ABSTRACT
This study aimed to evaluate the effect of maternally derived antibody on the immunogenicity of Sabin IPV. A total of 600 infants were randomized to receive one of the five different vaccines: the high- (group A), medium- (group B) or low-dose (group C) of investigational Sabin IPV, the control Salk IPV (group D) or the control Sabin IPV (group E), at 2, 3 and 4 months of age. The post-vaccination GMTs, GMIs and seroconversion rates of poliovirus type–specific neutralizing antibody were analyzed for different maternal antibody levels. The correlations between maternal antibody levels and post-vaccination antibody responses were also modeled by linear regressions. The post-vaccination GMTs were significantly lower among infants with high maternal antibody titers for poliovirus type 1 or 2 mainly in the groups B, C, D and E. The GMIs and seroconversion rates decreased significantly with the increase of maternal antibody levels in all the five groups. In the groups A, B and C, maternal antibody levels were negatively associated with the post-vaccination antibody titers (for poliovirus type 1 and 2) and the fold increases of post-vaccination antibody (for all the 3 poliovirus types). With the reduce of potency of the investigational Sabin IPVs, the linear regression coefficients increased accordingly in the groups A, B and C. In conclusion, high levels of maternal poliovirus antibody could attenuate the immune responses to the Sabin IPVs. Altering the potency of the investigational Sabin IPVs could alter the associations between maternal antibody levels and the serologic responses of infants.
Introduction
In the pre-vaccine era, poliomyelitis (or polio) was the leading cause of permanent disability.Citation1 Two polio vaccines, inactivated poliovirus vaccine (IPV) and oral poliovirus vaccine (OPV), are used throughout the world to rapidly control the prevalence of polio since the 1950s.Citation2,Citation3 Most developed countries, such as many Western European countries, have recommended schedules in the past that depended on only OPV for the prevention of polio. Although OPV is safe, there are still potential risks that OPV use may cause vaccine-associated paralytic poliomyelitis (VAPP) and spread of either circulating vaccine-derived polioviruses (cVDPVs) or immunodeficiency-associated VDPVs (iVDPVs).Citation4-Citation7 In nearly two decades, encouraged by the progress of the Global Polio Eradication Initiative (GPEI)Citation8 and the public attention to reduce or eliminate the cases of VAPP and VDPV infection,Citation9,Citation10 many of the high- and middle-income countries have revised their routine vaccination schedules from using OPV exclusively to a sequential schedule of IPV followed by OPV or using IPV exclusively for the prevention of poliomyelitis. For example, the United States changed from an OPV-only schedule to a sequential IPV-OPV schedule in 1997 and to an IPV-only schedule in 2000.Citation11
IPV is currently produced using three wild-type poliovirus strains. Production and quality control of wild-type IPV require at least a biosafety level 3 containment facility, which significantly increases the economic burden of IPV production.Citation12,Citation13 Compared with the OPV, the cost per vaccine dose of IPV is too high to be affordable for most low- or middle-income countries.Citation14 Meanwhile, there is also the risk that inadvertent release of wild viruses from facilities in the IPV production process.Citation12 Manufacture of IPV based on the attenuated poliovirus strains, such as Sabin strains, will have a lower biosafety risk and can increase the availability and affordability of IPV in the low- or middle-income countries.Citation14 In China, the Sinovac Biotech Company has developed a Sabin IPV which was prepared from live attenuated Sabin strains of poliovirus grown in Vero cells using microcarrier technology, and conducted a phase Ⅱ, randomized, positive-controlled trial to assess the safety and immunogenicity of the Sabin IPV (Clinical Trials.gov identifier NCT02985320). The primary clinical evaluation of this trial was completed and this Sabin IPV showed good safety and immunogenicity in Chinese infants.Citation15
Many studies have documented that high level of maternal poliovirus antibodies may somewhat attenuate the antibody response of the infant to an IPV primary series schedule and decrease seroconversion rates.Citation16-Citation19 Since the effect of maternal antibody on the antibody response after primary immunization with Sabin IPV is not yet documented, we designed a sub-study to assess the effect of maternally derived antibody on the immunogenicity of Sabin IPV based on the phase Ⅱ, randomized, positive-controlled Sabin IPV clinical trial mentioned above.
