Fractional Doses of Inactivated Poliovirus Vaccine in Oman

new england
journal of medicine
The
established in 1812
june 24, 2010
vol. 362 no. 25
Fractional Doses of Inactivated Poliovirus Vaccine in Oman

Ali Jafer Mohammed, M.D., Salah AlAwaidy, M.D., Shyam Bawikar, M.D., M.P.H.,
Padmamohan J. Kurup, M.D., M.P.H., Emadaldin Elamir, M.D., M.P.H., Mahmoud M.A. Shaban, M.D.,
Sharif M. Sharif, M.D., M.R.C.S., Harrie G.A.M. van der Avoort, Ph.D., Mark A. Pallansch, Ph.D.,
Pradeep Malankar, M.D., Anthony Burton, B.S., Meghana Sreevatsava, M.P.H.,
and Roland W. Sutter, M.D., M.P.H.T.M.
A BS T R AC T
Background
We conducted a clinical trial of fractional doses of inactivated poliovirus vaccine administered to infants in Oman, in order to evaluate strategies for making the vaccine
affordable for use in developing countries.
Methods
We compared fractional doses of inactivated poliovirus vaccine (0.1 ml, representing one fifth of a full dose) given intradermally with the use of a needle-free jet
injector device, with full doses of vaccine given intramuscularly, with respect to immunogenicity and reactogenicity. Infants were randomly assigned at birth to receive
either a fractional dose or a full dose of inactivated poliovirus vaccine at 2, 4, and
6 months. We also administered a challenge dose of monovalent type 1 oral poliovirus vaccine at 7 months and collected stool samples before and 7 days after administration of the challenge dose.
From the Ministry of Health, Oman

(A.J.M., S.A., S.B., P.J.K., E.E., M.M.A.S.,
S.M.S.); the National Institute for Public
Health and the Environment, Bilthoven,
the Netherlands (H.G.A.M.A.); the Centers for Disease Control and Prevention,
Atlanta (M.A.P.); and the World Health
Organization, Geneva (P.M., A.B., M.S.,
R.W.S.). Address reprint requests to Dr.
Sutter at 20 Ave. Appia, CH-1211, Geneva
27, Switzerland, or at sutterr@who.int.
N Engl J Med 2010;362:2351-9.
Copyright 2010 Massachusetts Medical Society.
Results
A total of 400 infants were randomized, of whom 373 (93.2%) fulfilled the study
requirements. No significant baseline differences between the groups were detected. Thirty days after completion of the three-dose schedule, the rates of seroconversion to types 1, 2, and 3 poliovirus were 97.3%, 95.7%, and 97.9%, respectively,
in the fractional-dose group, as compared with 100% seroconversion to all serotypes
in the full-dose group (P=0.01 for the comparison with respect to type 2 poliovirus;
results with respect to types 1 and 3 poliovirus were not significant). The median
titers were significantly lower in the fractional-dose group than in the full-dose
group (P<0.001 for all three poliovirus serotypes). At 7 months, 74.8% of the infants in the fractional-dose group and 63.1% of those in full-dose group excreted
type 1 poliovirus (P=0.03). Between birth and 7 months, 42 hospitalizations were
reported, all related to infectious causes, anemia, or falls, with no significant difference between vaccination groups.
Conclusions
These data show that fractional doses of inactivated poliovirus vaccine administered
intradermally at 2, 4, and 6 months, as compared with full doses of inactivated
poliovirus vaccine given intramuscularly on the same schedule, induce similar levels of seroconversion but significantly lower titers. (Current Controlled Trials number, ISRCTN17418767.)
n engl j med 362;25 nejm.org june 24, 2010
The New England Journal of Medicine

