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Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013
Vaccine xxx (2016) xxx–xxx
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Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013 Muhammad Atif Habib a, Sajid Soofi a, Ondrej Mach b, Tariq Samejo a, Didar Alam a, Zaid Bhatti a, William C. Weldon c, Steven M. Oberste c, Roland Sutter b, Zulfiqar A. Bhutta a,⇑ a b c
Division of Women and Child Health, The Aga Khan University, Karachi, Pakistan Polio Eradication Departments, World Health Organization, Geneva, Switzerland Polio and Picornavirus Laboratory Branch, Centers for Disease Control and Prevention, Atlanta, USA
a r t i c l e
i n f o
Article history: Received 22 December 2015 Received in revised form 12 May 2016 Accepted 26 May 2016 Available online xxxx Keywords: Polio virus vaccine Injectable polio vaccine Immunity Seroconversion Seroprevalence Pakistan
a b s t r a c t Background: Considering the current polio situation Pakistan needs vaccine combinations to reach maximum population level immunity. The trial assessed whether inactivated poliovirus vaccine (IPV) can be used to rapidly boost immunity among children in Pakistan. Methods: A five-arm randomized clinical trial was conducted among children (6–24 months, 5–6 years and 10–11 years). Children were randomized in four intervention arms as per the vaccines they received (bOPV, IPV, bOPV + vitamin A, and bOPV + IPV) and a control arm which did not receive any vaccine. Baseline seroprevalence of poliovirus antibodies and serological immune response 28 days after intervention were assessed. Results: The baseline seroprevalence was high for all serotypes and the three age groups [PV1: 97%, 100%, 96%, PV2: 86%, 100%, 99%, PV3: 83%, 95%, 87% for the three age groups respectively]. There was significantly higher rate of immune response observed in the study arms which included IPV (95–99%) compared with bOPV only arms (11–43%), [p < 0.001]; Vitamin A was not associated with improved immune response. Immune response rates in the IPV only arm and IPV + bOPV arm were similar [p > 0.5]. Conclusion: IPV has shown the ability to efficiently close existing immunity gaps in a vulnerable population of children in rural Pakistan. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction The goal to eradicate polioviruses worldwide was adopted in 1988 and since then the number of paralyzed persons due to polioviruses has decreased by over 99.9%. In 2014, the World Health Organization (WHO) reported 359 cases of paralytic poliomyelitis due to wild polioviruses worldwide [1]. In the end of 2015, the remaining endemic areas with wild poliovirus circulation were limited to security compromised parts of Pakistan and Afghanistan. In Nigeria, no new cases of polio have been reported in 2015, and in September 2015 Nigeria has been removed from the list of poliovirus endemic countries by WHO [2]. Despite the dramatic reduction in cases of poliomyelitis, it is proving difficult for the Global Polio Eradication Initiative (GPEI) to finally complete the eradication by interrupting the last chains of transmission in these endemic areas; and exportations of wild polioviruses from the endemic areas into ⇑ Corresponding author at: Founding Director Center of Excellence in Women and Child Health, The Aga Khan University, Karachi 74800, Pakistan. E-mail address: [email protected] (Z.A. Bhutta).
polio-free countries have occurred in multiple occasions, sometimes causing large outbreaks of poliomyelitis [3]. In Pakistan, progress has been made in 2015 compared with 2014: as of October 2015, Pakistan had reported 36 cases of poliomyelitis caused by wild poliovirus; compared with 223 for the same period in 2014 [1]. Most of the success of the eradication program is due to large scale use of Oral Poliovirus Vaccine (OPV). The elimination of wild poliovirus type 2 in 1999, and possibly type 3 in 2013, as well as significant reduction of cases caused by wild poliovirus type 1 was achieved with OPV [4]. OPV has been proven to be an excellent vaccine with its ability to induce mucosal immunity; provide for secondary spread to contacts; ease of administration; and low price, however the vaccine has limitations such as low immunogenicity in some tropical countries [5,6]; and, in very rare circumstances, the live virus in OPV may cause paralysis to vaccine recipients (Vaccine Associated Paralytic Poliomyelitis or VAPP); in addition, OPV may genetically revert and regain neurovirulence and cause paralysis, this mutated virus with ability to spread within communicates is referred to as Circulating Vaccine Derived Poliovirus cVDPV [7,8]. To address the low OPV immunogenicity in
http://dx.doi.org/10.1016/j.vaccine.2016.05.065 0264-410X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Habib MA et al. Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.05.065
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certain settings, the GPEI developed new formulations of OPV, including monovalent and bivalent OPV (mOPV and bOPV) vaccines [9,10]. To overcome low OPV immunogenicity in some settings, GPEI has implemented multiple targeted campaigns with a combination of OPV and the Inactivated Poliovirus Vaccine (IPV) administered at the same time since 2013 [11]. IPV has been used for many decades in combination with OPV or on its own in routine immunization programs throughout the world. Its safety and high humoral immunogenicity is well established; and recent data demonstrated IPV’s ability to boost mucosal immunity in individuals who had been immunized with OPV previously [12–14]. In this trial, we compared serological response to poliovirus vaccines administered to previously OPV immunized children with the objective to assess whether IPV can be used to rapidly close the immunity gap among children in Pakistan who live in areas of high poliovirus transmission risk. We also explored whether adding one dose of vitamin A administered together with OPV will improve immunogenicity.
