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Vaccine 25 (2007) 8365–8371

Short communication

Role of genetic factors in polio eradication:New challenge for policy makers

Yash Paul ∗Maharaja Agrasen Hospital, Vidhyadhar Nagar, Jaipur 302023, India

Received 15 August 2007; received in revised form 21 September 2007; accepted 25 September 2007Available online 17 October 2007

bstract

In 1988 the World Health Assembly passed resolution WHA 41.28, for global eradication of poliomyelitis by the year 2000 by providingmmunization exclusively with oral polio vaccine (OPV). India happens to be the largest country in the world, where polio cases are occurringn large numbers. Despite increase in number of pulse polio immunization (PPI) rounds and introduction of monovalent oral polio vaccines

OPV1 and mOPV3, polio has not been eradicated from India. Global polio eradication cannot be achieved unless polio is eradicated fromndia because of the risk of exportation of wild poliovirus to other countries. India cannot become polio free unless Uttar Pradesh andihar become polio free. Because of genetic and some other factors, OPV cannot eradicate polio from Bihar and Uttar Pradesh. The present

cenario strongly suggests that due to some host factors in recipients OPV cannot eradicate polio. Rather than extending the deadline for polioradication again and again, it is time to prepare strategy for final push to polio.

2007 Elsevier Ltd. All rights reserved.

eywords: Polio eradication; Vaccine failure; Genetic factors in polio eradication; Final push to polio; Challenges for policy makers

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. Introduction

In 1988 the World Health Assembly, during its 41steeting passed resolution 28, declaring that “World Healthrganization (WHO) takes initiative for global eradication

xclusively by OPV”. This resolution is known as WHA1.28. At that point of time, i.e., in 1988 two types of polioaccines were available, (i) trivalent oral polio vaccine (tOPV,ommonly known as OPV), and (ii) enhanced inactivatedolio vaccine (eIPV) which had been licensed in 1987. OPVas chosen as a tool for polio eradication because of follow-

ng reasons:

. Cost factor, it costs much less than IPV.

. It is administered orally, whereas IPV is administeredintramuscularly.

∗ Correspondence address: A-D-7, Devi Marg, Bani Park, Jaipur 302016,ndia. Tel.: +91 1412314774; fax: +91 1412203738.

E-mail address: dryashpaul2003@yahoo.com.

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264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved.oi:10.1016/j.vaccine.2007.09.068

. Being a live vaccine, it was believed to confer long lastingimmunity.

. Quick acting vaccine, because of induction of intesti-nal mucosal immunity (secretory IgA), immunity beingachieved in a matter of days rather than months, whichmeant that it could be used in the event of local epidemic.

. Through secondary spread of live attenuated vaccinevirus, additional benefit to the community could occur,this issue of collective interest was considered a greatbeneficial point.

The scientific information regarding some limitations andrawbacks of OPV available during 1988 was as following:

. It can cause vaccine associated paralytic poliomyelitis(VAPP) in vaccine recipients because of some mutant

neurovirulent vaccine polioviruses.

. Secondary spread of mutant neurovirulent vaccinepolioviruses can cause VAPP in close contacts of thevaccinee, and is called contact VAPP case.

8366 Y. Paul / Vaccine 25 (2007) 8365–8371

Table 1Number of polio cases in different states from 1998 to 2007 as on 7th July 2007

S. no. States 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 CBRa

1 Andaman & Nicobar 0 0 0 0 0 0 0 0 0 0 19.12 Arunachal Pradesh 0 0 0 0 0 0 0 0 0 0 22.33 Dadra & Nagar Haveli 1 0 0 0 0 0 0 0 0 0 34.94 Daman & Diu 5 0 0 0 0 0 0 0 0 0 23.75 Goa 2 0 0 0 0 0 0 0 0 0 14.36 Kerala 0 1 0 0 0 0 0 0 0 0 17.97 Lakshadweep 0 0 0 0 0 0 0 0 0 0 26.18 Manipur 0 0 0 0 0 0 0 0 0 0 18.39 Meghalaya 0 0 0 0 0 0 0 0 0 0 28.5

