Pioneering
research conducted in India during the past five decades comprehensively
covered epidemiology of poliovirus infection and of polio, efficacy and
effectiveness of oral polio vaccine (OPV) and inactivated polio vaccine
IPV), as well as pathogenesis of wild and vaccine polioviruses [1-5].
The research findings were essential to explain biomedical barriers
against polio eradication and to overcome them by designing suitable
tactics [1, 2].
When launched in 1988, polio eradication intended
global interruption of only wild poliovirus [WPV] transmission, for
which exclusive use of OPV was prescribed for low and middle income
(LMI) countries [6]. In 2000, the eradication target year, five
countries including India remained polio endemic; initially India’s
failure was attributed to sub-optimal vaccination coverage – ‘failure to
vaccinate’. However, WPV type 2 was interrupted in 1999 proving that
coverage was adequate to eliminate the type against which vaccine
efficacy (VE) of trivalent OPV (tOPV) was satisfactory [1,2,7, 8].
To overcome the barrier of low VE against WPV 1 and 3
— ‘failure of vaccine’ — findings from old research were applied,
reinforced with new studies. Uttar Pradesh (UP) and Bihar had the
world’s lowest VE; success, finally achieved in 2011, proved that
biological barrier to WPV eradication could be overcome everywhere.
Research thus proved key to success.
The scientific definition of eradication as
interruption of poliovirus transmission, wild and vaccine, and the
ideation of using IPV to eradicate vaccine viruses, originated from
Indian research [1,9-11]. They form the basis of ‘Global Polio
Eradication and End Game Strategic Plan 2013-18’ of the World Health
Organization (WHO), attesting to the pioneering nature of our research
[1,9,10,12]. This paper is a look-back on Indian research relevant to
polio elimination nationally and eradication globally.
Measuring the Magnitude of Polio
The model of polio surveillance created in Vellore in
1980 was not nationally up-scaled until 1997 when eradication efforts
were failing [13-15]. The lack of nation-wide surveillance had resulted
in gaps of information on four fronts: the magnitude of polio burden
[13,16-18]; iatrogenic polio [19,20]; barriers to polio
prevention/control [1,2,7]; and vaccine-associated paralytic polio
(VAPP) [21-23].
The annual incidence of WPV infection prior to
vaccine introduction was 48 per 100 pre-school children (range: 63/100
in infancy and 23/100 in 4-year-olds) [24]. Infection occurred in
successive waves of the three WPV types — on average 4% of all stool
samples were positive in urban and 1.52% in rural children, showing
faster spread in towns [2,24,25]. High infection incidence, predictable
age distribution and urban-rural variation of speed of spread, all
suggested child-to-child transmission determined by frequency of
contacts – houses are more crowded in urban and dispersed in rural
communities [24-26].
Different methods measured the prevalence of polio
[13,27]. Using denominator-based annual incidence in Vellore and UP, the
national disease burden was calculated as 200,000-400,000 per year or
500-1000 per day [13,18,23,28]. The age distribution was: median age at
12-15 months and saturation by age 5-7 years; the steepest part of the
curve was during 6 to 12 months when fecal contamination of feeds is
least likely [29, 30]. This pattern is consistent only with direct,
person-to-person instead of chance fecal-oral transmission, and no known
fecally-orally transmitted agent has similar epidemio-logic pattern
[24-30]. No water-borne or food-borne common source polio outbreak,
which should have been inevitable if transmission was mainly fecal-oral,
has occurred in India [26].
Iatrogenic polio had received little attention
[19,20]. Intramuscular injections, particularly diphtheria-pertussis-tetanus
vaccine (DPT), increase the risk of polio paralysis (called provocation
polio) several-fold [19,20]. Under Expanded Program on Immunization
(EPI), launched in 1978, 27 million DPT injections were given in
1978-79, while no child had been given 3 doses of OPV [31]. In the next
3 years, the numbers of DPT injections were 24, 24 and 29 millions,
respectively, while 3 doses of OPV were given only to 0.5, 1.3 and 2.3
millions respectively [31]. After initiating massive scale DPT
injections polio cases (reported through sentinel centers) increased;
this paradoxical rise of polio after launching EPI was presumably on
account of provocation polio [1,2,19, 20].