2. Methods The Ethical Review Committee of the Aga Khan University, the National Bioethics Committee of Pakistan and the Ethical Review Committee of the World Health Organization, Geneva granted the approval of this randomized controlled trial. We took written informed consent from the parents or care givers of the selected participants. All activities followed the guidelines of Good Clinical Practice; the trial protocol was registered with the Australian New Zealand Clinical Trials Registry bearing identifier ACTRN 12612000264886. The Aga Khan University, Pakistan conducted this study. The World Health Organization provided technical and financial support. Sera for antibody titers were tested at Centers of Disease Control and Prevention, Atlanta, USA. This was a five arm community based randomized controlled superiority trial in a Pakistani children residing in district of Matiari in Sindh province. The trial activities were conducted between March 2012 and August 2013. The primary outcome of the study was the immune response against the booster doses of polio vaccine given to previously vaccinated children. There were five arms in the study four of them were intervention arms while the fifth one was control arm. The arms were classified as (bOPV), (IPV), (bOPV + Vitamin A), (bOPV + IPV) and (Control) arms. We enrolled healthy children aged 6–24 months, 5–6 years and 10–11 years, permanently residing in the study area after having a written informed consent the parents. Children with known bleeding disorders, chronic illness, severe malnutrition and acute infections were excluded. Enrolled children were randomized into one of five study arms. All study personnel were trained in Good Clinical Practices (GCP). For this study we obtained OPV and IPV from WHO-prequalified producers. IPV (lot number G0445-1) was procured from Novartis and bOPV (lot number H5328-1) was procured from Glaxo Smith Kline. The bOPV was formulated to contain at least 106CCID50 of Sabin poliovirus type 1 and at least 105.8CCID50 of Sabin poliovirus type 3. Each IPV dose (0.5 mL) is formulated to contain 40 D antigen units of type 1, 8 D antigen units of type 2, and 32 D antigen units of type 3 poliovirus. We estimated the sample size by using the ANOVA Multiple comparison technique in a single factor ANOVA study. Sample size of 202 was calculated for each group assuming a baseline seroprevalence of 80%, power of 80% the between group difference of 20% at a significance level of 0.05. Assuming an attrition of 20%, the final sample size was set to be 1350 (270 in each study arm). The participants were randomized in one of the study Arm, the randomization was done after the formal consent procedure. The
study supervisor did the randomization through hidden entry envelope randomization technique to assign the groups. Randomization lists and envelopes were prepared by an independent research officer at data management unit of Aga Khan University. The randomization numbers and groups were inserted in the envelopes starting from 0001 to 1590 having equal number of allocations in each group in the block of 30. Following randomization we enrolled children in the study and data was collected on socio demographic indicators and prior vaccination history. Height and weights were also measured to establish the nutritional status of the children. Blood sample (3 mL) was collected by trained phlebotomist using standard venipuncture techniques on Day 0 and Day 28. After collection the blood samples were allowed to clot, centrifuged to separate serum, and transported to the Nutrition Research Laboratory (NRL) at the Aga Khan University in Karachi under cold chain conditions where they were stored at 20 °C until shipment to the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA. Neutralizing antibodies were determined by the method recommended by the World Health Organization [15] at the Enterovirus Laboratory, CDC. Serial dilutions of serum (starting at 1:8 and ending at 1:1024) were incubated with 100 TCID50 of poliovirus types 1, 2, and 3 at 36 °C for 3 h before 1–2 104 HEp-2 (Cincinnati) cells were added to each well. The HEp-2 (Cincinnati) cell line is particularly sensitive for polioviruses. We assigned unobserved titers values of less than 8 if they were less than the starting dilution, and of more than or equal to 1448 if they were more than the final dilution. Vaccination history for OPV received through routine immunization was assessed from vaccination cards when available or by parental recall if card were not available. OPV doses received through Supplemental Immunization Activities (SIAs) were estimated by the number of SIA rounds that were conducted in the study area during the life of each child. Enrolled subjects were not vaccinated with any supplementary OPV doses during the study period. Adverse events following vaccination were identified by site investigators and reviewed by the principal investigator. Children were observed for 30 min following the administration of the vaccine for immediate adverse events; parents were instructed to immediately report back to the health centers if adverse events occurred. Serious adverse events were reported for review to the Data and Safety Monitoring Board, Ethical Review Committees of the Aga Khan University and the World Health Organization. After the enrolment procedures the child was followed on Day 3 and Day 7 for any possible adverse event and then was brought again at the study clinic on day 28 for blood draw. This blood sample was drawn to assess the sero conversion and boosting that occurred in different vaccine combinations compared to the control group. The primary outcome measure for the study was the seroconversion and boosting in immunity. Seropositivity was defined as reciprocal titers of poliovirus neutralizing antibodies P8; seroconversion was defined as the change from seronegative to seropositive (from reciprocal titer of <8 to P8); and boosting was defined as P4-fold increase in titers. In this study, ‘‘immune response” combines both boosting and seroconversion. The analysis of immune response was restricted to infants with a baseline serological titer of 6362 to ensure that a 4-fold boosting response could be achieved since the highest titer tested was 1:1448 [16]. 2.1. Data management and analysis Data was dual entered on pre structured screens on visual fox pro. Demographic, clinical and Laboratory data were merged and the Statistical analysis was per-formed using STATA version 12. The proportion of seroconversion in different study arms was compared
Please cite this article in press as: Habib MA et al. Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.05.065
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by chi square test for quantitative variables. Analysis of variance (ANOVA) was used to compare the mean difference across the study arms. K-sample equality of median test was performed to compare the median titers across the study arms and 95% confidence intervals for median titers were calculated.
3. Results Overall, 1350 participants were recruited in the study of which 450 were recruited in each age group respectively. A total of 1231/1350 (91.2%) participants completed the study visit on day 28. The sample size was achieved in all age groups and intervention arms (Fig. 1). Basic demographic characteristics were comparable among study arms. Of note is high proportion of children in all age groups with estimated more than four OPV vaccines received (>85% in the youngest age group and >90% in the older ones). Rates of stunting and wasting found in our sample were consistent with overall rates found in Pakistan in the past [17]. In this community, the access to clean water was reported in 100% of households; on the other hand, mothers’ literacy rate was reported to be very low (<5%). (Table 1). Baseline seroprevalence (on day 0) for poliovirus type 1 was high in all age groups (>95%) and did not decrease with age; for type 2 the seroprevalence was the highest in the 5–6 year olds (close to 100%) and was still high in the other age groups; it also did not decrease with age; for type 3 the seroprevalence was
highest in the 5–6 year olds (95.3%) and decreased in the older age group (86.7%) (Table 1). Seroprevalence on day 28 was close to 100% for serotype 1 for all intervention study arms and in all age groups. For serotype 2, the seroprevalence increased in the IPV arms but remained mostly unchanged in the bOPV and control arms. For serotype 3, the seroprevalence increased most significantly in the IPV arms (Tables S1–S3). The proportion of children who mounted an immune response (seroconversion or boosting) which was assessed between day 0 and day 28 was significantly higher (p < 0.001) in IPV only (PV1 – 98.9, PV2 – 95.5, PV3 – 95.9) and OPV IPV (PV1 – 98.3, PV2 – 94.6, PV3 – 96.5) groups compared to OPV (PV1 – 31.3, PV2 – 26.2, PV3 – 33.9), OPV + Vitamin A (PV1 – 27.4, PV2 – 26.2, PV3 – 25.5) and control group (PV1 – 17.0, PV2 – 9.8, PV3 – 11.9). In our study Vitamin A was not associated with improved immune response when administered together with bOPV. The immune response is shown in Fig. 2. Seroconversion was assessed in those children who were seronegative on day 0. In all age groups, the seroconversion after one dose of IPV (with or without bOPV) was >95% for all three serotypes; seroconversion after one dose of bOPV (with or without vitamin A) ranged between 25% and 36% for serotypes 1 and between 11% and 43% for serotype 3. For serotype 2, the seroconversion in the bOPV only arms ranged between 21% and 33%; and seroconversion in the control arm (no vaccine) ranged between 8% and 20% (Table 2). There was no statistical difference in seroconversion observed between IPV only arm and IPV + bOPV arm. In the youngest age group, the rate of seroconversion in OPV only arms
Assessed for Enrolment (1821) Excluded (332) Children brought to Study Site (1489) Excluded (139)
Loss to follow up Before Day 28 (19)
Day 28 Completed (251)
IPV Only (270)
Loss to follow up Before Day 28 (26)
Day 28 Completed (244)
bOPV + IPV (270)
Loss to follow up Before Day 28 (28)
Day 28 Completed (242)
bOPV + Vit A (270)
Loss to follow up Before Day 28 (23)
Day 28 Completed (247)
Control (270)
Loss to follow up Before Day 28 (23)
Day 28 Completed (247)
DAY 28
bOPV Only (270)
DAY 0
Children Randomized & Enrolled (1350)
Fig. 1. Consort diagram.
