Fase 3.2
Fase 3.2
Fase 3.2
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.
Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
Research in context
Evidence before this study Added value of this study
The declaration of eradication of wild poliovirus type 3 on The present study was done specifically to investigate the
October 17, 2019 means only the continuing circulation of wild responses to two or three doses of f-IPV in polio vaccine-naive
poliovirus type 1 in Afghanistan and Pakistan confounds the infants as primary vaccinations, and to directly compare these
goal of global eradication of wild polioviruses. Once eradication with equivalent schedules using full dose IPV. By using a
is achieved current planning suggests that children will still delayed schedule we were also able to assess the effect of the
need to be immunised against polio for at least another decade timing of these vaccinations on the immune responses, and the
primarily because of the ongoing threat posed by circulating influence of pre-existing maternal antibodies on the final
vaccine-derived polioviruses. To accomplish this strategy while immunogenicity.
removing the source of circulating vaccine-derived polioviruses
Implications of all the available evidence
will require the replacement of all routine use of oral poliovirus
This study provides the first clear and direct comparison of f-IPV
vaccines (OPV) with inactivated poliovirus vaccines (IPV).
with full-dose IPV as primary immunisation of infants against
Because the manufacturing capacity of IPV is currently
poliovirus in delayed schedules. It confirms that
inadequate for projected global demand and their cost makes
immunogenicity can be conferred using f-IPV doses to make
them unaffordable for many low-income countries, WHO and
such dose-sparing immunisations affordable in low-income
associated bodies have recommended use of fewer doses or
and middle-income countries provided the immunisation
fractional doses of IPV (f-IPV) administered intradermally.
schedule is adapted to ensure maternal antibodies do not
We searched PubMed from the inception of the database until interfere with the response. As such, it will inform policy makers
April 27, 2020, using the terms “polio”, “vaccine”, “fractional”, to formulate future immunisation recommendations following
and “immunogenicity”. We found 20 reviews and clinical global eradication of wild-type polioviruses and cessation of all
studies in which f-IPV was used as priming or booster doses, but OPV use.
few of these were clinical studies in which f-IPV was used for the
full infant primary immunisation series.
recommended alternative IPV vaccination schemes be for Harmonisation and Good Clinical Practice guidelines.
introduced, including intradermal application of fractional The trial is registered on ClinicalTrials.gov, NCT03239496.
IPV (f-IPV) doses rather than full-dose IPV.12,13 Although
the supply situation has improved,14 the potential global Randomisation and masking
withdrawal of all OPV following the declaration of global At enrolment infants were randomly assigned (1:1:1:1,
eradication of all wild-type polioviruses will necessitate 1:1:1:2, or 2:1:1:1) in varying block sizes of four or five to
increased use of IPV or f-IPV as the sole source of one of four vaccination schedules: three IPV doses (three
poliovirus immunity for infants. IPV group), two IPV doses (two IPV group), three f-IPV
Alfaro-Murillo and colleagues15 have suggested that doses (three f-IPV group), or two f-IPV doses (two f-IPV
OPV withdrawal could be done in regions, such as the group). Study nurses were trained in the injection
Americas, where paralytic disease is entirely caused by technique for intradermal administration. Because of the
vaccine-associated paralytic poliomyelitis and circulating nature of the trial assessing four different vaccination
vaccine-derived polioviruses. There is no risk of vaccine- schedules, administrators, nurses giving the vaccine, and
associated paralytic poliomyelitis or emergence of the infants and their parents or guardians were not
vaccine-derived poliovirus associated with IPV use. masked to treatment allocation, but laboratory staff
Alfaro-Murillo and colleagues15 also acknowledged that a responsible for measuring the immunogenicity out
switch from OPV to IPV in some regions will be difficult comes for the primary outcomes were masked to
to achieve because of cost and the shortfall in supply of treatment group and timepoint the sample was taken.
