Articles

Safety and immunogenicity of inactivated poliovirus vaccine

schedules for the post-eradication era: a randomised
open-label, multicentre, phase 3, non-inferiority trial
Ananda S Bandyopadhyay, Chris Gast, Luis Rivera, Xavier Sáez-Llorens, M Steven Oberste, William C Weldon, John Modlin, Ralf Clemens,
Sue Ann Costa Clemens, Jose Jimeno, Ricardo Rüttimann

Summary
Background Following the global eradication of wild poliovirus, countries using live attenuated oral poliovirus vaccines Lancet Infect Dis 2021;
will transition to exclusive use of inactivated poliovirus vaccine (IPV) or fractional doses of IPV (f-IPV; a f-IPV dose is 21: 559–68

one-fifth of a normal IPV dose), but IPV supply and cost constraints will necessitate dose-sparing strategies. We Published Online
October 23, 2020
compared immunisation schedules of f-IPV and IPV to inform the choice of optimal post-eradication schedule.
https://doi.org/10.1016/
S1473-3099(20)30555-7
Methods This randomised open-label, multicentre, phase 3, non-inferiority trial was done at two centres in Panama For the Spanish translation of the
and one in the Dominican Republic. Eligible participants were healthy 6-week-old infants with no signs of febrile abstract see Online for
illness or known allergy to vaccine components. Infants were randomly assigned (1:1:1:1, 1:1:1:2, 2:1:1:1), using appendix 1
computer-generated blocks of four or five until the groups were full, to one of four groups and received: two doses of Polio, Global Development,
intradermal f-IPV (administered at 14 and 36 weeks; two f-IPV group); or three doses of intradermal f-IPV Bill & Melinda Gates
Foundation, Seattle, USA
(administered at 10, 14, and 36 weeks; three f-IPV group); or two doses of intramuscular IPV (administered at 14 and (A S Bandyopadhyay MBBS,
36 weeks; two IPV group); or three doses of intramuscular IPV (administered at 10, 14, and 36 weeks; three IPV J Modlin MD); Biostatistics
group). The primary outcome was seroconversion rates based on neutralising antibodies for poliovirus type 1 and Consultant, Seattle,
Washington, USA (C Gast PhD);
type 2 at baseline and at 40 weeks (4 weeks after the second or third vaccinations) in the per-protocol population to
Hospital Maternidad Nuestra
allow non-inferiority and eventually superiority comparisons between vaccines and regimens. Three co-primary Señora de la Altagracia,
outcomes concerning poliovirus types 1 and 2 were to determine if seroconversion rates at 40 weeks of age after a Santo Domingo, Dominican
two-dose regimen (administered at weeks 14 and 36) of intradermally administered f-IPV were non-inferior to a Republic (L Rivera MD);
Department of Infectious
corresponding two-dose regimen of intramuscular IPV; if seroconversion rates at 40 weeks of age after a two-dose IPV
Disease, Hospital del Niño
regimen (weeks 14 and 36) were non-inferior to those after a three-dose IPV regimen (weeks 10, 14, and 36); and if Dr José Renán Esquivel,
seroconversion rates after a two-dose f-IPV regimen (weeks 14 and 36) were non-inferior to those after a three-dose Panama City, Panama
f-IPV regimen (weeks 10, 14, and 36). The non-inferiority boundary was set at –10% for the lower bound of the two- (X Sáez-Llorens MD,
J Jimeno MD); Division of Viral
sided 95% CI for the seroconversion rate difference. Safety was assessed as serious adverse events and important
Diseases, National Center for
medical events. This study is registered on ClinicalTrials.gov, NCT03239496. Immunization and Respiratory
Diseases, CDC, Atlanta, GA, USA
Findings From Oct 23, 2017, to Nov 13, 2018, we enrolled 773 infants (372 [48%] girls) in Panama and the Dominican (M S Oberste PhD,
W C Weldon PhD); Global
Republic (two f-IPV group n=217, three f-IPV group n=178, two IPV group n=178, and three IPV group n=200).
Research in Infectious Diseases,
686 infants received all scheduled vaccine doses and were included in the per-protocol analysis. We observed non- Rio de Janeiro, Brazil
inferiority for poliovirus type 1 seroconversion rate at 40 weeks for the two f-IPV dose schedule (95·9% [95% CI (R Clemens MD,
92·0–98·2]) versus the two IPV dose schedule (98·7% [95·4–99·8]), and for the three f-IPV dose schedule (98·8% S A Costa Clemens); and
Fighting Infectious Diseases in
[95·6–99·8]) versus the three IPV dose schedule (100% [97·9–100]). Similarly, poliovirus type 2 seroconversion rate at Emerging Countries, Miami,
40 weeks for the two f-IPV dose schedule (97·9% [94·8–99·4]) versus the two IPV dose schedule (99·4% [96·4–100]), FL, USA (R Ruttimann MD)
and for the three f-IPV dose schedule (100% [97·7–100]) versus the three IPV dose schedule (100% [97·9–100]) were Correspondence to:
non-inferior. Seroconversion rate for the two f-IPV regimen was statistically superior 4 weeks after the last vaccine dose Dr Ananda S Bandyopadhyay,
in the 14 and 36 week schedule (95·9% [92·0–98·2]) compared with the 10 and 14 week schedule (83·2% [76·5–88·6]; Polio, Global Development,
Bill & Melinda Gates Foundation,
p=0·0062) for poliovirus type 1. Statistical superiority of the 14 and 36 week schedule was also found for poliovirus
Seattle, WA 98119, USA
type 2 (14 and 36 week schedule 97·9% [94·8–99·4] vs 10 and 14 week schedule 83·9% [77·2–89·2]; p=0·0062), and ananda.bandyopadhyay@
poliovirus type 3 (14 and 36 week schedule 84·5% [78·7–89·3] vs 10 and 14 week schedule 73·3% [65·8–79·9]; gatesfoundation.org
p=0·0062). For IPV, a two dose regimen administered at 14 and 36 weeks (99·4% [96·4–100]) was superior a 10 and
14 week schedule (88·9% [83·4–93·1]; p<0·0001) for poliovirus type 2, but not for type 1 (14 and 36 week schedule
98·7% [95·4–99·8] vs 10 and 14 week schedule 95·6% [91·4–98·1]), or type 3 (14 and 36 week schedule 97·4% [93·5–99·3]
vs 10 and 14 week schedule 93·9% [89·3–96·9]). There were no related serious adverse events or important medical
events reported in any group showing safety was unaffected by administration route or schedule.