Please cite this article in press as: Habib MA et al. Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.05.065
4
6–24 months
5–6 years
10–11 years
bOPV only
IPV only
bOPV + Vit. A
bOPV + IPV
Control
bOPV only
IPV only
bOPV + Vit. A
bOPV + IPV
Control bOPV only
IPV only
bOPV + Vit. A
bOPV + IPV
Control
N (%) or ± SD
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
Female
46 (51.1) 40 (44.4) 38 (42.2)
42 (46.7)
40 (44.4) 43 (47.8) 44 (48.9) 42 (46.7)
43 (47.8)
45 (50)
85 (94.4)
88 (97.8) 87 (96.7) 85 (94.4) 83 (92.2)
89 (98.9)
84 (93.3)
88 (97.8)
0 OPV dose 4 + OPV doses
4 (4.4) 3 (3.3) 1 (1.1) 78 (86.7) 78 (86.7) 83 (92.2)
1 (1.1) 80 (88.9)
2 (2.2) 1 (1.1) 0 (0) 1 (1.1) 82 (91.1) 87 (96.7) 90 (100) 89 (98.9)
1 (1.1) 87 (96.7)
0 (0) 89 (98.9)
2 (2.2) 83 (92.2)
Average number of OPV doses received
6.5 ± 3.1 5.8 ± 2.7 6.5 ± 2.7
6.7 ± 3
6.3 ± 2.9 7.6 ± 2.8 7.8 ± 2.6 7.9 ± 2.8
7.8 ± 2.8
44 (48.9) 85 (94.4) 2 (2.2) 86 (95.6) 4.2 ± 1.4
38 (42.2)
86 (95.6) 88 (97.8) 86 (95.6)
45 (50.0) 86 (95.6) 85 (94.4) 0 (0) 3 (3.3) 89 (98.9) 85 (94.4) 4.1 ± 0.7 3.9 ± 1
45 (50)
Mother Illiterate
44 (48.9) 85 (94.4) 1 (1.1) 87 (96.7) 7.4 ± 2.9
4.1 ± 0.9
4.1 ± 1.3
Stunting
79 (29.5) 81 (30.2) 78 (29.2)
79 (29.3)
91 (33.8) 81 (32.3) 83 (34.3) 79 (32.2)
79 (32.8)
85 (34)
89 (35.6)
26 (25.2) 19 (19.6) 20 (21.1)
22 (22.2)
20 (20.8) 10 (12.8) 22 (26.2) 24 (29.6)
20 (25.3)
32 (39.5)
29 (33.3)
Access to improved Water
90 (100) 90 (100) 90 (100)
90 (100)
90 (100) 90 (100) 89 (98.9) 90 (100)
90 (100)
79 (32.2) 37 (46.8) 90 (100)
75 (30.9)
Wasting
90 (100)
90 (100)
Improved Toilet facility
44 (48.9) 50 (55.6) 43 (47.8)
44 (48.9)
39 (43.3) 47 (52.2) 41 (45.6) 43 (47.8)
45 (50)
80 (32.7) 21 (26.6) 90 (100) 46 (51.1)
51 (56.7)
47 (52.2)
PV 1 Baseline seroprevalence and median titer (CI 95%) (per age group) PV 2 Baseline seroprevalence and median titer (CI 95%) (per age group) PV 3 Baseline seroprevalence and median titer (CI 95%) (per age group) PV1, 2 and 3: poliovirus serotype 1, 2 and; SP: Seroprevalence.
SP: 437/450 (97.1%) SP: 386/450 (85.8%) SP: 374/450 (83.1%)
Titer: 910 (288, 1448.2) Titer: 362 (45, 1448.2) Titer: 204 (18, 1152)
SP: 448/449 (99.6%) SP: 447/449 (99.6%)
Titer: 724 (288, 1448.2) Titer: 455 (227, 1152)
SP: 428/449 (95.3%)
Titer: 181 (56, 724)
23 (28)
84 (33.3) 34 (41)
90 (100) 90 (100) 40 (44.4) 40 (44.4)
44 (48.9) SP: 434/450 (96.4%) SP: 444/450 (98.7%) SP: 390/450 (86.7%)
Titer: 227 (288, 1448.2) Titer: 288 (91, 724) Titer: 72 (18, 227)
M.A. Habib et al. / Vaccine xxx (2016) xxx–xxx
Please cite this article in press as: Habib MA et al. Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.05.065
Table 1 Baseline characteristics.
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bOPV only
IPV only
bOPV+Vit.A
bOPV+IPV
Control
100 90
Immune response %
80 70 60 50 40 30 20 10 0 PV1
PV2
PV3
Fig. 2. Immune response between day 0 and day 28 in all groups and for all three serotypes after study dose with baseline titer 6362. Bars represent 95% confidence intervals calculated with the Clopper–Pearson method.
Table 2 Seroconversion between day 0 and day 28 among seronegative children on day 0. Type 1
Type 2
Type 3
Arm
n
% (95% CI)
p-value
n
% (95% CI)
p-value
n
% (95% CI)
p-value
6–24 months bOPV only IPV only bOPV + Vit. A bOPV + IPV Control
9/25 19/19 9/24 31/33 6/22
36 (16.6–55.4) 100 (–) 37.5 (17.5–57.5) 93.9 (85.6–100) 27.3 (8–46.5)
0.522 <0.001 0.460 <0.001 Ref.
8/38 45/48 9/40 40/43 7/35
21.1 (7.8–34.3) 93.8 (86.8–100) 22.5 (9.3–35.7) 93 (85.3–100) 20 (6.5–33.5)
0.911 <0.001 0.792 <0.001 Ref.
12/46 46/50 9/50 46/50 5/42
26.1 (13.2–39) 92 (84.4–99.6) 18 (7.2–28.8) 92 (84.4–99.6) 11.9 (1.9–21.9)
0.092 <0.001 0.418 <0.001 Ref.
5–6 years bOPV only IPV only bOPV + Vit. A bOPV + IPV Control
8/32 22/23 8/32 27/27 5/29
25 (9.6–40.4) 95.7 (87.1–100) 25 (9.6–40.4) 100 (–) 17.2 (3.1–31.4)
0.460 <0.001 0.460 <0.001 Ref.
8/38 31/33 9/34 36/39 1/38
21.1 (7.8–34.3) 93.9 (85.6–100) 26.5 (11.3–41.6) 92.3 (83.8–100) 2.6 (-2.6–7.8)
0.013 <0.001 0.003 <0.001 Ref.
16/55 48/50 12/48 50/52 4/50
29.1 (16.9–41.3) 96 (90.5–100) 25 (12.6–37.4) 96.2 (90.9–100) 8 (0.4–15.6)
0.006 <0.001 0.023 <0.001 Ref.
