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Immunogenicity of a new routine vaccination schedule for global poliomyelitis prevention: an open-label, randomised controlled trial

Sunday, 13th of December 2015 Print

 

The Lancet, Volume 386, No. 10011, p2413–2421, 12 December 2015

Immunogenicity of a new routine vaccination schedule for global poliomyelitis prevention: an open-label, randomised controlled trial

Dr Roland W Sutter, MD,

Sunil Bahl, MD,

Jagadish M Deshpande, PhD,

Harish Verma, MBBS,

Mohammad Ahmad, MD,

Prof P Venugopal, MD,

Prof J Venkateswara Rao, MD,

Prof Sharad Agarkhedkar, MD,

Prof Sanjay K Lalwani, MD,

Abhishek Kunwar, MD,

Raman Sethi, MSc,

Marina Takane, MSc,

Lalitendu Mohanty, MBBS,

Arani Chatterjee, MBBS,

T Jacob John, FRCP,

Hamid Jafari, MBBS,

R Bruce Aylward, MD

Published Online: 17 September 2015

 

DOI: http://dx.doi.org/10.1016/S0140-6736(15)00237-8

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Article Info 

Publication History

Published Online: 17 September 2015

© 2015 Elsevier Ltd. All rights reserved.

 

 

Summary

Background

Polio eradication needs a new routine immunisation schedule—three or four doses of bivalent type 1 and type 3 oral poliovirus vaccine (bOPV) and one dose of inactivated poliovirus vaccine (IPV), but no immunogenicity data are available for this schedule. We aimed to assess immunogenicity of this vaccine schedule.

Methods

We did an open-label, randomised controlled trial in four centres in India. After informed consent was obtained from a parent or legally acceptable representative, healthy newborn babies were randomly allocated to one of five groups: trivalent OPV (tOPV); tOPV plus IPV; bOPV; bOPV plus IPV; or bOPV plus two doses of IPV (2IPV). The key eligibility criteria were: full-term birth (≥37 weeks of gestation); birthweight ≥2·5 kg; and Apgar score of 9 or more. OPV was administered at birth, 6 weeks, 10 weeks, and 14 weeks; IPV was administered intramuscularly at 14 weeks. The primary study objective was to investigate immunogenicity of the new vaccine schedule, assessed by seroconversion against poliovirus types 1, 2, and 3 between birth and 18 weeks in the per-protocol population (all participants with valid serology results on cord blood and at 18 weeks). Neutralisation assays tested cord blood and sera collected at 14 weeks, 18 weeks, 19 weeks, and 22 weeks by investigators masked to group allocation. This trial was registered with the India Clinical Trials Registry, number CTRI/2013/06/003722.

Findings

Of 900 newborn babies enrolled between June 13 and Aug 29, 2013, 782 (87%) completed the per-protocol requirements. Between birth and age 18 weeks, seroconversion against poliovirus type 1 in the tOPV group occurred in 162 of 163 (99·4%, 95% CI 96·6–100), in 150 (98·0%, 94·4–99·6) of 153 in the tOPV plus IPV group, in 153 (98·7%, 95·4–99·8) of 155 in the bOPV group, in 155 (99·4%, 96·5–100) of 156 in the bOPV plus IPV group, and in 154 (99·4%, 96·5–100) of 155 in the bOPV plus 2IPV group. Seroconversion against poliovirus type 2 occurred in 157 (96·3%, 92·2–98·6) of 163 in the tOPV group, 153 (100%, 97·6–100·0) of 153 in the tOPV plus IPV group, 29 (18·7%, 12·9–25·7) of 155 in the bOPV group, 107 (68·6%, 60·7–75·8) of 156 in the bOPV plus IPV group, and in 121 (78·1%, 70·7–84·3) of 155 in the bOPV plus 2IPV group. Seroconversion against poliovirus type 3 was achieved in 147 (90·2%, 84·5–94·3) of 163 in the tOPV group, 152 (99·3%, 96·4–100) of 153 in the tOPV plus IPV group, 151 (97·4%, 93·5–99·3) of 155 in the bOPV group, 155 (99·4%, 96·5–100) of 156 in the bOPV plus IPV group, and 153 (98·7%, 95·4–99·8) of 155 in the bOPV plus 2IPV group. Superiority was achieved for vaccine regimens including IPV against poliovirus type 3 compared with those not including IPV (tOPV plus IPV vs tOPV alone, p=0·0008; and bOPV plus IPV vs bOPV alone, p=0·0153). 12 serious adverse events occurred (six in the tOPV group, one in the tOPV plus IPV group, three in the bOPV group, zero in the bOPV plus IPV group, and two in the bOPV plus 2IPV group), none of which was attributed to the trial intervention.

