Articles

Immunogenicity of bivalent types 1 and 3 oral poliovirus vaccine: a randomised, double-blind, controlled trial

Roland W Sutter, T Jacob John, Hemant Jain, Sharad Agarkhedkar, Padmasani Venkat Ramanan, Harish Verma, Jagadish Deshpande, Ajit Pal Singh, Meghana Sreevatsava, Pradeep Malankar, Anthony Burton, Arani Chatterjee, Hamid Jafari, R Bruce Aylward

Summary Lancet 2010; 376: 1682–88 Background Poliovirus types 1 and 3 co-circulate in poliomyelitis-endemic countries. We aimed to assess the Published Online immunogenicity of a novel bivalent types 1 and 3 oral poliovirus vaccine (bOPV). October 26, 2010 DOI:10.1016/S0140- Methods We did a randomised, double-blind, controlled trial to assess the superiority of monovalent type 2 OPV 6736(10)61230-5 (mOPV2), mOPV3, or bOPV over trivalent OPV (tOPV), and the non-inferiority of bivalent vaccine compared with Comment See page 1624 mOPV1 and mOPV3. The study was done at three centres in India between Aug 6, 2008, and Dec 26, 2008. Random World Health Organization, allocation was done by permuted blocks of ten. The primary outcome was seroconversion after one monovalent or Geneva, Switzerland (R W Sutter MD, bivalent vaccine dose compared with a dose of trivalent vaccine at birth. The secondary endpoints were seroconversion M Sreevatsava MPH, after two vaccine doses compared with after two trivalent vaccine doses and cumulative two-dose seroconversion. Parents P Malankar MD, A Burton, or guardians and study investigators were masked to treatment allocation. Because of multiple comparisons, we defi ned R B Aylward MD); India Expert p≤0·01 as statistically signifi cant. This trial is registered with Current Controlled Trials, ISRCTN 64725429. Advisory Group on Polio Eradication, Vellore, India (Prof T J John FRCP[E]); Results 900 newborn babies were randomly assigned to one of fi ve vaccine groups (about 180 patients per group); of Mahatma Gandhi Memorial these 70 (8%) discontinued, leaving 830 (92%) for analysis. After the fi rst dose, seroconversion to poliovirus type 1 Medical College, Indore, Madhya Pradesh, India was 20% for both mOPV1 (33 of 168) and bOPV (32 of 159) compared with 15% for tOPV (25 of 168; p>0·01), to (Prof H Jain MD); Dr D Y Patil poliovirus type 2 was 21% (35 of 170) for mOPV2 compared with 25% (42 of 168) for tOPV (p>0·01), and to poliovirus Medical College, Pimpri, Pune, type 3 was 12% (20 of 165) for mOPV3 and 7% (11 of 159) for bOPV compared with 4% (7 of 168) for tOPV (mOPV3 Maharashtra, India vs tOPV p=0·01; bOPV vs tOPV; p>0·01). Cumulative two-dose seroconversion to poliovirus type 1 was (Prof S Agarkhedkar MD); Sri Ramachandra Medical 90% (151 of 168) for mOPV1 and 86% (136 of 159) for bOPV compared with 63% (106 of 168) for tOPV (p<0·0001), to College and Research Institute, poliovirus type 2 was 90% (153 of 170) for mOPV2 compared with 91% (153 of 168) for tOPV (p>0·01), and to poliovirus Porur, Chennai, Tamil Nadu, type 3 was 84% (138 of 165) for mOPV3 and 74% (117 of 159) for bOPV compared with 52% (87 of 168) for tOPV India (Prof P V Ramanan MD); (p<0·0001). The vaccines were well tolerated. 19 serious adverse events occurred, including one death; however, these National Polio Surveillance Project, World Health events were not attributed to the trial interventions. Organization, New Delhi, India (H Verma MB, H Jafari MD); Interpretation The fi ndings show the superiority of bOPV compared with tOPV, and the non-inferiority of bOPV Enterovirus Research Centre, compared with mOPV1 and mOPV3. Mumbai, India (J Deshpande PhD); and Panacea Biotec, New Delhi, India Funding GAVI Alliance, World Health Organization, and Panacea Biotec. (A P Singh MB, A Chatterjee MB) Correspondence to: Introduction rate and propensity for geographical spread of poliovirus Dr Roland Sutter, Polio The global poliomyelitis eradication initiative has type 1 is higher than for poliovirus type 3, and therefore Eradication Department, World Health Organization, 20, Avenue reported substantial progress since 1988, when the the strategic priority of the initiative was to rapidly Appia, CH-1211 Geneva 27, World Health Assembly resolved to eradicate polio- increase population immunity against poliovirus type 1 Switzerland myelitis by 2000.1 Mass vaccination with trivalent oral with mOPV1 while attempting to control the other [email protected] poliovirus vaccine (tOPV) led to a reduction in the serotypes with tOPV or mOPV3. This action might number of poliomyelitis-endemic countries from at have led to gaps in immunity and facilitation of the least 125 in 1988 to four in 2005 (and in 2010), and the spread of poliovirus type 3 and vaccine-derived poliovirus For the WHO global number of poliomyelitis cases fell from about 350 000 in type 2.3,7 poliomyelitis eradication 1988 to 1606 in 2009.2 The introduction of monovalent In 2007, the advisory committee on poliomyelitis initiative, see http://www. type 1 OPV (mOPV1) in April, 2005, in supplemental eradication recommended assessment of a bivalent polioeradication.org immunisation activities led to further reductions in type 1 and 3 OPV (bOPV).8 Such a vaccine would remove transmission of wild poliovirus type 1 but has the interference of the Sabin poliovirus type 2 contained not stopped transmission in the poliomyelitis- in the trivalent vaccine in inducing type-specifi c endemic countries (India, Afghanistan, Pakistan, immunity to types 1 and 3.9–11 Although diff erent and Nigeria).3–5 formulations of the bivalent vaccines were used in small The availability of types 1 and 3 monovalent vaccines quantities in the late 1950s and early 1960s in eastern provided the global poliomyelitis eradication initiative Europe,12–14 the immunogenicity of these vaccines was with additional vaccine options6 but complicated not assessed against other poliovirus vaccines and the decision making about vaccine selection. The paralytic hypothesis of vaccine interference was not tested.