Extrapolating from European data on frequency of
VAPP, at least 2 cases per million birth cohort was predicted in India
[32]. Using data from polio surveillance in India, international
assessment was very low risk [21]. Re-analysing data using scientific
methodology, 6 cases per million birth cohort — five times higher risk
than in the USA – were found, demanding upward revision the estimated
burden of VAPP in developing countries [22,23]. During 4 decades of
exclusive use of OPV, over 3000 children would have developed VAPP in
India; ethics demanded shifting the policy to IPV [32, 33].
Studies on Vaccine Efficacy of OPV
Until vaccine failure polio was detected in India in
1960s, VE of 3 doses of trivalent OPV (tOPV) was assumed to be 100 per
cent universally [29,34]. In India, antibody induction (seroconversion)
rates were low for types 1 and 3 (~65%), but satisfactory for type 2
(~96%) [7,35]. Closely similar seroconversion rates were confirmed in a
study in Maharashtra; so the problem was widespread [36]. The low VE led
to increasing numbers of vaccine-failure polio as tOPV coverage
increased, posing one more ethical problem [1,2].
Seroconversion after each additional dose was at the
same frequency as after the first dose – a basic phenomenon determining
response to OPV, described first in India [1,2,7,37,38]. The responses
to sequential doses follow arithmetic proportionality and not
prime-boost principle [1,2,7,37,38]. Cumulative VE of multiple doses is
obtained by repetition of per-dose efficacy. Thus, VE of two doses, E2 =
E1 + [E1[100 – E1]], where E1 is per-dose efficacy; VE of three doses,
E3, is E2 + [E1[100 – E2]] [1, 2,37,38]. In this way we calculated the
cumulative VE of 5 doses, which closely matched measured antibody
responses [1,2,37,38]. To match three-dose VE elsewhere, we needed 9-10
doses [2,7]. The fact that WPV transmission was interrupted in most of
India when an average of 8-9 doses per child was reached fits with this
observation [39].
The reason for low antibody response was failure to
establish infection by vaccine viruses in a substantial proportion,
rather than inability to mount immune response after infection
[1,2,7,40]. This was contrary to international opinion that our children
have suboptimal immune responses to oral live vaccines. Did antibodies
in breast milk inhibit intestinal infection with vaccine viruses? [41].
A definitive study showed that such antibodies, although present, did
not interfere with vaccine virus take and immune responses [42].
The contrast of easy natural infection with WPV and
failure to get infected even with a million vaccine virus inoculum, is
probably due to heightened innate immunity consequent to repeated
intestinal infections with various microbes. Innate immunity does
distinguish between wild and vaccine polioviruses [43].
Several solutions to overcome low VE were
successfully tested in Vellore. One was to simply increase the number of
doses per child to five [1,2,37]. The immunogenicity of OPV given to
neonates was tested and found to be non-inferior to immunogenicity at
older ages [44,45]. Thus, five doses could be given under EPI with 5
contacts in infancy starting from the first week of life. Another
solution was to give monovalent OPV; against types 1 and 3, VE of
monovalent vaccine was 2.5 to 3 times higher [46]. A third solution was
pulse immunization, a highly effective method that kept Vellore
polio-free from 1982 [47]. Finally the VE and effectiveness of 2 doses
of IPV were shown to be superior to even 10 doses of OPV [48].
In UP, the per-dose efficacy of tOPV against WPV-1
was only 13%, the lowest recorded anywhere [39]. Indeed, very low VE had
been described in 1970 in New Delhi [49]. Per-dose VE calculated using
the formula described above was 15% against type 1 and 20% against type
3 [31, 49]. In UP, seroconversion after 8 doses of tOPV was only 54% and
65% against types 1 and 3, respectively [50]. Extrapolated, the per-dose
efficacy was 10% and 12% against types 1 and 3, respectively [51]. In UP
and Bihar, WPV transmission could not have been interrupted using tOPV
with such low VE. Comparison of VE of tOPV and monovalent OPV (mOPVs) in
Vellore had shown mOPV with two-and-half times higher VE for types 1 and
3 [46]. Based on that observation, the National Regulatory Authority
licensed mOPV types 1 and 3 [mOPV-1 and mOPV-3] in 2005. The high VE of
mOPV-1 was then confirmed in a fresh study in India [52]. In UP and
Bihar, WPV 1 was eliminated using mOPV-1.