Interpretation

The new vaccination schedule improves immunogenicity against polioviruses, especially against poliovirus type 3.

Funding

WHO, through a grant from Rotary International ( grant number 59735 ).

Introduction

Polio eradication is entering the final phase, with elimination of wild poliovirus type 2 in 1999, no wild poliovirus type 3 detected since November, 2012, no poliovirus type 1 reported in Africa since August, 2014, and certification of four of six WHO regions, comprising more than 80% of the worlds population, as polio free.1

However, wild poliovirus type 1 continues to circulate in Asia (ie, Pakistan and Afghanistan), and persistent circulating vaccine-derived poliovirus type 2 (cVDPV2) transmission continued in parts of northern Nigeria and Pakistan in 2014, and into early 2015.1 cVDPVs originate from Sabin strains contained in the oral poliovirus vaccine (OPV) that have probably gained the neurovirulence and transmission characteristics of wild polioviruses.2 These viruses are of grave concern to the global polio eradication initiative because they could potentially re-establish poliovirus endemicity, and thus negate the accomplishments of eradication efforts.

Recognising progress and present and future risks to global polio eradication, a strategic plan—Polio Eradication and Endgame Strategic Plan: 2013–2018—has been developed by the Global Polio Eradication Initiative with the objective of eradication of all wild and vaccine-related polioviruses. The strategic plan calls for globally coordinated sequential removal of Sabin strains from the programme, beginning with Sabin type 2. The plan also recommends introduction of one or more dose of inactivated poliovirus vaccine (IPV) for risk mitigation.3 The Strategic Advisory Group of Experts (SAGE) on immunisation adopted a new schedule for routine vaccination against poliomyelitis in November, 2013,4 and the related WHO position paper5 on polio vaccines was updated accordingly in January, 2014.

Research in context

Evidence before this study

We completed a literature review of published data for bivalent oral polio virus vaccine (bOPV) immunogenicity. We searched PubMed for papers published between Jan 1, 1959, and Sept 30, 2013, with the terms “oral polio vaccine”, “bivalent oral polio vaccine”, “trivalent oral polio vaccine”, and “inactivated polio vaccine”. Because of the large numbers of references, we restricted our review to 372 clinical trials. Only one publication used bOPV when we did our literature search; subsequently, two additional papers were published. However, we were aware of the preliminary data of these trials. None of the papers included administration of bOPV and inactivated poliovirus (IPV) in a routine schedule.

Added value of this study

In October, 2013, WHO approved a new routine vaccination schedule for poliomyelitis prevention. The schedule takes into account: the proposed switch from trivalent OPV (tOPV) to bOPV (ie, withdrawal of Sabin type 2), as part of the new polio eradication strategy planning; and calls for addition of one or more doses of IPV in all OPV-using countries for risk mitigation. The routine schedule consists of three or more bOPV doses at birth (optional), 6 weeks, and 10 weeks, and bOPV and IPV simultaneously at 14 weeks. To our knowledge, this is the first study to assess the new bOPV and IPV schedule for poliomyelitis prevention. The data show the superior immunogenicity of the new schedule against poliovirus type 3, compared with a schedule of tOPV alone. Equivalence for all comparisons (bOPV vs tOPV, tOPV vs tOPV plus IPV, bOPV vs bOPV plus IPV, and bOPV plus IPV vs tOPV) with very high immunogenicity, was achieved for poliovirus type 1 (>99% seroconversion), and as expected, inferiority was documented against type 2 poliovirus with a single dose of IPV but without a type 2-containing OPV vaccine. Two doses of IPV resulted in seroconversion against poliovirus type 2 in all study participants, and thus, closed the remaining immunity gaps.

Implications of all the available evidence

Our data provide strong scientific support for implementation of the new routine immunisation schedule for poliomyelitis prevention.

