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New Strategies for the Elimination of Polio from India

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The feasibility of global polio eradication is being questioned as a result of continued transmission in a few localities that act as sources for outbreaks elsewhere. Perhaps the greatest challenge is in India, where transmission has persisted in Uttar Pradesh and Bihar despite high coverage with multiple doses of vaccine. We estimate key parameters governing the seasonal epidemics in these areas and show that high population density and poor sanitation cause persistence by not only facilitating transmission of poliovirus but also severely compromising the efficacy of the trivalent vaccine. We analyze strategies to counteract this and show that switching to monovalent vaccine may finally interrupt virus transmission.
Vaccine efficacy and effectiveness. (A) The relative odds of infection with laboratoryconfirmed type 1 paralytic poliovirus in India (bars) plotted against the number of doses of OPV received. These estimates show an exponential decline with the number of doses, consistent with a constant probability of protection per dose of 13% (dashed line). In fact the regression model with a constant vaccine efficacy does not give a significantly worse fit than a model that allows efficacy to vary by number of previous doses (likelihood ratio test, P = 0.11). For this reason, a log-linear regression model is used to estimate per-dose protective efficacy, as described in (6). The error bars indicate 95% confidence intervals. (B) The absolute and relative increase in the average number of doses of OPV received by children less than 5 years old that would be required to achieve the same reduction in the effective reproductive number for poliovirus transmission as a given increase in vaccine efficacy. (C) A contour plot indicating the percentage of all doses of OPV administered that should be monovalent type 1 to minimize the average effective reproductive number of wild poliovirus types 1 and 3, for different relative efficacies of the monovalent versus trivalent vaccine and different relative transmissibility R 0 of type 1 versus type 3 (6). The expected relative efficacy of the monovalent vaccine is between 2 and 2.5 and is highlighted on the plot by the gray rectangle. Below the 0% contour, all doses should be trivalent. In (B) and (C), vaccine efficacy is assumed to be 9%, with an average child having received 15 doses of vaccine, in agreement with data from UP at the end of 2005.
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DOI: 10.1126/science.1130388
, 1150 (2006); 314Science
et al.Nicholas C. Grassly,
India
New Strategies for the Elimination of Polio from
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product was similar to that of unglycosylated
GFP (Fig. 3D), and thus the glycosylation reac-
tion occurred on the folded GFP. Thus, PglB
modified a peptide displayed on a folded protein,
although i t is likely that the grafted loop itself is
relatively flexible.
To check the folding-dependent recog-
nition of consensus sequons by PglB, we ana-
lyzed the PglB-dependent in vitro glycosylation
of the eukaryotic glycoprotein bovine ribonu-
clease A (RNaseA). The native N-glycosylation
site N34 of t his protein i s located in a struc-
tured domain. Different folding variants of the
RNaseA allowed us to analyze the effect of un-
folding on glyco sylation. Cons equently, RNaseA
was expressed with a single point mutation
(S32D), producing a bacterial consensus site
at the native N-glycosylation site N34. Oxida-
tive refolding of RNaseS32D from inclusion
bodies (20) yielded enzymatically active pro-
tein (fig. S3), showing that RNaseS32D was
able to fold into its native conformation despite
the mutation.
Chemical treatments with denaturing, re-
ducing, oxidizing, and alkylating agents yielded
two RNaseS32D oxidation isomers (Fig. 4A).
In reduced and alkylated RNaseS32D (RA), all
four disulfide bonds were reduced in dena-
turing solution, and cysteines were alkylated
to inhibit further disulfide bond formation. Rap-
id oxidation before alkylation led to another set
of oxidatio n isomers, scrambled RNaseS32D
(SC). Scrambled RNases contain randomly oxi-
dized SS bonds, producing a heterogeneous pop-
ulation of proteins. A third RNaseS32D form
was synthesized by limited proteolysis with
subtilisin (20), which removes the N-terminal
21 amino acids of the protein. The resulting
RNase S-protein (SP), like the RA and SC
forms, was enzymatically inactive (fig. S3), but
retained its native disulfide bonds and thus
about 50% secondary structure, whereas the
SC and RA forms appeared as random coils, as
judged from far-ultraviolet circular dichroism
(far-UV-CD) spectroscopy (Fig. 4B) (23). All
four forms served as substrates for PglB (Fig.