10–11 years bOPV only IPV only bOPV + Vit. A bOPV + IPV Control
19/58 46/46 15/61 57/57 7/55
32.8 (20.5–45) 100 (–) 24.6 (13.6–35.5) 100 (–) 12.7 (3.8–21.7)
0.011 <0.001 0.104 <0.001 Ref.
18/54 52/53 14/48 46/47 5/60
33.3 (20.6–46.1) 98.1 (94.4–100) 29.2 (16.1–42.2) 97.9 (93.7–100) 8.3 (1.2–15.4)
0.001 <0.001 0.005 <0.001 Ref.
31/73 68/69 21/67 68/68 10/68
42.5 (31–53.9) 98.6 (95.7–100) 31.3 (20.1–42.6) 100 (–) 14.7 (6.2–23.2)
0.000 <0.001 0.022 <0.001 Ref.
Overall bOPV only IPV only bOPV + Vit. A bOPV + IPV Control
36/115 87/88 32/117 115/117 18/106
31.3 (22.8–39.8) 98.9 (96.6–100) 27.4 (19.2–35.5) 98.3 (95.9–100) 17 (9.8–24.2)
0.013 <0.001 0.064 <0.001 Ref.
34/130 128/134 32/122 122/129 13/133
26.2 (18.6–33.8) 95.5 (92–99) 26.2 (18.4–34.1) 94.6 (90.6–98.5) 9.8 (4.7–14.9)
0.001 <0.001 0.001 <0.001 Ref.
59/174 162/169 42/165 164/170 19/160
33.9 95.9 25.5 96.5 11.9
<0.001 <0.001 0.002 <0.001 Ref.
was not significantly different than seroconversion in no-vaccine arm (P > 0.05 for all serotypes). No serious adverse events associated to study procedures were detected.
4. Discussion Serological data from our trial confirmed that IPV is very efficient in closing an existing humoral immunological gap and providing protection against paralytic disease. Furthermore, our
(26.8–41) (92.8–98.9) (18.8–32.1) (93.7–99.3) (6.8–16.9)
data demonstrated that additional OPV dose in already highly OPV vaccinated populations have limited benefits: it appears that a small proportion of children in this environment simply does not respond to OPV despite receiving multiple doses. IPV, on the other hand, seems to provide uniformly high Seroconversion in all populations regardless of these underlying conditions. Factors influencing the immunogenicity of OPV have been researched in the past. Malnutrition, enteric infections and environmental enteropathy concurrent with OPV administration were associated with lower OPV immunogenicity [16,18–21]. On
Please cite this article in press as: Habib MA et al. Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.05.065
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the other hand, Zinc supplementation or administration of sodium bicarbonate or sodium citrate buffers together with OPV were not associated with higher OPV immunogenicity [22,23]. In our study, we did not observe any effect of administration of one dose of vitamin A together with OPV on its immunogenicity. The finding of decreasing seroprevalence with age for type 3 has been observed previously and is believed not to be correlated with loss of protection but rather with natural waning of humoral antibodies [24]. Immune response as well as seroconversion for poliovirus type 2 in the bOPV only arms was high (20–30%) and significantly higher than for children in the control arm (<10%). This finding, consistent with previous observations, is likely due to heavy environmental contamination with tOPV related polioviruses; and due to possible cross reactivity between bOPV and type 2 response in previously type 2 exposed children [16]. This study had some limitations. The OPV dose history may have been influenced by parental recall bias, especially given the number of polio campaigns conducted in Matiari in the past several years. In addition, secondary exposure of study children to environmental vaccine viruses might have biased the immune response estimates; however, we believe that this bias was uniformly distributed among study arms. As part of the implementation of the Polio Endgame Strategic Plan [25], the Strategic Advisory Group of Experts (SAGE) recommended in 2012 the introduction of at least one dose of IPV in all routine immunization programs for risk mitigation before OPV2 withdrawal [26]. A dose of IPV is expected to induce seroconversion or priming in close to 100% of naïve infants [27]. Should poliovirus type 2 be reintroduced, a second IPV dose would rapidly boost antibody titers and prevent, or decrease the magnitude of, an outbreak. Furthermore, IPV would be expected to close the remaining immunity gaps for serotypes 1 and 3. In Pakistan, when introduced in the second part of 2015, IPV will be administered together with one dose of OPV to children reaching 14 weeks of age. In addition to IPV use in routine immunization, targeted IPV campaigns for children under five years of age living in areas with persistent wild poliovirus circulation are an opportunity to close the existing immunity gap and accelerate poliovirus eradication [28]. Kenya, Nigeria, Afghanistan as well as Pakistan have conducted targeted IPV campaigns and demonstrated programmatic feasibility of a house-to-house campaign with an injectable vaccine [11]. We believe that additional targeted IPV campaigns, for example in high risk zones of the Federally Administered Tribal Areas (FATA), or in high risk areas of Karachi, would significantly accelerate poliovirus eradication from Pakistan. Declaration of interests Authors did not declare any conflict of interest. Role of the funding source Funding for this study was provided by the World Health Organization, Geneva. Acknowledgements The Centers for Disease Control and Prevention supported the project in-kind by provision of laboratory testing and expertise in interpretation. We thank Dr. Mark A. Pallansch, Director Division of Viral Diseases at the CDC and the team conducting the neutralization assays at the CDC Laboratory: Deborah Moore, Yiting Zhang, Sharla McDonald, Patricia Mitchell, William Hendley, Larin McDuffie and Tamanna Ahmed. Dr. Elias Durry (Polio Team
Lead, WHO, Pakistan), Dr. Salah Tumsah (WHO team leader – Polio Program Sindh). We would like to acknowledge Mr. Imran Ahmed from Aga Khan University and Marina Takane from the World Health Organization for her biostatistical support. Finally we would like to acknowledge Mr. Asmatullah and the study field team including doctors, nurses, data collectors who worked selflessly for the successful completion of this study. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2016.05. 065. References [1] Cases of wild poliovirus by country and year. Available at: [accessed 27/08/2015]. [2] WHO. WHO removes Nigeria from polio-endemic list. Available at:
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M.A. Habib et al. / Vaccine xxx (2016) xxx–xxx [24] Gamage D, Palihawadana P, Mach O, Weldon WC, Oberste SM, Sutter RW. Achieving high seroprevalence against polioviruses in Sri Lanka – results from a serological survey, 2014. J Epidemiol Glob Health 2015. [25] Polio eradication and endgame strategic plan 2013–2018. Available at:. [26] Meeting of the Strategic Advisory Group of Experts on Immunization, November 2012 – conclusions and recommendations. Releve
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epidemiologique hebdomadaire/Section d’hygiene du Secretariat de la Societe des Nations = Weekly epidemiological record/Health Section of the Secretariat of the League of Nations, vol. 88; 2013. p. 1–16. [27] Resik S, Tejeda A, Sutter RW, et al. Priming after a fractional dose of inactivated poliovirus vaccine. N Engl J Med 2013;368:416–24. [28] Parker EP, Molodecky NA, Pons-Salort M, O’Reilly KM, Grassly NC. Impact of inactivated poliovirus vaccine on mucosal immunity: implications for the polio eradication endgame. Expert Rev Vaccines 2015;14:1113–23.