Although a large body of data supports use of IPV after trivalent oral poliovirus vaccine (tOPV),6, 7 the timing of IPV dose, and the expected effect on vaccine-associated paralytic poliomyelitis,8, 9 no data are available for immunogenicity of the routine immunisation schedule recommended by SAGE for the Sabin type 2 withdrawal era (ie, three or four doses of bivalent types 1 and 3 OPV [bOPV] and one or more dose of IPV). The previous schedule consisted of administration of three doses of OPV in all countries; a fourth dose of OPV was provided as a birth dose in countries with recent poliovirus transmission.

We initiated a clinical trial in India to assess the immunogenicity of this newly recommended sequential schedule of bOPV and IPV.

Methods

Study design

This open-label, randomised controlled trial was done between June 13, 2013, and Jan 30, 2014, at four centres in India (Andhra Medical College, Visakhapatnam, Andhra Pradesh; Gandhi Medical College and Hospital, Secunderabad, Telangana; Dr D Y Patil Medical College, Pimpri, Pune, Maharashtra; and Bharati Vidyapeeth Deemed University Medical College, Pune, Maharashtra). We selected this period to ensure that the study did not conflict with supplemental immunisation activities in these sites.

The study was approved by the ethics review committees of WHO, the respective trial sites, and authorised by the Drug Controller General (India) for implementation.

Participants

Expectant mothers were contacted and informed about the study during prenatal visits, or during admission for delivery. We used a two-stage consent process: oral consent for collection of cord blood, followed by written consent to participate in the trial after delivery (usually 6–8 hours later). If mothers opted out, we did not test cord bloods.

Newborn babies were eligible to participate if they were full-term (≥37 weeks of gestation); had vaginal or Caesarean section delivery; had a birthweight of 2·5 kg or more and Apgar score of 9 or more at 5 min; their family were willing to comply with study visits and procedures; they lived less than 30 km from study site; and their mother or legally acceptable representative provided written informed consent.

Newborn babies were excluded if they had a diagnosed or suspected medical disorder or a congenital defect that needed active management or admission to hospital; they (or a member of the immediate family) had a diagnosis or suspicion of immunodeficiency disorder; or they had a diagnosis of thrombocytopenia or other bleeding disorder.

Participants could withdraw from the study at any point, on mothers or legally acceptable representatives request. Reasons for withdrawal were collected where possible. Participants who withdrew were not replaced. Participants were judged to have withdrawn if they became non-traceable or non-compliant, if eligibility criteria were not met, or if, in the opinion of investigator, the participant had a medical disorder that could be compromised by continuation in the study.

Randomisation and masking

A randomisation list was generated by Panacea Biotec, with SAS version 9.3.10 Serial numbers from 1–900 were distributed into five groups (tOPV only; tOPV plus IPV; bOPV only; bOPV plus IPV; or bOPV plus two doses of IPV [2IPV]) through block randomisation (block size of 15) by Panacea Biotec. Panacea Biotec staff had no further involvement in the study. Site investigators had access to the list of serial numbers and group from Panacea Biotec, and numbers were allocated to eligible participants serially. Sites were provided with sealed envelopes that contained the allocation assignment.

The open-label design was selected because the vaccines could not be masked (oral vs injectable) and to avoid unnecessary injections (with a placebo), but laboratory investigators were masked to group assignments.

Procedures

We assessed five study groups: tOPV only; tOPV and IPV; bOPV only; bOPV and IPV; and bOPV plus 2IPV. The routine schedule in India was applied for the tOPV only group and the bOPV only group, with OPV doses administered at birth, 6 weeks, 10 weeks, and 14 weeks. The other study groups received an IPV dose with OPV at week 14, and the bOPV plus 2IPV group received a second IPV dose at week 18. Serum specimens were collected at birth (cord blood), at 14 weeks, and at 18 weeks for all groups, and at 22 weeks for groups who received IPV. Additionally, to assess a priming immune response in the bOPV plus 2IPV group, blood was collected at 19 weeks (1 week after second dose of IPV). The tOPV, tOPV plus IPV, and bOPV plus IPV groups received a challenge dose of tOPV at 18 weeks (and stool was collected immediately pre-challenge, at 19 weeks, and at 22 weeks). At the end of the study, participants in the bOPV only group were offered two doses of IPV to protect against poliovirus type 2.

