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Randomized Trial of Inactivated and Live Polio Vaccine Schedules in Guatemalan Infants

  1. Edwin J. Asturias1,3,
  2. Erica L. Dueger1,3,
  3. Saad B. Omer1,
  4. Arturo Melville4,
  5. Silvia V. Nates5,
  6. Majid Laassri2,
  7. Konstantin Chumakov2 and
  8. Neal A. Halsey1
  1. 1Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore
  2. 2Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland
  3. 3Center for Health Studies, University del Valle de Guatemala, Guatemala City, Guatemala
  4. 4Department of Pediatrics, Hospital Roosevelt Guatemala, Guatemala City, Guatemala
  5. 5Instituto de Virología “Dr. J. M. Vanella,” Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
  1. Reprints or correspondence: Dr. Neal A. Halsey, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe St., W5515, Baltimore, MD 21205 (nhalsey{at}jhsph.edu).
 
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Abstract

Background. The immunogenicity of inactivated poliovirus vaccine (IPV) in developing countries is not well documented. This study compared the immune response to IPV with that to oral poliovirus vaccine (OPV) in Guatemalan infants.

Methods. This was an open-label, randomized comparison of IPV only, OPV only, or IPV followed by OPV in Guatemalan public health clinics. Serum samples were tested for neutralizing antibodies, and stool samples were tested for Sabin strain polioviruses.

Results. Seropositivity rates 2 months after 2 doses of IPV were 98%–100% for polio types 1, 2, and 3 and were 97.1%, 99.3%, and 92.1% for OPV-only recipients (P < .001 for the response to type 3). One month after the third dose, 100% of IPV-only recipients had protective antibodies against all 3 types, compared with 99%, 100%, and 97% against polio types 1, 2, and 3 respectively, among recipients of OPV only. Infants who received IPV only had higher geometric mean titers than infants who received OPV only. Maternal antibodies lowered the final antibody responses to IPV but did not prevent the development of protective levels of antibody. Of 191 stool samples from infants who received IPV only, 5 (2.6%) were positive for poliovirus vaccine strains.

Conclusions. IPV alone and IPV followed by OPV are safe and effective for Guatemalan infants.

Although some researchers have questioned the likelihood of success, remarkable progress has been made toward the global eradication of wild-type polioviruses [1–3]. Oral polio vaccine (OPV) has been the cornerstone of this effort because of its ease of administration, low cost, and induction of optimal intestinal immunity [4]. However, in many developing countries, OPV provides incomplete protection after 3 or 4 doses [5–8]. Also, OPV causes 250–500 cases of vaccine-associated paralytic poliomyelitis (VAPP) [2, 9] each year globally and has caused outbreaks of paralytic disease due to vaccine-derived polioviruses (VDPVs) [10–12]. The use of IPV has eliminated the risk of VAPP and maintained population- and individual-level protection in most of Europe, Canada, and the United States [13]. We compared the response to inactivated poliovirus vaccine (IPV) with that to OPV in Guatemalan infants and assessed the impact of passively acquired maternal antibodies on the immune response.

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Patients, Materials, and Methods

Study design. This was an open-label, randomized study to determine whether the antibody responses after the administration of IPV alone or after 2 doses of IPV followed by 1 dose of OPV were inferior to responses after an OPV-only schedule administered at 2, 4, and 6 months of age. Secondary objectives were to assess the rate of excretion of live Sabin strain polioviruses in the stools of IPV recipients due to exposure to children who received OPV and to evaluate seropositivity rates after the 12- month booster dose.

Patients and procedures. Healthy, full-term, 6–11-week-old infants attending 3 well-child public clinics in Guatemala City were eligible. Infants were excluded if they had (1) received polio, hepatitis B (HB), Haemophilus influenzae type b (Hib), or diphtheria-tetanus toxoids—pertussis (DTP) vaccines; (2) a history of any disease preventable by these vaccines; (3) a confirmed immunosuppressive condition; (4) received immunosuppressive drugs or blood-derived products; (5) major congenital defects or serious chronic illness; (6) a history of any neurological disorders or seizures; or (7) allergies to any component of the vaccines.