4C). Glycosylation of the active RNaseS32D
occurred with low efficiency (Fig. 4C), and the
small amount of glycosylated RNaseS32D was
active, as indicated by the zymogram assay
(20) (Fig. 4C). The other forms were modified
quantitatively (Fig. 4C). Thus, nonstructured
protein domains are better substrates for PglB
glycosylation than are folded ones. No glyco-
sylation at all was observed with the same
substrate proteins that lacked the S32D muta-
tion (fig. S4B).
Our results show that completely folded pro-
teins can be glycosylated both in vivo and in
vitro. Bacterial OTase glycosylates native AcrA
protein as well as an acceptor sequence grafted
into the active GFP protein. In contrast, fully
folded RNaseS32D was weakly glycosylated,
whereas partial or complete unfolding strongly
improved substrate activity .
The observation that the folding states of the
acceptor protein affects glycosylation efficiency
leads us to conclude that a specific substrate
conformation must be adopted during the
glycosylation process, most likely the Asn-turn
(24). This makes potential acceptor sites present
in a fixed environment suboptimal substrates
for the bacterial OTase. We predict that native
glycosylation sites in bacterial proteins will be
located in locally flexible structures.
In contrast, the coupling of glycosylation
and translocation in eukaryotes releases N-
glycosylation from such structural constraints
and, in combination with the less stringent pri-
mary sequence requirement, results in a more
versatile and general glycosylation system.
References and Notes
1. A. Helenius, M. Aebi, Annu. Rev. Biochem. 73,1019
(2004).
2. M. R. Wormald et al., Eur. J. Biochem. 198, 131 (1991).
3. N. Sharon, H. Lis, Essays Biochem. 30, 59 (1995).
4. P. M. Rudd, T. Elliott, P. Cresswell, I. A. Wilson, R. A.
Dwek, Science 291 , 2370 (2001).
5. Y. Kaneko, F. Nimmerjahn, J. V. Ravetch, Science 313,
670 (2006).
6. D. J. Kelleher, R. Gilmore, Glycobiology 16, 47R
(2006).
7. W. Chen, A. Helenius, Mol. Biol. Cell 11, 765 (2000).
8. P. Whitley, I. M. Nilsson, G. von Heijne, J. Biol. Chem.
271, 6241 (1996).
9. M. Chavan, W. Lennarz, Trends Biochem. Sci. 31,17
(2006).
10. G. Bolt, C. Kristensen, T. D. Steenstrup, Glycobiology 15,
541 (2005).
11. N. M. Young et al., J. Biol. Chem. 277, 42530
(2002).
12. M. Wacker et al., Science 298, 1790 (2002).
13. M. Kowarik et al., EMBO J. 25, 1957 (2006).
14. Abbreviations for the amino acid residues are as follows:
D, Asp; N, Asn; Q, Gln; S, Ser; and T, Thr.
15. M. Wacker et al., Proc. Natl. Acad. Sci. U.S.A. 103, 7088
(2006).
16. J. D. Thomas, R. A. Daniel, J. Errington, C. Robinson, Mol.
Microbiol. 39, 47 (2001).
17. J. H. Weiner et al., Cell 93, 93 (1998).
18. A. Rodrigue, A. Chanal, K. Beck, M. Muller, L. F. Wu,
J. Biol. Chem. 274, 13223 (1999).
19. K. J. Glover, E. Weerapana, S. Numao, B. Imperiali,
Chem. Biol. 12, 1311 (2005).
20. Materials and methods are available as supporting
material on Science Online.
21. Y. L. Liu, G. C. Hoops, J. K. Coward, Bioorg. Med. Chem.
2, 1133 (1994).
22. M. R. Abedi, G. Caponigro, A. Kamb, Nucleic Acids Res.
26, 623 (1998).
23. C. Ritter, A. Helenius, Nat. Struct. Biol. 7, 278
(2000).
24. B. Imperiali, T. L. Hendrickson, Bioorg. Med. Chem. 3,
1565 (1995).
25. We thank K. Kolygo and E. Weber-Ban (ETH rich) for
help with the UV-CD measurements, and M. nzler and
Ch. von Ballmos for critical reading of the manuscript.