The study vaccines were provided by Panacea Biotec. tOPV was formulated to contain 106 CCID50 or more of Sabin-strain poliovirus type 1, 105 CCID50 or more of Sabin-strain poliovirus type 2, and 105.8 CCID50 or more of Sabin-strain poliovirus type 3. bOPV was formulated to contain 106 CCID50 or more of Sabin-strain poliovirus type 1, and 105.8 CCID50 or more of Sabin-strain poliovirus type 3. IPV was formulated to contain a ratio of 40:8:32 D-antigen content for poliovirus types 1, 2, and 3. These vaccines were fill-finished with imported bulk, including blended IPV bulks prepared by formalin inactivation of the three wild poliovirus production strains, Mahoney, MEF-1, and Saukett. Pentavalent vaccine was co-administered with the study vaccines at 6 weeks, 10 weeks, and 14 weeks.

All specimens were tested by the Enterovirus Research Laboratory, Mumbai, Maharashtra, India, a Specialized Global Polio Eradication Network laboratory, with standard protocols for neutralisation assays,11 using Sabin poliovirus types 1, 2, and 3, and stool isolation procedures12 recommended by WHO. A titre of less than 1:8 was defined as seronegative (not detectable), a titre of 1:8 or more was considered seropositive, and the highest titre reported was 1:≥1448. Seroconversion was defined as either of the following: a change from undetectable to detectable titre; or a four times increase in titre over the expected decrease in maternally derived antibodies (assuming a half-life of 28 days). All median titres and 95% CIs are based on participants with detectable titre, except where indicated.

Outcomes

The primary study objective was to assess the immunogenicity of the new vaccine schedule, compared with other vaccine regimens. The secondary objectives were: to measure the effect of the IPV dose co-administered with OPV at 14 weeks; and to assess the magnitude of priming immune responses. Safety was assessed by comparing the number of adverse events across different groups. Participants were monitored by study staff for adverse events in the first 30 min after vaccination, followed up by a home visit 3 days later, and were questioned during the next scheduled study visit. Additionally, parents were instructed to contact investigators if they observed anything unusual.

Statistical analysis

The sample size calculation was based on the superiority of four doses of bOPV compared with four doses of tOPV administered in the routine immunisation schedule, for seroconversion to poliovirus types 1 and 3. For bOPV, we assumed seroconversion rates to poliovirus type 1 to be 100% and to type 3 to be 90%; for tOPV, we assumed seroconversion to poliovirus type 1 to be 90% and to type 3 to be 75%. We then used the type 3 seroconversion rates (90% vs 75%), applied an α of 0·05, a power of 0·9, and used a two-sided test to obtain a sample size of 133 per study group. We increased the sample size to 180 to account for possible attrition. Thus, for this five-group study, the total sample size was 900.

We report primarily the results of the per-protocol analysis because the primary outcome measure is seroconversion between birth and 18 weeks, and therefore, only participants with valid serology results on cord blood and at 18 weeks could potentially contribute. However, we have done a modified intention-to-treat analysis on the primary outcome, including all participants with serology results, whether within 3 days from the target date of collection or not.

We did statistical analyses with R (R Foundation, version 3.1.1).13 For the proportion of participants seroconverted, we computed Clopper-Pearson 95% CIs.14, 15 We used the Fishers exact test (two-sided) and χ2 test (two-sided) to compare the proportion of participants who seroconverted among study groups. For poliovirus antibody median titres, we calculated 95% CI with bootstrapping with 10 000 replications.16 We used the Mann-Whitney U test with continuity correction to compare poliovirus antibody distribution.14 This trial is registered with the India Clinical Trials Registry, number CTRI/2013/06/003722, and is closed to new participants. The standing Data and Safety Monitoring Board (DSMB) for polio monitored this study.

Role of the funding source

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

900 participants were enrolled in four study sites between June 13 and Aug 29, 2013. 824 (92%) of 900 participants completed all study requirements (birth to 18-week visit), provided sufficient serum, and had valid neutralisation assay results, and were included in the modified intention-to-treat analyses. 782 (87%) participants were included in the per-protocol analysis. 59 (7%) participants withdrew or were lost between birth and the 6-week visit, 37 (4%) between the 6-week and 18-week visits, and 22 (2%) between the 18-week and 22-week visits (figure 1).

