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Background In 1988, the World Health Assembly resolved to eradicate poliomyelitis. Although substantial progress toward this goal has been made, eradication remains elusive. In 2004, the World Health Organization called for the development of a potentially more immunogenic monovalent type 1 oral poliovirus vaccine.
Methods We conducted a trial in Egypt to compare the immunogenicity of a newly licensed monovalent type 1 oral poliovirus vaccine with that of a trivalent oral poliovirus vaccine. Subjects were randomly assigned to receive one dose of monovalent type 1 oral poliovirus vaccine or trivalent oral poliovirus vaccine at birth. Thirty days after birth, a single challenge dose of monovalent type 1 oral poliovirus vaccine was administered in all subjects. Shedding of serotype 1 poliovirus was assessed through day 60.
Results A total of 530 subjects were enrolled, and 421 fulfilled the study requirements. Thirty days after the study vaccines were administered, the rate of seroconversion to type 1 poliovirus was 55.4% in the monovalent-vaccine group, as compared with 32.1% in the trivalent-vaccine group (P<0.001). Among those with a high reciprocal titer of maternally derived antibodies against type 1 poliovirus (>64), 46.0% of the subjects in the monovalent-vaccine group underwent seroconversion, as compared with 21.3% in the trivalent-vaccine group (P<0.001). Seven days after administration of the challenge dose of monovalent type 1 vaccine, a significantly lower proportion of subjects in the monovalent-vaccine group than in the trivalent-vaccine group excreted type 1 poliovirus (25.9% vs. 41.5%, P=0.001). None of the serious adverse events reported were attributed to the trial interventions.
Conclusions When given at birth, monovalent type 1 oral poliovirus vaccine is superior to trivalent oral poliovirus vaccine in inducing humoral antibodies against type 1 poliovirus, overcoming high preexisting levels of maternally derived antibodies, and increasing the resistance to excretion of type 1 poliovirus after administration of a challenge dose. (Current Controlled Trials number, ISRCTN76316509
[controlled-trials.com]
.)
Through 2004, progress toward the goal of eradicating poliomyelitis had been particularly difficult in the densely populated tropical and subtropical areas of Asia and Africa. To provide the eradication initiative with a more immunogenic vaccine, the Global Polio Eradication Initiative was advised in October 2004 to develop, as quickly as possible, a monovalent type 1 oral poliovirus vaccine,4 partly to correct for the low immunogenicity of the trivalent oral poliovirus vaccine in developing countries.5,6,7,8,9,10,11,12,13,14,15,16,17 The manufacturers responded rapidly, and the first monovalent type 1 oral poliovirus vaccine was developed and licensed by a large vaccine producer in less than 6 months.
Although a monovalent type 1 oral poliovirus vaccine (as well as monovalent type 2 and type 3 oral poliovirus vaccines) had been used extensively in 1959 and the early 1960s in many industrialized and developing countries, the licensure of a trivalent oral poliovirus vaccine in 1963 in the United States relegated the monovalent vaccines to history. A monovalent type 1 oral poliovirus vaccine has been used in the past 30 years only in Hong Kong, the Gaza Strip, Kuwait, and South Africa,18,19 and for control of the 1978 outbreak in the Netherlands.20 A review of available trials of the monovalent type 1 oral poliovirus vaccine21 suggests that it is two to three times as immunogenic as the trivalent oral poliovirus vaccine, even at potency levels that are substantially lower than the corresponding potency of the trivalent vaccine. A case–control study examining the use of monovalent type 1 oral poliovirus vaccine in Northern India in 2005 showed that the efficacy of the monovalent vaccine was approximately three times as high as the efficacy of the trivalent vaccine.22
To permit an unbiased evaluation of monovalent type 1 oral poliovirus vaccine, we selected a clinical study design in which newborns were enrolled and vaccinated with either monovalent type 1 or trivalent oral poliovirus vaccine before they had an opportunity to be exposed to poliovirus through routine vaccination with trivalent oral poliovirus vaccine (since 2003, Egypt has recommended a dose of trivalent oral poliovirus vaccine at birth),23 secondary exposure to vaccine virus from recently vaccinated children, or infection with wild-type poliovirus. The study was designed to provide a head-to-head comparison of the immunogenicity of monovalent type 1 and trivalent oral poliovirus vaccines.