Could mOPV types 1 and 3 be combined as bivalent OPV
(bOPV) without loss of VE of the components? This question was
investigated in India and the result showed non-inferior VE to that of
mOPV given separately [53]. Polio elimination in UP and Bihar was
sustained using bOPV for sub-national pulses, mOPV for mop up, and tOPV
for routine immunization and for national pulse immunization given twice
each year.
Issue of Safety of OPV
The textbook definition of attenuation of vaccine
polioviruses is loss of neurovirulence while retaining efficiency of
infection of the parent WPVs [54,55]. However, there was no evidence for
perceptible local transmission of vaccine viruses in India. We had shown
that attenuation had resulted in considerable loss of infection
efficiency, which would translate to low transmission efficiency between
humans [56]. A novel animal model of poliovirus infection and disease
had been created in India, in bonnet monkey (Macaca radiata)
[1,3-5,56-58]. The median monkey oral infectious dose of attenuated
poliovirus type 1 was 10,000 times higher than that of wild type 1
Mahoney strain [56,57]. Thus, attenuation had indeed reduced infectivity
and transmissibility. This was critical information.
Neurovirulence could be regained by genetic reversion
during virus replication in cell culture or human intestine, explaining
why OPV causes VAPP. Our finding of low infection efficiency begged the
question: would it not also be regained through genetic reversion? It
was reasonable to assume it would. If a strain of vaccine virus regained
both properties, it would be wild-like in neurovirulence and
transmissibility [59,60]. This prediction proved correct in Hispaniola,
where a circulating vaccine-derived poliovirus (cVDPV) type 1 caused a
polio outbreak in 2000 [61]. Since then cVDPV type 2 outbreaks have
occurred in many countries and cVDPV type 1 and 3 infrequently in a few
countries [12]. The continued use of OPV is incompatible with true polio
eradication, as per our definition of zero incidence of wild and vaccine
poliovirus infection [1,9-11].
Vaccine Efficacy and Effectiveness of IPV
Research on IPV continued during 1970s and 1980s only
in Bilthoven (Netherlands) and Vellore (India). Very high VE of IPV (3
doses) in infants was documented in India in early 1980s [62,63]. The
Bilthoven group created an improved version of IPV with higher antigenic
content in early 1980s [64]. We measured its VE – in Vellore it was
named ‘enhanced potency IPV (E-IPV); the VE of two doses was higher than
that of 5 doses of tOPV [48,65]. Seroconversion rates were better in
infants 8 weeks or older at first dose, than in infants 6 weeks old,
and, near 100% when interval between doses was 8 weeks or more, instead
of the conventional 4 weeks [48,65]. Intradermal inoculation was highly
immunogenic [66-68].
In a field study, in nearly 7000 child-years of
observation after IPV, none had polio while in equal number of control
children without IPV, there were 17 cases; vaccine effectiveness was 100
per cent [1,2,25]. In another study, weekly stool samples were collected
from all children in a village, from birth to 3 years. At one point, IPV
was introduced in new birth cohorts and fecal shedding of WPVs were
compared; there was statistically highly significant reduction (1.52% to
0.52%, P<0.001). Retardation of circulation intensity of WPV is
the basis of herd effect; IPV exhibits herd effect, the epidemiological
marker of mucosa immunity [1,2,25,69].
Mucosal immunity of IPV was explored in the animal
model. After immunizing bonnet monkeys with IPV, they were
non-susceptible to oral infection with WPV, for one year [56,57]. In
1986, the Indian Council of Medical Research and the Directorate of
Health Services commissioned a study to measure the degree of control
that could be achieved with IPV in a large population (not published by
sponsoring agencies). The schedule of IPV was a dose at 2, 4 and 9
months. In 2.5 million population under IPV, the incidence of polio fell
from 14 to 0.3 per 100,000 population (97% decline) when the 3-dose
coverage had reached 84 per cent [14,70]. The greater decline relative
to the coverage confirmed herd effect [14,69].