IPV. This highlights the urgent need for scientific
evidence to clarify the optimal IPV scheme to implement Procedures
for the long term, following cessation of all OPV use. The study vaccine was a WHO-prequalified Salk IPV
This study aimed to compare immune responses to vaccine (Poliomyelitis Vaccine [Inactivated], Serum
intramuscular full-dose IPV with intradermal f-IPV in Institute of India, Pune, India), which is representative of
two different schedules in poliovirus-naive infants in all available IPV vaccines. Each 0·5 mL dose contained
Panama and the Dominican Republic where there have 40 D antigen units Mahoney strain (poliovirus type 1),
been no wild poliovirus or detectable circulating vaccine- 8 D antigen units MEF-1 strain (poliovirus type 2), and
derived polioviruses transmission since the 2000–01 32 D antigen units Saukett strain (poliovirus type 3),
outbreak.16 Infant vaccination schedules vary between the 2·5 mg of 2-phenoxyethanol, and up to 12·5 μg of
two countries. In 2014, Panama replaced OPV with formaldehyde. Full intramuscular IPV doses were
hexavalent (diphtheria-tetanus-pertussis-hepatitis B-IPV- administered in the anterolateral aspect of the thigh using
Haemophilus influenzae type b) combination vaccine for a standard needle and syringe. Fractional doses, one-fifth
the three dose infant schedule, with bivalent OPV of the full dose presented in 0·1 mL, were administered
boosters at 18 months and 4 years of age. Whereas, the intradermally in the upper arm using a 0·1 mL autodisable
Dominican Republic uses IPV at 2 months followed by syringe. Vaccines were administered to the two f-IPV
bivalent OPV at 4, 6, 18 months, and 4 years of age. group on weeks 14 and 36; to the three f-IPV group on
Absence of any outbreak response use of poliovirus type weeks 10, 14, and 36; to the two IPV group on weeks 14
2 OPV in these two countries provided an ideal and 36 weeks; and to the three IPV group on weeks 10, 14,
epidemiological setting to study poliovirus vaccine and 36. For this study infants in both countries received
immunogenicity that simulates the post-OPV era. the same routine vaccines in the same schedules (figure 1).
This was necessary because the standard hexavalent IPV-
Methods containing combination vaccine had to be replaced with a
Study design and participants pentavalent one (diphtheria, tetanus, whole-cell pertussis,
This randomised, open-label, multicentre, phase 3, non- hepatitis B, and Haemophilus influenzae type b) to allow
inferiority trial was done at two urban sites in Panama and the IPV and f-IPV vaccines to be administered separately.
one urban site in the Dominican Republic. Eligible When necessary, the polio vaccines were administered
participants were healthy 6-week-old infants with no signs concomitantly with routine infant vaccines (pentavalent
of febrile illness or known allergy to vaccine components. combination, pneumococcal, rotavirus, and influenza),
Infants were excluded if they had received previous which were administered according to the national
poliovirus vaccination, had a known HIV infection, had immuni sation recommendations (figure 1). Infants in
any blood disorder contraindicating intramuscular or the two-dose groups (the two IPV group and the
intradermal injections, or if any household contacts had two f-IPV group) received additional IPV vaccinations
been vaccinated with OPV in the previous 4 weeks. after the study to ensure they met these requirements.
Institutional Review Boards of each study centre and Infants were monitored for 30 min after vaccination,
the respective national committees approved the study then parents recorded solicited local reactions (pain,
protocol. Parents or guardians of all participating infants induration, and redness) and body temperature for 7 days;
provided signed informed consent before enrolment and unsolicited adverse events were monitored throughout the
the study was done according to International Council study in e-diaries. Parents were to immediately report the
Enrolled
Weeks 6 10 14 18 20 30 36 40
Blood sampling
occurrence of any serious adverse events or important or two or three doses of f-IPV, to decrease the number
medical events throughout the duration of the study. of doses required to provide an adequate standard of
Serious adverse events were defined as death or events that immune protection in the community.
were either life-threatening, required hospitalisation, or Three co-primary outcomes concerning poliovirus
resulted in persistent or significant disability or incapacity. types 1 and 2 were to determine if seroconversion rates at
Important medical events were medically significant 40 weeks of age after a two-dose regimen of intradermally
See Online for appendix 2 events defined in the protocol (appendix 2) that did not administered f-IPV were non-inferior to a corresponding
meet any serious adverse events criteria but required two-dose regimen of intramuscular IPV; if seroconversion
medical consultation or intervention. rates at 40 weeks of age after a two-dose IPV regimen were
Four blood samples were taken from each participant: non-inferior to those after a three-dose IPV regimen; and if
at 10 or 14 weeks of age before the first vaccination, and at seroconversion rates after a two-dose f-IPV regimen are
18, 36, and 40 weeks of age (figure 1). Sera were stored at non-inferior to those after a three-dose f-IPV regimen.