10 Mizoram 0 0 0 0 0 0 0 0 0 0 16.911 Nagaland 0 0 0 0 0 0 0 0 0 0 11.812 Pondicherry 2 0 0 0 0 0 0 0 0 0 17.813 Sikkim 0 0 0 0 0 0 0 0 0 0 21.814 Tripura 0 0 0 0 0 0 0 0 0 0 16.515 Assam 1 0 0 1 0 1 0 0 2 0 26.916 Himachal Pradesh 0 0 0 0 0 0 0 0 1 0 22.117 Jammu & Kashmir 0 0 0 0 1 0 0 0 1 0 19.618 Tamil Nadu 91 7 0 0 0 2 1 0 0 0 19.219 Andhra Pradesh 96 21 0 0 0 21 1 0 0 2 21.320 Chandigarh 1 2 1 0 1 0 0 0 1 0 17.521 Chhattisgarh 15 3 0 0 1 0 0 0 0 0 26.722 Delhi 47 73 3 3 24 3 2 1 7 0 20.323 Gujarat 164 9 2 1 24 3 0 1 4 1 25.224 Haryana 39 19 4 5 37 3 2 1 19 1 26.925 Jharkhand 27 8 1 2 12 1 0 2 1 0 26.526 Karnataka 71 21 8 0 0 36 1 0 0 0 22.027 Madhya Pradesh 107 17 2 0 21 11 0 0 3 0 31.228 Maharashtra 121 18 7 4 6 3 3 0 5 1 20.929 Orissa 49 0 0 0 4 2 0 0 0 0 24.330 Punjab 9 4 0 5 2 1 0 1 8 0 21.531 Rajasthan 63 18 0 0 41 4 0 0 1 1 31.232 Uttarakhand 36 16 1 3 14 0 1 1 13 3 20.233 West Bengal 26 21 8 1 49 28 2 0 1 0 20.634 Bihar 131 115 49 27 121 18 41 30 61 18 31.935 Uttar Pradesh 845 757 178 216 1242 88 82 29 548 100 32.8

Total cases in India 1934 1126 265 268 1600 225 136 66 676 1290.67

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ource: Mittal and Mathew [21].a CBR: crude birth rate.

. Some children, specially from tropical and developingcountries, show poor immune response to OPV.

Very few recipient and contact VAPP cases had beeneported in the past from the developed countries and itas thought that few children may develop polio becausef OPV, and society may consider it a small price in largernterest of the community. It was also hoped that the prob-em of poor response to OPV may be over come by extraoses of OPV given during mass vaccination as well as byhe secondary spread of vaccine polioviruses in the commu-ity.

The precise reasons for poor response to OPV by chil-ren from developing countries were not fully understood.ot climate, poor sanitation and malnutrition are considered

ome of the reasons for poor response to OPV in some pop-lations. Role of genetic factors in variation in response to aaccine has been recognized recently [1]. Author proposes toiscuss the probable role played by genetic factors in failure

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f polio eradication in India. The hypothesis is based on somebservations.

In 1995 polio eradication campaign was launched in Indiaith two rounds of pulse polio immunization in a year in

ddition to the routine polio vaccination schedule. It wasoped that global polio eradication will occur by end of 2000.espite many extensions in the deadline for polio eradication,olio eradication has remained elusive.

In 2005 there were 66 virologically confirmed polio cases.onovalent oral polio vaccine mOPV1 and mOPV3 were

ntroduced in 2005, but there were 676 virologically con-rmed cases in 2006. In 2007, number of vaccination roundsave further been increased, and as on 7th August 2007 129olio cases have already been reported.

Two observations based on the official data of the Nationalolio Surveillance Project (NPSP) merit attention:

. Majority of polio cases are occurring in Bihar and UttarPradesh as can be seen in Table 1.

Y. Paul / Vaccine 25 (2007) 8365–8371 8367

Table 2Number of OPV doses received by polio cases, 1998–2006a

OPV doses 1998 (%) 1999 (%) 2000 (%) 2001 (%) 2002 (%) 2003 (%) 2004 (%) 2005 (%) 2006 (%)a

0 dose 15 14 14 9 16 14 4 0 21–3 doses 47 45 28 31 41 35 11 11 114–7 doses 32 34 35 41 33 34 41 44 26> 1

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ource: Bulletin of Polio Eradication Committee, Indian Academy of Pediaa As of 28 July 2006.