Methods
Study Objectives and Protocol
The study had three specific objectives: to compare humoral antibody responses (seroconversion and antibody titer) after a single dose of either monovalent type 1 or trivalent oral poliovirus vaccine; to quantify mucosal immunity after administration of a challenge dose of monovalent type 1 oral poliovirus vaccine in study participants; and to determine adverse events after oral poliovirus vaccination.
Written or oral informed consent for the participation of the newborns was obtained from parents or guardians in accordance with ethical principles, including the Declaration of Helsinki. The study was carried out in compliance with Good Clinical Practice guidelines and was approved by the Ministry of Health and Population in Egypt; the institutional review boards of Ain Shams University, Cairo, and the Centers for Disease Control and Prevention (CDC), Atlanta; and the ethical review committee of the World Health Organization (WHO), Geneva. The data and safety monitoring board was established for this trial and assumed the responsibility for monitoring adverse events and data quality. All the authors vouch for the completeness and accuracy of the data and analysis presented.
The field work of the study was conducted from August 2005 through October 2005 at three clinical sites (Ain Shams University, Cairo; Kasr El Aini Hospital, University of Cairo, Cairo; and Alexandria University, Alexandria); outreach activities, including the collection of stool samples, were conducted by the Ministry of Health and Population in Egypt. A minimum sample size of 138 participants in each of the two study groups was needed to detect a difference in response with the monovalent type 1 oral poliovirus vaccine as compared with the trivalent vaccine of 20% or more, at an alpha level of 0.05 and a beta level of 0.10 (two-tailed test).
Study Design
Expectant mothers and fathers were contacted either during prenatal visits or at the time of admission for delivery. They were provided information about the study and asked whether they were willing to participate. Newborns were eligible for participation if they were healthy at birth (and the delivery was not high-risk), if they had a birth weight of 2.75 kg or more, if they had an Apgar score of 9 or higher 5 minutes after delivery, if their family resided in the same governorate as the study site and not further than 30 km away, if the family did not plan to move during the study period, and if written or oral informed consent was given by at least one parent or guardian.
Subjects were randomly assigned to receive at birth either a dose of monovalent type 1 oral poliovirus vaccine (Z5181, Sanofi Pasteur), formulated to contain at least 106 median cell-culture infective doses (CCID50) of Sabin type 1 poliovirus strain, or a dose of trivalent oral poliovirus vaccine (Z5285, Sanofi Pasteur), formulated to contain at least 106, 105, and 105.6 CCID50 of Sabin types 1, 2, and 3 poliovirus, respectively. At 30 days of age, all subjects received a dose of monovalent type 1 oral poliovirus vaccine. The vaccines were shipped on dry ice from the manufacturer to Cairo.24
For the trivalent oral poliovirus vaccine, the mean potency values were provided by the manufacturer as part of lot-release testing. The potency titer for the monovalent vaccine was 106.8 for type 1 poliovirus. The titers for the trivalent vaccine were 106.9 for type 1, 105.5 for type 2, and 106.5 for type 3. Tests performed by the French Health Products Safety Agency (Agence Française de Sécurité Sanitaire des Produits de Santé) showed a titer of 106.7 for the monovalent type 1 oral poliovirus vaccine and titers of 106.6 for type 1, 105.4 for type 2, and 106.1 for type 3 for the trivalent vaccine.
Blood specimens were collected at birth (cord blood) and 30 and 60 days after birth. After coagulation, the serum was separated, frozen, and stored at –20°C at the study site until shipment to the CDC. The specimens were tested in triplicate with the use of modified neutralization assays for antibodies to types 1, 2, and 3 poliovirus.25 The initial dilution was a reciprocal titer of 8. Seropositivity was defined as a reciprocal titer of 8 or higher.25 Seroconversion was defined as an increase by a factor of 4 in the antibody titer over the expected decline in the titer of maternally derived antibodies in a successive specimen. The half-life of antibody decay was assumed to be 28 days. For subjects who were seronegative at enrollment, a change to seropositivity (i.e., a reciprocal titer 
8) was considered to indicate seroconversion; for those with titers just below the highest dilution tested, a change to the highest dilution was considered to represent seroconversion. For subjects with positive results at the highest dilution tested (reciprocal titer, 1448) for all three serum samples tested (those obtained at birth, 30 days, and 60 days), the samples were retested with a higher initial dilution (1:256) to determine whether they had undergone seroconversion.