Results
Participant characteristics
A total of 600 infants (120 infants per group) were assessed in the phase Ⅱ clinical trial. Of which, 113 in group A, 115 in group B, 114 in group C, 112 in group D and 114 in group E who had both pre- and post-vaccination antibody titers were fitted into the final analysis of this sub-study. The basic characteristics of the 568 participants were shown in . Seropositivity rates before vaccination in groups A, B, C, D and E ranged from 56.6% to 62.3% for type 1 poliovirus, 33.9% to 47.4% for type 2 poliovirus and 15.7% to 31.2% for type 3 poliovirus. GMTs before vaccination in groups A, B, C, D and E ranged from 10.0 to 12.6 for type 1 poliovirus, 6.5–8.3 for type 2 poliovirus and 4.9–6.5 for type 3 poliovirus. Those characteristics shown in were similar among the five different treatment groups.
Table 1. Baseline characteristics of infants participating in this study in China, 2016–2107.
Immune responses of infants to Sabin IPVs at different levels of maternal antibody
In the five groups, most of the infants had maternal antibody titers of <1:8 or 1:8 to <1:32. There were fewer infants with maternal antibody titers of 1:32 to <1:128 and was little or no infant with the titer of ≥1:128 (). The post-vaccination GMTs, GMIs and seroconversion rates of poliovirus type–specific neutralizing antibody after stratification analyses performed for different maternal antibody levels were shown in . In group A (the high-dose of investigational Sabin IPV), no significant differences of post-vaccination GMTs were observed among the T1, T2, T3 and T4 strata of maternal antibody levels for all the 3 poliovirus types (all P > 0.05). In group B (the medium-dose of investigational Sabin IPV), post-vaccination GMTs were significantly lower among infants with high maternal antibody titers for poliovirus type 1 (T1 = 5248.1, T2 = 5888.4, T3 = 2691.5, T4 = 1737.8; P = 0.013) and type 2 (T1 = 407.4, T2 = 239.9, T3 = 245.5; P = 0.014), while no significant differences of post-vaccination GMTs were observed for poliovirus type 3. In group C (the low-dose of investigational Sabin IPV), there was also significant reduction in post-vaccination GMTs among infants with high levels of maternal antibody for poliovirus type 1 (T1 = 5128.6, T2 = 2884.0, T3 = 2041.7, T4 = 1174.9; P < 0.001) and type 2 (T1 = 208.9, T2 = 125.9, T3 = 91.2, T4 = 52.5; P = 0.005). In group D (the control Salk IPV) and group E (the control Sabin IPV), only the poliovirus type 1 GMTs after vaccination showed significant differences among the four strata of maternal antibody levels (P = 0.005 and P = 0.001). The seroconversion rates of poliovirus type 1 were all 100.0% after stratification analyses according to the maternal antibody levels in group A and group E, while the seroconversion rates of poliovirus type 1 in group B (T1 = 97.8%, T2 = 100.0%, T3 = 94.1%, T4 = 71.4%; P = 0.002), C (T1 = 100.0%, T2 = 100.0%, T3 = 100.0%, T4 = 75.0%; P < 0.001) and D (T1 = 100.0%, T2 = 100.0%, T3 = 89.5%, T4 = 20.0%; P < 0.001) and the seroconversion rates of poliovirus type 2 and 3 in the five groups (all P < 0.001) were all decreased significantly with the increase of maternal antibody levels. Also, the GMIs were significantly lower among infants with high maternal antibody titers (all P < 0.001) for all the 3 poliovirus types in the five groups. Those results indicated that high level of maternal poliovirus antibodies could attenuate the antibody response of the infant to the Sabin and Salk IPV primary series schedule and decrease seroconversion rates, and the high-dose of investigational Sabin IPV might somewhat eliminate the effects of maternally derived antibodies on its post-vaccination antibody levels and seroconversion rates.