. Majority of polio cases had received many doses of OPVbefore onset of paralysis, indicating that OPV had failedto provide protection to these children, as can be seen inTables 2 and 3.

Policy makers have to face the facts and accept the reality.t is time to acknowledge that may be due to some geneticactors OPV has not succeeded in polio eradication at least inome parts of India. There is a need for a new vaccine whichill be effective in these populations for polio eradication.

. Factors influencing polio eradication

.1. Environmental factors

Overcrowding results in increased chances of spread ofir-borne infections and poor sanitation helps in transmis-ion of causative organisms where spread of infection occursy faecal-oral route. Polioviruses spread by both methods.vercrowding and poor sanitation help spread of disease and

hus, have adverse effect on polio eradication.

.2. Vaccine failure

In case adequate antibodies to provide protection are notenerated after appropriate number of doses of a vaccine, its called a case of vaccine failure. Factors for poor antibodyeneration by OPV may be in the vaccine and/or the host.

.2.1. In the vaccineThe potency of OPV can be affected during manufacture

less likely), transportation or storage (probably), as very effi-

ient cold-chain system is required because OPV is a veryeat labile vaccine. During the hot summer seasons, electricower is supplied in most parts of India for few hours a day,hich can adversely affect the potency of OPV.

able 3PV doses received by polio cases

umber of doses 0 (%) 1–3 (%) 4–7 (%) >7 (%)

ndia 2 11 26 61ttar Pradesh 1 10 25 64oradabad 0 12 12 76

ource: Bulletin of Polio Eradication Committee of IAP, 2006, Vol. 3, Issue.

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.2.2. In the hostMultiple factors in the vaccinee may be responsible for

oor response to the vaccine. In the vaccine recipientsresence of other enteroviruses, malnutrition, immunosup-ression due to disease or drugs can be reasons for a pooresponse to OPV. It is a well-known fact that in India andany other countries doctors, quacks and practitioners of

ther systems of medicine administer corticosteroids evenor trivial ailments [2].

. Why do more polio cases occur in Bihar and Uttarradesh

Shortage of health related infrastructure and health work-rs can also be contributing factors for low vaccine coverage.ihar and Uttar Pradesh lack behind on both these counts.ut, similar or near similar conditions exist in some of those

tates also where polio has been controlled. It would suggesthat the genetic factors play important role in success or fail-re of eradication of polio by OPV in different populations.

Children from Uttar Pradesh and Bihar show very pooresponse to OPV. Grassly et al. have stated regarding esti-ates of trivalent OPV efficacy in India, 1997–2005. Per dose

accine efficacy of OPV for type 1 was 9% (6–13) for Uttarradesh, 18% (9–26) for Bihar and 21% (15–27) for rest ofndia; for type 3 efficacy was 9% (3–15) for Uttar Pradesh,2% (4–36) for Bihar and 21% (8–33) for rest of India [3].hus, children from Uttar Pradesh show poor response toPV type 1 and 3, while children from Bihar show poor

esponse to OPV type 1 only.Although combined under five population of Uttar Pradesh

nd Bihar is approximately one third of national popula-ion, except for years 1998 and 2003, 70–91% of polio casesccurred in these two states as can be seen in Table 1.

. Differential response to OPV

According to polio incidence, India can be divided in fourroups—Table 1.

roup 1. The polio incidence declined rapidly followingmass vaccination with OPV in 1995 and poliocases are not occurring presently. Even during2002 and 2006 when there had been resurgence

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of polio cases in India, no polio case occurredin these states. There are 14 states, numbered1–14 in Table 1. Pondicherry was a French colonybefore independence of India. Goa, Diu & Daman,and Dadra & Nagar Haveli had been Portuguesecolonies. Rest of the states in this group have Mon-goloid and/or Negrito ethnic population.