This work was funded by grants from the Gebert-Rüf
Stiftung, the Swiss National Science Foundation, UBS AG
on behalf of a customer (to M.A.), the rich Glycomics
Initiative (GlycoInit, ETH rich), and the European Union
(grant Flippases MRTN-CT-2004-005330 to M.A).
Supporting Online Material
www.sciencemag.org/cgi/content/full/314/5802/1148/DC1
Materials and Methods
SOM Text
Figs. S1 to S4
Table S1
References
25 August 2006; accepted 9 October 2006
10.1126/science.1134351
New Strategies for the Elimination
of Polio from India
Nicholas C. Grassly,
1
* Christophe Fraser,
1
Jay Wenger,
2
Jagadish M. Deshpande,
3
Roland W. Sutter,
4
David L. Heymann,
4
R. Bruce Aylward
4
The feasibility of global polio eradication is being questioned as a result of continued transmission
in a few localities that act as sources for outbreaks elsewhere. Perhaps the greatest challenge is in
India, where transmission has persisted in Uttar Pradesh and Bihar despite high coverage with
multiple doses of vaccine. We estimate key parameters governing the seasonal epidemics in these
areas and show that high population density and poor sanitation cause persistence by not only
facilitating transmission of poliovirus but also severely compromising the efficacy of the trivalent
vaccine. We analyze strategies to counteract this and show that switching to monovalent vaccine
may finally interrupt virus transmission.
T
he World Health Assembly committed to
the global eradication of polio in 1988.
Since then, the eradication initiative has
achieved great successes, eliminating polio from
the Americas, the Western Pacific, and Europe.
However, in recent years the number of reported
cases has increased after export of infection from
the handful of remaining endemic countries. The
difficulty in eliminating these last reservoirs of
poliovirus transmission has led some to question
the feasibility of eradication (1). Particularly wor-
rying is the ongoing transmission in India, the
source of half the worlds reported paralytic cases
over the past decade. Children in India have re-
1
Department of Infectious Disease Epidemiology, Imperial
College London, Norfolk Place, London, UK.
2
National
Polio Surveillance Project, World Health Organization, New
Delhi, India.
3
Enterovirus Research Centre, Parel, Mumbai,
India.
4
Global Polio Eradication Initiative, World Health
Organization, Geneva, Switzerland.
*To whom correspondence should be addressed. E-mail:
n.grassly@imperial.ac.uk
17 NOVEMBER 2006 VOL 314 SCIENCE www.sciencemag.org1150
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ceived many more doses of vaccine than children
in other endemic countries through an intensive
supplementary immunization program. Under-
standing the cause of polio persistence in India is
a public health priority, both for the elimination
efforts and as a proof of concept for the global
eradication initiative. Potential explanations for
persistence include gaps in routine and sup-
plemental vaccine coverage (2), poor vaccine ef-
ficacy (3), and conditions highly favorable for the
transmission of fecal-oral pathogens, including
high population density and poor sanitation (2, 4).
Here, we examine these hypotheses formally, using
detailed surveillance data from 96,421 cases of
acute flaccid paralysis (AFP) collected since 1997.
The reproductive number R(t) of an infection is
the number of seconda ry infections that result from
a single infectious individual in the population at
time t (5). We estimated R(t) for type 1 poliovirus
transmissio n from the dates of onset of paralysis of
laboratory-confirmed AFP cases and estimates of
the incubation and infectious period (6). Although
only ~1 in 200 cases of wild poliovirus infection
result in paralysis (7, 8), and not all of these cases
are reported, this estimate of R(t) is independent of
the ratio of infections to reported paralytic cases.
