV through bio-terrorism. For the developing countries it has been suggested that they stop all polio immunization (in any case tOPV will no longer be available (to safeguard against bio-terrorism in developed countries) but continue strict AFP surveillance. WHO will hold stocks of different mOPVs to supply any developing country facing an outbreak.
As a country India has to take a decision and that too now, whether to follow the developed country's path or developing country's path. Let us consider the so-called developing country's path; that is to stop all immunization against polio, and continue AFP surveillance alone. This strategy would of course be cheap but is fraught with danger. Even with best of AFP surveillance, a case of WPV can be detected in not less than 6 weeks with current technology. Then India would need to put up a request with WHO to release stocks of mOPV to undertake NIDs or SNIDs. All this may take several months, during which the virus could travel miles and infect several thousand individuals in a polio naοve population (that will emerge within one year of stoppage of all immunization). Thus this 'cheaper' strategy is unacceptably dangerous. Besides, in any case India also is not immune to either cVDPV or to bio-terrorism.
The experience of Indonesia is very illustrative of the likely outcome if this type of strategy is followed. The country had not witnessed a single case of poliomyelitis after 1995. National immunization campaigns were held from 1995 to 1997 followed by sub-national rounds in 1999, 2000 and 2001 followed by another nation-wide campaign in 2002. Routine polio immunization was consistently reported to be above 90% and surveillance quality was at par with internationally accepted standards. In fact, an international team of experts noted in June 2003 that surveillance was well established and the system was capable of detecting wild poliovirus transmission. However, in April 2005, one wild poliovirus case (P1) was identified. This event was met with an "outbreak response immunization" targeting about 4,000 children; however "intensified surveillance" detected another 7 cases in the same village as the index case. Therefore, extensive mop up immunization activities covering over 6 million children were carried out in May and June as also a massive outbreak response immunization covering 78,000 children around the index case. Despite all this, before the year was out, 331 polio cases were reported of which 297 were caused by wild virus (P1) and 34 were vaccine associated paralytic poliomyelitis. This experience shows that the outbreak could not be contained despite undertaking massive rounds of pulse polio.
Therefore, it would be prudent to consider the so-called developed country's strategy; that is introduction of IPV in routine immunization. For this policy to be implemented India would need almost 100 million doses of IPV (or DPTP) per year. Import of such large number of doses year after year will not be economically feasible, but if the country does not wish to lose the gains already made under PE programme they would definitely need to consider this. The costs can definitely be brought down if India can start manufacturing the vaccine in India. After all, Hepatitis B vaccine was also launched in India as an elitist vaccine, but today the academic and political leaders are falling over each other in their haste to introduce it on a universal basis. Thus, India should start the process of licensing and indigenously manufacturing IPV (DPTP) right now to ensure availability of adequate number of doses in 3-5 years. A process like the one undertaken in case of Hepatitis B vaccine to break the monopoly of international companies will have to be devised and acted upon.
Introducing IPV in EPI
Since India is not likely to be able to indigenously manufacture enough doses of IPV for the whole country immediately nor sustain the cost of imports economically and logistically nor convince the WHO to support this exercise (being clubbed as a developing country and hence condemned to choose the option discussed previously); it will be prudent to spread the introduction of IPV over next 2-5 years in a phased manner as more and more doses become available indigenously. This gradual introduction would also help gain experience with the use of IPV. At the risk of repeating ourselves, the authors again propose below the most practical plan for introducing IPV in routine immunization.[15],[26]
IPV should be first introduced in states, which have been polio free for 3-6 years. Thus the states can be grouped in 3 categories [Table - 5] and the beginning could be made in 2008/2009 with the Group I states and then gradually extended to other states depending on the availability of IPV. Of course, it is possible to consider that introduction of IPV may be done with the worst states first or vice versa. Even with the latter option, scientifically speaking it will probably be best to start with states where zero polio status has been achieved over the last few years rather than those that have been polio free even prior to nation-wide eradication efforts (as these states are able to maintain their status with routine immunization and two NIDs- the ideal situation). It is important to emphasize that the decision on the order of inproducing states/regions should be done scientifically and not by considerations other than scientific.