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We aimed to assess the superiority of mOPV2, mOPV3, or guardians and study investigators were masked or bOPV over tOPV, and the non-inferiority of bOPV to treatment allocation. Coding was broken at data compared with mOPV1 and mOPV3. The superiority of analysis after completion of data collection and mOPV1 over tOPV has already been reported.15 laboratory analyses.

Methods Procedures Participants We gave infants one dose of vaccine immediately after We did a randomised, double-blind, controlled clinical random allocation (at birth). At 30 days, we took blood trial at three centres in India (Mahatma Ghandi Memorial samples, and the infants received a second dose of the Medical College, Dr D Y Patil Medical College, and Sri same vaccine. A third serum sample was obtained at Ramachandra Medical College and Research Institute) 60 days. The primary endpoint was seroconversion after between Aug 6, and Dec 26, 2008. Enrolment took place one dose of monovalent or bivalent vaccine compared for about 6 weeks. During antenatal visits or during with after a trivalent vaccine dose. The secondary admission for delivery, we told expectant mothers about endpoints were seroconversion after two vaccine doses the study and invited them to participate. Inclusion compared with after two trivalent vaccine doses and criteria were healthy newborn babies with a birthweight cumulative two-dose seroconversion. Infants who could of at least 2·5 kg and an Apgar score of at least 9 at 5 min, be assessed were included in the analysis (ie, modifi ed and a parent or guardian living less than 30 km from the intention-to-treat analysis). study site and who had no travel plans during the study Panacea Biotec formulated all fi ve vaccines using period. Newborn babies were excluded if they needed imported bulk from WHO-prequalifi ed producers of hospital admission or were at risk of immunodefi ciency trivalent vaccine in France and Indonesia. mOPV1 was (eg, those with a family history of immunodefi ciency). formulated to contain at least 10⁶ median cell culture