roup 2. The polio incidence declined rapidly, but, occa-sional polio cases have occurred in these states.There are four states in this group numbered 15–18.Though Assam has Mongoloid population, butamong north-east states Assam has highest ‘non-local’ population, majority of people are fromBihar, Uttar Pradesh and Rajasthan. HimachalPradesh and Jammu & Kashmir have Mongoloidpopulations, and these two states share border withPunjab. Polio cases have been reported from thesestates in areas adjacent to Punjab. Although TamilNadu does not have Mongoloid and Negrito pop-ulations, but polio incidence in Tamil Nadu haddeclined much earlier due to high vaccine cover-age initiated in 1970s of the 20th century becauseof personal efforts by Dr. Jacob John, and Dr. A.Parthasarathy and the initiative taken by the min-istry of health of this state.

roup 3. There are 15 states in this group, numbered 19–33.Decline in polio incidence occurred slowly, num-ber of polio cases occurring is small with no polioincidence reported in some years.

roup 4. Bihar and Uttar Pradesh numbered at 34 and 35,respectively have never been polio free, and haveconstantly reported high incidence of polio.

. Genetic factors

Response to OPV has been very variable. It was knownince long that children in tropical and developing countriesespond poorly to OPV [4–7]. Poor seroconversion had beeneported from India during 1970s [8–10]. But, precise reasonsor poor response were not known.

The problem of non-responders to hepatitis B vaccine isnown since 1980s and measles vaccine since 1990s [1] In004 Newport et al. had reported role of genetic factors inntibody response to OPV [11]. Human leukocyte antigenHLA) genes are located on the short arm of human chro-osome 6 and function by producing proteins that bind with

ntigenic peptide fragments (produced by processing of for-ign protein antigens) and display these to T cells, therebytimulating an immune response. Thus, the immune responseo foreign antigens is at least in part under genetic control byhe HLA genes and is intimately related to antigen: HLA

inding and presentation [1].

For the most part, class I HLA molecules present pro-essed peptides to CD8+ (suppressor) cells, and the class IIolecules present peptides to CD4+ (helper) cells. For both

07) 8365–8371

lass I and II mechanisms, only those processed peptideshat can bind within the peptide binding groove of the HLA

olecule can be presented. Through this mechanism, theres allele-specific restriction of peptide binding and, therefore,estricted antigen presentation limited to specific HLA alleles12–15].

Gm and Km genes code for the antigenic determinantsf the heavy and light chains of immunoglobulins, respec-ively. Gm groups are localized to the constant region of theheavy chain and thus are limited to IgG classes and each are

xclusive to one of the four 1gG subclasses. Gm allotypes areocated on chromosome 14. Many of the Gm factors are inher-ted together. The Km factors are present on the light chainsnd thus are represented in all classes of immunoglobulinsncluding 1gG, lgM, 1gD, 1gA, and 1gE. The Km allotypesre located on chromosome 2 [1]. Investigators have foundignificant variation in Gm and Km allotypes among differ-nt races in human populations [16–19]. Instead of the termraces’ in human population, term ‘ethnic groups’ will besed here.

Genetic factors have least effect on antibody formation byetanus Toxoid and substantial effect on antibody formationy OPV [11]. Thus, response to OPV can be very variable inifferent populations, though other factors being similar, but,nly due to genetic factors.

. Genetic factors in Indian scenario

Because of genetic variations, antibody formation maye variable in different populations, some populations mayhow excellent response while some selected populationsay show very poor response and other populations may

how intermediate response.The author had postulated that some genetic factors may

ave played important role for poor response to OPV in chil-ren from Bihar and Uttar Pradesh because of the followingbservations [20]:

. The states and union territories where decline in polio inci-dence occurred rapidly have higher Mongoloid, Negritoethnic population, or had been Portuguese or Frenchcolonies before becoming part of independent India.

. Tibet, China, Myanmar, Bangladesh and Nepal situatedto north and east of India have Mongoloid and Negritopopulation as majority, polio eradication occurred quicklyin these countries.

. Pakistan and Afghanistan do not have Mongoloid orNegrito ethnic population in any appreciable number, aresituated in the west of India and are still reporting poliocases.