The conclusion from these studies was that IPV is
highly suited for prevention and control of polio in India. In the face
of such important research findings, the exclusive use of OPV during
1980s through 2014 was inconsistent with science and ethics [71-73].
Indian research had predicted the inevitability of introduction of IPV
in India and globally [9-11,71-73]. This principle became reality in
2015 as all LMI countries have started introducing IPV in EPI as a
prelude to withdrawing type 2 vaccine virus, achieved in April 2016 in
globally synchronous manner, according to the current WHO strategic plan
[12].
Research for Solving Problems Towards Elimination of WPV
As WPV elimination was not achieved in 2000,
intensive immunization drive with tOPV was applied to improve coverage
with multiple doses, assuming that failure to vaccinate was the root
cause. By 2005 it became obvious that in UP and Bihar WPVs could not be
eliminated using tOPV, whose VE was too low against types 1 and 3 [39].
The per-dose efficacy was only 13% against type 1 [39]. Early research
had showed high VE of mOPV-1 and 3 [46]. The National Regulatory
Authority granted registration of mOPV-1 and 3 in 2005. A multicentric
vaccine trial with mOPVs confirmed the earlier finding of high VE [52].
With intensive application of mOPV-1, circulation of WPV-1 was
interrupted in January 2011.
While WPV-1 was targeted for elimination, outbreaks
of WPV-3 occurred in Bihar and UP, during 2007-2010. A new bivalent
combination of OPV types 1 and 3 (bOPV) was prepared and its VE was
found to be non-inferior to VE of mOPV-1 and mOPV-3 [53]. In 2010 bOPV
was introduced and UP and Bihar were maintained free of WPV-3 from last
quarter of 2010.
Research in Support of the End Game
In 2013, the target of eradication was expanded to
include vaccine viruses, for which IPV is essential [10,74]. The WHO
Polio Eradication and End Game Strategic Plan 2013-2018 retained the
term Eradication to interrupt WPV and the term End Game to eradicate
vaccine viruses using IPV, the process that had been named Phase 2
Eradication in Indian literature [9,12,73]. The design of End Game is to
introduce at least one dose of IPV in the routine immunization schedule,
at the time of the third dose of diphtheria-pertussis-tetanus vaccine
and tOPV, followed by the global synchronous withdrawal of type 2 strain
from tOPV. This process, called tOPV to bOPV switch would result in two
contributions to End Game: there will be no more VAPP due to type 2 and
the source of cVDPV-2 will be shut-off.
The immunization schedule in the early End Game
period will be bOPV at birth and at 6, 10 and 14 weeks plus one dose of
IPV at 14 weeks. This schedule is new and its immunogenicity has been
tested in India in a multicentre vaccine trial and confirmed to be
highly satisfactory [75]. The seroconversion rates were 99% to types 1
and 3, and 69-78% to type 2. A second dose of IPV closed completely the
immunity gap [75]. Earlier research had shown that one dose of IPV given
to children who had received several doses of OPV was sufficient to
cover any immunity-gap and to boost both humoral and mucosal immunity
[76].
Epilogue
Research in India on polio was far-sighted,
comprehensive and pioneering, presaging polio eradication. However, the
application of research findings in policy and programme for control and
final eradication of polio in India itself was unduly delayed. An
important observation from this saga is a serious fault line in India
between science and health-related policy. It is hoped that Government
will take note and avoid such disconnect between evidence and policy in
all other disease control programmes.
1. John TJ. Understanding the scientific basis of
preventing polio by immunization: Pioneering contributions from India.
Proc Indian Natl Sci Acad. 2003;B69:393-422.
2. John TJ. Immunisation against polioviruses in
developing countries, Rev Med Virol. 1993;3:149-160.
3. John TJ, Nambiar A, Samuel BU, Rajasingh J. Ulnar
nerve inoculation of poliovirus in the bonnet monkey: a new primate
model to investigate neurovirulence. Vaccine. 1992;10:529-32.
4. Ponnuraj EM, John TJ, Levin MJ, Simoes EAF. Sabin
attenuated LSc/2ab strain of poliovirus spreads to the spinal cord from
a peripheral nerve in bonnet monkeys [Macaca radiata]. J Gen
Virol. 2001;82:1329-38.