Interpretation Our observations suggest that adequate immunity against poliovirus type 1 and type 2 is provided by
two doses of either IPV or f-IPV at 14 and 36 weeks of age, and broad immunity is provided with three doses of f-IPV,
enabling substantial savings in cost and supply. These novel clinical data will inform global polio immunisation
policy for the post-eradication era.

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Funding Bill & Melinda Gates Foundation.
Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
Introduction
For decades, trivalent oral poliovirus vaccines (OPV;
poliovirus type 1, type 2, and type 3) were the preferred
vaccines for polio control and eradication, with trivalent
inactivated poliovirus vaccine (IPV) exclusively used in a
few high-income countries until 2000.1 Use of these
vaccines has driven the progress toward global eradication
of wild polioviruses.2 Eradication of wild poliovirus type 2
was declared on Sept 20, 2015, with the last reported case
in October 1999, and the eradication of wild poliovirus
type 3 was declared on Oct 17, 2019, following the
last reported case in November, 2012. Since 2017, wild
poliovirus type 1 cases have only been reported in
Afghanistan (14 cases in 2017, 21 cases in 2018, 29 cases in
2019, and 47 cases to date in 2020) and Pakistan (eight cases
in 2017, 12 cases in 2018, 147 cases in 2019, and 73 cases to
date in 2020).3
After the certification of global wild poliovirus type 2
eradication, the WHO Strategic Advisory Group of Experts
on Immunisation (SAGE) recommended global with­
drawal of live type 2 poliovirus vaccines from all use from
May, 2016, replacing trivalent OPV with bivalent OPV
(types 1 and 3), and the inclusion of at least one dose of
IPV in routine infant schedules. This dose of IPV is the
only source of immunity against poliovirus type 2; it is
administered to prevent paralysis because of the risks
Research in context
Evidence before this study
The declaration of eradication of wild poliovirus type 3 on
October 17, 2019 means only the continuing circulation of wild
poliovirus type 1 in Afghanistan and Pakistan confounds the
goal of global eradication of wild polioviruses. Once eradication
is achieved current planning suggests that children will still
need to be immunised against polio for at least another decade
primarily because of the ongoing threat posed by circulating
vaccine-derived polioviruses. To accomplish this strategy while
removing the source of circulating vaccine-derived polioviruses
will require the replacement of all routine use of oral poliovirus
vaccines (OPV) with inactivated poliovirus vaccines (IPV).
Because the manufacturing capacity of IPV is currently
inadequate for projected global demand and their cost makes
them unaffordable for many low-income countries, WHO and
associated bodies have recommended use of fewer doses or
fractional doses of IPV (f-IPV) administered intradermally.
We searched PubMed from the inception of the database until
April 27, 2020, using the terms “polio”, “vaccine”, “fractional”,
and “immunogenicity”. We found 20 reviews and clinical
studies in which f-IPV was used as priming or booster doses, but
few of these were clinical studies in which f-IPV was used for the
full infant primary immunisation series.
560
associated with circulating vaccine-derived polioviruses.3,4
Areas with low vaccination coverage, where homotypic
wild polioviruses have been eliminated, with epidemiologic
conditions—such as low socio­ economic status, poor
hygiene and sanitation, and high population density—that
favour poliovirus transmission are at increased risk of
circulating vaccine-derived poliovirus outbreaks caused by
reverted strains of live attenuated vaccine virus that have
regained trans­missibility and neurovirulence.5 Since the
global cessation of routine use of poliovirus type 2 Sabin
OPV, an increasing number of circulating vaccine-derived
poliovirus type 2 outbreaks have been reported. The
number of reported circulating vaccine-derived poliovirus
outbreaks more than tripled from nine between Jan 1, 2017
and June 30, 2018 to 29 between Jan 1, 2018 and June 30,
2019.6 This has led the WHO to designate these outbreaks
as a Public Health Emergency of International Concern.
Several clinical trials have contributed data to the
evidence base to support the adoption of combined
bivalent OPV and IPV schedules.7–11 Most low-income
countries now include one IPV dose with their bivalent
OPV primary series. IPV introduction was delayed in
approximately 40 low risk countries because of restricted
global manufacturing capacity resulting in supply con­
straints. Faced with supply and cost constraints the
WHO SAGE and regional Technical Advisory Groups
Added value of this study
The present study was done specifically to investigate the
responses to two or three doses of f-IPV in polio vaccine-naive
infants as primary vaccinations, and to directly compare these
with equivalent schedules using full dose IPV. By using a
delayed schedule we were also able to assess the effect of the
timing of these vaccinations on the immune responses, and the
influence of pre-existing maternal antibodies on the final
immunogenicity.
Implications of all the available evidence
This study provides the first clear and direct comparison of f-IPV
with full-dose IPV as primary immunisation of infants against
poliovirus in delayed schedules. It confirms that
immunogenicity can be conferred using f-IPV doses to make
such dose-sparing immunisations affordable in low-income
and middle-income countries provided the immunisation
schedule is adapted to ensure maternal antibodies do not
interfere with the response. As such, it will inform policy makers
to formulate future immunisation recommendations following
global eradication of wild-type polioviruses and cessation of all
OPV use.
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recommended alternative IPV vaccination schemes be
introduced, including intradermal application of fractional
IPV (f-IPV) doses rather than full-dose IPV.12,13 Although
the supply situation has improved,14 the potential global
withdrawal of all OPV following the declaration of global
eradication of all wild-type polioviruses will necessitate
increased use of IPV or f-IPV as the sole source of
poliovirus immunity for infants.
Alfaro-Murillo and colleagues15 have suggested that
OPV withdrawal could be done in regions, such as the
Americas, where paralytic disease is entirely caused by
vaccine-associated paralytic poliomyelitis and circulating
vaccine-derived polioviruses. There is no risk of vaccine-
associated paralytic poliomyelitis or emergence of
vaccine-derived poliovirus associated with IPV use.
Alfaro-Murillo and colleagues15 also acknowledged that a
switch from OPV to IPV in some regions will be difficult
to achieve because of cost and the shortfall in supply of
IPV. This highlights the urgent need for scientific
evidence to clarify the optimal IPV scheme to implement
for the long term, following cessation of all OPV use.
This study aimed to compare immune responses to
intramuscular full-dose IPV with intradermal f-IPV in
two different schedules in poliovirus-naive infants in
Panama and the Dominican Republic where there have
been no wild poliovirus or detectable circulating vaccine-
derived polioviruses transmission since the 2000–01
outbreak.16 Infant vaccination sche­dules vary between the
two countries. In 2014, Panama replaced OPV with
hexavalent (diphtheria-tetanus-pertussis-hepatitis B-IPV-
Haemophilus influenzae type b) combi­nation vaccine for
the three dose infant schedule, with bivalent OPV
boosters at 18 months and 4 years of age. Whereas, the
Dominican Republic uses IPV at 2 months followed by
bivalent OPV at 4, 6, 18 months, and 4 years of age.
Absence of any outbreak response use of poliovirus type
2 OPV in these two countries provided an ideal
epidemiological setting to study poliovirus vaccine
immunogenicity that simulates the post-OPV era.
Methods
Study design and participants
This randomised, open-label, multicentre, phase 3, non-
inferiority trial was done at two urban sites in Panama and
one urban site in the Dominican Republic. Eligible
participants were healthy 6-week-old infants with no signs
of febrile illness or known allergy to vaccine components.
Infants were excluded if they had received previous
poliovirus vaccination, had a known HIV infection, had
any blood disorder contraindicating intramuscular or
intradermal injections, or if any household contacts had