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Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013 Muhammad Atif Habib a, Sajid Soofi a, Ondrej Mach b, Tariq Samejo a, Didar Alam a, Zaid Bhatti a, William C. Weldon c, Steven M. Oberste c, Roland Sutter b, Zulfiqar A. Bhutta a,⇑ a b c
Division of Women and Child Health, The Aga Khan University, Karachi, Pakistan Polio Eradication Departments, World Health Organization, Geneva, Switzerland Polio and Picornavirus Laboratory Branch, Centers for Disease Control and Prevention, Atlanta, USA
a r t i c l e
i n f o
Article history: Received 22 December 2015 Received in revised form 12 May 2016 Accepted 26 May 2016 Available online xxxx Keywords: Polio virus vaccine Injectable polio vaccine Immunity Seroconversion Seroprevalence Pakistan
a b s t r a c t Background: Considering the current polio situation Pakistan needs vaccine combinations to reach maximum population level immunity. The trial assessed whether inactivated poliovirus vaccine (IPV) can be used to rapidly boost immunity among children in Pakistan. Methods: A five-arm randomized clinical trial was conducted among children (6–24 months, 5–6 years and 10–11 years). Children were randomized in four intervention arms as per the vaccines they received (bOPV, IPV, bOPV + vitamin A, and bOPV + IPV) and a control arm which did not receive any vaccine. Baseline seroprevalence of poliovirus antibodies and serological immune response 28 days after intervention were assessed. Results: The baseline seroprevalence was high for all serotypes and the three age groups [PV1: 97%, 100%, 96%, PV2: 86%, 100%, 99%, PV3: 83%, 95%, 87% for the three age groups respectively]. There was significantly higher rate of immune response observed in the study arms which included IPV (95–99%) compared with bOPV only arms (11–43%), [p < 0.001]; Vitamin A was not associated with improved immune response. Immune response rates in the IPV only arm and IPV + bOPV arm were similar [p > 0.5]. Conclusion: IPV has shown the ability to efficiently close existing immunity gaps in a vulnerable population of children in rural Pakistan. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction The goal to eradicate polioviruses worldwide was adopted in 1988 and since then the number of paralyzed persons due to polioviruses has decreased by over 99.9%. In 2014, the World Health Organization (WHO) reported 359 cases of paralytic poliomyelitis due to wild polioviruses worldwide [1]. In the end of 2015, the remaining endemic areas with wild poliovirus circulation were limited to security compromised parts of Pakistan and Afghanistan. In Nigeria, no new cases of polio have been reported in 2015, and in September 2015 Nigeria has been removed from the list of poliovirus endemic countries by WHO [2]. Despite the dramatic reduction in cases of poliomyelitis, it is proving difficult for the Global Polio Eradication Initiative (GPEI) to finally complete the eradication by interrupting the last chains of transmission in these endemic areas; and exportations of wild polioviruses from the endemic areas into ⇑ Corresponding author at: Founding Director Center of Excellence in Women and Child Health, The Aga Khan University, Karachi 74800, Pakistan. E-mail address: [email protected] (Z.A. Bhutta).
polio-free countries have occurred in multiple occasions, sometimes causing large outbreaks of poliomyelitis [3]. In Pakistan, progress has been made in 2015 compared with 2014: as of October 2015, Pakistan had reported 36 cases of poliomyelitis caused by wild poliovirus; compared with 223 for the same period in 2014 [1]. Most of the success of the eradication program is due to large scale use of Oral Poliovirus Vaccine (OPV). The elimination of wild poliovirus type 2 in 1999, and possibly type 3 in 2013, as well as significant reduction of cases caused by wild poliovirus type 1 was achieved with OPV [4]. OPV has been proven to be an excellent vaccine with its ability to induce mucosal immunity; provide for secondary spread to contacts; ease of administration; and low price, however the vaccine has limitations such as low immunogenicity in some tropical countries [5,6]; and, in very rare circumstances, the live virus in OPV may cause paralysis to vaccine recipients (Vaccine Associated Paralytic Poliomyelitis or VAPP); in addition, OPV may genetically revert and regain neurovirulence and cause paralysis, this mutated virus with ability to spread within communicates is referred to as Circulating Vaccine Derived Poliovirus cVDPV [7,8]. To address the low OPV immunogenicity in
http://dx.doi.org/10.1016/j.vaccine.2016.05.065 0264-410X/Ó 2016 Elsevier Ltd. All rights reserved.
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certain settings, the GPEI developed new formulations of OPV, including monovalent and bivalent OPV (mOPV and bOPV) vaccines [9,10]. To overcome low OPV immunogenicity in some settings, GPEI has implemented multiple targeted campaigns with a combination of OPV and the Inactivated Poliovirus Vaccine (IPV) administered at the same time since 2013 [11]. IPV has been used for many decades in combination with OPV or on its own in routine immunization programs throughout the world. Its safety and high humoral immunogenicity is well established; and recent data demonstrated IPV’s ability to boost mucosal immunity in individuals who had been immunized with OPV previously [12–14]. In this trial, we compared serological response to poliovirus vaccines administered to previously OPV immunized children with the objective to assess whether IPV can be used to rapidly close the immunity gap among children in Pakistan who live in areas of high poliovirus transmission risk. We also explored whether adding one dose of vitamin A administered together with OPV will improve immunogenicity.