To summarize, the authors propose that the way forward from the present messy situation on the polio eradication front is as follows:
Use of OPV alone should be continued towards maintaining "Effective polio control" and possibly achieving zero polio status.
Only two annual rounds of good quality NIDs be carried out with tOPV all over the country. All other SIA be stopped immediately.
The authors are aware that the suggested way forward may neither be the last word, nor meet the approval of all. However, it is hoped that this will generate a nation-wide debate to determine the right course of action in the best interests of the country. The whole programme should be examined in an entirely country specific manner without getting overawed by "global" needs.
References
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19.Halsey NA, Pinto J, Espinosa-Rosales F, Faure-Fontenla MA, da Silva E, Khan AJ, Webster AD, Minor P, Dunn G, Asturias E, Hussain H, Pallansch MA, Kew OM, Winkelstein J, Sutter R; Polio Project Team. Search for poliovirus carriers among people with primary immune deficiency diseases in the United States, Mexico, Brazil and the United Kingdom. Bull WHO 2004; 82: 3-8. [PUBMED]
20.MacLennan C, Dunn G, Huissoon AP, Kumararatne DS, Martin J, O'Leary P, Thompson RA, Osman H, Wood P, Minor P, Wood DJ, Pillay D. Failure to clear persistent vaccine-derived neurovirulent poliovirus infection in an immunodeficient man. Lancet 2004; 363 : 1509-1513. [PUBMED] [FULLTEXT]
21.Arita M, Zhu SL, Yoshida H, Yoneyama T, Miyamura T, Shimizu H. A Sabin 3-derived poliovirus recombinant contained a sequence homologous with indigenous human enterovirus species C in the viral polymerase coding region. J Virol 2005; 79: 12650-7. [PUBMED] [FULLTEXT]
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2 Postgraduate Institute of Medical Education and Research, Chandigarh, India
Despite remarkable decline in the number of poliomyelitis cases, the dream of polio eradication in India remains elusive. This is despite considerable effort and expenditure for well over a decade. Various reasons have been cited for this and interventions implemented accordingly. None of these seem to have borne fruit. It is appropriate to have a relook at the polio eradication strategies in order to learn from past errors and determine a feasible solution to achieve the goal. This article examines important tissues that hamper the eradication effort and proposes a way forward.
Keywords: Poliomyelitis; Eradication; IPV; OPV
For the past several years, there have been expectations that India and therefore, the South Asian region and by extension the world itself stands very near to the stage of eradicating poliomyelitis. Against this mood of chest thumping and backslapping, dissenting views on important challenges that hamper this goal and make the achievement unlikely, have been ignored altogether. However, the situation today is not as rosy as one is led to believe. In fact, the authors are witnessing a replay of the events of 1999 and 2002. The year 2006 is again recording a "resurgence" of polio in India - 280 cases having been reported by mid-September,[1] most of them from chronically endemic areas of Moradabad district and adjoining areas of Uttar Pradesh. Meanwhile cases continue to occur in a sporadic manner in other states of India as they get exported from the endemic area. As of date there are eight states from where cases have been reported.
It is not as if efforts towards eradication have been deficient. In fact, since the year 2000 when the first target date for a polio free world was missed, an ever intensifying polio eradication drive has been carried out in India with a very large number of National and Sub-national Immunization Days (NIDs and SNIDs) and house to house campaigns. Lately pulse polio rounds have been carried out in the endemic areas almost every month and under-5 children have received more then 20-25 doses in these areas. Since April 2005, 6-8 rounds of SNIDs have been carried out with a monovalent vaccine (mOPV1) in the hope of rapidly achieving the goal of zero polio, but even this has been to no avail. A sense of panic nay despair has set in among policy planners and health ministry officials. Less and less people believe in the possibility of achieving the goal of zero polio. There are plans afoot to introduce Injectable Polio Vaccine (IPV) in the endemic areas, which may meet even greater community (communal) resistance than '2 drops' of oral polio vaccine.