been vaccinated with OPV in the previous 4 weeks.
Institutional Review Boards of each study centre and
the respective national committees approved the study
protocol. Parents or guardians of all participating infants
provided signed informed consent before enrolment and
the study was done according to International Council
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Articles
for Harmonisation and Good Clinical Practice guidelines.
The trial is registered on ClinicalTrials.gov, NCT03239496.
Randomisation and masking
At enrolment infants were randomly assigned (1:1:1:1,
1:1:1:2, or 2:1:1:1) in varying block sizes of four or five to
one of four vaccination schedules: three IPV doses (three
IPV group), two IPV doses (two IPV group), three f-IPV
doses (three f-IPV group), or two f-IPV doses (two f-IPV
group). Study nurses were trained in the injection
technique for intradermal administration. Because of the
nature of the trial assessing four different vaccination
schedules, admin­istrators, nurses giving the vaccine, and
the infants and their parents or guardians were not
masked to treatment allocation, but laboratory staff
responsible for measuring the immunogenicity out­
comes for the primary outcomes were masked to
treatment group and timepoint the sample was taken.
Procedures
The study vaccine was a WHO-prequalified Salk IPV
vaccine (Poliomyelitis Vaccine [Inactivated], Serum
Institute of India, Pune, India), which is representative of
all available IPV vaccines. Each 0·5 mL dose contained
40 D antigen units Mahoney strain (poliovirus type 1),
8 D antigen units MEF-1 strain (poliovirus type 2), and
32 D antigen units Saukett strain (poliovirus type 3),
2·5 mg of 2-phenoxyethanol, and up to 12·5 μg of
formaldehyde. Full intramuscular IPV doses were
administered in the anterolateral aspect of the thigh using
a standard needle and syringe. Fractional doses, one-fifth
of the full dose presented in 0·1 mL, were administered
intradermally in the upper arm using a 0·1 mL autodisable
syringe. Vaccines were administered to the two f-IPV
group on weeks 14 and 36; to the three f-IPV group on
weeks 10, 14, and 36; to the two IPV group on weeks 14
and 36 weeks; and to the three IPV group on weeks 10, 14,
and 36. For this study infants in both countries received
the same routine vaccines in the same schedules (figure 1).
This was necessary because the standard hexavalent IPV-
containing combi­nation vaccine had to be replaced with a
pentavalent one (diphtheria, tetanus, whole-cell pertussis,
hepatitis B, and Haemophilus influenzae type b) to allow
the IPV and f-IPV vaccines to be administered separately.
When necessary, the polio vaccines were administered
concomitantly with routine infant vaccines (pentavalent
combination, pneumococcal, rotavirus, and influenza),
which were administered according to the national
immuni­ sation recommendations (figure 1). Infants in
the two-dose groups (the two IPV group and the
two f-IPV group) received additional IPV vaccinations
after the study to ensure they met these requirements.
Infants were monitored for 30 min after vacci­nation,
then parents recorded solicited local reactions (pain,
induration, and redness) and body temperature for 7 days;
unsolicited adverse events were monitored throughout the
study in e-diaries. Parents were to immediately report the
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Concomitant routine vaccinations Study polio vaccinations
DTwP-HBV-Hib at weeks 6, 10 & 14 Three IPV group
+ Rota & Pneumo at weeks 6 & 14
Two IPV group
Three f-IPV group
Two f-IPV group
Enrolled
Weeks 6 10 14 18
Blood sampling
Three IPV group All All
and three f-IPV group groups groups
Figure 1: Study design
The experimental study schedule used in the four study groups in both the Dominican Republic and Panama illustrating the administration of IPV and f-IPV, the
concomitant routine vaccinations, and the blood sampling timepoints for assessment of poliovirus neutralising antibodies. IPV was administered intramuscularly. f-IPV
was administered intradermally. f-IPV was one-fifth of a normal IPV dose. IPV=inactived poliovirus vaccine. f-IPV=fractional-inactived poliovirus vaccine.DTwP=diptheria-
tetanus-whole-cell pertussis vaccine. HBV=hepatitis B vaccine. Hib=Haemophilus influenzae type b vaccine. Rota=rotavirus vaccine. Pneumo=pneumococcal vaccine.
occurrence of any serious adverse events or important
medical events throughout the duration of the study.
Serious adverse events were defined as death or events that
were either life-threatening, required hospitalisation, or
resulted in persistent or significant disability or incapacity.
Important medical events were medically significant
See Online for appendix 2 events defined in the protocol (appendix 2) that did not
meet any serious adverse events criteria but required
medical consultation or intervention.
Four blood samples were taken from each participant:
at 10 or 14 weeks of age before the first vaccination, and at
18, 36, and 40 weeks of age (figure 1). Sera were stored at
temperatures of –20°C or lower for measurement of
neutralising antibodies against polioviruses type 1,
type 2, and type 3 using the WHO standard micro­
neutralisation assay (WHO EPI GEN 93.9) adapted at the
Centres for Disease Control and Prevention laboratories
(Atlanta, GA, USA), as previously described.17 Sero­
protection rates (group proportions with a reciprocal
neutralising antibody titre ≥8 for each poliovirus type)
and group geometric mean titres at each timepoint were
calculated using a logarithmic (base 2) scale. Immune
responses were expressed as seroconversion rates (total
proportions of each group that changed from seronegative
to sero­ positive, or baseline seropositive infants who
displayed a four-times or higher increase in antibody
titres after vaccination assuming an exponential decay of
maternal antibodies with a half-life of 24 days).
Outcomes
The primary objective of the study was to determine
whether the immune response induced against
poliovirus type 1 and type 2—the two poliovirus types
that as wild polioviruses or circulating vaccine-derived
poliovirus are responsible for all current cases of paralytic
disease—4 weeks after completion of the primary series
were similar between infants who received vaccine
schedules that consisted of two or three doses of IPV,
562
After the study, 1 or 2 additional full
IPV intramuscular doses were given to
complete the recommended dose
schedule
20 30 36 40
Two IPV group All
and two f-IPV group groups
or two or three doses of f-IPV, to decrease the number
of doses required to provide an adequate standard of
immune protection in the community.
Three co-primary outcomes concerning poliovirus
types 1 and 2 were to determine if seroconversion rates at
40 weeks of age after a two-dose regimen of intradermally
administered f-IPV were non-inferior to a corresponding
two-dose regimen of intramuscular IPV; if seroconversion
rates at 40 weeks of age after a two-dose IPV regimen were
non-inferior to those after a three-dose IPV regimen; and if
seroconversion rates after a two-dose f-IPV regimen are
non-inferior to those after a three-dose f-IPV regimen.
Secondary outcomes included assess­ments of superiority
of seroconversion rates for polio­virus types 1 and 2 of the
four regimens with different administration schedules,
immunogenicity of different regimens in terms of
neutralising antibody titres, and safety. Exploratory
outcomes included the primary and secondary outcomes
for poliovirus type 1 and type 2, applied to poliovirus type 3.
Statistical analysis
To maintain statistical power without increasing the
required number of participants, primary objective
comparisons were restricted to poliovirus type 1 and type 2
considering the current global epidemiology of polio­
viruses. They also represent examples of poliovirus types
that are included (type 1) and excluded (type 2) from the
bivalent OPV vaccines used in both study countries in case
the ongoing use of these live viruses in the study
environment influences the responses. Before the study,
seroconversion rates of 80% for the three IPV group,
96% for the two IPV group, 64% for the three f-IPV group,
and 95% for the two f-IPV group after the second dose
were assumed, and seroconversion rates of 99% for the
three IPV group and 96% for the three f-IPV group after
the third dose were assumed. Sample sizes were chosen
such that the primary non-inferiority comparison would
have 80% or higher power for a joint comparison of
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785 screened