Stool specimens were collected 30 days after birth and on days 7, 14, 21, and 28 thereafter; specimens were transported on the day of collection to a central storage location in Alexandria or Cairo and placed immediately in a freezer until shipment to the National Institute for Public Health and the Environment, Bilthoven, the Netherlands, for assessment for the presence of poliovirus. Isolation and identification of poliovirus in the stool specimens were made by the observation of growth on L20B cells, typing by polymerase-chain-reaction (PCR) and serum neutralization assays, and differentiation between wild-type and vaccine-related strains by PCR and by enzyme-linked immunoassay with cross-absorbed antiserum, according to standard procedures established by the World Health Organization (WHO).26
Statistical Analysis
Statistical analyses were performed with the use of R27 and SAS28 statistical packages. Comparisons of the proportion of subjects with seroconversion in the two groups were made with the use of the chi-square test with Yates' correction. The differences in the distribution of antibody titers were tested with the use of the Kolmogorov–Smirnov nonparametric method.29 The 95% confidence intervals were calculated for the median values.30
Results
Study Population
The parents or guardians of 583 newborns were contacted; the parent of 1 newborn refused to participate, and 52 newborns did not meet the enrollment criteria. Of the 530 newborns enrolled, 43 (8.1%) were withdrawn during the 60-day follow-up period, and 3 died; 484 subjects completed the study. Sixty-three subjects were excluded from the analyses because they received extra doses of trivalent oral poliovirus vaccine through routine immunization services. Thus, a total of 421 subjects (79.4% of those enrolled in the study) completed the study requirements and were included in the analyses (Figure 1).
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There were no significant differences among the study subjects in baseline characteristics (sex, birth weight, interval from birth to vaccine administration, and levels of seroprevalence) according to study site. After random assignment to either the monovalent-vaccine group or the trivalent-vaccine group, the subjects in the two groups did not differ significantly with respect to baseline characteristics, seroprevalence, or titers of poliovirus antibodies. Seroprevalence was 97.0% in the monovalent-vaccine group and 95.8% in the trivalent-vaccine group for type 1 poliovirus, 92.6% and 96.8%, respectively, for type 2 poliovirus, and 82.3% and 86.8%, respectively, for type 3 poliovirus (Table 1).
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64) underwent seroconversion, as compared with 75 of 163 subjects (46.0%) with high levels (defined as a reciprocal titer of >64) (P<0.001). In the trivalent-vaccine group, 32 of 54 subjects (59.3%) with low levels of maternally derived antibodies underwent seroconversion, as compared with 29 of 136 (21.3%) with high levels (P<0.001). Among subjects with high levels of maternally derived antibodies, the between-group differences in seroconversion were significant (46.0% in the monovalent-vaccine group vs. 21.3% in the trivalent-vaccine group, P<0.001). In the trivalent-vaccine group, 56 of 67 subjects (83.6%) with low levels of type 2 maternally derived antibodies underwent seroconversion, as compared with 62 of 123 (50.4%) with high levels (P<0.001), and 21 of 105 subjects (20.0%) with low levels of type 3 maternally derived antibodies underwent seroconversion as compared with 11 of 85 (12.9%) with high levels (P=0.27). In the monovalent-vaccine group, seroconversion was significantly affected by socioeconomic status, with the rate of seroconversion to type 1 poliovirus increasing from 38.6% (22 of 57 subjects) among subjects whose mothers had received less than 5 years of formal education to 50.7% (36 of 71 subjects) among those whose mothers had received between 5 and 9 years of formal education and to 68.0% (70 of 103 subjects) among those whose mothers had received 10 years or more of formal education. In the trivalent-vaccine group, the mother's formal education did not affect the rate of seroconversion to type 1 poliovirus: less than 5 years of formal education, 31.6% (18 of 57 subjects); 5 to 9 years, 33.3% (16 of 48); and 10 years or more, 31.8% (27 of 85). Seroconversion was not affected by birth weight, the number of children younger than 5 years of age in the household, or the interval between birth and administration of the study vaccine.