The annual variation in the estimated R(t)is
particularly marked, with peak transmission about
150% greater than the annual average, compared,
for example, with about 30% for measles in
industrialized countries (9) (Fig. 1). Despite such
strong seasonal forcing of transmission, sharp
annual peaks in incidence are observed, rather
than the more complex dynamics observed
for some childhood infections (10). This is due
to the long infectious period for fecal-orally
transmitted polio. In contrast to Uttar Pradesh
(UP) and B ihar, the estimated annual average
R( t) for poliovirus transmission outside these
states has remained below one for the past 3
years, indicating that endemic transmission is no
longer supported (Fig. 1C). This is confirmed by
analysis of the genetic sequences of wild polio-
virus isolates from AFP cases, with all genetic
lineages circulating in India since 2003 derived
from lineages circulating in UP in earlier years
(11). The spatiotemporal dynamics of polio in-
cidence now resemble classic sink-source
dynamics (12), with the virus persisting in UP
and Bihar (the source) and expanding during
the high-transmission season to infect other
areas, including major cities such as Mumbai,
but without the establishment of long-term
transmission in these areas (Movie S1).
Why is poliovirus transmission persisting in
UP and Bihar? Logistic regression reveals a sig-
nificant association between continued report-
ing of laboratory-confirmed polio AFP cases by
districts during 2000 to 2005 and (i) population
density, (ii) the prevalence of diarrhea, and (iii)
low routine coverage with three doses of tri-
valent oral polio vaccine (tOPV), after account-
ing for differences in the absolute number of
children in each district (table S1). Those dis-
tricts predicted by the regression model to have
persistent poliovirus transmission are located
mainly in UP and Bihar (Fig. 2). Of course, the
regression simply reveals an association be-
tween these factors and continued reporting of
poliovirus. This may be useful programmatical-
ly to identify those districts at higher risk of
poliovirus transmission. However , there is likely
to be a causal role for high population density,
and the poor sanitary conditions that lead to a
high prevalence of diarrhea, in the persistence
of polio, consistent with the importance of
these risk factors for other fecal-oral pathogens
(13, 14). High population density and poor
sanitation can lead to more frequent infectious
contacts and increase levels of excreted polio-
virus in the environment. Routine immuniza-
tion is also likely to be important, providing the
very young with a dose of tOPV before they
receive doses through supplementary immuni-
zation activities. However, routine immuniza-
tion coverage relies on existing health services
and is therefore confounded by socioeconomic
and sanitary conditions. This is confirmed in
the logistic regression, where the fraction of
households reported to have a latrine was sig-
nificantly associated with polio persistence when
routine coverage was excluded from the analysis
(table S2).
Children in India receive the majority of their
tOPV doses through supplementary immuniza-
tion activities. These have been increasingly fo-
cused on UP and Bihar , such that since 2004,
children in these states were reported to have on
average received more doses of vaccine than
children in other parts of India (Fig. 1, D and E).
In fact, at the end of 2005, children under 5 years
old were reported to have received on average 15
doses of tOPV in UP and Bihar, compared with
10 in the rest of India, and only 4% of children
were reported to have received fewer than 3
doses, of whom 90% were under 6 months old.
Even under conditions highly favorable for the
fecal-oral transmission of wild poliovirus, this
level of vaccine coverage should have eliminated
infection. We therefore estimated the efficacy of
tOPV by comparing the reported number of
doses of vaccine received by polio cases with
nonpolio AFP controls (6). We found a decline in
the relative odds of infection with paralytic polio
with increasing number of doses of tOPV that is
consistent with a constant, but unexpectedly low,
probability of protection per dose (Fig. 3A). The
estimated protective efficacy against type 1 polio-
virus was just 9% per dose in UP, significantly
lower than an estimated 21% per dose in the rest
of India (Table 1). Similar results are obtained for
Fig. 1. Poliovirus and
vaccin ation dynamics,
1997 to 2005. (A)Thees-
timated daily incidence
of laboratory-confirmed
type 1 paralyti c polio-
virus A(t) in UP and Bihar
(red) and the rest of India
(black) . (B and C)The
estimated reproductive
number R(t)in(B)UP
and Bihar and (C) the
rest of India, averaged
over a sliding window of
43 days (the mean infec-
tious period; sol id line)
and over a year (red
bars). The gray areas
and error bars present
the bootstrap 95% con-
fidence intervals about
these estimates. (D)The
distribution of reported
time since last OPV dose
and (E)averagenumber
of OPV doses received
among 0- to 4-year-old
childreninUPandBihar
(red)andtherestofIndia
(black), based on age-
standardized nonpolio
AFP cases. The pulsed
declines in the average
number of doses, and
increases in time sin ce
last OPV dose, closely match the timing of the national immunization days (NIDs) (black arrows) and
subnational immunization days (SNIDs) (green arrows).
www.sciencemag.org SCIENCE VOL 314 17 NOVEMBER 2006 1151
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type 3 poliovirus, although confidence intervals
(CI) are wider , reflecting the lower number of
reported cases. Estimates of vaccine efficacy were
not significantly affected by the period of analysis
ortheyearofonsetofparalysis.