It is apparent to all concerned that we are presently at a critical stage of polio eradication and a thorough reappraisal of the situation is called for, before bringing out any more policy changes on the ground. The present communication attempts to look at the Polio eradication drive in India in its entirety and suggests a possible way out of the present "messy situation"
What Has Been Achieved
Since the inception of the polio eradication (PE) initiative in India, there has been a dramatic decline in the number of paralytic poliomyelitis cases from an estimated 35,000 cases annually in 1994-1995, to less than 200 cases each year (barring the epidemic of 2002 and the current resurgence). P2 strain has been eradicated and P3 strain also appears to be on its last legs with just 5 cases reported so far in 2006. Even for P1, only 2 genotypes continue to circulate as compared to as many as 8 in 2004.[2] This encouraging trend is attributed to excellent Supplementary Immunization Activities (SIA); the quality (over 90% coverage) and quantity (22 NIDs and another 22 SNIDs, besides countless region specific rounds) which are at present apparently better than ever before. Another great gain of the polio eradication drive is that India now has an excellent surveillance system in place that can quickly detect areas of transmission of the wild virus. Surveillance quality reportedly far exceeds international standards for the same.[3]
Despite these tremendous gains, the goal of zero polio status appears to be as elusive as in 2000 and India continues to be a major problem area for the global polio eradication programme. It may be pointed out that very little progress has been made since the year 2000 (when the Intensified pulse polio campaign was launched) in the total number of wild polio virus (WPV) cases in the country.
What has gone wrong
It is worth mentioning that the strategy of strengthening routine polio immunization supplemented with 2 rounds of pulse polio has succeeded in eradicating poliomyelitis from most countries of the world. Naturally one is interested to know why it has not succeeded in India. Various reasons have been put forward for this apparent failure or delay in achieving zero polio status in some areas of UP and Bihar. These include.[4],[5] (1) Very low routine immunization, (2) High prevalence of non polio entero-viruses and abysmally poor environmental sanitation making OPV less effective thereby requiring at least 10 doses of OPV in these areas to achieve sero-positivity in 97% of individuals, (3) Resistance among Muslim Community (4) Lack of political and administrative will and (5) Pockets of un-immunized children allowing continued circulation of WPV. To this the authors may add increasing apathy and dishonesty among health workers who are being asked to reach every child every month, amidst increasing community resistance. It is obvious that one cannot win a race riding an unwilling /unmotivated horse. Also the rather heartless and ad hoc manner (every case of polio is met with a SIA), without any long-term perspective with which the PE is being carried out may also be responsible for the current situation.
Adhocism in planning
The National Poliomyelitis Surveillance Project (NPSP) is currently the only body co-ordinating all strategies pertaining to polio eradication and their implementation in India. It not only plans and implements the strategies (right from detecting cases to SIA) but also evaluates and monitors the success or otherwise of the programme. Thus it serves as policeman, jury and judge. An India Expert Advisory Group (IEAG) has been constituted which meets every 4-6 months. At this meeting an overview of the current situation is presented (by NPSP), discussed and action to be taken during next 6 months is decided. A few weeks prior to the IEAG meetings the Adhoc Advisory Group of Polio Eradication (AAPGE) of WHO meets and actually decides about the plan of action for next 6 months which is then simply adopted by the IEAG as its 'own' decision. The WHO group takes a global view and suggests country specific action. But the IEAG hardly ever takes a countrywide view and merely dittoes the concerns and actions outlined by the AAGPE. The decisions are always taken for "next 4-6 months" and there has never been any long-term India-specific plan.[6],[7]
As the Polio eradication group of WHO is still pursuing the ever elusive goal of zero polio, the whole emphasis of the IEAG and NPSP is also towards combating continuing WPV circulation in the problem districts rather then taking a holistic view of the problem in the country, keeping the interest of polio free states as well as other health priorities of the country in mind.