Table 2. GMTs, GMIs and seroconversion rates of poliovirus type–specific neutralizing antibody in infants after 3 doses of Sabin IPV in China, 2016–2017, by maternal antibody level.a
Correlations between maternal antibody levels and the serologic responses of infants to Sabin IPVs
Besides the stratification analyses, the associations of maternal antibody levels (categorized as four grades) and post-immunization antibody titers in each treatment group were also estimated using multivariable linear regression models (results were shown in the ). There were significantly negative associations between maternal antibody levels (categorized as four grades) and post-vaccination antibody titers for poliovirus type 1 in group A [ßadjusted = −1.23 per a grade increase; 95% confidence interval (CI): −1.45 to −1.07], group B [ßadjusted = −1.38 per a grade increase; 95% CI: −1.78 to −1.07], group C [ßadjusted = −1.62 per a grade increase; 95% CI: −1.95 to −1.35] and group E [ßadjusted = −1.48 per a grade increase; 95% CI: −1.78 to −1.20]. While in group D, maternal antibody levels showed notably positive associations with post-vaccination antibody titers of poliovirus type 1 [ßadjusted = 1.38 per a grade increase; 95% CI: 1.12 to 1.70]. For poliovirus type 2 antibodies, inverse correlations were seen between preexisting antibody levels and post-immunization antibody titers mainly in group A [ßadjusted = −1.29 per a grade increase; 95% CI: −1.58 to −1.02], group B [ßadjusted = −1.41 per a grade increase; 95% CI: −1.91 to −1.07] and group C [ßadjusted = −1.48 per a grade increase; 95% CI: −1.86 to −1.17]. For poliovirus type 3 antibodies, higher levels of preexisting antibody were associated with reductions in the subsequent antibody response mainly in group D [ßadjusted = −1.41 per a grade increase; 95% CI: −1.91 to −1.05] and group E [ßadjusted = −1.91 per a grade increase; 95% CI: −3.02 to −1.20]. Multivariable linear regression models were also used to estimate the relationships between maternal antibody levels (categorized as four grades) and the fold increases of poliovirus type–specific neutralizing antibody after immunization. The results showed that maternal antibody levels were negatively associated with the fold increases of post-vaccination antibodies for all the 3 poliovirus types in the five groups (all P < 0.001, ).
Table 3. Associations of maternal antibodies and the titers of poliovirus type–specific neutralizing antibody in infants after 3 doses of Sabin IPV in China, 2016–2017.a
Table 4. Associations of maternal antibodies and the fold increases of poliovirus type–specific neutralizing antibody in infants after 3 doses of Sabin IPV in China, 2016–2017.a
Discussion
This study was the first to provide evidence of the effect of maternal antibody level on the serologic response after primary immunization with IPVs (especially Sabin IPVs) in Chinese healthy infants. Nowadays in China, many infants have detectable maternal poliovirus antibodies, and this may be due to the use of OPV on a large scale for many decades and their mothers had been vaccinated previously with OPV at a young age. The OPV has been used since 1965 in China, and the national Expanded Program on Immunization (EPI), which used a trivalent OPV schedule, was implemented in 1978.Citation20 As a consequence, maternal immunity in our study is acquired primarily through the vaccination, and can be transported to the offspring during pregnancy. In our study, the seropositivity rates before vaccination in infants ranged from 56.6% to 62.3% for type 1 poliovirus, 33.9% to 47.4% for type 2 poliovirus and 15.7% to 31.2% for type 3 poliovirus; the GMTs before vaccination in infants ranged from 10.0 to 12.6 for type 1 poliovirus, 6.5 to 8.3 for type 2 poliovirus and 4.9 to 6.5 for type 3 poliovirus. There was another phase Ⅱ trial of a Sabin IPV, implemented in Pingle City, GuanXi Province, China, between 1 July 2009 and 1 May 2010, reporting lower maternal antibody level than that in our study for all the 3 poliovirus types in 2-month-old infants (the seropositivity rates before vaccination in infants ranged from 43% to 55% for type 1 poliovirus, 26% to 41% for type 2 poliovirus and 15% to 24% for type 3 poliovirus; the GMTs before vaccination in infants ranged from 3.0 to 6.9 for type 1 poliovirus, 1.9 to 3.4 for type 2 poliovirus and 1.5 to 2.1 for type 3 poliovirus).Citation12 While during 2012–2014, a phase Ⅲ trial of a Sabin IPV which was also conducted in Binyang and Pingle counties, Guangxi Province, China, reported similar level of maternal poliovirus antibody in infants with our study.Citation21 The differences in maternal antibody levels among these studies (including our study) might result from the regional disparity and the fluctuation of antibody level in different years.