Written, informed consent was obtained from a parent or guardian. The study was approved by the ethical and institutional review boards of Hospital Roosevelt and University del Valle in Guatemala and the Committee for Human Research from the Johns Hopkins Bloomberg School of Public Health.

Randomization. Infants were randomized using a permuted block design of 6–12 at a 1:1:1 ratio within each study center. Allocation to study group was done by opening sealed, sequentially numbered envelopes.

Vaccines and immunization schedules. Vaccines (except OPV) were administered by intramuscular injection in the anterolateral thigh. Group 1 received a DTaP/IPV/Hib combination vaccine (Pentaxim; Sanofi Pasteur) and HB vaccine (EngerixB; GlaxoSmithKline) at each visit. Each 0.5-mL dose of DTaP/IPV/Hib contained ⩾30 IU of diphtheria toxoid; ⩾40 IU of tetanus toxoid; 25 µg of adsorbed pertussis toxoid; 25 mg of filamentous hemagglutinin; 40, 8, and 32 D-antigen units of polio virus type 1, 2, and 3, respectively, in the presence of aluminum hydroxide as adjuvant; and 10 µg of Hib polyribosylribitol phosphate (PRP) conjugated to 10–20 µg of tetanus toxoid. Group 2 received a DTwP-HB/Hib combination vaccine (TritanrixB and Hiberix; GlaxoSmithKline), IPV for the first 2 doses (Imovax Polio; Sanofi Pasteur) and OPV (Sanofi Pasteur) for the subsequent 2 doses. Each 0.5-mL dose of DTwP-HB contained ⩾30 IU of diphtheria toxoid, ⩾40 IU of tetanus toxoid, and >4 IU of Bordetella pertussis in the presence of aluminium hydroxide as adjuvant, and each dose of Hib contained 10 µg of Hib PRP conjugated to 20–40 µg of tetanus toxoid. Each 0.5-mL dose of IPV contained 40, 8, and 32 D-antigen units of polio virus type 1, 2, and 3, respectively. Group 3 received a DTwP-HB/Hib combination vaccine (TritanrixB and Hiberix) and OPV for all 4 doses. Enrollment began 3 weeks after the national immunization week in March 2004, when there was selective vaccination of infants who were behind schedule.

Adverse event evaluation. Diary cards and digital thermometers were used by parents to record adverse events, local reactions (tenderness, swelling, and redness) and systemic adverse events (fever, irritability, lethargy, and vomiting) on the day of vaccination and for 3 subsequent days or until symptoms resolved. Diary cards were collected at the next scheduled visit, and the parent was interviewed to ensure completeness of the information.

Antibody testing. Blood was drawn by venipuncture at 2, 6, 7 (1 month after the third dose), 12, and 13 (1 month after the booster dose) months of age, and serum was stored at −70°C until it was tested at the Virology Laboratory in Córdoba, Argentina. Neutralizing poliovirus antibodies were assessed by microneutralization assay in accordance with the modified World Health Organization (WHO) method, and wild-type poliovirus strains were used as challenge virus [14]. Serum samples were inactivated by heating at 56°C for 30 min, and 2-fold serial dilutions (from 1:4 to 1:8192) were tested against the 3 reference poliovirus serotypes (Mahoney, MEF, and Saukett). Duplicate dilutions (50 µL) of serum samples were mixed with an equal amount of virus suspension containing 100 TCID50 of each poliovirus and were incubated for 3 h at 37°C in a 96-well microcultured plate in a 5% CO2 atmosphere. Then, 100 µL of Hep-2 Cincinnati cell suspension (160,000 cells/mL) was added to each well and incubated for 6 days. Antipoliovirus 1, 2, and 3 serum neutralizing antibody titers were the reciprocal of the highest dilution that protected 50% of the cultured cells against 100 TCID50 of the challenge virus in duplicate wells. A titer ⩾1:8 was considered to be protective. The data are reported as seroprotection rates rather than seroconversion rates because some residual passive maternal antibody is expected at 2 months of age.