2. Methods The Ethical Review Committee of the Aga Khan University, the National Bioethics Committee of Pakistan and the Ethical Review Committee of the World Health Organization, Geneva granted the approval of this randomized controlled trial. We took written informed consent from the parents or care givers of the selected participants. All activities followed the guidelines of Good Clinical Practice; the trial protocol was registered with the Australian New Zealand Clinical Trials Registry bearing identifier ACTRN 12612000264886. The Aga Khan University, Pakistan conducted this study. The World Health Organization provided technical and financial support. Sera for antibody titers were tested at Centers of Disease Control and Prevention, Atlanta, USA. This was a five arm community based randomized controlled superiority trial in a Pakistani children residing in district of Matiari in Sindh province. The trial activities were conducted between March 2012 and August 2013. The primary outcome of the study was the immune response against the booster doses of polio vaccine given to previously vaccinated children. There were five arms in the study four of them were intervention arms while the fifth one was control arm. The arms were classified as (bOPV), (IPV), (bOPV + Vitamin A), (bOPV + IPV) and (Control) arms. We enrolled healthy children aged 6–24 months, 5–6 years and 10–11 years, permanently residing in the study area after having a written informed consent the parents. Children with known bleeding disorders, chronic illness, severe malnutrition and acute infections were excluded. Enrolled children were randomized into one of five study arms. All study personnel were trained in Good Clinical Practices (GCP). For this study we obtained OPV and IPV from WHO-prequalified producers. IPV (lot number G0445-1) was procured from Novartis and bOPV (lot number H5328-1) was procured from Glaxo Smith Kline. The bOPV was formulated to contain at least 106CCID50 of Sabin poliovirus type 1 and at least 105.8CCID50 of Sabin poliovirus type 3. Each IPV dose (0.5 mL) is formulated to contain 40 D antigen units of type 1, 8 D antigen units of type 2, and 32 D antigen units of type 3 poliovirus. We estimated the sample size by using the ANOVA Multiple comparison technique in a single factor ANOVA study. Sample size of 202 was calculated for each group assuming a baseline seroprevalence of 80%, power of 80% the between group difference of 20% at a significance level of 0.05. Assuming an attrition of 20%, the final sample size was set to be 1350 (270 in each study arm). The participants were randomized in one of the study Arm, the randomization was done after the formal consent procedure. The
study supervisor did the randomization through hidden entry envelope randomization technique to assign the groups. Randomization lists and envelopes were prepared by an independent research officer at data management unit of Aga Khan University. The randomization numbers and groups were inserted in the envelopes starting from 0001 to 1590 having equal number of allocations in each group in the block of 30. Following randomization we enrolled children in the study and data was collected on socio demographic indicators and prior vaccination history. Height and weights were also measured to establish the nutritional status of the children. Blood sample (3 mL) was collected by trained phlebotomist using standard venipuncture techniques on Day 0 and Day 28. After collection the blood samples were allowed to clot, centrifuged to separate serum, and transported to the Nutrition Research Laboratory (NRL) at the Aga Khan University in Karachi under cold chain conditions where they were stored at 20 °C until shipment to the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA. Neutralizing antibodies were determined by the method recommended by the World Health Organization [15] at the Enterovirus Laboratory, CDC. Serial dilutions of serum (starting at 1:8 and ending at 1:1024) were incubated with 100 TCID50 of poliovirus types 1, 2, and 3 at 36 °C for 3 h before 1–2 104 HEp-2 (Cincinnati) cells were added to each well. The HEp-2 (Cincinnati) cell line is particularly sensitive for polioviruses. We assigned unobserved titers values of less than 8 if they were less than the starting dilution, and of more than or equal to 1448 if they were more than the final dilution. Vaccination history for OPV received through routine immunization was assessed from vaccination cards when available or by parental recall if card were not available. OPV doses received through Supplemental Immunization Activities (SIAs) were estimated by the number of SIA rounds that were conducted in the study area during the life of each child. Enrolled subjects were not vaccinated with any supplementary OPV doses during the study period. Adverse events following vaccination were identified by site investigators and reviewed by the principal investigator. Children were observed for 30 min following the administration of the vaccine for immediate adverse events; parents were instructed to immediately report back to the health centers if adverse events occurred. Serious adverse events were reported for review to the Data and Safety Monitoring Board, Ethical Review Committees of the Aga Khan University and the World Health Organization. After the enrolment procedures the child was followed on Day 3 and Day 7 for any possible adverse event and then was brought again at the study clinic on day 28 for blood draw. This blood sample was drawn to assess the sero conversion and boosting that occurred in different vaccine combinations compared to the control group. The primary outcome measure for the study was the seroconversion and boosting in immunity. Seropositivity was defined as reciprocal titers of poliovirus neutralizing antibodies P8; seroconversion was defined as the change from seronegative to seropositive (from reciprocal titer of <8 to P8); and boosting was defined as P4-fold increase in titers. In this study, ‘‘immune response” combines both boosting and seroconversion. The analysis of immune response was restricted to infants with a baseline serological titer of 6362 to ensure that a 4-fold boosting response could be achieved since the highest titer tested was 1:1448 [16]. 2.1. Data management and analysis Data was dual entered on pre structured screens on visual fox pro. Demographic, clinical and Laboratory data were merged and the Statistical analysis was per-formed using STATA version 12. The proportion of seroconversion in different study arms was compared
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by chi square test for quantitative variables. Analysis of variance (ANOVA) was used to compare the mean difference across the study arms. K-sample equality of median test was performed to compare the median titers across the study arms and 95% confidence intervals for median titers were calculated.
3. Results Overall, 1350 participants were recruited in the study of which 450 were recruited in each age group respectively. A total of 1231/1350 (91.2%) participants completed the study visit on day 28. The sample size was achieved in all age groups and intervention arms (Fig. 1). Basic demographic characteristics were comparable among study arms. Of note is high proportion of children in all age groups with estimated more than four OPV vaccines received (>85% in the youngest age group and >90% in the older ones). Rates of stunting and wasting found in our sample were consistent with overall rates found in Pakistan in the past [17]. In this community, the access to clean water was reported in 100% of households; on the other hand, mothers’ literacy rate was reported to be very low (<5%). (Table 1). Baseline seroprevalence (on day 0) for poliovirus type 1 was high in all age groups (>95%) and did not decrease with age; for type 2 the seroprevalence was the highest in the 5–6 year olds (close to 100%) and was still high in the other age groups; it also did not decrease with age; for type 3 the seroprevalence was
highest in the 5–6 year olds (95.3%) and decreased in the older age group (86.7%) (Table 1). Seroprevalence on day 28 was close to 100% for serotype 1 for all intervention study arms and in all age groups. For serotype 2, the seroprevalence increased in the IPV arms but remained mostly unchanged in the bOPV and control arms. For serotype 3, the seroprevalence increased most significantly in the IPV arms (Tables S1–S3). The proportion of children who mounted an immune response (seroconversion or boosting) which was assessed between day 0 and day 28 was significantly higher (p < 0.001) in IPV only (PV1 – 98.9, PV2 – 95.5, PV3 – 95.9) and OPV IPV (PV1 – 98.3, PV2 – 94.6, PV3 – 96.5) groups compared to OPV (PV1 – 31.3, PV2 – 26.2, PV3 – 33.9), OPV + Vitamin A (PV1 – 27.4, PV2 – 26.2, PV3 – 25.5) and control group (PV1 – 17.0, PV2 – 9.8, PV3 – 11.9). In our study Vitamin A was not associated with improved immune response when administered together with bOPV. The immune response is shown in Fig. 2. Seroconversion was assessed in those children who were seronegative on day 0. In all age groups, the seroconversion after one dose of IPV (with or without bOPV) was >95% for all three serotypes; seroconversion after one dose of bOPV (with or without vitamin A) ranged between 25% and 36% for serotypes 1 and between 11% and 43% for serotype 3. For serotype 2, the seroconversion in the bOPV only arms ranged between 21% and 33%; and seroconversion in the control arm (no vaccine) ranged between 8% and 20% (Table 2). There was no statistical difference in seroconversion observed between IPV only arm and IPV + bOPV arm. In the youngest age group, the rate of seroconversion in OPV only arms
Assessed for Enrolment (1821) Excluded (332) Children brought to Study Site (1489) Excluded (139)
Loss to follow up Before Day 28 (19)
Day 28 Completed (251)
IPV Only (270)
Loss to follow up Before Day 28 (26)
Day 28 Completed (244)
bOPV + IPV (270)
Loss to follow up Before Day 28 (28)
Day 28 Completed (242)
bOPV + Vit A (270)
Loss to follow up Before Day 28 (23)
Day 28 Completed (247)
Control (270)
Loss to follow up Before Day 28 (23)
Day 28 Completed (247)
DAY 28
bOPV Only (270)
DAY 0
Children Randomized & Enrolled (1350)
Fig. 1. Consort diagram.