Downloaded from www.nejm.org on September 21, 2010. For personal use only. No other uses without permission.
Copyright 2010 Massachusetts Medical Society. All rights reserved.
2351
The
n e w e ng l a n d j o u r na l
n 1988, the world health assembly resolved to eradicate poliomyelitis by the year
2000.1 Substantial progress toward this goal
has been made, although eradication remains elusive. One poliovirus serotype, wild poliovirus type
2, has apparently been eradicated, with the last
isolation reported in India in October 1999.2 The
number of countries in which the presence of
wild poliovirus was never interrupted decreased
to 4 in 2009 (from more than 125 polio-endemic
countries in 1988), and the number of cases of
poliomyelitis decreased by more than 99% during
the same period.3,4
As the eradication efforts accelerated, the preparations for the posteradication era intensified
in parallel. A critical decision to stop the routine
use of oral poliovirus vaccine was proposed in
19975 and was endorsed in 2004 by the Advisory
Committee on Polio Eradication (ACPE).6 The prerequisites for cessation of the use of the oral poliovirus vaccine have been elaborated,7 the vaccination options have been identified,8 and the
risks for paralytic disease after cessation of the
use of the oral poliovirus vaccine have been quantified.9
In 2007, the ACPE added to the list of prerequisites a requirement for an affordable inactivated poliovirus vaccine that would be appropriate for use in developing countries.10 The current
weighted average purchase prices per dose of vaccine, when purchased by the United Nations Childrens Fund (UNICEF), are $0.15 for the trivalent
oral poliovirus vaccine and approximately $3 for
the inactivated poliovirus vaccine. To realize an
affordable inactivated poliovirus vaccine, a number of strategies are being pursued, including a
schedule reduction (the administration of fewer
doses in a routine schedule); a reduction of the
antigen dose (i.e., fractional-dose inactivated poliovirus vaccine); the use of adjuvants, resulting
in a decreased need for antigen; optimization of
production processes (i.e., increasing cell densities, creating new cell lines, or using alternative
inactivation agents); and the development of an
inactivated poliovirus vaccine produced from
Sabin strains that would be appropriate for production in developing countries. Undoubtedly, the
most important of these options in the near term
is the development of an inactivated poliovirus
vaccine produced from Sabin strains.11-13
One approach to stretching the available supplies of inactivated poliovirus vaccine and reducing the cost per vaccination, with a potential for
2352
of
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rapid implementation, is antigen-sparing through

intradermal delivery. The intradermal route of
administration to improve immunogenicity and
achieve a reduction in cost has been evaluated
for many vaccines.14-19 The intradermal administration of inactivated poliovirus vaccine was first
evaluated by Salk.20,21 More recently, in small studies conducted in India, fractional-dose inactivated
poliovirus vaccine given intradermally resulted in
seroconversion rates that were similar to those
achieved with the full-dose vaccine.22-24
One potential problem associated with intradermal injection is the difficulty of administering
the vaccine reliably with a needle and syringe.
Several devices are in development to permit reliable intradermal delivery, and several needle-free
devices are now available for investigational use.
Inactivated poliovirus vaccine administered intramuscularly with the use of jet injectors has previously been shown to elicit satisfactory immune
responses.25,26
Because the immunogenicity of inactivated poliovirus vaccine is greatly affected by the levels of
maternally derived antibodies,27,28 a clinical study
design was selected in which newborns were enrolled and were vaccinated at 2, 4, and 6 months
of age with either fractional doses or full doses
of inactivated poliovirus vaccine.
Me thods
Study Objectives and Protocol
The study had four objectives: to compare humoral antibody responses (seroconversion and antibody titer) after completion of a three-dose schedule of fractional-dose inactivated poliovirus vaccine
with the responses after completion of a threedose schedule of full-dose inactivated poliovirus
vaccine; to evaluate the dose-specific immune responses; to assess mucosal immunity after a threedose schedule of inactivated poliovirus vaccine;
and to determine adverse events after vaccination
with either fractional-dose or full-dose inactivated
poliovirus vaccine.
Oral or written informed consent for the participation of the newborns was obtained from
parents in accordance with ethical principles, including the Declaration of Helsinki. The study was
approved by the Ministry of Health in Oman, the
institutional review board of the Ministry of
Health in Oman, and the ethics review committee of the World Health Organization (WHO) in
Geneva and was carried out in compliance with