Introduction of mOPV1 in the SNIDs
The manner of introduction of mOPV1 in the polio eradication program will serve to demonstrate the decision making process in the country. In September 2004, the AACPE (WHO) met in Geneva and recommended that mOPV1 be licensed, manufactured and used in the SNIDs in India.[8] IEAG group in its 12th meeting held in New Delhi in December 2004 endorsed the view.[9] Panacea Biotech, a pre-qualified United Nations manufacturer of polio vaccine, but till then only a bottler and distributor of OPV, was licensed to produce mOPV1 from stocks provided from various sources.[10] The company established Vero cell/monkey kidney cell culture for culturing and processing of mOPV1, and the vaccine so produced was tested for stability and licensed to be used in the national programme of India and other developing countries in March 2005, under the accelerated programme (italics authors). The whole process was accomplished in 3 months[11], a remarkable feat considering that WHO normally take a minimum of 3 years of good manufacturing practices (GMP) before licensing a vaccine.
To add insult to the injury, a phase IV clinical trial was built into the introduction of mOPV1 in the national PE programme in India. " Special permission of GOI and drug controller of India was taken (and given!) to introduce this vaccine ( as phase IV clinical trial) without parental consent". Also no special monitoring system was incorporated into the trial to assess its safety and efficacy with large volume use in Indian conditions. While the results (if any) of the trial are still awaited, the vaccine has failed to show any impact on the circulation of WPV. On the other hand, careful analysis of AFP surveillance data shows an abnormal increase in the number of P1 vaccine virus in non Polio AFP cases in the year 2005 and 2006, while the number of stool samples showing pure growth of P2 and P3 vaccine viruses have remained almost static over the years [Table - 1]. It is noteworthy that P1 virus cases among non-polio AFP have remained constant in all other countries of the WHO South East Asia Region [Table - 2].[12]
Heartless AFP Surveillance
The story of AFP surveillance is another poignant aspect of heartless and unscientific manner in which PE campaign is being carried out. Ever since AFP surveillance was launched in the country in 1997, non-polio AFP rate of 1/100,000 was taken as a benchmark of adequate and sensitive AFP surveillance.[3],[13] This was not revised despite suggestions that the actual baseline rate of AFP in India may be higher. In fact, based on data from states with zero polio reporting, the authors had proposed in 1999 that the baseline rate be revised upward to at least 1.5/100,000.[14],[15] Of course, this suggestion was ignored. It is noteworthy that for all the years from 1999 to 2003, the non-polio AFP rate remained constantly above 1.5, varying between 1.6 and 2.1. Then suddenly the number of AFP cases increased drastically from late 2004 onwards, with non polio AFP rates as high as 12.3/100,000 from polio endemic states of U.P and Bihar; which also influenced the all India rate going up to 5.5/100,000 in 2005. Similar high rates are continuing to be reported in 2006 [Figure - 1]. Again it is significant that these rates have not increased in any other country of the SEARO region during the same period [Table - 3].
No satisfactory explanation is offered by NPSP for this abnormal increase, although it has been attributed to increased sensitivity of surveillance.[4] What is even worse is that no detailed analysis of these large number (over 27000 cases annually) of AFP cases has been undertaken to know the causes and outcomes (especially residual paralysis after 60 days) of these cases.
What about Vaccine Associated Paralytic Poliomyelitis (VAPP)
Despite extensive virological surveillance, no data is being provided of VAPP or cVDPV cases in India. In 1999, the authors had calculated that 83 cases of VAPP were expected for that year[15],[16] based on the number of OPV doses given and the incidence of VAPP as reported from the USA and other countries. NPSP analyzed the AFP surveillance data for the same year and estimated that 181 cases of VAPP would have occurred in that year in India and claimed that the incidence in India was much lower than seen in USA without giving any reasons for the same.[17] Since the year 1999, PE activities have been greatly intensified and if anything the number of VAPP cases is bound to be much more but no data is being provided for the same. Using the criterion that isolation of a single strain of the Vaccine virus (P1, P2 or P3 in pure form) from cases of AFP, in the absence of isolation of wild poliovirus is 'compatible with VAPP', then over 300-600 such cases of VAPP are occurring every year in India since 1999 [Table - 4].