It is well known that trivalent OPV tends to
be less efficacious in developing countries (even
after accounting for vaccine formulation, qual-
ity, and administration) because of host and en-
vironmental problems, particularly interference
with seroconversion by other enteroviruses and
failure of the vaccine virus to establish infection
in children with diarrhea (1517). However, the
per-dose estimate of efficacy for UP is signif-
icantly lower than earlier estimates of ~30%,
based on seroconversion and small case-control
studies in India (15, 1820) [as compared with
~65% in industrialized countries (21)]. Pre-
release potency testing of tOPV used in India
has been satisfactory and loss of potency before
administration is unlikely, because vaccine is
distributed rapidly and vaccine vial monitors
have been used since 1998 to ensure that only
vaccine stored at the right temperature is used.
Vaccine efficacy may be underestimated if con-
trols are less exposed to wild poliovirus than
cases, or if parents overreport the number of
doses of vaccine received by their children.
However, the potential for differences in expo-
sure was minimized by closely matching cases
and controls by location, age, and date of onset
of paralysis, and the matching criteria were
chosen such that estimates of efficacy were ro-
bust to their value (6). Also, although some
over-reporting of doses may occur, sensitivity
analysis demonstrates that a vaccine efficacy
comparable to the ~30% per dose found in
earlier studies would require reporting of four
doses for every one dose received, which is in-
consistent with detailed case investigations.
Instead, the lower efficacy in UP compared with
earlier, mainly urban, studies is likely to be the
result of more severe environmental problems.
This conclusion is supported by the significantly
lower efficacy estimated for tOPV administered
in UP compared with other states where pop-
ulation is less dense and sanitary conditions are
better.
High population densities and poor sanita-
tion therefore appear to explain the persistence
of polio. These factors act to facilitate the trans-
mission not only of poliovirus but also of other
enteroviruses and diarrhea, which interfere with
the live-attenuated oral vaccine. Therefore, de-
spite the higher number of doses received by
children in UP and Bihar, we estimate that only
71% of children under 5 years old in these
states were successfully immunized against
type 1 poliovirus in early 2005, compared with
85% in the rest of India [based on vaccine
coverage estimated from the nonpolio AFP
data (6)].
The government of India and its partners
have responded to this problem with a combi-
nation of new approaches and vaccine strat-
egies. The currently high reported coverage
with tOPVand low vaccine efficacy means that
benefits from increasing vaccine efficacy will
outweigh those from increasing vaccine dis-
tribution (Fig. 3B). For example, doubling the
efficacy of the current vaccine would be equiv-
alent to increasing the average number of doses
received by children in UP and Bihar from 15 to
28. The global eradication of type 2, and the
elimination of type 3 polio cases in recent years
from all of India except a cluster of districts in
western Uttar Pradesh, has motivated the intro-
duction of monovalent vaccine, effective onl y
against type 1 poliovirus, to immunization days
in selected states beginning in April 2005.
Monovalent vaccine has potentially higher
efficacy than the trivalent vaccine because of
the absence of interference with the two other
OPV types (22). However, exclusive use of
monovalent vaccine during immunization days
can put the population at risk of outbreaks of
type 3 poliovirus.
Mathematical analysis shows that the opti-
mal balance of monovalent and trivalent vac-
cine use depends on the relative efficacy of the
monovalent vaccine and the transmissibility
(basic reproductive number R
0
) of type 1 com-
pared with type 3 wild poliovirus (Fig. 3C).