Fr actional Doses of Inactivated Poliovirus Vaccine in Oman
Good Clinical Practice guidelines. GlaxoSmithKline donated the study vaccines, and Bioject provided the needle-free devices, disposables, and
regulatory documents and assisted with the training of the study staff. Neither company had any
role in the design of the study, the accrual or
analysis of the data, or the preparation of the
manuscript. All authors vouch for the completeness and accuracy of the data and analyses presented.
The field work of the study was conducted
between March 1, 2007, and December 31, 2007,
in five sites in Oman (Salalah, Dhofar Governorate; Sohar, North Batinah Governorate; Musanah
and Rustaq, South Batinah Governorate; and Sur,
Sharqiyah Governorate).
Study Design
Expectant mothers and prospective fathers were

contacted during prenatal visits. They were provided information about the study and asked
whether they were willing to participate. Newborns were eligible for participation if oral or
written informed consent was obtained from the
parents, if the infants Apgar score at 5 minutes
was 9 or 10, if the infants birth weight was at
least 2.5 kg, if the infant was healthy (not requiring hospitalization), and if the family was not
planning to move out of the study area during the
study period. Infants were excluded if a diagnosis
or suspicion of immunodeficiency disorder in the
infant or a family member was revealed.
Infants were randomly assigned to receive either the fractional-dose inactivated poliovirus vaccine (0.1 ml, representing one fifth of a full dose)
or the full-dose inactivated poliovirus vaccine
(0.5 ml) at 2, 4, and 6 months of age. Both vaccines were produced by GlaxoSmithKline and
were formulated to contain at least 40 D-antigen
units of poliovirus serotype 1 (Mahoney strain),
8 D-antigen units of poliovirus serotype 2 (MEF-1
strain), and 32 D-antigen units of poliovirus serotype 3 (Saukett strain). When the infants were
7 months of age, they were administered a challenge dose of monovalent type 1 oral poliovirus
vaccine (GlaxoSmithKline) formulated to contain
at least 106 median cell-culture infectious doses
(CCID50) of Sabin poliovirus type 1. The vaccines
were shipped under appropriate cold-chain conditions from the manufacturer to Muscat.29
Inactivated poliovirus vaccine was administered
either intradermally with the use of a needle-free
device (Biojector 2000, Bioject) or intramuscularly
with the use of an auto-disable syringe and needle. The needle-free device was approved by the
Food and Drug Administration for intramuscular and subcutaneous administration and on a
case-by-case basis for investigational intradermal
administration with the use of a spacer.30-35 Parents were aware of the study-vaccination assignment of their children.
After vaccination, study personnel observed the
infants for 30 minutes to monitor immediate adverse events. The infants were administered liquid paracetamol, and instructions were given to
parents to administer 50 mg every 8 hours for
3 days. Infants were evaluated for adverse events
through home visits conducted at 24 hours after
each vaccination by qualified medical staff members who were aware of the study-vaccination assignments. In addition, a hospital discharge survey was conducted to capture all hospitalization
events in the study population. All other routine
antigens (diphtheria and tetanus toxoids, pertussis, Haemophilus influenzae type b, and hepatitis B)
were administered concurrently, with the use of
a pentavalent combination vaccine.
At 7 months of age, all the infants received a
dose of monovalent type 1 oral poliovirus vaccine.
Stool samples were collected before and 7 days
after administration of the monovalent type 1 vaccine. Because one site stored the stool samples in
the refrigerator instead of the freezer for some
time, we excluded those samples from the analyses. Stool samples were analyzed according to
WHO guidelines36 at the National Institute for
Public Health and the Environment, Bilthoven,
the Netherlands.
Blood specimens were collected at birth (cord
blood) and at 2, 4, 6, and 7 months. An automated
single-use heel-stick device (Tenderfoot, International Technidyne) was used to collect the blood
specimens from the infant. After coagulation, the
serum was separated, frozen, and stored at the
study site (or at the central stores in the capital)
at 20C until shipment to the Centers for Disease
Control and Prevention (CDC). The specimens
were tested in triplicate with the use of modified
neutralization assays for antibodies to types
1, 2, and 3 poliovirus27,37 by laboratory staff who
were unaware of the vaccination group of the infants whose specimens they were analyzing. The
initial dilution was a reciprocal titer of 8. Seropositivity was defined as a reciprocal titer of at
least 8.27,37 Seroconversion was defined as an increase by a factor of 4 in the antibody titer over the