12 ineligible

773 randomised

200 to the three IPV group 178 to the two IPV group 178 to the three f-IPV group 217 to the two f-IPV group

5 withdrawn by parents 6 withdrawn by parents 8 withdrawn by parents 10 withdrawn by parents

195 received first dose 172 received first dose 170 received first dose 207 received first dose

9 discontinued 4 discontinued 4 discontinued 4 discontinued

1 death 4 withdrawn by parents 2 lost to follow-up 2 lost to follow-up
2 lost to follow-up 2 withdrawn by parents 1 other
1 protocol violation 1 withdrawn by parents
1 serious adverse event
4 withdrawn by parents

186 received all doses and completed 168 received all doses and completed all 166 received all doses and completed all 203 received all doses and completed all
all visits visits visits visits

8 excluded 9 excluded 6 excluded 8 excluded

4 protocol violations 5 protocol violations 3 protocol violations 2 missing lab data
1 major study window 3 major study window 2 major study window 1 wrong study procedure
deviation deviations deviations 2 major study window
2 wrong study procedure 1 out of window final 1 prohibited concomitant deviations
1 unrelated serious adverse sample vaccination 3 out of window final
event* samples

178 included in per protocol analysis 159 included in per protocol analysis 160 included in per protocol analysis 195 included in per protocol analysis

Figure 2: Trial profile

IPV=inactived poliovirus vaccine. f-IPV=fractional-inactived poliovirus vaccine. *Infant had sepsis and fully recovered. Sepsis occurred at 18 weeks and could have interfered with the immune response
to vaccination. IPV was administered intramuscularly. f-IPV was administered intradermally.