Figure 1

Trial profile, modified intention-to-treat and per-protocol analyses, India, 2013–14

tOPV=trivalent oral poliovirus vaccine. IPV=inactivated poliovirus vaccine. bOPV=bivalent oral poliovirus vaccine. *Out-of-window definition is more than 3 days after scheduled study visit date.

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Baseline demographics and type-specific seroprevalence are shown by study group in table 1. We identified no significant differences among the five study groups or trial sites. The prevalence of detectable maternally derived antibodies at birth was 636 (81%) of 782 for poliovirus type 1, 661 (85%) for poliovirus type 2, and 461 (59%) for poliovirus type 3.

Table 1 

Baseline characteristics and seroprevalence

 

Data are n (%) or median (95% CI), unless indicated otherwise. tOPV=trivalent oral poliovirus vaccine. IPV=inactivated poliovirus vaccine. bOPV=bivalent OPV.

A schedule of polio vaccine at birth (tOPV or bOPV), 6 weeks (tOPV or bOPV), 10 weeks (tOPV or bOPV), and 14 weeks (tOPV or bOPV, with or without IPV), showed excellent immunogenicity to poliovirus types 1, 2 (in those receiving a type 2 poliovirus vaccine), and 3.

Table 2 displays the per-protocol analyses, and table 3 shows the results of the modified intention-to-treat analyses. Figure 2 shows the superiority of tOPV plus IPV compared with tOPV only (p=0·0008 for poliovirus type 3), and bOPV plus IPV compared with bOPV only (p=0·0153 for poliovirus type 3); the equivalence of all schedules for poliovirus type 1; and the inferiority of bOPV plus IPV compared with tOPV only for poliovirus type 2 (p<0·0001). For poliovirus type 2, bOPV plus 2IPV at 22 weeks and tOPV only at 18 weeks were equivalent.

Table 2 

Seroconversion for poliovirus (types 1, 2, and 3) from week 0 and week 18, and median antibody titres at week 18 by study group (per protocol)

 

Data are n (%, 95% CI) or median (95% CI). tOPV=trivalent oral poliovirus vaccine. IPV=inactivated poliovirus vaccine. bOPV=bivalent OPV.

Table 3 

Seroconversion for poliovirus (types 1, 2, and 3) from week 0 and week 18, and median antibody titres at week 18 by study group (modified intention to treat)

 

Data are n (%, 95% CI) or median (95% CI). tOPV=trivalent oral poliovirus vaccine. IPV=inactivated poliovirus vaccine. bOPV=bivalent OPV.

Figure 2

Differences in antibody responses to vaccination, India 2013–14

tOPV=trivalent oral poliovirus vaccine. IPV=inactivated poliovirus vaccine. bOPV=bivalent OPV. Differences in proportions of seroconversion to types 1, 2, and 3 polioviruses were measured between test groups (tOPV plus IPV, bOPV plus IPV, and bOPV only) and control group (tOPV only) with two-sided 95% CIs.

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The reverse cumulative antibody curves for poliovirus type 1, 2, and 3 for birth to age 18 weeks (appendix) show the excellent immunogenicity of the assessed schedules, and confirm the higher antibody titres achieved with IPV, especially for poliovirus type 3.

To achieve more robust point estimates of seroconversion (and 95% CI) we combined data from study groups where feasible (appendix), in some cases combining three groups (eg, three doses of bOPV), in others combining two groups (eg, two doses of tOPV).

Table 4 shows the effect of a single dose of IPV (simultaneously with tOPV in the tOPV plus IPV group, or with bOPV in the bOPV plus IPV and bOPV plus 2IPV groups) given at week 14. IPV closed most of the immunity gaps, especially for poliovirus type 3, in the tOPV plus IPV, and the bOPV plus IPV and the bOPV and 2 IPV groups, and induced an immunisation base to poliovirus type 2 in the bOPV plus IPV and bOPV plus 2IPV groups (107 [69%] of 156 in the bOPV plus IPV group and 121 [78%] of 155 in the bOPV plus 2IPV group had seroconverted by age 18 weeks; table 2).