Those receiving the trivalent vaccine from routine infectious dose (CCID50) Sabin poliovirus type 1 per vaccination services were excluded. No supplemental dose, mOPV2 at least 10⁵ CCID50 Sabin poliovirus · immunisation activities were undertaken during the type 2, and mOPV3 at least 10⁵ ⁸ CCID50 Sabin poliovirus study period. type 3. The bivalent vaccine was formulated to contain · Voluntary and informed consent for participation of at least 10⁶ CCID50 of Sabin poliovirus type 1 and 10⁵ ⁸ newborn babies was obtained at enrolment from parents CCID50 of Sabin poliovirus type 3. The trivalent vaccine or guardians in accordance with ethical principles. The was formulated to contain at least 10⁶ CCID50 of Sabin study was approved by the drugs controller general poliovirus type 1, 10⁵ CCID50 of Sabin poliovirus type 2, · (India), the institutional review boards of the three and 10⁵ ⁸ CCID50 of Sabin poliovirus type 3. Prerelease institutions, and WHO. vaccine potencies were assessed by Panacea Biotec and by the National Control Laboratory (Kasauli, India). Randomisation and masking Study vaccines were shipped from the trial sites to Immediately after delivery, we obtained cord blood and WHO collaborating centres in Europe before the start infants were allocated the next consecutive study and after the end of the study to assess the minimum number. We used random permuted blocks of ten that target potencies. were generated by the sponsor (Panacea Biotec, New After we obtained blood samples, they were allowed Delhi, India) with SAS (version 9.1.3). The study group to clot, centrifuged and serum separated, and then allocations were coded on the vaccine vial labels. Parents stored frozen at –20ºC at the study sites until shipment

900 randomised

180 assigned to mOPV1 181 assigned to mOPV2 179 assigned to mOPV3 182 assigned to tOPV 178 assigned to bOPV

12 discontinued 11 discontinued 14 discontinued 14 discontinued 19 discontinued 2 moved 4 moved 10 moved 10 moved 12 moved 5 refusal from parent 1 non-compliance 2 non-compliance 1 non-compliance 3 non-compliance or guardian 4 refusal from parent 2 refusal from parent 3 other 3 refusal from parent 5 other or guardian or guardian or guardian 2 other 1 other

168 included in analyses 170 included in analyses 165 included in analyses 168 included in analyses 159 included in analyses

Figure 1: Trial profi le mOPV=monovalent oral poliovirus vaccine. tOPV=trivalent oral poliovirus vaccine. bOPV=bivalent oral poliovirus vaccine. www.thelancet.com Vol 376 November 13, 2010 1683 Articles

mOPV1 (n=168) mOPV2 (n=170) mOPV3 (n=165) tOPV (n=168) bOPV (n=159) Male sex 98 (58%) 97 (57%) 78 (47%) 88 (52%) 86 (54%) Birthweight (kg) 2·8 (2·7–2·8) 2·8 (2·7–2·8) 2·8 (2·8–2·9) 2·8 (2·8–2·9) 2·8 (2·8–2·9) Interval from birth to vaccine administration (min) 115 (92–152) 115 (98–131) 110 (95–146) 118 (95–138) 115 (87–140) Poliovirus type 1 Seroprevalence 147 (88%) 144 (85%) 149 (90%) 153 (91%) 146 (92%) Titre 45 (28–57) 40 (28–45) 45 (28–57) 57 (28–74) 36 (28–45) Poliovirus type 2 Seroprevalence 139 (83%) 144 (85%) 145 (88%) 140 (83%) 135 (85%) Titre 28 (23–45) 28 (23–45) 28 (23–36) 28 (23–45) 36 (23–45) Poliovirus type 3 Seroprevalence 109 (65%) 97 (57%) 109 (66%) 108 (64%) 112 (70%) Titre 11 (10–14) 10 (<8–11) 11 (11–14) 11 (9–18) 14 (11–18)

Data are number (%) or median (95% CI). mOPV=monovalent oral poliovirus vaccine. tOPV=trivalent oral poliovirus vaccine. bOPV=bivalent oral poliovirus vaccine.