poliovirus type 1 and type 2 (90% for each type individually).
Secondary comparisons of superiority and non-inferiority
also had 80% power or higher, except for the comparison
between the two f-IPV group and the three IPV group,
which could not have been meaningfully increased without
an infeasibly large sample size. The sample size for each
group was further increased, assuming a 10% dropout and
non-evaluability rate. All non-inferiority comparisons of
seroconversion rates between vaccine regimens and
vaccine types were made with the lower bound of two-
sided score-based CIs (α=0·05) with a 10% non-inferiority
margin. The non-inferiority margin was chosen via the
fixed-margin method, including preservation of 90%
benefit (lower CI of seroconversion rate from previous
studies),18,19 expected for comparator groups involved in
primary objective comparisons. All comparisons were
made with the sample taken 4 weeks after the last
vaccination for each specified regimen, including those in
which the participant age differed at this time point (eg,
the three IPV group vs the two IPV group after the first two
doses), accounting for the decay of maternally derived
antibody as previously described. Superiority comparisons
of seroconversion rates were made using one-sided
Fisher’s exact test (α=0·025). Comparisons of neutralising
antibody titres between regimens at the same timepoint
were done using geometric mean titre ratios, facilitated by
an analysis of covariance model of the log₂ titre to adjust
for the baseline concentration and study site as fixed
effects. Non-inferiority of regimen 1 to regimen 2 was
declared if the lower 95% bound of the two-sided CI for the
geometric mean titre ratio is greater than 0·67, selected as
the more stringent of common margins for non-inferiority
evaluations of geometric mean titres between vaccines or
vaccine regimens in accordance with WHO guidance on
the clinical evaluation of vaccines. No adjustment for
multiple comparisons was done in this study.

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Three IPV group Two IPV group Three f-IPV group Two f-IPV group Poliovirus Poliovirus Poliovirus type
(n=195) (n=172) (n=170) (n=207) type 1 type 2 3 (95% CI)
(95% CI) (95% CI)
Mean age, weeks (SD) 5·5 (0·70) 5·5 (1·02) 5·5 (0·68) 5·4 (1·05)
Boys 104 (53%) 83 (48%) 93 (55%) 105 (51%) Non-inferiority comparisons

Girls 91 (47%) 89 (52%) 77 (45%) 102 (49%) Two f-IPV group vs –2·2 –0·8 –12·2
two IPV group (–6·3 to 1·8) (–4·1 to 2·6) (–18·4 to –6·5)
Ethnicity
Two IPV group vs –1·9 –1·3 –3·1
Black 3 (2) 1 (1) 7 (4) 3 (1) three IPV group (–5·4 to 0·3) (–4·5 to 0·9) (–7·2 to –1·0)
Hispanic 105 (54) 107 (62) 100 (59) 131 (63) Two f-IPV group vs –2·9 –2·1 –9·1
Latin American 84 (43) 64 (37) 62 (36) 69 (33) three f-IPV group (–6·8 to 0·8) (–5·2 to 0·3) (–15·7 to –2·7)
White 3 (2) 0 (0) 1 (1) 4 (2) Three f-IPV group vs –1·3 0 –6·3
Mean weight, kg (SD) 4·4 (0·63) 4·4 (0·63) 4·4 (0·66) 4·4 (0·55) three IPV group (–4·4 to 0·9) (–2·9 to 2·5) (–11·1 to –3·4)
Range, kg 3·2–6·3 2·9–6·5 2·2–6·0 2·0–5·9 Two f-IPV group vs –4·1 –2·1 –15·4
three IPV group (–7·9 to –1·9) (–5·2 to 0·1) (–21·1 to –11·0)
Baseline seropositivity rate*
Three f-IPV group vs 0·6 1·3 –3·1
Poliovirus type 1 84 (43%) 46 (27%) 79 (46%) 52 (25%) two IPV group (–2·8 to 4·3) (–1·1 to 4·5) (–8·4 to 1·7)
Poliovirus type 2 97 (50%) 43 (25%) 71 (42%) 49 (24%) Superiority comparisons
Poliovirus type 3 44 (23%) 17 (10%) 31 (18%) 24 (12%) Two IPV group vs 2·6 9·9 3·0
Data are n (%) unless otherwise specified. The three IPV group received intramuscular vaccine at 10, 14, and 36 weeks. three IPV group after (–1·5 to 6·9) (5·2 to 15·5)† (–1·8 to 7·9)
The two IPV group received intramuscular vaccine at 14 and 36 weeks. The three f-IPV group received intradermal two doses
vaccine at 10, 14, and 36 weeks. The two f-IPV group received intradermal vaccine at 14 and 36 weeks. f-IPV was Two f-IPV group vs 12·7 14·1 11·3
one-fifth of a normal IPV dose. IPV=inactivated poliovirus vaccine. f-IPV=fractional inactivated poliovirus vaccine. three f-IPV group (6·6 to 19·6)† (8·6 to 20·8)† (2·9 to 20·0)‡
*Baseline measured at 10 weeks for the three dose regimens and at 14 weeks for the two dose regimens. after two doses