5. Samuel BU, Ponnuraj EM, Singh R, John TJ.
Experimental poliomyelitis in bonnet monkeys. Clinical features,
virology and pathology. Develop Biol Standard. 1993;78:71-8.
6. Forty First World Health Assembly. Global
Eradication of Poliomyelitis by the Year 2000. Geneva. World Health
Organization; 1988.
7. John TJ, Jeyabal P. Oral polio vaccination of
children in the tropics. 1. The poor seroconversion rates and absence of
viral interference. Am J Epidemiol. 1972; 96:263-9.
8. John TJ. Polio eradication: bringing science to
public health. Indian J Med Res. 2007;126:91-3.
9. John TJ. Can we eradicate poliomyelitis? In.
Sachdev HPS, Choudhury P, eds. Frontiers in Pediatrics. New Delhi:
Jaypee Brothers: 1996. p. 76-90.
10. John TJ, Vashishtha VM. Eradicating vaccine
polio-viruses: why, when and how? Indian J Med Res. 2009;130:491-4.
11. John TJ. Common strategy and flexible tactics in
our war on polioviruses. Public Health Rev. 1993;21:151-2.
12. Global Polio Eradication Initiative. Polio
Eradication and Endgame Strategic Plan 2013-2018. Geneva: World Health
Organisation; 2013.
13. Joseph B, Ravikumar R, John M, Natarajan K,
Steinhoff MC, John TJ. Comparison of techniques for the estimation of
the prevalence of poliomyelitis in developing countries. Bull WHO.
1983;61:833-7.
14. John TJ, Samuel R, Balraj V, John R. Disease
surveillance at district level: a model for developing countries.
Lancet. 1998;352:58-61.
15. John TJ. Polio eradication at cross roads. Indian
Pediatr. 1998;35:307-10.
16. Gharpure PV. Poliomyelitis – a problem in India.
J Postgrad Med. 1963;9:1-20.
17. Jhala CI, Goel RKD, Dave SK, Dave AD. Morbidity
due to poliomyelitis in urban and rural areas of Gujarat in pediatric
population – a house to house survey. Indian Pediatr. 1976;13:821-5.
18. John TJ. Poliomyelitis in India. Problems and
prospects of control. Rev Infect Dis. 1984; 6:S432-41.
19. Wyatt HV. Provocation of poliomyelitis by
multiple injections. Trans Royal Soc Trop Med Hyg. 1985;79:355-8.
20. John TJ. Did India have the world’s largest
outbreak of poliomyelitis associated with injections of adjuvanted DPT?
Indian Pediatr. 1998;35:73-5.
21. Kohler KA, Banerjee K, Hlady WG, Andrus JK,
Sutter RW. Vaccine-associated paralytic poliomyelitis in India during
1999: decreased risk in spite of massive use of oral poliovaccine. Bull
WHO. 2002;80:210-6.
22. John TJ. Vaccine-associated paralytic
poliomyelitis in India. Bull WHO. 2002;80: 917.
23. John TJ. A developing country perspective on
vaccine-associated paralytic poliomyelitis. Bull WHO. 2004;82: 53-8.
24. John TJ, Kamath KR, Feldman RA, Christopher S.
Infection and disease in a group of south Indian families. IX.
Poliovirus infection among preschool children. Indian J Med Res.
1970;58:551-5.
25. John TJ, Selvakumar R, Balraj V, Rajarathinam A.
Field studies using killed poliovirus vaccine. In: Proceedings of
the Third International Seminar on Vaccination in Africa, Niger.
Association for the Promotion of Preventive Medicine, Paris. 1987. p.
173-81.
26. John TJ. Anomalous observations on IPV and OPV
vaccination. Dev Biol. 2001; 105;197-208.
27. John TK, John TJ. Is poliomyelitis a serious
problem in developing countries? The Vellore Experience. J Trop Pediatr.
1980;28:11-6.
28. Basu RN. Magnitude of problem of poliomyelitis in
India. Indian Pediatr. 1981; 18:507-11.
29. Ratnaswamy L, John TJ, Jadhav M. Paralytic
poliomyelitis: Clinical and Virological Studies. Indian Pediatr. 1973;
10: 443-7.