temperatures of –20°C or lower for measurement of Secondary outcomes included assessments of superiority
neutralising antibodies against polioviruses type 1, of seroconversion rates for poliovirus types 1 and 2 of the
type 2, and type 3 using the WHO standard micro four regimens with different administration schedules,
neutralisation assay (WHO EPI GEN 93.9) adapted at the immunogenicity of different regimens in terms of
Centres for Disease Control and Prevention laboratories neutralising antibody titres, and safety. Exploratory
(Atlanta, GA, USA), as previously described.17 Sero outcomes included the primary and secondary outcomes
protection rates (group proportions with a reciprocal for poliovirus type 1 and type 2, applied to poliovirus type 3.
neutralising antibody titre ≥8 for each poliovirus type)
and group geometric mean titres at each timepoint were Statistical analysis
calculated using a logarithmic (base 2) scale. Immune To maintain statistical power without increasing the
responses were expressed as seroconversion rates (total required number of participants, primary objective
proportions of each group that changed from seronegative comparisons were restricted to poliovirus type 1 and type 2
to sero positive, or baseline seropositive infants who considering the current global epidemiology of polio
displayed a four-times or higher increase in antibody viruses. They also represent examples of poliovirus types
titres after vaccination assuming an exponential decay of that are included (type 1) and excluded (type 2) from the
maternal antibodies with a half-life of 24 days). bivalent OPV vaccines used in both study countries in case
the ongoing use of these live viruses in the study
Outcomes environment influences the responses. Before the study,
The primary objective of the study was to determine seroconversion rates of 80% for the three IPV group,
whether the immune response induced against 96% for the two IPV group, 64% for the three f-IPV group,
poliovirus type 1 and type 2—the two poliovirus types and 95% for the two f-IPV group after the second dose
that as wild polioviruses or circulating vaccine-derived were assumed, and seroconversion rates of 99% for the
poliovirus are responsible for all current cases of paralytic three IPV group and 96% for the three f-IPV group after
disease—4 weeks after completion of the primary series the third dose were assumed. Sample sizes were chosen
were similar between infants who received vaccine such that the primary non-inferiority comparison would
schedules that consisted of two or three doses of IPV, have 80% or higher power for a joint comparison of
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
195 received first dose 172 received first dose 170 received first dose 207 received first dose
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
178 included in per protocol analysis 159 included in per protocol analysis 160 included in per protocol analysis 195 included in per protocol analysis
poliovirus type 1 and type 2 (90% for each type individually). which the participant age differed at this time point (eg,
Secondary comparisons of superiority and non-inferiority the three IPV group vs the two IPV group after the first two
also had 80% power or higher, except for the comparison doses), accounting for the decay of maternally derived
between the two f-IPV group and the three IPV group, antibody as previously described. Superiority comparisons
which could not have been meaningfully increased without of seroconversion rates were made using one-sided
an infeasibly large sample size. The sample size for each Fisher’s exact test (α=0·025). Comparisons of neutralising
group was further increased, assuming a 10% dropout and antibody titres between regimens at the same timepoint
non-evaluability rate. All non-inferiority comparisons of were done using geometric mean titre ratios, facilitated by
seroconversion rates between vaccine regimens and an analysis of covariance model of the log₂ titre to adjust
vaccine types were made with the lower bound of two- for the baseline concentration and study site as fixed
sided score-based CIs (α=0·05) with a 10% non-inferiority effects. Non-inferiority of regimen 1 to regimen 2 was
margin. The non-inferiority margin was chosen via the declared if the lower 95% bound of the two-sided CI for the
fixed-margin method, including preservation of 90% geometric mean titre ratio is greater than 0·67, selected as
benefit (lower CI of seroconversion rate from previous the more stringent of common margins for non-inferiority
studies),18,19 expected for comparator groups involved in evaluations of geometric mean titres between vaccines or
primary objective comparisons. All comparisons were vaccine regimens in accordance with WHO guidance on
made with the sample taken 4 weeks after the last the clinical evaluation of vaccines. No adjustment for
vaccination for each specified regimen, including those in multiple comparisons was done in this study.
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.