2353
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400 Subjects underwent randomization
200 Were assigned to full-dose group
200 Were assigned to fractional-dose

group
6 Were withdrawn before

study vaccination
7 Were withdrawn before

study vaccination
193 Started study vaccination
194 Started study vaccination
7 Discontinued study
6 Had protocol violation
1 Moved
7 Discontinued study
6 Had protocol violation
1 Moved
186 (93.0%) Completed all study requirements and were included in analysis
187 (93.5%) Completed all study requirements and were included in analysis
Figure 1. Randomization and Treatment of Infants.

Infants in the fractional-dose group were administered the vaccine intradermally with the use of a needle-free
device; infants in the full-dose group were administered the vaccine intramuscularly.
expected decline in the titer of maternally derived

antibodies in a successive specimen. In addition,
if an infant did not undergo seroconversion according to this definition, the infant was also
evaluated for seroconversion after all three doses
had been administered (at 2, 4, and 6 months) or
after any two consecutive doses (doses administered at 2 and 4 months or at 4 and 6 months).
The half-life of antibody decay was assumed to be
28 days. In the case of infants who were seroneg
ative, a change to seropositive in a successive
specimen was considered to indicate seroconversion.
At the end of the study, the parents of infants
assigned to the fractional-dose group were administered a brief questionnaire that inquired whether they preferred a needle and syringe or a needle-free injection device for the administration
of a vaccine.
Statistical Analysis
We calculated that with a minimum sample size

of 139 infants in each of the two study groups,
the study would have the power to determine the
noninferiority of the fractional-dose inactivated
poliovirus vaccine as compared with the full-dose
2354
inactivated poliovirus vaccine, with a noninferiority threshold of an absolute value of 20%, at a twosided alpha level of 0.05 and a beta level of 0.10.
Statistical analyses were performed with the
use of the R38 and SAS39 statistical software packages. Comparisons of the proportion of infants
in each group who underwent seroconversion
were performed with the use of Yates-corrected
chi-square tests. The differences in the distribution of antibody titers were tested with the use
of the KolmogorovSmirnov nonparametric method.40 We calculated the 95% confidence intervals around the median values.41
R e sult s
Study Population
A total of 400 parents consented to have their infants enrolled in the trial. Cord blood was collected from all 400 newborns. A total of 13 infants
were withdrawn from the study between birth and
the first vaccination visit at 2 months of age because the parents refused to have their infants
continue in the study (12 infants) or because the
family moved out of the study area (1). Another
14 were withdrawn or excluded during the remain-

der of the study period because of a protocol violation (12 infants, of whom 1 received an incorrect vaccine and 11 were replacements for other
infants who had left the study and were therefore
not allowed to be included in the protocol analysis), because the family moved out of the study area
(1), or because an insufficient amount of serum
was collected (1). A total of 373 infants (93.2%)
completed all the study requirements (Fig. 1).
Baseline Characteristics and Seroprevalence
After random assignment to either the fractional-dose group or the full-dose group, the infants
in the two groups did not differ significantly with
respect to baseline characteristics, seroprevalence,
or titers of poliovirus antibodies. Seroprevalence
was 97.9% in the fractional-dose group and 98.4%
in the full-dose group for type 1 poliovirus; 95.7%
and 96.8%, respectively, for type 2 poliovirus; and
82.9% and 78.0%, respectively, for type 3 poliovirus (Table 1).
Table 1. Baseline Characteristics of the Infants Enrolled in the Study,

According to Study Group.*
Characteristic
Male sex no./total no. (%)
Fractional Dose
(N=187)
94/187 (50.3)
Full Dose
(N=186)
98/186 (52.7)
Birth weight kg
Median
3.19
3.17
95% CI
3.123.29
3.103.23
Interval from birth to study vaccine

administration days
Median
62
62
95% CI
6162
6262
Type 1 poliovirus
Seroprevalence at birth %
Reciprocal titer median (95% CI)
97.9
98.4
228 (181287)
325 (205456)
95.7
96.8
144 (91181)
144 (114228)
Type 2 poliovirus
Type 3 poliovirus
Seroconversion
The rates of seroconversion to types 1, 2, and