30. Hovi UT, John TJ. Poliomyelitis. In:
Lankinen KS, Bergstrom S, Makela PH, Peltomaa M (eds) Health and Disease
in Developing Countries. London: Macmillan Press: 1994. P.
247-54.
31. John TJ. National immunisation policy – A
critical review. In: Epidemiology in Medicine, Ed. Menon GN, Interline
Publishing, Bangalore, 1992; p.75-83.
32. John TJ. Oral polio vaccine. How safe is safe?
Curr Sci. 2000;79:687-9.
33. John TJ. Lessons from the polio eradication
campaign. Seminar. 2012;631:16-20.
34. John TJ. Problems with oral polio vaccine in
India. Indian Pediatr. 1972;9:252-6.
35. Patriarca PA, Wright PF, John TJ. Factors
affecting the immunogenicity of oral poliovirus vaccine in developing
countries. Rev Infect Dis. 1991;13: 926-39.
36. Pangi NS, Master JM, Dave KH. Efficacy of oral
poliovaccine in infancy. Indian Pediatr. 1977;14:523-8.
37. John TJ. Antibody response of infants to five
doses of oral polio vaccine. British Med.J. 1976;667:811-2.
38. John TJ, Vashishtha VM. Polio vaccination in
Pakistan. Lancet . 2012;380:1645.
39. Grassly NC, Fraser C, Wenger J, Deshpande JM,
Sutter RM, Heymann D, Aylward RB. New strategies for the elimination of
poliomyelitis from India. Science. 2006;314:1150-3.
40. John TJ. Oral polio vaccination in children in
the tropics. 2. Antibody response in relation to vaccine virus
excretion. Am J Epidemiol. 1975;102:414-21.
41. John TJ, Devarajan LV. Poliovirus antibody in
milk and sera of lactating women. Indian J Med Res. 1973;61: 1009-12.
42. John TJ, Devarajan LV, Luther L, Vijayaratnam P.
Effect of breast feeding on seroresponse of infants to oral poliovirus
vaccination. Pediatrics. 1976;57:47-53.
43. Mohanty MC, Deshpande JM. Differential induction
of Toll-like receptors and type 1 interferons by Sabin attenuated and
wild type 1 polioviruses in human neuronal cells. Indian J Med Res.
2013;138:209-18.
44. John TJ. Immune response of neonates to oral
poliomyelitis vaccine. British Med J. 1984;289: 881.
45. John TJ. Polio vaccination of the newborn. Indian
J Pediatr. 1985;52:385-6.
46. John TJ, Devarajan LV, Balasubramanian A.
Immunisation in India with trivalent and monovalent oral poliovirus
vaccines of enhanced potency. Bull WHO. 1976;54:115-7.
47. John TJ, Pandian R, Gadomski A, Steinhoff MC,
John M, Ray M. Control of poliomyelitis by pulse immunization in
Vellore. British Med J. 1983;286:31-2.
48. Simoes EA, Padmini B, Steinhoff MC, Jadhav M,
John TJ. Antibody response of infants to two doses of inactivated
poliovirus vaccine of enhanced potency. Am J Dis Child. 1985;139:977-80.
49. Ghosh S, Kumari S, Balaya S. Antibody response to
oral poliovaccine in infancy. Indian Pediatr. 1970; 7:780-1.
50. Hasan A, Malik A, Shukla I, Malik MA. Antibody
levels to polioviruses in children after pulse polio immunization.
Indian Pediatr. 2004;41:1040-4.
51. John TJ. Antibody response to pulse polio
immunization in Aligarh. Indian Pediatr. 2005;42:91-2.
52. John TJ, Jain H, Ravishanker K, Amaresh A, Verma
H, Dewshpande J, et al. Monovalent type 1 oral poliovirus vaccine
among infants in India. Report of two randomized double-blind controlled
clinical trials. Vaccine. 2011;29:5793-807.
53. Sutter R, John TJ, Jain H, Agarkhedkar S, Ramanan
PV, Verma H, Deshpande J, et al. Immunogenicity of bivalent types
1 and 3 oral poliovirus vaccine: a randomized, double-blind, controlled
trial. Lancet. 2010;376:1682-8.
54. Monto AS. The epidemiology of viral infections.
In: Topley and Wison’s Microbiology and Microbial Infections, 9th
Edition, Volume 1. London: Arnold Publishers; 1998. p. 235-57.