Immunogenicity of the Challenge Dose
At the 30-day visit, all subjects received a challenge dose of monovalent type 1 oral poliovirus vaccine. Among those who had not undergone seroconversion to the birth dose, the rate of seroconversion to type 1 in the monovalent-vaccine group was 58.3% (60 of 103 subjects), and the rate of seroconversion to type 1 in the trivalent-vaccine group was 66.7% (86 of 129 subjects, P=0.24) (Table 2). At the end of the study (at the 60-day visit), 81.4% of the subjects (188 of 231) in the monovalent-vaccine group (who had received two doses of monovalent type 1 oral poliovirus vaccine) had undergone seroconversion, as compared with 77.4% of the subjects (147 of 190) in the trivalent-vaccine group (who had received a dose of trivalent oral poliovirus vaccine at birth and a dose of monovalent type 1 oral poliovirus vaccine at the 30-day visit) (P=0.37).
Virus Excretion after the Challenge Dose
Mucosal immunity was assessed by measuring viral excretion after the challenge dose of monovalent type 1 oral poliovirus vaccine, administered at the 30-day visit. Stool specimens were collected immediately before the challenge (day 0 of the challenge) and on days 7, 14, 21, and 28 thereafter. On day 0 of the challenge, 9.5% of the subjects (40 of 421) excreted type 1 poliovirus, 12.1% (51 of 421) excreted type 2 poliovirus, 6.7% (28 of 421) excreted type 3 poliovirus, and 0.5% (2 of 421, both of whom were in the monovalent-vaccine group) excreted a mixture of type 2 and type 3. No wild-type poliovirus was detected in any of the stool samples. Overall, 42.3% of the study infants (161 of 381) excreted type 1 poliovirus at any visit after the challenge — 32.7% (66 of 202) of the subjects in the monovalent-vaccine group as compared with 53.1% (95 of 179) in the trivalent-vaccine group (P<0.001). The subjects in the monovalent-vaccine group had lower excretion rates than those in the trivalent-vaccine group at each assessment point (7, 14, 21, and 28 days) after the challenge (Table 3). The difference in excretion of type 1 poliovirus between the two groups was significant before the challenge (day 0) (P=0.03) and on day 7 after the challenge (P=0.001) but not at the other postchallenge visits.
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No immediate serious adverse events and only five minor adverse events (all involving vomiting) were noted during a 30-minute observation period after administration of the vaccine. Five subjects were admitted to the hospital within 2 days after birth to receive phototherapy for jaundice. One subject was hospitalized because of heart failure due to a congenital heart defect. Three other subjects were reported to have severe adverse events (pneumonia, sepsis, and congenital heart disease); all three subjects (who were from the same study site) died; two of the infants (one with pneumonia and one with sepsis) were in the monovalent-vaccine group, and one infant (with congenital heart disease) was in the trivalent-vaccine group. None of the adverse events or deaths were attributed to the trial intervention.
Discussion
These data have implications for the use of monovalent type 1 oral poliovirus vaccine in the global initiative to eradicate poliomyelitis. First, this vaccine is significantly more immunogenic than trivalent oral poliovirus vaccine in inducing a type-specific seroconversion; second, vaccination with monovalent type 1 as compared with trivalent oral poliovirus vaccine significantly decreases subsequent excretion of type 1 oral poliovirus after a challenge with the monovalent vaccine; and third, vaccination with the monovalent vaccine after initial vaccination with the trivalent vaccine appears to be as effective in closing the type 1 immunity gaps as vaccination with the monovalent vaccine in previously unvaccinated infants or in those who have undergone initial vaccination with the monovalent vaccine.
One of the reasons that this monovalent vaccine is significantly more immunogenic in inducing a type-specific antibody response than the trivalent vaccine may be that this monovalent vaccine has a higher potency than previous monovalent vaccines used in the United States and other industrialized countries in the 1960s21 (i.e., 1,000,000 CCID50, vs. 200,000 CCID50). The higher potency was selected on the basis of a review of previous trials in developing countries21 and as part of the regulatory approval strategy to remove the unnecessary Sabin strains from the trivalent oral poliovirus vaccine while maintaining all other requirements for the formulation of the trivalent oral poliovirus vaccine.
Excretion on day 7 after the challenge was significantly reduced in the monovalent-vaccine group. Resistance to excretion after exposure may be the most important mechanism for interrupting the remaining chains of poliovirus transmission.