Table 1: Baseline characteristics of all patients that received at least one vaccine The three IPV group received intramuscular vaccine at 10, 14, and 36 weeks.
The two IPV group received intramuscular vaccine at 14 and 36 weeks. The three
f-IPV group received intradermal vaccine at 10, 14, and 36 weeks. The two f-IPV
group received intradermal vaccine at 14 and 36 weeks. *Using values at 18 weeks
Poliovirus type 1 Poliovirus type 2 Poliovirus type 3
for the three dose regimens, 4 weeks after administration of second dose.
n/N (% [95% CI]) n/N (% [95% CI]) n/N (% [95% CI])
†p<0·0001. ‡p=0·0062.
Three IPV group at week 18 172/180 160/180 169/180
after two doses (96% [91·4–98·1]) (88% [83·4–93·1]) 93·9 (89·3–96·9) Table 3: Superiority and non-inferiority comparisons between the per-
Three IPV group at week 40 178/178 178/178 178/178 protocol population of each vaccine schedule group
after three doses (100% [97·9–100]) (100% [97·9–100]) 100 (97·9–100)
Two IPV group at week 40 152/154 153/154 150/154 Results
after two doses (99% [95·4–99·8]) (99% [96·4–100]) (97% [93·5–99·3])
From Oct 23, 2017, to Nov 13, 2018, we enrolled
Three f-IPV group at week 18 134/161 135/161 118/161
after two doses (83% [76·5–88·6]) (84% [77·2–89·2]) (73% [65·8–79·9]) 773 (372 [48%] girls) infants in Panama and the Dominican
Three f-IPV group at week 40 158/160 160/160 150/160
Republic. Enrolment was balanced by site in Panama and
after three doses (99% [95·6–99·8]) (100% [97·7–100]) (94% [88·8–97·0]) the Dominican Republic and infants were randomly
Two f-IPV group at week 40 186/194 190/194 164/194 assigned to the four study groups (two f-IPV group n=207,
after two doses (96% [92·0–98·2]) (98% [94·8–99·4]) (85% [78·7–89·3]) three f-IPV group n=170, two IPV group n=172, and
Data are n (%) unless otherwise specified. The three IPV group received intramuscular vaccine at 10, 14, and 36 weeks. three IPV group n=195). 744 (96%) received at least one
The two IPV group received intramuscular vaccine at 14 and 36 weeks. The three f-IPV group received intradermal polio vaccination (367 IPV and 377 f-IPV) representing
vaccine at 10, 14, and 36 weeks. The two f-IPV group received intradermal vaccine at 14 and 36 weeks. f-IPV was
the safety population (figure 2). Of whom, 723 (94%)
one-fifth of a normal IPV dose. IPV=inactivated poliovirus vaccine. f-IPV=fractional inactivated poliovirus vaccine.
completed their vaccination regimens at week 40, and
Table 2: Seroconversion rates by poliovirus type in the per-protocol population of each vaccine schedule 692 (90%) were eligible for the immunogenicity analysis
group (figure 2). Baseline characteristics and demographics in
the safety population are reported in table 1. Seroconversion
Role of the funding source rates by poliovirus type for each vaccine schedule are
ASB and JM were full-time employees of the Bill & reported in table 2. In a combined assessment of the
Melinda Gates foundation, which provided grant funding three IPV group and the three f-IPV group at 10 weeks of
for the study. RR was a full-time employee of Fighting age, 163 (45%) of 365 infants were seropositive for
Infectious Diseases in Emerging Countries, the study poliovirus type 1, 168 (46%) seropositive for poliovirus
sponsor. All were responsible for the study design and type 2, and 75 (21%) seropositive for poliovirus type 3. In a
protocol. Contract research organisations monitored the combined assessment of antibodies in the two IPV group
trial and managed the data (VaxTrials) and did the and the two f-IPV group, the baseline seropositivity rates at
statistical analysis (Assign DMB). All authors had full 14 weeks of age were 98 (26%) of 379 infants for poliovirus
access to the data, prepared the manuscript (with type 1, 92 (24%) for poliovirus type 2, and 41 (11%) for
the assistance of an independent professional medical poliovirus type 3, illustrating the waning of maternal
writer funded by the study sponsor), and agreed to its antibodies when compared with the combined three dose
submission. groups at 10 weeks.

564 www.thelancet.com/infection Vol 21 April 2021

 Articles

A Poliovirus type 1
262 144 Three IPV group
Two IPV group
65 536 Three f-IPV group
Two f-IPV group
Serum neutralising antibody titres (log scale)

16 384

4096

1024

256

64

16

B Poliovirus type 2
1 048 576

262 144
Serum neutralising antibody titres (log scale)

65 536

16 384

4096

1024

256

64

16

C Poliovirus type 3
16 384

4096
Serum neutralising antibody titres (log scale)

1024

256
Figure 3: Geometric mean
titres of poliovirus type-
64 specific serum neutralising
antibodies in each group at
16 each sampling timepoint
Error bars are 95% CIs. f-IPV
was one-fifth of a normal IPV
4 dose. IPV was administered
intramuscularly. f-IPV was
administered intradermally.
1 IPV=inactived poliovirus
10 weeks 14 weeks 18 weeks 36 weeks 40 weeks
vaccine. f-IPV=fractional-
Timepoint inactived poliovirus vaccine.