Poliovirus detection in stool. Stool samples were obtained at the scheduled visits at 2, 4, 6, and 7 months of age and were stored at −70°C before they were tested by polymerase chain reaction (PCR).

All stool samples available from the IPV-only group (group 1) at the 2-, 4-, 6-, and 7-month visits were tested by PCR to estimate the rate of exposure to OPV from contacts. All specimens collected at the 4-month visit from the OPV-only group (group 3) and at the 7-month visit from the IPV/OPV group (group 2) were tested by multiplex reverse-transcription PCR. The preparation of stool extracts and RNA isolation were performed as described elsewhere [15]. The following sets of primers were used: for Sabin 1, sense primer 2563Sab1F (5′-CGCTCTCCCAAACACTGAAG-3′) and antisense primer 2961Sab1R (5′-CATAATTTGGTACACTTGATTTAAG-3′); for Sabin 2, sense primer 2235Sab2F (5′-TAGGGTTGTTGTCCCGTTG-3′) and antisense primer 1912Sab2R (5′-CAATGCATGTCCGTTATTTGCAT- 3′); and for Sabin 3, sense primer 775Sab3F (5′-CGCTCACGAGAATTCTAACC-3′) and antisense primer 1601Sab3R (5′-GCATTCACATATGGTAGGACAATA-3′) (at 52°C; nt 1601—1578). The DNA was prepared as described elsewhere [15], using antisense primers (2961Sab1R, 1912Sab2R, and 1601Sab3R).

PCR was performed using the following protocol: 15 min at 95°C; 40 cycles of 15 s at 94°C, 15 s at 58°C, and 1 min at 72°C; and final incubation for 7 min at 72°C. The resulting products were analyzed by electrophoresis in 2% agarose gel prepared in 1× Tris borate—EDTA buffer containing 0.2 mg/mL of ethidium bromide. Quantitative PCR was performed as described elsewhere for all PCR-positive samples [16].

Statistical analyses. The initial sample size of 150 infants per group was based on the need for 136 evaluable participants to determine whether seroprotection rates for poliovirus types 1 and 3 in groups 1 and 2 were not inferior to the expected 95% rate for group 3 one month after the third dose and on the assumption that there would be a 10% dropout rate. Four months after the start of enrollment, a dropout rate >10% at one clinic resulted in the decision to increase recruitment to a total of 500 infants. Noninferiority was defined as the upper limit of the 95% confidence interval (CI) for the absolute differences in seropositivity rates between groups (1 vs. 3 and 2 vs. 3) being <10 percentage points after the third dose. There was 84.5% power to detect noninferiority (difference, <10%) for each poliovirus type with a reference value of 95%, on the assumption of a 5% 2-sided type I error rate. The proportion of individuals with antibody titers ⩾1:8 were compared between groups (1 vs. 3 and 2 vs. 3) using Fisher's exact test. Data were entered using Teleform software (version 8; Cardiff) and analyzed using STATA software (version 9; StataCorp). The normal approximate method for geometric mean titers (GMTs) was used for calculation of 95% CIs. For calculation of GMTs, titers <1:4 were assigned a value of 1:2. The according-to-protocol (ATP) analysis included all subjects without any major protocol deviation for the primary study objective 1 month after the third dose of vaccine. All randomized subjects who received at least 1 dose of vaccine were included in the intent-to-treat (ITT) analysis. The primary immunogenicity analysis was based on the ITT cohort; there were no significant differences in results, compared with ATP results. To be certain that the differences in responses by study group were not due to preexisting maternal antibodies, multiple linear regression was used to compute the differences in log titer after 2 and 3 doses of vaccine by study group for the 3 poliovirus types, adjusting for the presence of antibody titers ⩾1:8 before the first dose of vaccine.

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Results

From April through November 2004, 500 infants were enrolled; 444 (88.8%) were available for primary end-point analysis, and 439 (87.8%) completed the last study visit (figure 1). The primary reason for consent withdrawal was refusal of blood draws. The 3 study groups were similar at enrollment (table 1). The mean ± SD age at the time of doses 1, 2, and 3 was 59.5 ± 11.1, 122.0 ± 21.0, and 183.7 ± 19.0 days, respectively.