3 poliovirus after completion of the three-dose
inactivated poliovirus vaccine schedule were 97.3%,
95.7%, and 97.9%, respectively, in the fractional-dose group, as compared with 100% for all
serotypes in the full-dose group; the only significant difference was for seroconversion to
type 2 (P=0.01) (Table 2). Among infants who
underwent seroconversion, there were significant
differences in median titers according to serotype
or study treatment (Table 2). At the end of the
study, the overall median reciprocal titers in the
fractional-dose group were less than half those in
the full-dose group (Fig. 2). The dose-specific seroconversion rates according to treatment group
are shown in Table 3.
The presence of maternally derived antibodies
was a risk factor for failure to undergo seroconversion to all three poliovirus serotypes in the
fractional-dose and full-dose groups. On the basis of the antibody distribution, we stratified the
maternally derived antibody in quartiles and then
calculated stratified seroconversion rates for each
quartile according to the study treatment. For each
poliovirus serotype, there was a significant association between higher quartiles of maternally derived antibodies and lower seroconversion rates.
Seroconversion was not significantly affected by
birth weight or sex.
82.9
78.0
29 (2336)
23 (2336)
* None of the differences between the groups were significant at the 0.05 level.
CI denotes confidence interval.
Seroprevalence refers to a reciprocal antibody titer of 8 or higher.
Poliovirus Excretion after Challenge Dose
At 7 months of age, all infants received a challenge

dose of monovalent type 1 oral poliovirus vaccine.
Virus isolation data are summarized in Table 4.
The stool excretion data presented here include
data from 312 infants from three governorates.
All the poliovirus isolates in this study were vaccine-related poliovirus. Before the challenge with
monovalent type 1 oral poliovirus vaccine, a total
of four infants excreted poliovirus (in the fractional-dose group, one infant excreted type 2 and
one excreted type 3; in the full-dose group, one
excreted a mixture of types 1 and 3, and one excreted type 2). At day 7 after administration of the
monovalent type 1 oral poliovirus vaccine, 74.8%
of the infants in the fractional-dose group excreted type 1 poliovirus, as compared with 63.1%
in the full-dose group (P=0.03).
Adverse Events after Vaccination
A total of 42 serious adverse events (all requiring

hospitalization) were recorded in the study population 18 in the fractional-dose group and 24

2355
The
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Table 2. Rates of Seroconversion after Completion of a Three-Dose Schedule of Inactivated Poliovirus Vaccine
and Median Reciprocal Titers of Antibodies at the 7-Month Visit among Infants Who Underwent Seroconversion,
According to Study Group.*
Fractional Dose
(N=187)
Vaccination Response
Full Dose
(N=186)
P Value
Type 1 poliovirus
Seroconversion %
97.3
100
0.07
228 (144287)
724 (575912)
<0.001
95.7
100
0.01
287 (228456)
1149 (9121149)
<0.001
Type 2 poliovirus
Seroconversion %
Type 3 poliovirus
Seroconversion %
97.9
100
0.13
362 (287456)
1448 (14481448)
<0.001
* The doses of inactivated poliovirus vaccine were administered at 2, 4, and 6 months. Seroconversion was defined as an
increase by a factor of 4 in the antibody titer over the expected value given the decline in the titer of maternally derived
antibodies of a successive specimen. CI denotes confidence interval.
in the full-dose group (P=0.40). The events were

related to infectious causes (39 events, of which
the vast majority were diarrhea or upper respiratory infection, with no significant differences between the groups), anemia (1), and falls (2). Five
hospitalizations (11.9% of the events) occurred
when the infants were between birth and 2 months
of age, before the administration of any study vaccine. There were no significant between-group differences in serious adverse events. Other than the
42 hospitalizations, there were no adverse events
of any degree of severity that were considered to
have been related to participation in the study.
Assessment of Treatment Preference
The parents of infants enrolled in the study were