Table 1: Demographics, baseline characteristics, and seroprevalence at birth

mOPV1 (n=168) mOPV2 (n=170) mOPV3 (n=165) tOPV (n=168) bOPV (n=159) p value At 30 days To poliovirus type 1 33/168 (20%, 14–26%) 9/170 (5%, 3–10%) 7/165 (4%, 2–8%) 25/168 (15%, 10–21%) 32/159 (20%, 14–27%) NS To poliovirus type 2 7/168 (4%, 2–8%) 35/170 (21%, 15–27%) 4/165 (2%, 1–6%) 42/168 (25%, 19–32%) 6/159 (4%, 2–8%) NS To poliovirus type 3 5/168 (3%, 1–7%) 0 (0%, 0–2%) 20/165 (12%, 8–18%) 7/168 (4%, 2–8%) 11/159 (7%, 4–12%) 0·01 for mOPV3 vs tOPV At 60 days To poliovirus type 1 117/135 (87%, 80–92%) 19/161 (12%, 8–18%) 13/158 (8%, 5–13%) 77/143 (54%, 46–62%) 102/127 (80%, 73–87%) <0·0001 for mOPV1 and bOPV vs tOPV To poliovirus type 2 14/161 (9%, 5–14%) 114/135 (84%, 78–90%) 17/161 (11%, 6–16%) 107/126 (85%, 78–90%) 12/153 (8%, 4–13%) NS To poliovirus type 3 8/163 (5%, 2–9%) 8/170 (5%, 2–9%) 117/145 (81%, 74–87%) 79/161 (49%, 41–57%) 105/148 (71%, 63–78%) <0·0001 for mOPV3 vs bOPV;* 0·0002 for bOPV vs tOPV Cumulative To poliovirus type 1 151/168 (90%, 85–94%) 29/170 (17%, 12–23%) 21/165 (13%, 8–19%) 106/168 (63%, 56–70%) 136/159 (86%, 79–90%) <0·0001 for mOPV1 and bOPV vs tOPV To poliovirus type 2 22/168 (13%, 9–19%) 153/170 (90%, 85–94%) 21/165 (13%, 8–19%) 153/168 (91%, 86–95%) 18/159 (11%, 7–17%) NS To poliovirus type 3 13/168 (8%, 4–13%) 8/170 (5%, 2–9%) 138/165 (84%, 77–89%) 87/168 (52%, 44–59%) 117/159 (74%, 66–80%) <0·0001 for mOPV3 and bOPV vs tOPV

Data are n/N (%, 95% CI). Only p values ≤0·01 are presented for poliovirus type-specifi c comparisons. mOPV=monovalent oral poliovirus vaccine. tOPV=trivalent oral poliovirus vaccine. bOPV=bivalent oral poliovirus vaccine. NS=not signifi cant. *p=0·04 (not considered signifi cant because of multiple comparisons) for mOPV3 versus bOPV.

Table 2: Seroconversion 30 and 60 days after vaccination

mOPV1 (n=168) mOPV2 (n=170) mOPV3 (n=165) tOPV (n=168) bOPV (n=159) At birth (cord blood) Poliovirus type 1 45 (28 to 57) 40 (28 to 45) 45 (28 to 57) 57 (28 to 74) 36 (28 to 45) Poliovirus type 2 28 (23 to 45) 28 (23 to 45) 28 (23 to 36) 28 (23 to 45) 36 (23 to 45) Poliovirus type 3 11 (10 to 14) 10 (<8 to 11) 11 (11 to 14) 11 (9 to 18) 14 (11 to 18) At 30 days Poliovirus type 1 28 (23 to 45) 14 (14 to 18) 14 (14 to 23) 32 (23 to 36) 23 (18 to 36) Poliovirus type 2 13 (11 to 14) 23 (14 to 36) 11 (9 to 14) 23 (16 to 36) 11 (11 to 18) Poliovirus type 3 <8 (<8 to <8) <8 (<8 to <8) <8 (<8 to 9) <8 (<8 to <8) <8 (<8 to 9) At 60 days Poliovirus type 1* 910 (809 to 1176) 11 (9 to 11) 11 (9 to 11) 114 (64 to 181) 576 (455 to 724) Poliovirus type 2† 9 (<8 to 11) 362 (288 to 455) 9 (<8 to 11) 288 (228 to 362) 9 (<8 to 9) Poliovirus type 3‡ <8 (<8 to <8) <8 (<8 to <8) 362 (288 to 455) 45 (11 to 114) 228 (144 to 228)