www.thelancet.com/infection Vol 21 April 2021 565

 Articles

increased at 14 and 18 weeks after the first and second

Three IPV group Two IPV group Three f-IPV group Two f-IPV group
(n=195) (n=172) (n=170) (n=207) vaccinations, and peaked at 40 weeks after the third dose at
36 weeks (figure 3). In the two IPV group and the two f-IPV
Patients with serious adverse 10 (5%; 6 (3%; 7 (4%; 9 (4%;
events (%; number of events)* 12 events) 7 events) 10 events) 9 events) group baseline was at 14 weeks, when maternal antibody
Deaths 1 (1%) 0 0 0 titres were lower than in the three IPV group and the three
Life threatening adverse events 0 0 0 1 (1%)
f-IPV group. In three dose regimens, IPV vaccination
Required hospitalisation 8 (4%) 5 (3%) 7 (4%) 9 (4%)
induced higher titres than f-IPV at 18 weeks, 4 weeks after
Congenital anomaly or birth 1 (1%) 1 (1%) 0 0
vaccination. Titres then waned by week 36, when the
defect second dose increased poliovirus type 1 and 2 antibodies
Patients with important 4 (2%; 0 2 (1%; 2 (1%; such that the three f-IPV group and the two f-IPV group
medical events (%; number of 8 events) 4 events) 2 events) geometric mean titres were similar at 40 weeks. The
events)* highest geometric mean titres to poliovirus type 1 and
Fever† 0 1 (1%) 1 (1%) 1 (1%) type 2 were reported in the two IPV group after two IPV
Local adverse events doses (at 40 weeks), but the highest geometric mean titre
Total number of doses 565 338 499 410 to type 3 was reported in the three IPV group at 40 weeks.
Pain 1 (0·2%) 1 (0·3%) 12 (2·4%) 1 (0·2%) No reactions within 30 min of vaccination occurred. One
Redness 5 (0·9%) 2 (0·6%) 10 (2·0%) 9 (2·2%) infant in the Dominican Republic in the three IPV group
Inflammation 0 1 (0·3%) 2 (0·4%) 1 (0·2%) died because of shock and cardio­respiratory arrest 15 weeks
Data are n (%). The three IPV group received intramuscular vaccine at 10, 14, and 36 weeks. The two IPV group received after the second IPV vaccination, but this was not
intramuscular vaccine at 14 and 36 weeks. The three f-IPV group received intradermal vaccine at 10, 14, and 36 weeks. considered to be causally associated with the study. There
The two f-IPV group received intradermal vaccine at 14 and 36 weeks. *All events were unrelated to study regimens.
were 38 serious adverse events (ten in the Dominican
†All cases of fever were reported after the first vaccination.
Republic and 28 in Panama) reported in 32 infants,
Table 4: Summary of adverse events and important medical events 19 events in 16 infants in both the two IPV groups and the
two f-IPV groups (table 4). One infant with three serious
The three co-primary immunogenicity outcomes adverse events (anaemia, diarrhoea, and sepsis) due to the
regarding seroconversion rates for poliovirus types 1 and 2 congenital condition adrenal hyper­ plasia received one
were positively met (table 3)—namely, non-inferiority of vaccination and was then withdrawn, but they remained in
the two f-IPV group compared with the two IPV group, the otherwise good health at final contact. None of the serious
two IPV group compared with the three IPV group, and adverse events or 14 important medical events (eight mild
the two f-IPV group compared with the three f-IPV group. and six moderate) reported in eight infants were considered
In all cases the lower confidence bound of the absolute to be causally associated with vaccination.
differences in the percentages of immune responses was Solicited injection site reactions were infrequent in all
higher than –10%. Exploratory non-inferiority comparisons groups (table 4); in the 739 infants monitored after their
showed that three doses of f-IPV (the three f-IPV group) first vaccination there were six reports of tenderness, ten of
were non-inferior to two (the two IPV group) or three redness, and four of inflammation, all mild to moderate
(three IPV group) doses of IPV for the type 1 and type 2 and transient. Mild injection site redness was reported in
seroconversion rates (table 3). nine of 724 infants after the second vaccination and seven
When poliovirus type 3 responses were analysed, non- of 349 after their third vaccination, with no reports of pain
inferiority was only shown between the two IPV group and or inflammation in these groups. There were three reports
the three IPV group (table 3). In most comparisons of mild fever—one each in the two IPV, the three f-IPV,
between the f-IPV and IPV regimens, the f-IPV type 3 and the two f-IPV groups—after the first vaccination but
responses were inferior, with the exception of the three none after subsequent doses.
f-IPV group compared with the two IPV group.
In superiority analyses done to assess the influence of Discussion
timing of vaccinations, two IPV doses at 14 and 36 weeks Following certification of the global eradication of wild
elicited significantly higher seroconversion rates against poliovirus type 1 and interruption of circulating vaccine-
type 2 poliovirus than when administered at 10 and derived poliovirus transmission, it will be crucial to
14 weeks, but responses to poliovirus type 1 and type 3 did maintain immunity against poliovirus for the immediate
not differ between these two-dose schedules. Sero­ period after eradication. Our study provides novel data that
conversion rates to all poliovirus types were all signi­ficantly can inform global, regional, and national policy decisions
higher when two f-IPV doses were administered at 14 and on IPV-only schedules for the post-eradication era, with an
36 weeks rather than 10 and 14 weeks (table 3). option for dose-sparing and cost-saving in settings where
Following vaccination in the three IPV group and the routine use of full doses of IPV are challenging because of
three f-IPV group, antibody geometric mean titres cost or availability. We show that two intradermal f-IPV
increased for all three poliovirus types from baseline; doses can elicit robust immune responses—as shown by
antibodies at baseline were presumed to be maternal. the seroconversion rate for poliovirus type 1 and type 2—
In these groups geometric mean titres progressively that are non-inferior to two full doses of IPV, but these