55. Jamison DT, Torres AM, Chen LC, Melnick JL.
Poliomyelitis. In: Jamison DT, Mosly WH, Measham AR, Bobadilla
JL. Disease Control Priorities in Developing Countries, Eds DT Jamison,
WH Mosly, AR. Oxford: Oxford University Press; 1993. p. 117-29.
56. Selvakumar R, John TJ. Intestinal immunity
induced by inactivated poliovirus vaccine. Vaccine. 1987;5:141-4.
57. Selvakumar R, John TJ. Intestinal immunity to
poliovirus develops only after repeated infections in monkeys. J Med
Virol. 1989;27:112-6.
58. Ponnuraj EM, John TJ, Levin MJ, Simoes EAF. Cell
to cell spread of poliovirus in the spinal cord of bonnet monkeys (Macaca
radiata). J Gen Virol. 1998;79: 2393-403.
59. John TJ. Poliovirus attenuation and
neurovirulence: a conceptual framework. Dev Biol Standa. 1983;78:117-9.
60. John TJ. The final stages of the global
eradication of polio. New Eng J Med. 2000;343:806-7.
61. Kew O, Morris-Glasgow V, Landaverde M, Bernes C,
Shaw J, Garib Z, et al. Outbreak of poliomyelitis in Hispaniola
associated with circulating type 1 vaccine-derived poliovirus. Science.
2002;296;356-9.
62. Krishnan R, Jadav M, Selvakumar R, John TJ.
Immune response of infants in tropics to injectable poliovaccine. Brit
Med J. 1982;284:164-5.
63. Krishnan R, Jadhav M, John TJ. Efficacy of
inactivated poliovirus vaccine in India. Bull WHO. 1983;61:689-92.
64. van Wezel AL, van Steenis G, van der Marcel P,
Osterhaus AD. Inactivated poliovirus vaccine: current production methods
and new developments. Rev Infect Dis. 1984;6:S335-40.
65. Simoes EA, John TJ. The antibody response of
seronegative infants to inactivated poliovirus vaccine of enhanced
potency. Dev Biol Stand. 1986;14: 127-31.
66. Samuel BU, Cherian T, Sridharan G, Mukundan P,
John TJ. Immune response to intradermally injected inactivated
poliovirus vaccine. Lancet. 1991;338:343-4.
67. Samuel BU, Cherian T, Rajasingh J, Raghupathy P,
John TJ. Immune response of infants to inactivate dpoliovirus vaccine
given intradermally. Vaccine. 1992;10: 135.
68. Nirmal S, Cherian T, Samuel BU, Rajasingh J,
Raghupathy P, John TJ. Immune response of infants to fractional doses of
intradermally administered inactivated poliovirus vaccine. Vaccine.
1998;16:928-31.
69. John TJ, Samuel R. Herd immunity and herd effect.
New insights and definitions. Eur J Epidemiol. 2000;16:601-6.
70. John TJ. The golden jubilee of vaccination
against poliomyelitis. Indian J Med Res. 2004;119:1-17.
71. John TJ. Towards a national policy on
poliomyelitis. Indian Pediatr. 1981;18: 503-6.
72. John TJ. Immunization against poliomyelitis.
Present concepts and practice. Indian J Public Health. 1985;29:162-7.
73. John TJ. Role of injectable and oral polio
vaccines in polio eradication. Expert Rev Vacc. 2009;8:5-8.
74. John TJ. Will India need inactivated poliovirus
vaccine (IPV) to complete polio eradication? Indian J Med Res.
2005;122:365-7.
75. Sutter RW, Behl S, Deshpande JM, Verma H, Verma
H, Ahmad M, et al. Immunogenicity of a new routine vaccination
schedule for global poliomyelitis prevention: an open label, randomized
controlled trial. Lancet. 2015;386:2413-21.
76. Estivariz CF, Jafari H, Sutter RW, John TJ, Jain
V, Agarwal A, et al. Immunogenicity of supplemental doses of
poliovirus vaccines for childrenaged 6-9 months in Moradabad, India. A
community based randomized controlled trial. Lancet Infect Dis.
2011;12:128-35.