Data are median (95% CI). Only p values ≤0·01 are presented for poliovirus type-specifi c comparisons. mOPV=monovalent oral poliovirus vaccine. tOPV=trivalent oral poliovirus vaccine. bOPV=bivalent oral poliovirus vaccine. *p=0·005 for mOPV1 vs bOPV; p<0·0001 for mOPV1 or bOPV vs tOPV. †p=0·05 for mOPV2 vs tOPV (not considered signifi cant because of multiple comparisons). ‡p=0·05 for mOPV3 vs tOPV (not considered signifi cant because of multiple comparisons).

Table 3: Titre at birth and 30 and 60 days after vaccination

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100 Poliovirus mOPV1 Vaccines containing poliovirus type 1 90 type 1 bOPV tOPV mOPV1 80 mOPV2 70 mOPV3 bOPV 60 50 tOPV 40 Infants (%) 30 20 Vaccines containing poliovirus type 3 10 0 mOPV3

100 Poliovirus bOPV 90 type 2 80 tOPV 70 1 0·8 0·6 0·4 0·2 60 Proportion of infants with seroconversion 50 40 Infants (%) Figure 3: Non-inferiority and superiority assessments after a cumulative 30 two-dose schedule of vaccines 20 Bars=95% CI. mOPV=monovalent oral poliovirus vaccine. bOPV=bivalent oral 10 poliovirus vaccine. tOPV=trivalent oral poliovirus vaccine. 0

100 Poliovirus Serious adverse events were reviewed by the data and 90 type 3 safety monitoring board. 80 70 Statistical analysis 60 For sample size calculations, we defi ned non-inferiority 50 as less than an absolute value 20% diff erence in sero- 40 Infants (%) conversion between bivalent vaccine and types 1 or 3 30 20 monovalent vaccine. We defi ned superiority as at least 10 an absolute value 20% diff erence in seroconversion 0 between bOPV and tOPV, mOPV2 and tOPV, and 1 10 100 1000 10 000 mOPV3 and tOPV. The 20% represents a balance in Antibody titre (day 60) terms of study size and implications of fi ndings for Figure 2: Reverse poliovirus antibody distribution curves vaccination programmes. A sample size of 139 patients mOPV=monovalent oral poliovirus vaccine. bOPV=bivalent oral poliovirus in each of the fi ve groups was needed to show non- vaccine. tOPV=trivalent oral poliovirus vaccine. inferiority or superiority (α=0·05, β=0·10 [two-tailed to the Enterovirus Research Centre (Mumbai, India). test]). This sample size was also used in a trial of We tested samples in triplicate with modifi ed neutral- mOPV1.15 To correct for attrition, we aimed to enrol isation assays for antibodies to poliovirus types 1, 2, 180 patients in all fi ve study groups, with a total of and 3.16,17 Seropositivity was defi ned as a reciprocal titre 900 patients. of at least eight. Seroconversion was defi ned as a titre We did statistical analyses with R (version 2.9.2)20 and four times higher than the expected fall in maternal SAS (version 9.1)21 statistical packages. The proportion of antibody concentrations between successive serum seroconversion was compared by χ² tests (Yates corrected), samples. The half-life of antibody decay was assumed to and Komolgorov-Smirnoff statistics were calculated to be 28 days.18 Seroconversion results are presented after compare distribution of median values across study the fi rst dose (between birth and 30 days), after the groups.22 95% CIs around median values were calculated.23 second dose (30–60 days, excluding infants who had Superiority is defi ned as non-overlapping 95% CIs and already seroconverted after the fi rst dose), and as a non-inferiority as overlapping 95% CIs between the cumulative two-dose seroconversion (adding all infants vaccination groups. Because of multiple comparisons, that seroconverted irrespective of dose). At one site we defi ned p≤0·01 as statistically signifi cant. (Mahatma Gandhi Memorial Medical College), we This trial is registered with Current Controlled Trials, collected stool samples at 7, 30, 37, and 60 days after ISRCTN 64725429. birth to assess the proportion of patients with excreted virus in their stool. These samples were processed at Role of the funding source the Enterovirus Research Centre according to WHO GAVI Alliance had no role in the study design, data guidelines.19 Adverse events were identifi ed by site collection, data interpretation, or writing of the report. investigators and reviewed by the principal investigator. Panacea Biotec, sponsor of the study, formulated the www.thelancet.com Vol 376 November 13, 2010 1685 Articles