. It is unlikely that quick decline in some states could be

due to better vaccine coverage and superior cold chainmaintenance. In addition to the above mentioned pointsthe author would like to add that high birth rate in Biharand Uttar Pradesh is offered as an explanation for difficulty

Y. Paul / Vaccine 25 (2007) 8365–8371 8369

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in polio eradication. It can be seen in Table 1 that in group1, Dadra & Nagar Haveli at number 3 has crude birthrate of 34.9 and Meghalaya at number 9 has crude birthrate of 28.5. Similarly Madhya Pradesh at number 27 andRajasthan at number 31 both in group 3 have crude birthrate of 31.2. Children from Dadra & Nagar Haveli andMeghalaya have shown very good response to OPV andchildren from Madhya Pradesh and Rajasthan also haveshown better response than children from Bihar (31.9)and Uttar Pradesh (32.8). In Fig. 1, the states are assignednumbers according to Table 1.

. Because of some genetic factors the children from UttarPradesh and Bihar are poor responders to current poliovaccines, as shown in a study by Grassly et al. [3].

This author would like to state that except for the studyf Grassly et al. [3] where response of children from Biharnd Uttar Pradesh to OPV has been found to be low, authoras based his hypothesis on some observations only. Thushere is a need for some studies to ascertain the contributionf genetic factors in polio eradication programme failure.

. Final push to polio: how and when

Can the currently available trivalent and monovalent oralolio vaccines eradicate polio from Bihar and Uttar Pradesh?

During the year 2007, OPV is being administered almost

nce a month in Bihar and Uttar Pradesh. As on 7th July007, there were 129 polio cases in India, 100 cases in Uttarradesh and 18 cases in Bihar as can be seen in Table 1. But,n 15th September 2007 there were 223 polio cases in India,

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ighbouring countries.

74 cases in Uttar Pradesh and 35 cases in Bihar. This showshat even over-saturation with OPV has failed to control polio.n the other hand, incidence of polio has shown a steep rise.hus, there is a need for rethink of whole strategy as well asaccine to achieve polio eradication.

Following options are available: (i) compulsory OPVmmunization, (ii) IPV for mass immunization, (iii) com-ination of OPV and IPV for mass immunization, and (iv)evelopment of a new vaccine.

.1. Compulsory OPV vaccination

Some have suggested that OPV administration be madeompulsory for eradication of polio [22,23]. Now it isnown that children from UP and Bihar are poor respon-ers to OPV, so it is not possible to tell how many dosesf trivalent and/or monovalent OPV vaccines will provideull protection to a child, and how to ensure administra-ion of that many doses to a child before he or she isnfected by wild poliovirus. Moreover number of vaccinessociated paralytic poliomyelitis (VAPP) caused by OPVould be very high [24]. In 2005 the author had stated:

On the other hand, it can be said that the present erad-cation program (with OPV) ensures that polio cases willontinue to occur because of vaccine failure and due toutant vaccine polioviruses”. Infected immunocompromised

hildren will continue to spread wild as well as mutantaccine polioviruses for a prolonged period in the commu-

ity [25]. Although OPV has eradicated polio from manyountries but it cannot eradicate polio from UP and Bihar,hus from India, because the children in UP and Biharre poor responders to OPV, due to some un-identified

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easons, but some genetic factors may be responsible for this20].

.2. IPV for mass vaccination

Two points need consideration:

(i) Can IPV eradicate polio?ii) Will parents accept it?

.2.1. Can IPV eradicate polio?Monovalent oral polio vaccine had eradicated polio from

gypt, but, it failed in Uttar Pradesh. During 1980s of lastentury IPV had shown encouraging results in Tamil Nadun India, but, it is not necessary that IPV would be highlyffective in Uttar Pradesh also. Thus a pilot study for IPVhould be done in Uttar Pradesh and Bihar before resortingo mass vaccination with IPV.

.2.2. Will parents accepts it?For more than 12 years people have been told that OPV is

ery effective, but, now OPV shall be replaced with IPV forass vaccination. Lately many parents have shown resistance

o administer OPV to their children, under such circum-tances many more parents may resist administration of IPVnder mass vaccination programme. Had IPV been intro-uced earlier people might have accepted it readily becausePT vaccine which is also injectable has been part of theational immunization programme for many years.