Is polio eradicable
When in 1988, World Health Assembly adopted the goal of polio eradication and set the target date of 2000 for the same, it was fully hoped that polio would be eradicable. And that once polio had been eradicated, there would be no further need of polio vaccination and stoppage of the same (OPV) globally would ultimately eradicate both the wild and the vaccine virus resulting in savings of billions of dollars to the world. However, recent knowledge and events have belied these hopes. Some of these events are:
(a) Occurrence of cVDPV (circulating vaccine derived poliovirus) outbreaks [18] : Sabin (vaccine) polio virus is not only non-pathogenic but also does not have the ability to circulate. That is the very basis of using it to achieve eradication. However, some mutant strains have now been reported which have not only acquired abilities to cause paralysis but also to circulate via the oro-fecal route. These strains have been labeled as cVDPV. Several small outbreaks with cVDPV have been described with occurrence of more than 30 paralytic cases (Hispaniola 2000- 22 cases, Philippines 2001-3 cases, Madagascar 2002- 4 cases and China 2004-4 cases). Retrospective analysis in Egypt suggests another 32 cases during the period 1988-93. Although the outbreaks have largely occurred in areas with low immunization status, the threat posed by them to the goal of polio eradication cannot be taken lightly.
(b) Persistence of vaccine in immune-compromised individuals [19],[20] : Some mutant strains of vaccine virus have been described which are being continuously excreted by immune-compromised individuals over as long as 7 years period. These have been designated as iVDPV. At present at least 28 such individuals with 9 varieties of immunodeficiency have been identified all over the world, the majority being in developed countries. Although no paralytic case is reported to have occurred due to these strains, there is concern that they may have the potential to mutate back to the wild state and cause paralysis in the index case as well as others.
(c) Environmental persistence of wild polio virus : It was earlier believed that wild polio virus survives only for a very short period of time in the environment. This is the basis on which absence of polio cases over a period of time is taken to mean that the virus has been eradicated. However, recent environmental surveillance has revealed that wild poliovirus may survive in the environment even after these areas have not had any clinical case of polio for several months. This has been noted in India also from the only site where sewage samples are analyzed.[4] Thus zero polio status may no longer be consistent with eradication status.
(d) Persistence of wild polio virus in the guts of immunized individuals : Recent evidence that even immunized individuals can participate in continuing the orofeacal circulation of wild polio virus, has also raised doubts about the ability to completely eliminate the wild virus. If this alone were not enough, there is data suggesting that the vaccine virus can recombine with other entero-viruses causing AFP that cannot be differentiated from polio.[21]
In view of the above mentioned features, it appears that polio eradication in the true sense (i,e absence of both wild and vaccine virus) may never be possible. Many world renowned authorities who started as strong believers in the feasibility of polio eradication now concede otherwise and have started advocating effective polio control rather than polio eradication.[22],[23] Developed countries of the world have therefore, decided to continue routine immunization with IPV indefinitely even after achievement of global zero polio status to prevent cases of cVDPV or possible bioterrorism.
Can India achieve zero polio status
Despite intensive, house-to-house efforts several times in a year, over last several years, India continues to have cases of paralytic polio due to wild poliovirus. This year India seems to be in the midst of a possible epidemic albeit in limited number of districts. Various reasons for failure of even intensified strategies in some areas have been given, as described above. The latest explanation being offered is that because of particularly heavy load of NPEV in the affected areas, OPV is even less effective and as many as 10 doses of the same may be required to achieve 97% seroconversion in these areas.[24] As administration of 10 doses may occur over as long as 2 year period, a large number of infants would remain susceptible in the community at all times and catch the virus before effective vaccination. They would continue to participate in the circulation of the wild virus in the community. Although an attractive possibility, this theory does not explain why children in Bihar (living in similarly abysmal conditions) have done so much better; the improvement coinciding with a change of political leadership.
The authors strongly feel that the major reason of failure in UP is essentially a failure of system rather than of the strategy. In fact overenthusiastic strategy seems to be counterproductive and zero or near zero polio status is probably still possible with continued use of OPV in both routine and pulse immunization (vide infra).