Low socioeconomic status, defined as fewer years of formal maternal education, was a risk factor for failure to undergo seroconversion to type 1 poliovirus in the monovalent-vaccine group but not in the trivalent-vaccine group for types 1, 2, and 3. Low socioeconomic status has been identified in several studies of trivalent oral poliovirus vaccine as a risk factor for failure to undergo seroconversion after a full series with trivalent oral poliovirus vaccine.6,17
The seroconversion rate with monovalent type 1 oral poliovirus vaccine in our study was similar to that in previous studies conducted in developing countries. In these studies, seroconversion rates of 50 to 70% were reported with monovalent type 1 oral poliovirus vaccines of various potencies.21,31,32,33,34,35,36
In our study, none of the serious adverse events that were reported among the study subjects during the follow-up period were attributed by the investigators or by the data and safety monitoring board to the receipt of either of the study vaccines. The number of deaths was consistent with expectations based on infant mortality rates in Egypt.
An important limitation of this study is that we restricted enrollment to newborns. However, we chose to study the vaccine in newborns because infants in developing countries receive multiple doses of trivalent oral poliovirus vaccine, typically starting with a dose administered at birth or shortly thereafter. The study of newborns allows an evaluation of monovalent type 1 and trivalent oral poliovirus vaccines before the subjects are potentially exposed to poliovirus. However, newborns have the highest levels of maternally derived antibodies, which are known to interfere with seroconversion.37 Therefore, our findings with respect to the immunogenicity of monovalent type 1 oral poliovirus vaccine are probably biased toward the lower ranges of immunogenicity as compared with those we might have observed after administration of the vaccine in slightly older infants (1 month of age).
In conclusion, our data confirm the potential contribution of supplemental doses of monovalent type 1 oral poliovirus vaccine to accelerate the interruption of the final chains of poliovirus transmission and eventually achieve the goal of global eradication of poliomyelitis.2
Supported by grants from the Gates Foundation (37460) and the WHO.
No potential conflict of interest relevant to this article was reported.
We thank the study staff at each of the three sites, especially Zeinab Ibraheim, Shereen Saad, and Dalia Helmy from Ain Shams; Heba Abouhussin, Nermin Ramy, Yasmin Mansy, and Hisham Elgazaly Abouhussin from Kasr-El-Aini; and Mohamed Tawfik Abdel-Latif, Mohamed Abdel Fattah, Ibrahim Medhat, Emad Darwish, Hesham Ghazal, Mohamed Hussein, Mohamed Nader, and Ashraf Fadel from Alexandria; Samiha Mukhtar and Ashraf Wahdan from the High Institute of Public Health, Alexandria University (Biostatistics) for data entry; the staff of the Ministry of Health and Population in Egypt for their assistance with all outreach activities; the national regulatory authorities in France and Egypt for the provision of potency data; the families that participated in this study; and the laboratory staff at the CDC who performed the serologic testing, including Debbie Moore, Barbara Anderson, and Naomi Dybdahl-Sissokko, and the staff members of the National Institute for Public Health and the Environment, Bilthoven, the Netherlands, who performed viral isolation and characterization, including Sabine van der Sanden, Martijn van Luit, and Albert Ras. Sanofi Pasteur, Lyon, France, donated the study vaccines.
Source Information
From the Ministry of Health and Population, Cairo (N.E.-S., A.K.); Ain Shams University, Cairo (Y.E.-G., E.H.); Alexandria University, Alexandria (A.-A.A., A.S.); Kasr El Aini Hospital, Cairo University, Cairo (I.S., H.A.H.); and the World Health Organization, Eastern Mediterranean Regional Office, Cairo (M. Salama, M.H.W.) — all in Egypt; Centers for Disease Control and Prevention, Atlanta (M.A.P.); the National Institute for Public Health and the Environment, Bilthoven, the Netherlands (H.G.A.M.A.); and the World Health Organization, Geneva (A.H.B., M. Sreevatsava, P.M., R.W.S.).
Address reprint requests to Dr. Sutter at the Polio Eradication Department, World Health Organization, 20, Avenue Appia, CH-1211 Geneva 27, Switzerland, or at sutterr{at}who.int.
References
N, Soneji AD, Harland PS. Factors affecting the efficacy of live poliovirus vaccine in warm climates: efficacy of type 1 Sabin vaccine administered together with antihuman gamma-globulin horse serum to breast-fed and artificially fed infants in Uganda. Bull World Health Organ 1974;51:333-347. [ISI][Medline]
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