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.
responses are dependent on the age of the infant at the of immune priming with initial doses of f-IPV.19 The same
time of administration and also probably affected by the investigators showed that responses to intramuscular f-IPV
time interval between vaccinations. Seroconversion rates at 4 and 8 months were non-inferior to the intradermal
to two doses of f-IPV given at 14 and 36 weeks were route.29 A three-dose primary series of intradermal f-IPV in
significantly superior for all three virus types than when infants at 2, 4, and 6 months of age elicited similar
the doses were given at 10 and 14 weeks. When given at seroconversion rates for each of the three poliovirus types
14 and 36 weeks, f-IPV was non-inferior to IPV for as full dose IPV, but significantly lower titres.18
poliovirus type 1 and type 2, although rates for type 3 Intradermal vaccine administration will require training
were inferior, and geometric mean titres were lower. These of health-care staff, but there are examples to show that
observations of equi valent seroconversion rates are this was done successfully with the introduction of
important because seroconversion to polioviruses at any intradermal f-IPV.30 Our study provides novel clinical data
timepoint confers protection against paralytic disease.20,21 on the administration of two or three doses of IPV or f-IPV
When IPV is administered alone or in a combination in delayed schedules proposed by SAGE. We found that
with diphtheria-tetanus-pertussis-based vaccines it has two doses of intramuscular IPV or intradermal f-IPV at 14
proven to be safe, with no causal association with any and 36 weeks provide acceptable serocon version rates
adverse events other than temporary, minor, local reactions, against all three poliovirus types although geometric mean
such as erythema (<1%), induration (3–11%), or tenderness titres—most notably to poliovirus type 3—were lower.
(14–29%).22–24 Our data confirm these observations, with no However, a three-dose f-IPV regimen might be considered
vaccine-related serious adverse event or important medical ideal given the suboptimal immunogenicity against
event. Reactogenicity mainly consisted of infrequent, mild- poliovirus type 3 and lower geometric mean titres overall
to-moderate injection site reactions, with only three reports with two f-IPV doses. Consistent with SAGE recom
of mild fever, all after the first vaccination. mendations for future two-dose regimens, our study
With global eradication of wild polioviruses, all live polio supports delaying the first IPV dose until 14 weeks of age
vaccines will be withdrawn from routine use to eliminate to minimise interference by maternally derived antibodies.
the risk of emergence of vaccine-derived polioviruses and The study was open-label because of the evident
vaccine-associated paralytic poliomyelitis. Countries using differences in presentation and mode of administration of
bivalent OPV will switch to IPV-only schedules for routine IPV and f-IPV, but the laboratory personnel responsible for
infant immunisations. Faced with the challenges of measuring immunogenicity for the primary objective were
increasing manufacturing capacity to meet future global masked to treatment group and timepoints. Other
requirements for IPV13 and the higher cost of IPV per dose assessments, including local reactions arising from the
than OPV, the use of intradermal f-IPV is an attractive intradermal administration of f-IPV compared with
option.22 IPVs manufactured from wild Salk poliovirus the intramuscular administration of IPV, might have
strains or attenuated Sabin poliovirus strains inactivated been affected. For example, more frequent observation of
with formaldehyde are available and are generally severe redness or induration at the injection site might arise
considered to be equivalent to each other in terms of from greater overall reporting of such local reactogenicity
immuno genicity. These inactivated vaccines can be because of the different route of administration.
administered by subcutaneous or intramuscular injection, Our study is the first to inform decisions on polio
often in diphtheria-tetanus-pertussis-based combinations, immunisation schedules for an era with no elective use of
and fractional doses of stand-alone IPV can be administered OPVs. The findings offer strong evidence of the potential
intradermally. However, all IPV vaccines have been to mitigate cost and supply constraints related to IPV for
licensed based on three-dose infant schedules with the the concluding phase of the eradication programme. We
first dose administered in the second month of life and report that near-universal immune responses can be
there is only a small amount of information on the optimal elicited with two full doses of intramuscular IPV when
schedule for f-IPV. given in the delayed schedules reported in this study,
Studies with alternative f-IPV schedules have generally implying substantial cost and supply savings because the
shown lower seroconversion rates than full IPV doses current practice is to use four or more full doses of IPV in
depending on age at administration, but two f-IPV doses routine immunisation schedules in countries where OPV
can substitute for one full IPV dose.24,25 Studies in is not being used. We also report that two f-IPV doses
Bangladesh26 and Cuba27 found intradermal f-IPV elicited administered via the intradermal route are protective
significantly lower sero conversion rates and geometric against the two serotypes that are circulating as wild-type
mean titres than intramuscular IPV for all three poliovirus or circulating vaccine-derived poliovirus, and that three
types when administered at 6, 10, and 14 weeks of age. In f-IPV doses are protective against all three polio serotypes,
another study in Bangladesh, a priming dose of f-IPV which will provide additional cost and supply savings.