Earlier studies of seroconversion from develop-
ing countries, including India, suggest a relative
monovalent vaccine efficacy between 2.0 and
2.5 times that for trivalent vaccine (15, 22, 23). If
types 1 and 3 were to have equivalent R
0
,then
support for monovalent vaccine use would be
borderline (Fig. 3C). However, the lower inci-
dence of type 3 despite broadly equivalent ef-
ficacy of tOPV against types 1 and 3both in
this study (Table 1) and in developing-country
studies of seroconversion after administration
of balanced formulations of tOPV (15)
suggests a lower transmissibility and/or lower
pathogenicity (case-to-infection ratio) for type 3
(8). Lower transmissibility is consistent with
the observation of a lower prevalence of anti-
bodies against type 3 in India before vaccination
(24, 25). In this case, use of monovalent vaccine
A
B
Regression model prediction
0 - 0.24
0.25 - 0.49
0.5 - 0.74
0.75 - 1
no data
Polio AFP cases by district
0
1
2-4
5-15
>15
Type Number
1 3
UP
Bihar
UP
Bihar
UP
Bihar
Fig. 2. Location of persistent poliovirus transmission in India. (A) Incident laboratory-confirmed
type 1 and type 3 polio cases by district for the period 2000 to 2005. (B) Regression model
estimate of the probability of poliovirus persistence (1 case of polio over 2000 to 2005) in each
district, based on the number and density of children, the reported prevalence of diarrhea, and
routine coverage with three doses of tOPV.
17 NOVEMBER 2006 VOL 314 SCIENCE www.sciencemag.org
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against type 1 is supported, with the amount
distributed depending on the relative trans-
missibility (Fig. 3C). In districts where type 3
has been absent for several ye ars, a greater
fraction of vaccine doses distributed can be
monovalent, depending on the risk of impor-
tation of type 3. In these districts, monovalent
vaccine use has the potential to halve the pop-
ulation susceptible to type 1, assuming that
coverage is maintained at its current level, sub-
stantially increasing the probability of interrupt-
ing transmission.
W ith new vaccine strategies based on careful
use of monovalent vaccine targeted at districts
with high population densities and poor sanita-
tion, the analyses presented here suggest that
wild poliovirus could soon be eliminated from
India. Achieving this goal may also be facilitated
by future improvements in sanitation, which can
reduce transmission of both poliovirus and other
infections that interfere with tOPV. Critical to the
success of these new strategies will be continued
dialogue and engagement with local commu-
nities to ensure high coverage with the appropriate
vaccine.
References and Notes
1. I.Arita,M.Nakane,F.Fenner,Science 312,852
(2006).
2. N. Thacker, N. Shendurnikar, Indian J. Pediatr. 71, 241
(2004).
3. Y. Paul, Vaccine 23, 3097 (2005).
4. P. Webster, Lancet 366, 359 (2005).
5. R. M. Anderson, R. M. May, Infectious Diseases of
Humans: Dynamics and Control (Oxford Univ. Press,
Oxford, 1991).
6. Materials and methods are available as supporting
material on Science Online.
7. J. L. Melnick, N. Led inko, Am. J. Hyg. 58, 207 (1953).
8. K. Penttinen, R. Patiala, Ann. Med. Exp. Biol. Fenn. 39,
195 (1961).
9. D. J. D. Earn, P. Rohani, B. M. Bolker, B. T. Grenfell,
Science 287, 667 (2000).
10. P. Rohani, M. J. Keeling, B. T. Grenfell, Am. Nat. 159,
469 (2002).
11. Centers for Disease Control and Prevention, Morb.
Mortal. Wkly. Rep. 53, 238 (2004).
12. H. R. Pulliam, Am. Nat. 132, 652 (1988).
13. S. R. A. Huttly, S. S. Morris, V. Pisani, Bull. WHO 75, 163
(1997).
14. J. Martines, M. Phillips, R. G. Feachem, in Disease Control
Priorities in Developing Countries, D. T. Jamison, W. H.
Mosely, A. R. Measham, J. L. Bobadilla, Eds. (Oxford Univ.
Press, 1993), pp. 91116.
15. P. A. Patriarca, P. F. Wright, T. J. John, Rev. Infect. Dis.
13, 926 (1991).
16. M. D. Cirne et al., J. Infect. Dis. 171, 1097 (1995).
17. D. L. Posey, R. W. Linkins, M. J. C. Oliveria, D. Monteiro,
P. A. Patriarca, J. Infect. Dis. 175, S258 (1997).
18. V. Balraj, T. John, M. Thomas, S. Mukundan, Int. J.
Epidemiol. 19, 711 (1990).