Will introduction of IPV in hyper endemic areas be beneficial
This question is relevant because some experts have suggested use of 2 doses of IPV in the endemic areas in a one off manner to achieve the zero polio status. Introduction of IPV singly or in a combination with DPT in hyper-endemic area will definitely help in boosting immunity. However, this may prove to be a double-edged sword - as the community resistance to an injectable vaccine (of the same agent which was allegedly being given only to make their children sterile) may be much greater. Besides, the logistics of giving injections to lakhs of children over one to two days with the requirement of trained vaccinators as well as other aspects (precautions against possible reactions to injections) forbid this attractive option. Further, injections may increase the incidence of provoked paralysis in areas where WPV continues to circulate. In any case overall acceptance of an injectable vaccine is going to be much less and a large number of children may remain unvaccinated in which case the entire exercise may turn out to be fruitless or even counter productive. And what if even after giving two doses of IPV, the WPV continues to circulate What will we do next Thus introduction of IPV in the hyper-endemic areas, in a pulse manner, will not only not be beneficial but may be counter productive and reach a point of no return in the efforts to control/eradicate polio.
What then is to be done What is the way forward
It is clear that polio eradication drive in India is at the crossroads and no one can be sure of the path to be taken in future. However, the intensified efforts till now have not helped the cause, but in many ways might have contributed to the present messy situation by increasing apathy, dishonesty and even outright antagonism among both the health workers and the community. It is clear that fatigue has set in the system and unless corrective measures are taken immediately, polio eradication program may go the same way as the erstwhile National Malaria Eradication Programme (NMEP). It is therefore, necessary that a level-headed re-appraisal of the whole situation is urgently undertaken with a view to consolidate the already achieved success rather than to continue panic response to every case of wild polio with a round of supplementary immunization activities (SIA).
Firstly, it should be remembered that almost all countries of the world and large parts of India became polio free with just 2 rounds of pulse polio coupled with decent levels of routine OPV coverage. Even in the so-called difficult areas, the situation has only marginally improved since 2000 when all the intensified drives were initiated. Thus it appears that intensification of polio eradication drive with multiple rounds of NIDs, SNIDs and SIA etc, has not achieved much. Instead it has only helped to increase the panic and sense of despondency and defeat. It has certainly adversely affected the routine immunization and other child health services. In any case gains if any, are not commensurate with thousands of crores spent on these intensifications in last few years. What therefore may be of help is to cool down the PE drive to just 2 good rounds of NIDs all over the country and step up efforts to increase routine immunization with OPV in the difficult areas. This strategy will help to rebuild the confidence among health workers and the public at large and help to regain the confidence of opposing communities. With stepped up efforts at routine immunization, it may even help to achieve zero or near zero polio status in 2-3 years. In any case it will help to maintain effective polio control. What is most important is that the PE drive would be carried out within reasonable resources without disrupting or neglecting the other health services.
Long-term policy
A long- term policy is needed for the whole country. Most of the states have been Polio free for more than 3-6 years. They deserve a plan for the so-called "post eradication" stage. As per current WHO guidelines[25], after global polio eradication, tOPV will no longer be available. Each country will be free to decide its own strategy. WHO has suggested that developed countries continue to use IPV in routine immunization to prevent possibilities of import of cVDPV or WPV through bio-terrorism. For the developing countries it has been suggested that they stop all polio immunization (in any case tOPV will no longer be available (to safeguard against bio-terrorism in developed countries) but continue strict AFP surveillance. WHO will hold stocks of different mOPVs to supply any developing country facing an outbreak.
As a country India has to take a decision and that too now, whether to follow the developed country's path or developing country's path. Let us consider the so-called developing country's path; that is to stop all immunization against polio, and continue AFP surveillance alone. This strategy would of course be cheap but is fraught with danger. Even with best of AFP surveillance, a case of WPV can be detected in not less than 6 weeks with current technology. Then India would need to put up a request with WHO to release stocks of mOPV to undertake NIDs or SNIDs. All this may take several months, during which the virus could travel miles and infect several thousand individuals in a polio naοve population (that will emerge within one year of stoppage of all immunization). Thus this 'cheaper' strategy is unacceptably dangerous. Besides, in any case India also is not immune to either cVDPV or to bio-terrorism.