administered a questionnaire during the last study
visit. Of 187 eligible parents, 185 (98.9%) responded. When asked about their preference with respect to the method of administration of the next
vaccination, 8 parents (4.3%) preferred vaccination
with the use of needle and syringe, 172 (93.0%)
preferred the needle-free device, and 5 (2.7%) expressed no preference.
Discussion
This trial in Oman represents a large-scale evaluation of fractional-dose inactivated poliovirus vaccine administered intradermally at 2, 4, and
6 months of age with the use of a needle-free device. Our findings suggest that fractional-dose in2356
activated poliovirus vaccine given intradermally

with the use of a needle-free device results in rates
of seroconversion to all poliovirus serotypes that
are similar to those achieved with full-dose inactivated poliovirus vaccine given intramuscularly;
however, the median titers were significantly lower in the fractional-dose group than in the fulldose group. In addition, after a challenge with
monovalent type 1 oral poliovirus vaccine, a significantly higher proportion of infants in the fractional-dose group than in the full-dose group excreted virus. Both routes of administration were
well tolerated, and no adverse events were attributable to the trial intervention.
These results confirm earlier findings that suggested that intradermal administration of fractional doses could result in high seroconversion
rates.22-24 Although the median titers in both
groups were high, the median titers in the fractional-dose group were less than half those in the
full-dose group. These titers were achieved despite a routine policy in Oman of providing vaccinated infants with paracetamol, a drug that was
shown in one study to blunt the effect of the vaccine.42 Since any detectable titer would be expected
to prevent paralytic disease,43 and the median titers in the fractional-dose group are similar to
those reported in previous studies of full-dose
inactivated poliovirus vaccine,44 it is unlikely that
the differences in titer between the two groups in
our study would have practical implications.45,46
A somewhat higher proportion of infants in

Table 3. Rates of Seroconversion, According to Vaccine Dose and Study

Group.*
A Type 1 Poliovirus
10
Full-dose
vaccine
Median Titer
Seroconversion
P Value
no./total no. (%)

Fractional-dose
vaccine
Before first vaccination at 2 mo

Dose 1
Dose 2
Birth
NS
19/184 (10.3)
40/182 (22.0)
0.005
110/165 (66.7) 125/142 (88.0)
<0.001
Dose 3
48/55 (87.3)
2/7 (28.6)
17/17 (100)
NS
NS
5/184 (2.7)
0/182 (0)
NS
2/187 (1.1)
6/186 (3.2)
NS
31/185 (16.8)
57/180 (31.7)
0.001
103/154 (66.9) 106/123 (86.2)
<0.001
Type 2 poliovirus
Full-dose
vaccine
4/186 (2.2)
Other
None
10
3/187 (1.6)
After vaccination
B Type 2 Poliovirus
Median Titer
Full Dose
Type 1 poliovirus
Month

After vaccination
6
Fractional-dose
vaccine
Dose 1
Dose 2
Dose 3
Other
2
Birth
Month
Full-dose
vaccine
8
6
Fractional-dose
vaccine
4
2
Birth
17/17 (100)
NS
0/8 (0)
NS
0/180 (0)
0.01
1/187 (0.5)
3/186 (1.6)
NS
Dose 1
17/186 (9.1)
82/183 (44.8)
<0.001
Dose 2
117/169 (69.2)
93/101 (92.1)
<0.001
Dose 3
48/52 (92.3)
8/8 (100)
Other
0/4 (0)
NS
4/186 (2.2)
0/183 (0)
NS
Type 3 poliovirus
After vaccination
10
43/51 (84.3)
8/185 (4.3)
None
C Type 3 Poliovirus
Median Titer
Fractional Dose
None
NS
* Seroconversion was defined as an increase by a factor of 4 in the antibody titer over the expected value given the decline in the titer of maternally derived
antibodies of a successive specimen. NS denotes not significant.
Other indicates seroconversion after doses 1 and 2, 2 and 3, or 1, 2, and 3.
Month
Figure 2. Overall Median Titers of Types 1, 2, and