Figure 1
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Figure 1

Trial flow chart. IPV, inactivated poliovirus vaccine; OPV, oral polio vaccine.

Figure 2
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Figure 2

Geometric mean antibody titers (GMTs; 95% confidence intervals) by poliovirus type, dose, and schedule. IPV, inactivated poliovirus vaccine; OPV, oral polio vaccine.

Table 1
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Table 1

Baseline characteristics, by study group.

Antibody responses. A smaller proportion of infants in the IPV-only group had protective antibody titers at baseline than infants in the OPV-only group (table 2). The infants without detectable antibodies at baseline did not differ from the infants with antibody in terms of socioeconomic status. High (>97%) seroprotection rates after 2 doses of vaccine were achieved in all 3 groups against poliovirus types 1 and 2. However, protection against poliovirus type 3 was significantly lower for OPV-only recipients than for IPV-only recipients (92.1% vs. ⩾98%; P < .01). One month after the third dose, all infants who received IPV only or IPV/OPV had developed protective antibodies against all 3 polioviruses. Infants who received 3 doses of OPV had 99% and 100% rates of protective antibodies against poliovirus types 1 and 2, respectively, but the 97% rate of protective antibodies against poliovirus type 3 was significantly (P = .01) lower than the 100% rate for infants who received IPV at 2 and 4 months of age.

Table 2
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Table 2

Subjects with antibody titers ⩾1:8 to polioviruses (1, 2, and 3), by study visit.

Infants who received IPV only or IPV/OPV had significantly higher GMTs to all poliovirus serotypes than infants who received OPV vaccine alone after the second, third, and booster doses of vaccine, but the differences were not significant at 12 months of age (figure 2). Participants in the IPV-only and IPV/OPV groups who had serum polio antibody titers ⩾1:8 at baseline had significantly lower GMTs for types 1 and 2 after 2 doses than did infants without baseline antibody; IPV-only recipients had higher antibody responses than OPV-only recipients for infants with or without maternal antibody titers ⩾1:8 at baseline (table 3). In OPV-only recipients with maternal antibody titers ⩾1:8 at baseline, there were lower responses for type 3 antibody after 3 doses. After adjustment for baseline antibody titers ⩾1:8 using multiple linear regression, antibody titers after 3 doses of vaccine remained significantly higher for all 3 polio types for IPV-only and IPV/OPV recipients than for infants who received OPV only.

Table 3
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Table 3

Geometric mean antibody titers (GMTs) at visits 3 and 4 by study group and poliovirus type, stratified by the presence of a GMT ⩾1:8 at baseline.

Five (2.6%) of 191 stool samples from infants who had received IPV only tested positive for polio vaccine viruses during the first 7 months of life (table 4). The copy number was 106.1 two months after the first dose for OPV-only recipients, 105.9 one month after the first dose of OPV for IPV/OPV recipients, and 101.9 for the 4 IPV-only recipients with virus in their stool at 6 months of age. The serum antibody titers in the 4 infants with virus in their stools were similar to those of IPV-only recipients who did not have poliovirus in their stool (data not shown).

Table 4
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Table 4

Proportion of infants with positive stool polymerase chain reaction results, by study group, visit no., and vaccine type.

Adverse events. Twenty-one infants experienced 26 serious adverse events (SAEs); most were hospitalizations due to diarrhea and respiratory illnesses. One child was diagnosed with patent ductus arterious after enrollment, had 5 associated hospitalizations, and died of complications after surgical correction. No SAEs were considered to be related to the study vaccines.

Infants in group 1 who received a DTaP-containing vaccine had significantly lower rates of adverse events than infants in groups 2 and 3 who received DTwP combination vaccines, including fever (temperature ⩾38°C; 17.8% vs. 41.1%; P < .001), irritability (5.5% vs. 13.5%; P < .001), lethargy (2.4% vs. 9.3%; P < .01), and local reactions (pain at injection site, induration, and tenderness; 31.0% vs. 50.1%; P < .001).