The experience of Indonesia is very illustrative of the likely outcome if this type of strategy is followed. The country had not witnessed a single case of poliomyelitis after 1995. National immunization campaigns were held from 1995 to 1997 followed by sub-national rounds in 1999, 2000 and 2001 followed by another nation-wide campaign in 2002. Routine polio immunization was consistently reported to be above 90% and surveillance quality was at par with internationally accepted standards. In fact, an international team of experts noted in June 2003 that surveillance was well established and the system was capable of detecting wild poliovirus transmission. However, in April 2005, one wild poliovirus case (P1) was identified. This event was met with an "outbreak response immunization" targeting about 4,000 children; however "intensified surveillance" detected another 7 cases in the same village as the index case. Therefore, extensive mop up immunization activities covering over 6 million children were carried out in May and June as also a massive outbreak response immunization covering 78,000 children around the index case. Despite all this, before the year was out, 331 polio cases were reported of which 297 were caused by wild virus (P1) and 34 were vaccine associated paralytic poliomyelitis. This experience shows that the outbreak could not be contained despite undertaking massive rounds of pulse polio.
Therefore, it would be prudent to consider the so-called developed country's strategy; that is introduction of IPV in routine immunization. For this policy to be implemented India would need almost 100 million doses of IPV (or DPTP) per year. Import of such large number of doses year after year will not be economically feasible, but if the country does not wish to lose the gains already made under PE programme they would definitely need to consider this. The costs can definitely be brought down if India can start manufacturing the vaccine in India. After all, Hepatitis B vaccine was also launched in India as an elitist vaccine, but today the academic and political leaders are falling over each other in their haste to introduce it on a universal basis. Thus, India should start the process of licensing and indigenously manufacturing IPV (DPTP) right now to ensure availability of adequate number of doses in 3-5 years. A process like the one undertaken in case of Hepatitis B vaccine to break the monopoly of international companies will have to be devised and acted upon.
Introducing IPV in EPI
Since India is not likely to be able to indigenously manufacture enough doses of IPV for the whole country immediately nor sustain the cost of imports economically and logistically nor convince the WHO to support this exercise (being clubbed as a developing country and hence condemned to choose the option discussed previously); it will be prudent to spread the introduction of IPV over next 2-5 years in a phased manner as more and more doses become available indigenously. This gradual introduction would also help gain experience with the use of IPV. At the risk of repeating ourselves, the authors again propose below the most practical plan for introducing IPV in routine immunization.[15],[26]
IPV should be first introduced in states, which have been polio free for 3-6 years. Thus the states can be grouped in 3 categories [Table - 5] and the beginning could be made in 2008/2009 with the Group I states and then gradually extended to other states depending on the availability of IPV. Of course, it is possible to consider that introduction of IPV may be done with the worst states first or vice versa. Even with the latter option, scientifically speaking it will probably be best to start with states where zero polio status has been achieved over the last few years rather than those that have been polio free even prior to nation-wide eradication efforts (as these states are able to maintain their status with routine immunization and two NIDs- the ideal situation). It is important to emphasize that the decision on the order of inproducing states/regions should be done scientifically and not by considerations other than scientific.
To summarize, the authors propose that the way forward from the present messy situation on the polio eradication front is as follows:
Use of OPV alone should be continued towards maintaining "Effective polio control" and possibly achieving zero polio status.
Only two annual rounds of good quality NIDs be carried out with tOPV all over the country. All other SIA be stopped immediately.
The authors are aware that the suggested way forward may neither be the last word, nor meet the approval of all. However, it is hoped that this will generate a nation-wide debate to determine the right course of action in the best interests of the country. The whole programme should be examined in an entirely country specific manner without getting overawed by "global" needs.
References
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