3 Poliovirus, According to the Infants Age and Study
Group.
I bars indicate 95% confidence intervals.
the fractional-dose group than in the full-dose

group excreted poliovirus type 1 after the administration of a challenge dose of monovalent type
1 oral poliovirus vaccine. The practical implications of this finding are unclear.
Nevertheless, in terms of antigen content used
(a factor that greatly affects the production cost),
three fractional doses add up to 0.3 ml, representing three fifths of a full dose. Even if we were to
aim for 100% seroconversion with four fractional

doses instead of three full doses, the cost per infant vaccinated with inactivated poliovirus vaccine
would be less than $3 with the fractional-dose
vaccine, as compared with $9 for the full-dose vaccine, a savings of $6 per vaccinated infant. The cost
for a four-dose fractional inactivated poliovirus
vaccine would still be substantially higher than
that of a three-dose trivalent oral poliovirus vaccine schedule (which is approximately $0.45).
However, in order to achieve in the developing
world levels of seroconversion with trivalent oral
poliovirus vaccine that are the same as those
achieved with inactivated poliovirus vaccine, supplemental doses of trivalent oral poliovirus vaccine

2357
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Table 4. Excretion of Poliovirus Serotypes and Nonpolio Enteroviruses, before and after a Challenge with Monovalent
Oral Poliovirus Vaccine, According to Study Group.*
Vaccine
Type 1
Poliovirus
Type 2
Poliovirus
Type 3
Poliovirus
Nonpolio
Enteroviruses
Negative
number/total number (percent)

Fractional dose
Before challenge
7 Days after challenge
1/156 (0.6)
1/156 (0.6)
27/156 (17.3)
127/156 (81.4)
116/155 (74.8)
1/155 (0.6)
1/155 (0.6)
7/155 (4.5)
31/155 (20.0)
1/159 (0.6)
1/159 (0.6)
1/159 (0.6)
28/159 (17.6)
128/159 (80.5)
99/157 (63.1)
1/157 (0.6)
14/157 (8.9)
43/157 (27.4)
Full dose
Before challenge
7 Days after challenge
* All the poliovirus isolates in this study were vaccine-related poliovirus.

There was a significant difference between the groups in the proportion of infants who excreted type 1 poliovirus at
7 days after the challenge (P=0.03).
One infant excreted both type 1 and type 3 poliovirus.
One infant excreted both type 1 and type 2 poliovirus.
would be needed, thus narrowing the differences

in vaccine costs between the two approaches.
The intradermal administration of fractional
doses of inactivated poliovirus vaccine appears to
be safe and preferred by parents and health care
providers. A questionnaire administered to parents of infants in the fractional-dose group reported a strong preference for this route of administration. When the parents were asked why they
preferred intradermal administration, the vast majority of parents responded with a comment that
the baby does not cry. The number of hospitalizations recorded during the course of our study
probably reflects a sensitive health care system
that errs on the side of being conservative and
hospitalizes infants with minor ailments.
Our study has several limitations. First, we did
not evaluate whether a fractional-dose inactivated
poliovirus vaccine given intramuscularly would
have yielded results similar to those seen with
the fractional-dose given intradermally. Second,
although we captured serious adverse events, we
were not able to capture local or systemic adverse
events that occurred after the home visit that took
place 24 hours after the vaccination (unless these
resulted in hospitalization); in another study,
a combination of redness and induration (mostly
<5 mm) developed in some infants after intra
dermal administration of the vaccine.47 Finally, we
cannot exclude the possibility that some infants
enrolled in the study were exposed secondarily to
trivalent oral poliovirus vaccine, which is used
routinely in Oman. However, as indicated by both
seroconversion data between birth and 2 months
2358
of age and the prechallenge viral isolation data,