Table 4 

Cumulative seroconversion and median antibody titres by study group

 

Data are n (%) or median (95% CI). tOPV=trivalent oral poliovirus vaccine. IPV=inactivated poliovirus vaccine. bOPV=bivalent OPV.

*Groups received a challenge dose with tOPV at 18 weeks; thus, the results of 18–22 weeks seroconversion and 22 week antibody titres include the effects of this additional dose.

†For participants who seroconverted since previous visit.

Of the participants in the bOPV plus 2IPV goup who had not seroconverted to poliovirus type 2 by week 18, 26 of 26 responded with rapid anamnestic response to a second dose 7 days after IPV administration (suggesting a previous priming immune response). However, the median titre among these participants at 22 weeks was fairly low, 91 (95% CI 72–114).

To assess resistance to poliovirus excretion after challenge with tOPV, we collected stool samples on days 0 (pre-challenge), 7, and 28 from the tOPV group, the tOPV plus IPV group, and the bOPV plus IPV group. The bOPV group was not administered a challenge dose of tOPV, and is thus the control group for secondary transmission from contacts to study participants. Excretion rates were low (around 10% or less) for poliovirus types 1 and 3, but high for poliovirus type 2 in the bOPV plus IPV group (94 [60%] of 156 at day 7, and 32 [21%] of 156 at day 28). This result contrasts with results of groups who had received tOPV (including Sabin type 2), and showed much lower excretion after challenge for type 2 poliovirus.

137 adverse events were reported. Of these, 128 were minor (21–32 per study group), with most (53%) being upper respiratory tract infections (appendix). 12 serious adverse events were reported for the entire study population (table 5). Of these, three serious adverse events occurred outside the per-protocol analysis, including one that resulted in death from neonatal sepsis. None of these adverse events was causally related to trial interventions as per the assessment and conclusions of the principal investigator and the Data and Safety Monitoring Board.

Table 5 

Serious adverse events

 

tOPV=trivalent oral poliovirus vaccine. IPV=inactivated poliovirus vaccine. bOPV=bivalent OPV.

Discussion

Results of our study showed that the new routine vaccination schedule recommended for global poliomyelitis prevention induces high levels of immunity in India. A schedule of four doses of bOPV given at birth, 6 weeks, 10 weeks, and 14 weeks, supplemented by a dose of IPV at 14 weeks, induced seroconversion to poliovirus type 1 in 99% of participants, against type 2 in 69–78%, and against type 3 in 99% of participants. A second dose of IPV closed the immunity gap to poliovirus type 2 by day 7 in the bOPV plus 2IPV group (suggesting that these participants had been primed after a first dose of IPV). Results of our study showed that mucosal immunity achieved after IPV only moderately decreased excretion after challenge. This conclusion was based on direct study data (94 [60%] of 156 excreted poliovirus type 2 in the bOPV plus IPV group compared with three [2%] of 153 in the tOPV plus IPV group at 7 days). Historical data show that excretion prevalence after challenge is similar in IPV-vaccinated participants and unvaccinated controls.17

The immunogenicity of this new schedule was higher than expected for poliovirus types 1 and 3, and in line with expectations for poliovirus type 2.18, 19, 20, 21 In the present context of the final stage of polio eradication, type 2 immunity is of concern. Will the immunity base induced with one dose of IPV in our study (levels of 69–78%) and the shortened excretion in IPV-vaccinated individuals21 be sufficient to prevent the emergence of cVDPV2 after Sabin type 2 withdrawal?

The immunogenicity of OPV seems to have improved in countries of the Indian subcontinent during the past 5–10 years, from fairly low baseline values.18, 19, 20 This observation is supported by data from Bangladesh,22 India,23, 24 and Pakistan.25, 26 In our study, the baseline maternally derived antibody titres were low, providing one possible explanation. Whether other improvements, such as access to clean water and improved sanitation, rising socioeconomic status, or other factors, might have contributed is not known.