.3. Wait for some new polio vaccine

It may take many years to develop and make it avail-ble for clinical use. The ideal polio vaccine should havei) high immunogenicity, (ii) high genetic stability and (iii)o or low neuropathogenicity. The currently available triva-ent and monovalent oral polio vaccines score low on thesearameters.

Thus time has come to take some tough decisions ratherhan extending the deadline for polio eradication. The oralolio vaccines have brought down the incidence of polio,ut, it has not succeeded in polio eradication. Rather thanlaming those parents who had not administered OPV to theirhildren for failure of eradication programme, it should becknowledged that OPV has not provided the expected resultsn India and is unlikely to succeed in future also. It is difficulto predict that IPV as a tool for mass vaccination will beccepted by the parents and will succeed in polio eradication.

Any new strategy of IPV for mass vaccination, com-ination of trivalent and monovalent oral polio vaccines,ombination of IPV and OPV or a new vaccine should be

ntroduced if it can be ensured that it will work in Bihar andttar Pradesh, otherwise irrepairable damage will occur to

he polio eradication programme and in future really effectiveaccine may not be acceptable to the parents.

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The next step for polio eradication in form of mass vacci-ation with IPV or some new vaccine should be considereds the last and final step. There would certainly be no moreext chance. What do we do till then? This is a challenge forhe policy makers.

. Conclusions

Global polio eradication was launched in 1988, and erad-cation was expected to occur by 2000. Polio had beenradicated from many parts of the world according to the stip-lated schedule, but, in spite of concerted efforts poliovirusransmission could not be stopped in some countries. Theountries which failed to eradicate polio have caused spreadf wild polioviruses to polio free countries from time toime. Presently wild poliovirus is confined to few countriesnly, but global polio eradication cannot be achieved till evenne country harbours wild polioviruses because of the riskf spread of polioviruses to other countries. India happenso be the largest country among the few countries whereolioviruses persist. Thus, India must become polio free tochieve global polio eradication. India cannot become polioree till Bihar and Uttar Pradesh continue to report polio cases.

It can be said that all those factors which have adverseffects on polio eradication, exist in Bihar and Uttar Pradesh.ecause of shortage of electric power, potency of vaccineay be adversely affected. Environmental factors like over-

rowding and poor sanitation help in quick transmission andpread of wild polioviruses in the community. Malnutrition,nter-current infections and some genetic factors in the hosts

ay be responsible for poor response to OPV.There is very high incidence of polio cases in Bihar

nd Uttar Pradesh. Majority of polio cases in other statesre occurring in migratory population from Bihar and Uttarradesh. This indicates that due to some host factors, chil-ren from these two states remain susceptible to polio diseaseven after taking many doses of polio vaccine.

Thus, there is no simple answer as to why OPV has failedo eradicate polio from Bihar and Uttar Pradesh. Similarly,o simple solution can be offered. The dead line for polioradication has been extended many times without givinglausible explanation to people for repeated extensions. Thisas caused damage to our creditability. It should be real-zed that current trivalent and monovalent oral polio vaccinesave bought down the incidence of polio appreciably, but,annot eradicate polio, and IPV or some new vaccine woulde required to achieve polio eradication.

New strategy may not be accepted by people due to lackf trust because of the past record of polio eradication pro-ramme. Before introduction of any vaccine it should bensured that the new vaccine can provide the desired results,

ecause we may not get another chance to change the strategy.

Though, the environmental factors like sanitation, overrowding, health related issues like malnutrition, inter-urrent infections and strategic issues like potency of vaccine,

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oor medical facilities and low participation in vaccinationan be modified and altered, but, presently contributionsade by genetic factors cannot be interfered. Thus a vac-

ine which will be effective in children from Bihar and Uttarradesh is needed. May be two or more different types ofaccines may be required for different people for global polioradication.

Thus, the four challenges before policy makers are:

. Ascertain the role of genetic factors in response to poliovaccines.

. Find a vaccine which is effective in children from Biharand Uttar Pradesh.

. Regain the lost trust of people.

. What do we do till new vaccine becomes available?

cknowledgements

Funding: None.Competing interests: Author is member, National Com-

ittee of Polio Eradication Committee of Indian Academyf Pediatrics.

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