the level of such exposure was probably low and
would have affected both study groups equally and
thus should not substantially affect the interpretation of the results.
Our study shows that intradermal administration of a fractional-dose inactivated poliovirus vaccine could serve as a dose-sparing strategy when
used in a primary routine vaccination schedule
in which doses are administered at 2, 4, and
6 months of age. Other approaches to lowering
the production cost of vaccination (i.e., optimization of the production process, the use of alternative inactivation agents, and the use of adjuvants)
or decreasing the number of doses of inactivat
ed poliovirus vaccine (e.g., a two-dose schedule)
should continue to be evaluated.
Supported by the Ministry of Health, Oman, the Program for
Appropriate Technology in Health (PATH), Seattle, and the
World Health Organization, Geneva.
Financial and other disclosures provided by the authors are
available with the full text of this article at NEJM.org.
Potency data were provided by GlaxoSmithKline and the national regulatory authority in Belgium. GlaxoSmithKline donated the study vaccines and Bioject, Portland, Oregon, provided
the needle-free devices, disposables, and regulatory documents
and assisted with the training of the study staff.
We thank the study staff from the field sites of Rustaq (Musanah), Sohar, Salalah, and Sur hospitals and polyclinics; the Omani
families who participated in this study; Mr. Salem Al Mahrooqi
and the staff from the Expanded Program on Immunization and
Central Vaccine Store in the Department of Communicable Disease Surveillance and Control; Debbie Moore, Barbara Anderson,
and Naomi Dybahl-Sissokko at the Centers for Disease Control
and Prevention, Atlanta, for performing the serology tests; and
Sabine van der Sanden, Ran Zhang, Gokhan Uslu, Edin Jusuc and
Ron Altena at the National Institute for Public Health and the
Environment, Bilthoven, the Netherlands, for conducting the
stool isolation.


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new england

june 24, 2010

vol. 362 no. 25

Fractional Doses of Inactivated Poliovirus Vaccine in Oman

From the Ministry of Health, Oman

The New England Journal of Medicine

rapid implementation, is antigen-sparing through

n engl j med 362;25 nejm.org june 24, 2010

The New England Journal of Medicine

Fr actional Doses of Inactivated Poliovirus Vaccine in Oman

Expectant mothers and prospective fathers were

n engl j med 362;25 nejm.org june 24, 2010

The New England Journal of Medicine

400 Subjects underwent randomization

200 Were assigned to full-dose group

200 Were assigned to fractional-dose

6 Were withdrawn before

7 Were withdrawn before

193 Started study vaccination

194 Started study vaccination

Figure 1. Randomization and Treatment of Infants.

expected decline in the titer of maternally derived

We calculated that with a minimum sample size

n engl j med 362;25 nejm.org june 24, 2010

The New England Journal of Medicine

Fr actional Doses of Inactivated Poliovirus Vaccine in Oman

Table 1. Baseline Characteristics of the Infants Enrolled in the Study,

Interval from birth to study vaccine

The rates of seroconversion to types 1, 2, and

Reciprocal titer median (95% CI)

Poliovirus Excretion after Challenge Dose

At 7 months of age, all infants received a challenge

A total of 42 serious adverse events (all requiring

n engl j med 362;25 nejm.org june 24, 2010

The New England Journal of Medicine

in the full-dose group (P=0.40). The events were

The parents of infants enrolled in the study were

activated poliovirus vaccine given intradermally

n engl j med 362;25 nejm.org june 24, 2010

The New England Journal of Medicine

Fr actional Doses of Inactivated Poliovirus Vaccine in Oman

Table 3. Rates of Seroconversion, According to Vaccine Dose and Study

no./total no. (%)

Before first vaccination at 2 mo

110/165 (66.7) 125/142 (88.0)

103/154 (66.9) 106/123 (86.2)

Before first vaccination at 2 mo

Figure 2. Overall Median Titers of Types 1, 2, and

the fractional-dose group than in the full-dose

aim for 100% seroconversion with four fractional

n engl j med 362;25 nejm.org june 24, 2010

The New England Journal of Medicine

number/total number (percent)

* All the poliovirus isolates in this study were vaccine-related poliovirus.

would be needed, thus narrowing the differences

of age and the prechallenge viral isolation data,

n engl j med 362;25 nejm.org june 24, 2010

The New England Journal of Medicine

Fr actional Doses of Inactivated Poliovirus Vaccine in Oman

the year 2000. Geneva: World Health Organization, 1988.

and antibody response. Scand J Infect Dis

duces potent cellular and humoral immune

n engl j med 362;25 nejm.org june 24, 2010

The New England Journal of Medicine