Another secondary objective of this trial was to assess priming immune responses in participants who did not seroconvert after administration of the new schedule. We administered a second dose of IPV and measured the rapid anamnestic response 7 days later.27 All type-2-seronegative infants seemed to have a priming immune response. The median titre was fairly low, for unknown reasons, although the response could have been blunted by high heterologous titres to poliovirus types 1 and 3. The length of a priming immune response is unknown, although data from hepatitis A vaccination are encouraging.28

Mucosal immunity against poliovirus type 2 after a single dose of IPV was in line with expectations.6, 7, 17 In our study, about 60% of participants receiving only a single dose of IPV for active immunisation against this serotype excreted poliovirus type 2 virus after tOPV challenge on day 7. Results of previous studies showed that IPV-vaccinated infants excrete poliovirus with the same frequency as unvaccinated controls,29 but for shorter periods, and with lower virus titres in stool specimens.6, 7, 21

Sequential removal of Sabin poliovirus strains from populations is a key objective to achieve a polio-free world. The first step towards this goal is removal of Sabin type 2, because naturally occurring wild poliovirus type 2 was eradicated in 1999;1 Sabin type 2 poliovirus causes more than 95% of cVDPV cases; and Sabin type 2 contributed to 26–31% of vaccine-associated paralytic poliomyelitis, according to a review.9

Potential risks are associated with removal of Sabin type 2. Some of these risks can be predicted, others might be discovered after introduction of the new schedule. SAGE has adopted six readiness criteria and one key progress requirement before the switch from tOPV to bOPV vaccine (ie, removal of Sabin type 2) can be implemented. The most important criterion is elimination of persistent cVDPV circulation (ie, >6 months).2 Additionally, introduction of the single dose of IPV into routine immunisation schedules worldwide constitutes a substantial programmatic challenge. Progress thus far in this aspect has been unprecedented; all countries have said that they will introduce a dose of IPV by the end of 2015 or in early 2016, including the 73 GAVI-eligible and GAVI-graduated countries.

Our study had limitations. We did this trial in four sites across central India. Our findings might be generalisable to most developing country settings, but might not be achievable in some northern Indian states with low OPV immunogenicity. We were not able to mask the study staff or parents to group allocation. However, laboratory investigators were masked to the schedule assignments. We showed that a single dose of IPV can close the humoral type 2 immunity gaps in northern India,23 and boost mucosal immunity.21 Secondary transmission (from vaccinees to study participants) of Sabin type 2 into our study population occurred in our study. However, we do not believe that this transmission affects the validity or interpretation of our results.

Our results are encouraging and validate the newly recommended routine schedule for polio prevention. The new schedule induces high levels of seroconversion and high-level mucosal immunity against poliovirus types 1 and 3, and as expected, a strong immunity base against poliovirus type 2 (seroconversion and priming). The new polio eradication strategy is in its second year, and almost all countries have said that they will introduce a dose of IPV in 2015 or early 2016.30 Therefore, after April, 2016, no country should be using an OPV-only schedule for polio prevention, and withdrawal of Sabin type 2 seems to be on track for 2016.

This online publication has been corrected. The corrected version first appeared at thelancet.com on Dec 10, 2015

Contributors

RWS prepared the manuscript, and all authors reviewed and approved it. RWS, SB, JMD, HV, MA, AC, TJJ, HJ, and RBA did the study design, trial implementation strategy, and interpreted the data. HV, MA, PV, JVR, SA, SKL, and AK oversaw acquisition of data. JMD did the laboratory analyses. RS, MT, MA, HV, and RWS contributed to data analyses. LM contributed to data analysis, interpretation, and review of the trial report.

Declaration of interests

We declare no competing interests.

Acknowledgments

We acknowledge the contributions of the research staff and the management of the four study institutions and the involved laboratory personnel at the Enterovirus Research Centre Mumbai. We appreciate the commendable involvement and support of Usha Rani (Gandhi Medical College, Secunderabad, India), Shalaka Agarkhedkar (Dr D Y Patil Medical College, Pune, India), Sonali Palkar (BVDU Medical College, Pune, India), and Domathoti Ramaganeshan (Andhra Medical College, Visakhapatnam, India) at their respective study sites. Our special thanks go to the data team at National Polio Surveillance Project, WHO India, for handling the massive data management of this project. Panacea Biotec Limited provided an excellent support for the study with highly commendable role of Shilpi Jain and the research team. We are thankful to the Government of India, Ministry of Health and Family Welfare for providing technical, administrative, and operational support for this study.

Supplementary Material

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Supplementary appendix

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References

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