19. N. Deivanayagam, K. Nedunchelian, S. S. Ahamed,
S. R. Rathnam, Bull. WHO 71, 307 (1993).
20. R. J. Kim-Farley, K. H. Dave, J. Sokhey, V. B. Mandke,
Bull. WHO 67, 663 (1989).
21. R. W. Sutter, O. M. Kew, S. L. Cochi, in Vaccines,
S. A. Plotkin, W. A. Orenstein, Eds. (Saunders, Philadelphia,
ed. 4, 2004), pp. 651705.
22. V. M. Caceres, R. W. Sutter, Clin. Infect. Dis. 33, 531
(2001).
23. T. J. John, L. V. Devararjan, A. Balasubramanyan,
Bull. WHO 54, 115 (1976).
24. B. Sharma et al., Indian J. Pathol. Micr obiol. 29, 101
(1986).
25. S. R. Pal, G. Anerjee, B. K. Aikat, Indian J. Med. Res. 54,
507 (1966).
26. We thank all those involved in AFP surveillance and
laboratory testing, B. Burkholder from the World Health
Organizations Regional Office for South-East Asia, and
J. Truscott, C. Donnelly, T. Johnston, H. Jenkins, P. Gilks,
and H. Khalifeh for advice. Funded by Royal Society
Research Fellowships (to N.C.G. and C.F.).
Supporting Online Material
www.sciencemag.org/cgi/content/full/314/5802/1150/DC1
Materials and Methods
Figs. S1 and S2
Tables S1 and S2
Movie S1
24 May 2006; accepted 5 October 2006
10.1126/science.1130388
Fig. 3. Vaccine efficacy and effectiveness. (A)
The relative odds of infection with laboratory-
confirmed type 1 paralytic poliovirus in India
(bars) plotted against the number of doses of
OPV received. These estimates show an exponen-
tial decline with the number of doses, consistent
with a constant probability of protection per dose
of 13% (dashed line). In fact the regression
model with a constant vaccine efficacy does not
give a significantly worse fit than a model that
allows efficacy to vary by number of previous
doses (likelihood ratio test, P = 0.11). For this
reason, a log-linear regression model is used to
estim ate per-dose protective efficacy, as de-
scribed in (6). The error bars indicate 95% confidence intervals. (B) The absolute and relative
increase in the average number of doses of OPV received by children less than 5 years old that
would be required to achieve the same reduction in the effective reproductive number for poliovirus
transmission as a given increase in vaccine efficacy. (C) A contour plot indicating the percentage of
all doses of OPV administered that should be monovalent type 1 to minimize the average effective
reproductive number of wild poliovirus types 1 and 3, for different relative efficacies of the
monovalent versus trivalent vaccine and different relative transmissibility R
0
of type 1 versus type 3
(6). The expected relative efficacy of the monovalent vaccine is between 2 and 2.5 and is
highlighted on the plot by the gray rectangle. Below the 0% contour, all doses should be trivalent.
In (B) and (C), vaccine efficacy is assumed to be 9%, with an average child having received 15
doses of vaccine, in agreement with data from UP at the end of 2005.
Table 1. Estimates of trivalent OPV efficacy in India, 1997 to 2005. The per-dose protective efficacy
of the vaccine was estimated from the reported number of OPV doses received by polio AFP cases
compared with matched nonpolio AFP controls, using conditional logistic regression (6). Regression
model 1 provides an estimate for all India, whereas model 2 includes an interaction term between
efficacy and location.
Poliovirus
Regression
model
Location Cases Matches
Vaccine efficacy
(%) (95% CI)
Type 1 Model 1 All India 4421 1627 13 (1016)
Model 2 Rest of India 1512 361 21 (1527)
Bihar 387 158 18 (926)
Uttar Pradesh 2522 1108 9 (613)*
Type 3 Model 1 All India 1204 474 13 (718)
Model 2 Rest of India 221 79 21 (833)
Bihar 136 53 22 (436)
Uttar Pradesh 847 342 9 (315)
*Significantly different from rest of India, P < 0.01
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