566 www.thelancet.com/infection Vol 21 April 2021


responses are dependent on the age of the infant at the
time of administration and also probably affected by the
time interval between vaccinations. Seroconversion rates
to two doses of f-IPV given at 14 and 36 weeks were
significantly superior for all three virus types than when
the doses were given at 10 and 14 weeks. When given at
14 and 36 weeks, f-IPV was non-inferior to IPV for
poliovirus type 1 and type 2, although rates for type 3
were inferior, and geometric mean titres were lower. These
observations of equi­ valent seroconversion rates are
important because sero­con­version to polioviruses at any
timepoint confers protection against paralytic disease.20,21
When IPV is administered alone or in a combination
with diphtheria-tetanus-pertussis-based vaccines it has
proven to be safe, with no causal association with any
adverse events other than temporary, minor, local reactions,
such as erythema (<1%), induration (3–11%), or tenderness
(14–29%).22–24 Our data confirm these observations, with no
vaccine-related serious adverse event or important medical
event. Reactogenicity mainly consisted of infrequent, mild-
to-moderate injection site reactions, with only three reports
of mild fever, all after the first vaccination.
With global eradication of wild polioviruses, all live polio
vaccines will be withdrawn from routine use to eliminate
the risk of emergence of vaccine-derived polio­viruses and
vaccine-associated paralytic polio­myelitis. Countries using
bivalent OPV will switch to IPV-only schedules for routine
infant immunisations. Faced with the challenges of
increasing manufacturing capacity to meet future global
requirements for IPV13 and the higher cost of IPV per dose
than OPV, the use of intradermal f-IPV is an attractive
option.22 IPVs manufactured from wild Salk poliovirus
strains or attenuated Sabin poliovirus strains inactivated
with formaldehyde are available and are generally
considered to be equivalent to each other in terms of
immuno­ genicity. These inactivated vaccines can be
administered by subcutaneous or intramuscular injection,
often in diphtheria-tetanus-pertussis-based combin­a­tions,
and fractional doses of stand-alone IPV can be administered
intradermally. However, all IPV vaccines have been
licensed based on three-dose infant schedules with the
first dose administered in the second month of life and
there is only a small amount of information on the optimal
schedule for f-IPV.
Studies with alternative f-IPV schedules have generally
shown lower seroconversion rates than full IPV doses
depending on age at administration, but two f-IPV doses
can substitute for one full IPV dose.24,25 Studies in
Bangladesh26 and Cuba27 found intradermal f-IPV elicited
significantly lower sero­ conversion rates and geometric
mean titres than intra­muscular IPV for all three poliovirus
types when administered at 6, 10, and 14 weeks of age. In
another study in Bangladesh, a priming dose of f-IPV
6 weeks before subsequent OPV was also inferior to an IPV
schedule.28 Another Cuban study found that one or two
doses of f-IPV at 4 and 8 months induced significantly
lower seroconversion rates than IPV, but there was evidence
www.thelancet.com/infection Vol 21 April 2021
Articles
of immune priming with initial doses of f-IPV.19 The same
investigators showed that responses to intramuscular f-IPV
at 4 and 8 months were non-inferior to the intradermal
route.29 A three-dose primary series of intradermal f-IPV in
infants at 2, 4, and 6 months of age elicited similar
seroconversion rates for each of the three poliovirus types
as full dose IPV, but significantly lower titres.18
Intradermal vaccine administration will require training
of health-care staff, but there are examples to show that
this was done successfully with the introduction of
intradermal f-IPV.30 Our study provides novel clinical data
on the administration of two or three doses of IPV or f-IPV
in delayed schedules proposed by SAGE. We found that
two doses of intramuscular IPV or intradermal f-IPV at 14
and 36 weeks provide acceptable serocon­ version rates
against all three poliovirus types although geometric mean
titres—most notably to poliovirus type 3—were lower.
However, a three-dose f-IPV regimen might be considered
ideal given the suboptimal immunogenicity against
poliovirus type 3 and lower geometric mean titres overall
with two f-IPV doses. Consistent with SAGE recom­
mendations for future two-dose regimens, our study
supports delaying the first IPV dose until 14 weeks of age
to minimise interference by maternally derived antibodies.
The study was open-label because of the evident
differences in presentation and mode of administration of
IPV and f-IPV, but the laboratory personnel responsible for
measuring immunogenicity for the primary objective were
masked to treatment group and timepoints. Other
assessments, including local reactions arising from the
intradermal administration of f-IPV compared with
the intramuscular administration of IPV, might have
been affected. For example, more frequent observation of
severe redness or induration at the injection site might arise
from greater overall reporting of such local reactogenicity
because of the different route of admin­istration.
Our study is the first to inform decisions on polio
immunisation schedules for an era with no elective use of
OPVs. The findings offer strong evidence of the potential
to mitigate cost and supply constraints related to IPV for
the concluding phase of the eradication programme. We
report that near-universal immune responses can be
elicited with two full doses of intramuscular IPV when
given in the delayed schedules reported in this study,
implying substantial cost and supply savings because the
current practice is to use four or more full doses of IPV in
routine immunisation schedules in countries where OPV
is not being used. We also report that two f-IPV doses
administered via the intradermal route are protective
against the two serotypes that are circulating as wild-type
or circulating vaccine-derived poliovirus, and that three
f-IPV doses are protective against all three polio serotypes,
which will provide additional cost and supply savings.
Given the rapidly evolving landscape of poliovirus vaccine
development, with changing epidemiology of vaccine-
derived poliovirus following global type 2 OPV with­drawal
in 2016 and ongoing wild poliovirus type 1 circulation,
567
 Articles
policy decisions on novel IPV-only schedules will have to
be optimised as data on newer IPV formulations and
delivery methods, including the option to deliver fractional
doses via the intramuscular route, become available.30,31
Contributors
ASB, CG, JM, RC, SACC, and RR designed the study.
LR and XS-L were study investigators. JJ collected the data.
RR managed the project on behalf of the study sponsor. MSO and WCW
did the laboratory assessments. CG did the statistical analyses. ASB, CG,
and RR drafted the Article, with medical writing support. All authors
participated in interpretation of the data and reviewed and revised the
drafts and agreed to the final submission.
Declaration of interest
ASB and JM were full-time employees of the Bill & Melinda Gates
Foundation. CG, RC, and SACC are paid consultants for the Bill & Melinda
Gates Foundation. All other authors declare no competing interests.
Data sharing
Following complete publication, the data generated in this study will be
made available to researchers through the Gates Open Research portal.
For details see https://gatesopenresearch.org/for-authors/data-guidelines.
Acknowledgments
This work was sponsored by Fighting Infectious Diseases in Emerging
Countries with grant support provided by the Bill & Melinda Gates
Foundation (grant number OPP1160084). The authors wish to thank all of
the parents of the infants who participated in this study and wish to thank
the staff at the study centres for their expert assistance. We also thank
William Hendley, Kathryn Manly, Sharla McDonald, Deborah Moore,
Mario Nicolas and Yiting Zhang at the Centres for Disease Control and
Prevention for microneutralisation testing. We are grateful to Keith Veitch
for writing the first draft and providing subsequent editorial assistance.
The findings and conclusions in this report are those of the author(s) and
do not necessarily represent the official position of the Centers for Disease
Control and Prevention or other contributing agencies.
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