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Discussion

Antibody responses after the administration of OPV vaccine at 2, 4, and 6 months of age in Guatemalan infants were similar to response rates in the United States and Europe and were higher than rates reported from other developing countries in which the 6-, 10-, and 14-week WHO schedule was used [5, 8, 16].

Antibody response rates after IPV-only and IPV/OPV sequential vaccine schedules were as good as or better than responses to OPV only. The high response rates to IPV administered at 2, 4, and 6 months of age were similar to findings in more developed countries [13] and in a recent study in Puerto Rico [17]. Detection of poliovirus vaccine strains in the stool of IPV-only recipients was minimal, indicating that the high antibody responses were not due to exposure to OPV from other children or the environment. One month after a dose of OPV, 47% of the infants in group 2 who had received 2 doses of IPV were excreting polioviruses. The quantity of poliovirus in stool from these infants was lower than the quantity of virus in stool from infants in group 3 who received OPV only, despite the samples in the latter group having been collected 2 months after the first dose of OPV. Because the proportion of infants shedding virus and the quantity of virus in stool decreases with time since vaccination, the data from this study are consistent with those from other studies indicating a reduction of viral shedding in children who received at least 2 doses of IPV before exposure to OPV or wild-type viruses [13, 16, 18, 19].

The magnitude of the antibody response to IPV was modified somewhat by the presence of maternal poliovirus antibodies at 2 months of age, but all IPV-only recipients developed protective levels of antibody, and the magnitude of the responses exceeded the response to OPV only. The use of wild-type virus for testing antibody responses rather than Sabin strains could theoretically have contributed to the differences in magnitude of antibody responses detected, given that the IPV is produced from wild-type strains. Nevertheless, other studies using Sabin strains for antibody testing have shown that IPV recipients had higher antibody responses than OPV recipients, suggesting minimal influence of the assay [20, 21].

The WHO has determined that routine immunization with OPV must cease after the eradication of wild-type polioviruses because of the risk of generating outbreaks of circulating vaccine- derived polioviruses and the risk of VAPP [2, 9]. For regions in which wild-type polioviruses have been eliminated, moving to an IPV-only or IPV/OPV sequential schedule now would reduce or eliminate the risk of VAPP and outbreaks of circulating VDPVs, as well as increase the likelihood of countries agreeing to stop administering OPV after eradication is achieved [16, 18]. IPV could also be used with OPV in routine schedules to enhance the immune response and decrease the circulation of wild-type polioviruses in countries in which transmission has not been stopped. IPV alone was used successfully to eliminate wild-type polio in many European countries and has been used exclusively in the United States since January 2000 [13]. No cases of VAPP and no outbreaks of wildtype polio have occurred in the United States since the conversion to IPV. Also, circulation of an imported VDPV remained limited to an unvaccinated population in Minnesota [22].

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Acknowledgments

We thank the nurses and clinicians who participated in the trial and the infants and families who agreed to take part. Eric Desauziers, Vivian Jusot, Patricia Cervantes, and Stanley Plotkin participated in the planning and monitoring of the study and reviewed a draft of the manuscript. Tina Proveaux provided editorial assistance.

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Footnotes

  • Potential conflicts of interest: E.J.A. has received travel grants from Sanofi Pasteur and GlaxoSmithKline to participate in conferences and is a member of an independent data and safety monitoring board reviewing data for studies conducted by Sanofi Pasteur. S.B.O. has received reimbursement from Sanofi Pasteur for a trip to Guatemala in 2006 for a meeting to discuss the analysis of the research study on which this article is based. N.A.H. and E.J.A. have received salary support through the grant that funded the study. Representatives from Sanofi Pasteur participated in the study design but not in the data collection or analysis; representatives reviewed the manuscript and offered comments. The corresponding author had full access to all data and final responsibility for the decision to submit the manuscript for publication. All other authors report no conflicts.

  • Financial support: Sanofi Pasteur. Independent funds were used to support statistical analyses, and support for E.L.D. was provided by a Fogarty International Research Scientist Development Award (grant KO1 TW006659).

  • Received February 1, 2007.
  • Accepted March 28, 2007.
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  1. J Infect Dis. (2007) 196 (5): 692-698. doi: 10.1086/520546
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