80 7 day 30 day 37 day 60 day mOPV1 and for bOPV but was lower for the trivalent vaccine (p>0·01; table 2). After the second dose, 70 seroconversion was about 80% for mOPV1 and bOPV 60 compared with around 50% for trivalent vaccine (p<0·0001). Cumulative two-dose seroconversion was 50 around 90% for mOPV1 and bOPV but was lower for the

40 trivalent vaccine (p<0·0001). Seroconversion to poliovirus type 2 did not diff er between the type 2 monovalent 30 vaccine and trivalent vaccine after the fi rst or second

20 dose, or after seroconversion rates for both doses were combined (table 2). Seroconversion to poliovirus type 3

Infants with poliovirus type 1 in stool (%) with poliovirus Infants 10 did not diff er between tOPV and bOPV vaccine types but

0 was signifi cantly diff erent between mOPV3 and tOPV after the fi rst dose (p=0·01), but seroconversion was over 80 70% for monovalent type 3 and bivalent vaccine compared with around 50% for the trivalent vaccine after 70 the second dose (both p<0·0001), and when data for both 60 doses were combined (p<0·0001; table 2). Table 3 shows that at day 60 the overall median titres of poliovirus type 50 1 antibodies were signifi cantly lower for the trivalent 40 vaccine than for the bivalent (p<0·0001) or monovalent type 1 vaccines (p<0·0001) but did not diff er between 30 vaccine groups for poliovirus types 2 and 3. 20 The reverse cumulative distribution curves, which are a summary measure of antibody distribution, show similar Infants with poliovirus type 2 in stool (%) with poliovirus Infants 10 curves for vaccines with similar type-specifi c sero- 0 conversion rates (eg, for type 1 in mOPV1 and bOPV vs tOPV; fi gure 2). Figure 3 shows that mOPV1 and bOPV 80 (Sabin type 1-containing vaccines) and mOPV3 and bOPV (Sabin type 3-containing vaccines) have overlapping 70 95% CIs for cumulative seroconversion. However, the 60 95% CIs of these vaccines did not overlap with the trivalent vaccine. 50 The proportion of infants who had poliovirus in their 40 excrement 7 days after the birth dose and at 37 days (7 days after the second dose) was similar to the 30 seroconversion rates between birth and 30 days and 20 between 30 days and 60 days, respectively (table 2; fi gure 4). There was an excretion peak at 37 days and a Infants with poliovirus type 3 in stool (%) with poliovirus Infants 10 decrease in excretion at 60 days for all three types of 0 monovalent vaccine. For the bivalent vaccine, there was mOPV1 mOPV2 mOPV3 tOPV bOPV an excretion peak for poliovirus type 1 at 37 days, which Figure 4: Excretion of poliovirus in stool samples fell by 60 days, but the peak at 37 days and the drop at mOPV=monovalent oral poliovirus vaccine. tOPV=trivalent oral poliovirus vaccine. bOPV=bivalent oral 60 days were less pronounced for type 3 poliovirus. This poliovirus vaccine. pattern was similar to trivalent vaccine excretion rates for the types 1 and 3 components, but diff erent from the study vaccines, did the randomisation, and monitored excretion rates for the trivalent vaccine type 2 component, the trial. RWS had full access to all data in the study and which seemed similar to the excretion rates for the had fi nal responsibility for the decision to submit monovalent vaccines. for publication. 19 serious adverse events (ie, those that resulted in hospital admission) were reported (fi ve from Indore, Results three from Pune, and ten from Chennai), with one We randomly assigned 900 newborn babies, 70 (8%) of death from sudden infant death syndrome (table 4). whom discontinued (fi gure 1). Table 1 shows demo- 18 of 19 infants who were admitted recovered after a graphics, baseline characteristics, and seroprevalence in short time in hospital. 41 other adverse events were the various vaccine groups. Seroconversion to poliovirus reported, which were mostly caused by infections type 1 at 30 days after the fi rst dose was about 20% for (table 4). We noted no signifi cant diff erences in