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6–24 months
5–6 years
10–11 years
bOPV only
IPV only
bOPV + Vit. A
bOPV + IPV
Control
bOPV only
IPV only
bOPV + Vit. A
bOPV + IPV
Control bOPV only
IPV only
bOPV + Vit. A
bOPV + IPV
Control
N (%) or ± SD
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
Female
46 (51.1) 40 (44.4) 38 (42.2)
42 (46.7)
40 (44.4) 43 (47.8) 44 (48.9) 42 (46.7)
43 (47.8)
45 (50)
85 (94.4)
88 (97.8) 87 (96.7) 85 (94.4) 83 (92.2)
89 (98.9)
84 (93.3)
88 (97.8)
0 OPV dose 4 + OPV doses
4 (4.4) 3 (3.3) 1 (1.1) 78 (86.7) 78 (86.7) 83 (92.2)
1 (1.1) 80 (88.9)
2 (2.2) 1 (1.1) 0 (0) 1 (1.1) 82 (91.1) 87 (96.7) 90 (100) 89 (98.9)
1 (1.1) 87 (96.7)
0 (0) 89 (98.9)
2 (2.2) 83 (92.2)
Average number of OPV doses received
6.5 ± 3.1 5.8 ± 2.7 6.5 ± 2.7
6.7 ± 3
6.3 ± 2.9 7.6 ± 2.8 7.8 ± 2.6 7.9 ± 2.8
7.8 ± 2.8
44 (48.9) 85 (94.4) 2 (2.2) 86 (95.6) 4.2 ± 1.4
38 (42.2)
86 (95.6) 88 (97.8) 86 (95.6)
45 (50.0) 86 (95.6) 85 (94.4) 0 (0) 3 (3.3) 89 (98.9) 85 (94.4) 4.1 ± 0.7 3.9 ± 1
45 (50)
Mother Illiterate
44 (48.9) 85 (94.4) 1 (1.1) 87 (96.7) 7.4 ± 2.9
4.1 ± 0.9
4.1 ± 1.3
Stunting
79 (29.5) 81 (30.2) 78 (29.2)
79 (29.3)
91 (33.8) 81 (32.3) 83 (34.3) 79 (32.2)
79 (32.8)
85 (34)
89 (35.6)
26 (25.2) 19 (19.6) 20 (21.1)
22 (22.2)
20 (20.8) 10 (12.8) 22 (26.2) 24 (29.6)
20 (25.3)
32 (39.5)
29 (33.3)
Access to improved Water
90 (100) 90 (100) 90 (100)
90 (100)
90 (100) 90 (100) 89 (98.9) 90 (100)
90 (100)
79 (32.2) 37 (46.8) 90 (100)
75 (30.9)
Wasting
90 (100)
90 (100)
Improved Toilet facility
44 (48.9) 50 (55.6) 43 (47.8)
44 (48.9)
39 (43.3) 47 (52.2) 41 (45.6) 43 (47.8)
45 (50)
80 (32.7) 21 (26.6) 90 (100) 46 (51.1)
51 (56.7)
47 (52.2)
PV 1 Baseline seroprevalence and median titer (CI 95%) (per age group) PV 2 Baseline seroprevalence and median titer (CI 95%) (per age group) PV 3 Baseline seroprevalence and median titer (CI 95%) (per age group) PV1, 2 and 3: poliovirus serotype 1, 2 and; SP: Seroprevalence.
SP: 437/450 (97.1%) SP: 386/450 (85.8%) SP: 374/450 (83.1%)
Titer: 910 (288, 1448.2) Titer: 362 (45, 1448.2) Titer: 204 (18, 1152)
SP: 448/449 (99.6%) SP: 447/449 (99.6%)
Titer: 724 (288, 1448.2) Titer: 455 (227, 1152)
SP: 428/449 (95.3%)
Titer: 181 (56, 724)
23 (28)
84 (33.3) 34 (41)
90 (100) 90 (100) 40 (44.4) 40 (44.4)
44 (48.9) SP: 434/450 (96.4%) SP: 444/450 (98.7%) SP: 390/450 (86.7%)
Titer: 227 (288, 1448.2) Titer: 288 (91, 724) Titer: 72 (18, 227)
M.A. Habib et al. / Vaccine xxx (2016) xxx–xxx
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Table 1 Baseline characteristics.
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bOPV only
IPV only
bOPV+Vit.A
bOPV+IPV
Control
100 90
Immune response %
80 70 60 50 40 30 20 10 0 PV1
PV2
PV3
Fig. 2. Immune response between day 0 and day 28 in all groups and for all three serotypes after study dose with baseline titer 6362. Bars represent 95% confidence intervals calculated with the Clopper–Pearson method.
Table 2 Seroconversion between day 0 and day 28 among seronegative children on day 0. Type 1
Type 2
Type 3
Arm
n
% (95% CI)
p-value
n
% (95% CI)
p-value
n
% (95% CI)
p-value
6–24 months bOPV only IPV only bOPV + Vit. A bOPV + IPV Control
9/25 19/19 9/24 31/33 6/22
36 (16.6–55.4) 100 (–) 37.5 (17.5–57.5) 93.9 (85.6–100) 27.3 (8–46.5)
0.522 <0.001 0.460 <0.001 Ref.
8/38 45/48 9/40 40/43 7/35
21.1 (7.8–34.3) 93.8 (86.8–100) 22.5 (9.3–35.7) 93 (85.3–100) 20 (6.5–33.5)
0.911 <0.001 0.792 <0.001 Ref.
12/46 46/50 9/50 46/50 5/42
26.1 (13.2–39) 92 (84.4–99.6) 18 (7.2–28.8) 92 (84.4–99.6) 11.9 (1.9–21.9)
0.092 <0.001 0.418 <0.001 Ref.
5–6 years bOPV only IPV only bOPV + Vit. A bOPV + IPV Control
8/32 22/23 8/32 27/27 5/29
25 (9.6–40.4) 95.7 (87.1–100) 25 (9.6–40.4) 100 (–) 17.2 (3.1–31.4)
0.460 <0.001 0.460 <0.001 Ref.
8/38 31/33 9/34 36/39 1/38
21.1 (7.8–34.3) 93.9 (85.6–100) 26.5 (11.3–41.6) 92.3 (83.8–100) 2.6 (-2.6–7.8)
0.013 <0.001 0.003 <0.001 Ref.
16/55 48/50 12/48 50/52 4/50
29.1 (16.9–41.3) 96 (90.5–100) 25 (12.6–37.4) 96.2 (90.9–100) 8 (0.4–15.6)
0.006 <0.001 0.023 <0.001 Ref.