6 weeks before subsequent OPV was also inferior to an IPV Given the rapidly evolving landscape of poliovirus vaccine
schedule.28 Another Cuban study found that one or two development, with changing epidemiology of vaccine-
doses of f-IPV at 4 and 8 months induced significantly derived poliovirus following global type 2 OPV withdrawal
lower seroconversion rates than IPV, but there was evidence in 2016 and ongoing wild poliovirus type 1 circulation,
policy decisions on novel IPV-only schedules will have to 11 Bandyopadhyay AS, Modlin JF, Wenger J, Gast C. Immunogenicity
be optimised as data on newer IPV formulations and of new primary immunization schedules with inactivated
poliovirus vaccine and bivalent oral polio vaccine for the polio
delivery methods, including the option to deliver fractional endgame: a review. Clin Infect Dis 2018; 67 (suppl 1): S35–41.
doses via the intramuscular route, become available.30,31 12 Lewis I, Ottosen A, Rubin J, Blanc DC, Zipursky S, Wootton E.
A supply and demand management perspective on the accelerated
Contributors
global introductions of inactivated poliovirus vaccine in a
ASB, CG, JM, RC, SACC, and RR designed the study. constrained supply market. J Infect Dis 2017; 216 (suppl 1): S33–39.
LR and XS-L were study investigators. JJ collected the data.
13 Pan American Health Organization. TAG recommendations
RR managed the project on behalf of the study sponsor. MSO and WCW about the use of IPV. 2016. https://www.paho.org/hq/index.
did the laboratory assessments. CG did the statistical analyses. ASB, CG, php?option=com_content&view=article&id=12134:tag-
and RR drafted the Article, with medical writing support. All authors recommendations-ipv&Itemid=0&lang=en (accessed
participated in interpretation of the data and reviewed and revised the April 27, 2020).
drafts and agreed to the final submission. 14 UNICEF. Inactivated polio vaccine: supply update,
August 2019. 2019. https://www.unicef.org/supply/files/ipv-
Declaration of interest
inactivated-polio-vaccine-supply-update.pdf (accessed April 4, 2020).
ASB and JM were full-time employees of the Bill & Melinda Gates
15 Alfaro-Murillo JA, Ávila-Agüero ML, Fitzpatrick MC, Crystal CJ,
Foundation. CG, RC, and SACC are paid consultants for the Bill & Melinda
Falleiros-Arlant L-H, Galvani AP. The case for replacing live oral
Gates Foundation. All other authors declare no competing interests.
polio vaccine with inactivated vaccine in the Americas. Lancet 2020;
Data sharing 395: 1163–66.
Following complete publication, the data generated in this study will be 16 Kinder M. Eliminating Polio in Latin America and the Caribbean:
made available to researchers through the Gates Open Research portal. a case study. 2007. https://www.cgdev.org/sites/default/files/
For details see https://gatesopenresearch.org/for-authors/data-guidelines. archive/doc/millions/MS_case_5.pdf (accessed Oct 7, 2020).
17 Weldon WC, Oberste MS, Pallansch MA. Standardized methods for
Acknowledgments detection of poliovirus antibodies. In: Poliovirus: Methods in
This work was sponsored by Fighting Infectious Diseases in Emerging Molecular Biology. Martín J (ed). New York: Humana Press,
Countries with grant support provided by the Bill & Melinda Gates 2016: 145–76.
Foundation (grant number OPP1160084). The authors wish to thank all of 18 Mohammed AJ, Al Awaidy S, Bawikar S, et al. Fractional doses of
the parents of the infants who participated in this study and wish to thank inactivated poliovirus vaccine in Oman. N Engl J Med 2010;
the staff at the study centres for their expert assistance. We also thank 362: 2351–59.
William Hendley, Kathryn Manly, Sharla McDonald, Deborah Moore, 19 Resik S, Tejeda A, Sutter RW, et al. Priming after a fractional dose
Mario Nicolas and Yiting Zhang at the Centres for Disease Control and of inactivated poliovirus vaccine. N Engl J Med 2013; 368: 416–24.
Prevention for microneutralisation testing. We are grateful to Keith Veitch 20 Sutter RW, Pallansch MA, Sawyer LA, Cochi SL, Hadler SC.
for writing the first draft and providing subsequent editorial assistance. Defining surrogate serologic tests with respect to predicting
The findings and conclusions in this report are those of the author(s) and protective vaccine efficacy: poliovirus vaccination. Ann NY Acad Sci
do not necessarily represent the official position of the Centers for Disease 1995; 754: 289–99.
Control and Prevention or other contributing agencies. 21 Plotkin SA. Correlates of protection induced by vaccination.
Clin Vaccine Immunol 2010; 17: 1055–65.
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