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distribution of any adverse events by study group. mOPV1 mOPV2 mOPV3 tOPV bOPV Total None of the adverse events were attributed to trial interventions. Serious adverse events Vaccine potency data from the manufacturer and Lower respiratory infections 5 2 0 1 0 8 control laboratory were in line with expected potency Other infectious causes 2 0 0 2 1 5 fi ndings. The minimum target potencies were reached Hyperbilirubinaemia 0 1 0 0 1 2 for all the trial vaccines apart from mOPV1, which had a Non-infectious causes 1 0 1 2 0 4 · Total 8 3 1 5 2 19 potency of 10⁵ ⁹¹ CCID50 in the pre-study sample and · Other adverse events 10⁵ ⁹⁴ CCID50 in the study completion sample. Cough, cold, or upper respiratory infection 5 7 3 4 6 25 Discussion Diarrhoea or vomiting 1 0 1 1 1 4 Our fi ndings show the superiority of bOPV compared Conjunctivitis 0 1 0 1 1 3 with tOPV, and the non-inferiority of bOPV compared Otitis media 0 1 0 0 1 2 with mOPV1 and mOPV3. Our results also show the Skin infections 1 1 0 0 1 3 non-inferiority of mOPV2 compared with tOPV and the Other 3 0 0 0 1 4 superiority of mOPV3 compared with tOPV. By contrast Total 10 10 4 6 11 41 with published work outside India that showed the 15,24,25 mOPV=monovalent oral poliovirus vaccine. tOPV=trivalent oral poliovirus vaccine. bOPV=bivalent oral immunogenicity of OPV given at birth, our trial poliovirus vaccine. confi rmed the low seroconversion rates after a birth dose of OPV that were reported in previous trials in India Table 4: Adverse events (unpublished) and the good immunogenicity of mOPVs in 30-day-old infants.26 intermediate for the bivalent vaccine, and low for Our study confi rmed that the bivalent vaccine leads to poliovirus types 1 and 3 after the trivalent vaccine. For signifi cantly more seroconversion than the trivalent the bivalent vaccine, stool excretion data suggest vaccine. Additionally, the seroconversion rates and interference of type 1 poliovirus with type 3 poliovirus reverse cumulative distribution curves of neutralising in the stool samples (lower peak excretion at 37 days and antibody titres were similar between the bivalent higher excretion at 60 days of type 3 poliovirus compared vaccine and the respective monovalent vaccines. The with type 1 poliovirus). Similarly, the excretion pattern bivalent vaccine immunogenicity fi ndings were for trivalent vaccine suggested interference of type 2 discussed by the advisory committee on poliomyelitis poliovirus with type 1 and type 3 poliovirus. eradication on Nov 18–19, 2009, and led to specifi c The major limitation of our study is the generalisability recommendations for bOPV use during supplemental of our specifi c fi ndings to the poliomyelitis-endemic immunisation activities.27 The major advantages of the areas in northern India and other poliomyelitis-endemic bivalent vaccine according to the committee is that it countries. Although the study sites were distributed will enhance individual and population immunity over a wide geographical area in central and southern simultaneously for both poliovirus types 1 and 3, India, the immunogenicity of these vaccines in northern without any serious loss in immunogenicity compared India, especially Uttar Pradesh and Bihar States, could with the mOPVs. be lower than other parts of India.6,29 Although the Seroconversion rates and antibody titres did not diff er potency of mOPV1 was lower than the minimum between mOPV2 and tOPV, which shows that the intended potency, the immunogenicity of this vaccine trivalent vaccine can be used to control outbreaks of wild is unlikely to have been infl uenced by this low potency poliovirus type 2 or type 2 circulating vaccine-derived in view of the high seroconversion rates and titres poliovirus. However, a stockpile of mOPV2 should be reported in our trial. kept once poliomyelitis eradication has been achieved to bOPV is already being used on a large scale to increase allow type-specifi c control measures should type 2 population immunity against and accelerate the poliomyelitis be re-introduced. Also, our study provides elimination of the fi nal chains of transmission of these results on mOPV3 immunogenicity since it was two remaining wild polioviruses, especially in areas relicensed. mOPV3 has been used on a wide scale since where both poliovirus types 1 and 3 co-circulate. it was fi rst relicensed in 2005 for type-specifi c outbreak Contributors control. The re-licensed form of mOPV3 contains the RWS had the overall responsibility for the trial from WHO and same type 3 poliovirus potency as the trivalent vaccine, prepared the fi rst draft of manuscript. TJJ was principal investigator. which is higher than the original mOPV3 formulations HJ, SA, and PVR coordinated the fi eld work as site investigators in Indore, Pune, and Chennai, respectively. HV and PM were study 28 used during the early 1960s. monitors. JD did the laboratory analyses. MS and AB were the data The stool excretion data show that excretion of virus and statistical coordinators. APS and AC were involved in all aspects of 7 days after the birth dose is low and corresponds with the study from the sponsor (Panacea Biotec). All authors participated in the design of the study, reviewed the paper, and approved it the low seroconversion rates. By contrast, excretion rates for publication. at 37 days were high after the monovalent vaccines, www.thelancet.com Vol 376 November 13, 2010 1687 Articles