10–11 years bOPV only IPV only bOPV + Vit. A bOPV + IPV Control
19/58 46/46 15/61 57/57 7/55
32.8 (20.5–45) 100 (–) 24.6 (13.6–35.5) 100 (–) 12.7 (3.8–21.7)
0.011 <0.001 0.104 <0.001 Ref.
18/54 52/53 14/48 46/47 5/60
33.3 (20.6–46.1) 98.1 (94.4–100) 29.2 (16.1–42.2) 97.9 (93.7–100) 8.3 (1.2–15.4)
0.001 <0.001 0.005 <0.001 Ref.
31/73 68/69 21/67 68/68 10/68
42.5 (31–53.9) 98.6 (95.7–100) 31.3 (20.1–42.6) 100 (–) 14.7 (6.2–23.2)
0.000 <0.001 0.022 <0.001 Ref.
Overall bOPV only IPV only bOPV + Vit. A bOPV + IPV Control
36/115 87/88 32/117 115/117 18/106
31.3 (22.8–39.8) 98.9 (96.6–100) 27.4 (19.2–35.5) 98.3 (95.9–100) 17 (9.8–24.2)
0.013 <0.001 0.064 <0.001 Ref.
34/130 128/134 32/122 122/129 13/133
26.2 (18.6–33.8) 95.5 (92–99) 26.2 (18.4–34.1) 94.6 (90.6–98.5) 9.8 (4.7–14.9)
0.001 <0.001 0.001 <0.001 Ref.
59/174 162/169 42/165 164/170 19/160
33.9 95.9 25.5 96.5 11.9
<0.001 <0.001 0.002 <0.001 Ref.
was not significantly different than seroconversion in no-vaccine arm (P > 0.05 for all serotypes). No serious adverse events associated to study procedures were detected.
4. Discussion Serological data from our trial confirmed that IPV is very efficient in closing an existing humoral immunological gap and providing protection against paralytic disease. Furthermore, our
(26.8–41) (92.8–98.9) (18.8–32.1) (93.7–99.3) (6.8–16.9)
data demonstrated that additional OPV dose in already highly OPV vaccinated populations have limited benefits: it appears that a small proportion of children in this environment simply does not respond to OPV despite receiving multiple doses. IPV, on the other hand, seems to provide uniformly high Seroconversion in all populations regardless of these underlying conditions. Factors influencing the immunogenicity of OPV have been researched in the past. Malnutrition, enteric infections and environmental enteropathy concurrent with OPV administration were associated with lower OPV immunogenicity [16,18–21]. On
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the other hand, Zinc supplementation or administration of sodium bicarbonate or sodium citrate buffers together with OPV were not associated with higher OPV immunogenicity [22,23]. In our study, we did not observe any effect of administration of one dose of vitamin A together with OPV on its immunogenicity. The finding of decreasing seroprevalence with age for type 3 has been observed previously and is believed not to be correlated with loss of protection but rather with natural waning of humoral antibodies [24]. Immune response as well as seroconversion for poliovirus type 2 in the bOPV only arms was high (20–30%) and significantly higher than for children in the control arm (<10%). This finding, consistent with previous observations, is likely due to heavy environmental contamination with tOPV related polioviruses; and due to possible cross reactivity between bOPV and type 2 response in previously type 2 exposed children [16]. This study had some limitations. The OPV dose history may have been influenced by parental recall bias, especially given the number of polio campaigns conducted in Matiari in the past several years. In addition, secondary exposure of study children to environmental vaccine viruses might have biased the immune response estimates; however, we believe that this bias was uniformly distributed among study arms. As part of the implementation of the Polio Endgame Strategic Plan [25], the Strategic Advisory Group of Experts (SAGE) recommended in 2012 the introduction of at least one dose of IPV in all routine immunization programs for risk mitigation before OPV2 withdrawal [26]. A dose of IPV is expected to induce seroconversion or priming in close to 100% of naïve infants [27]. Should poliovirus type 2 be reintroduced, a second IPV dose would rapidly boost antibody titers and prevent, or decrease the magnitude of, an outbreak. Furthermore, IPV would be expected to close the remaining immunity gaps for serotypes 1 and 3. In Pakistan, when introduced in the second part of 2015, IPV will be administered together with one dose of OPV to children reaching 14 weeks of age. In addition to IPV use in routine immunization, targeted IPV campaigns for children under five years of age living in areas with persistent wild poliovirus circulation are an opportunity to close the existing immunity gap and accelerate poliovirus eradication [28]. Kenya, Nigeria, Afghanistan as well as Pakistan have conducted targeted IPV campaigns and demonstrated programmatic feasibility of a house-to-house campaign with an injectable vaccine [11]. We believe that additional targeted IPV campaigns, for example in high risk zones of the Federally Administered Tribal Areas (FATA), or in high risk areas of Karachi, would significantly accelerate poliovirus eradication from Pakistan. Declaration of interests Authors did not declare any conflict of interest. Role of the funding source Funding for this study was provided by the World Health Organization, Geneva. Acknowledgements The Centers for Disease Control and Prevention supported the project in-kind by provision of laboratory testing and expertise in interpretation. We thank Dr. Mark A. Pallansch, Director Division of Viral Diseases at the CDC and the team conducting the neutralization assays at the CDC Laboratory: Deborah Moore, Yiting Zhang, Sharla McDonald, Patricia Mitchell, William Hendley, Larin McDuffie and Tamanna Ahmed. Dr. Elias Durry (Polio Team
Lead, WHO, Pakistan), Dr. Salah Tumsah (WHO team leader – Polio Program Sindh). We would like to acknowledge Mr. Imran Ahmed from Aga Khan University and Marina Takane from the World Health Organization for her biostatistical support. Finally we would like to acknowledge Mr. Asmatullah and the study field team including doctors, nurses, data collectors who worked selflessly for the successful completion of this study. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2016.05. 065. References [1] Cases of wild poliovirus by country and year. Available at:
Please cite this article in press as: Habib MA et al. Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.05.065
M.A. Habib et al. / Vaccine xxx (2016) xxx–xxx [24] Gamage D, Palihawadana P, Mach O, Weldon WC, Oberste SM, Sutter RW. Achieving high seroprevalence against polioviruses in Sri Lanka – results from a serological survey, 2014. J Epidemiol Glob Health 2015. [25] Polio eradication and endgame strategic plan 2013–2018. Available at:
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epidemiologique hebdomadaire/Section d’hygiene du Secretariat de la Societe des Nations = Weekly epidemiological record/Health Section of the Secretariat of the League of Nations, vol. 88; 2013. p. 1–16. [27] Resik S, Tejeda A, Sutter RW, et al. Priming after a fractional dose of inactivated poliovirus vaccine. N Engl J Med 2013;368:416–24. [28] Parker EP, Molodecky NA, Pons-Salort M, O’Reilly KM, Grassly NC. Impact of inactivated poliovirus vaccine on mucosal immunity: implications for the polio eradication endgame. Expert Rev Vaccines 2015;14:1113–23.
Please cite this article in press as: Habib MA et al. Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.05.065