Confl icts of interest 14 Domök I, Baranyai E, Kovacs D, Karasszon D, Lengyel GY, AJS and AC are employees of Panacea Biotec. No other authors reported Szollosy E. Clinical and virological analysis of cases diagnosed as any confl icts of interest. poliomyelitis in Hungary in the years 1961–1967. In: 12th European Symposium of Poliomyelitis and Allied Diseases. Bucharest, Acknowledgments Romania: Publishing House of the Academy of the Socialist The trial was funded by GAVI Alliance and WHO. The study sponsor Republic of Romania, Bucharest, 1969. (Panacea Biotec) formulated the study vaccines, did the 15 El-Sayed N, El-Gamel Y, Abbassy AA, et al. Monovalent type 1 oral randomisation, and monitored the trial. We thank Sushma Nadkarni, poliovirus vaccine in newborns. N Engl J Med 2008; 16: 1655–65. Sneha Rane, Uma Nalavade, and Sonali Sawant from the Enterovirus 16 Expanded Programme on Immunization. Report of a WHO Research Centre, Mumbai, for doing the serology testing and stool Informal Consultation on Polio Neutralizing Antibody Assays, processing. We also thank the trial staff from the Chennai trial site, Nashville, 5-6 December 1991. Geneva: World Health Organization, especially A Prakash, V Vilvanathan, and B Rajesh; from Indore trial 1991 (WHO/EPI/RD/91.3 Rev 1). site, especially Ashish Dubey and Mukta Jain; and from the Pune trial 17 WHO Collaborative Study Group on Oral and Inactivated Poliovirus site, especially Shalaka Agarkhedkar, Geeta Karambelkar, and Vaccines. Combined immunization of infants with oral and Sampada Tambolkar, for their assistance with trial implementation. inactivated poliovirus vaccines: results of a randomized trial in The Gambia, Oman and Thailand. J Infect Dis 1997; References 175 (suppl 1): S215–27. 1 World Health Assembly. Global eradication of poliomyelitis by the 18 Cohen-Abbo A, Culley BS, Reed GW, et al. 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