Our findings of the effect of high levels of maternal antibody on reduction of the serologic response to the Sabin and Salk IPVs were consistent with other investigations.Citation16-Citation19 A study conducted in Guatemala showed that after 3 doses of IPV, administered at 2, 4 and 6 months of age, infants who had serum polio antibody titers ≥ 1:8 at baseline had significantly lower GMTs than infants without baseline antibody for poliovirus types 1 (1872 vs. 2844) and 2 (2065 vs. 3138).Citation18 In another study conducted in Puerto Rico, infants were assigned to either EPI arm (received IPV at 6, 10, and 14 weeks of age) or US arm (received IPV at 2, 4, and 6 months of age). For the IPV immunization started early in life after birth in the EPI arm and a higher proportion of infants in the EPI arm had high levels of maternal poliovirus antibody, the seroconversion rates after 3 doses of IPV were significantly lower among infants with high levels of maternal antibody for all 3 poliovirus types in the EPI arm (seroconversion rates among the infants with maternal antibody titers of ≥1:64 were 61.5%, 52.8%, and 73.3% against poliovirus types 1, 2, and 3, respectively, compared with 98.6%, 96.5%, and 98.6%, respectively, when the infants had maternal antibody titers of <1:64).Citation19 The IPVs in those previous researches were all wild-type IPVs, and just the same as the control Salk IPV in our study. In our study, the seroconversion rates in the group of the control Salk IPV consistently decreased with the increase of maternal antibody levels for all 3 poliovirus types, and the seroconversion rates were even 0.0% in the T4 strata of maternal antibody levels for poliovirus types 2 and 3. Meanwhile, with the increase of maternal antibody levels, there was a down trending (not significant) for the post-vaccination GMTs in the group of the control Salk IPV for poliovirus types 2 and 3. Similar with the wild-type IPVs, the GMTs and seroconversion rates after primary immunization with the experimental and control Sabin IPVs in our study were also attenuated by the high level of maternal poliovirus antibodies. However, in our study, no significant differences of post-vaccination GMTs were observed among the T1, T2, T3 and T4 strata of maternal antibody levels in group A (the high-dose of investigational Sabin IPV) for all the 3 poliovirus types, and this result suggested that high level of maternal antibodies might have little effect on the titers of post-immunization with the high-dose of investigational Sabin IPV.
In this study, because of the small sample size, fewer infants were stratified to the strata of higher level of maternal antibody and there was not adequate power to detect the differences of post-vaccination antibody response among different strata of maternal antibody. Additionally, there was an exceptional result in our study that the post-vaccination GMT for poliovirus types 1 in the wild-type IPV group was significantly higher among infants with high levels of maternal antibody. And this result was contradicted by other studiesCitation18,Citation19 in which maternal antibodies could lower the post-vaccination GMT for poliovirus types 1 after vaccination with wild-type IPVs. The exceptional result seemed lack of biological rationality and might also due to the small sample size and the insufficient sample representativeness of our study. Future research should increase the sample size to provide a more reliable estimate of the effect of maternal antibody on the immune response to the IPVs (especially Sabin IPV) in Chinese infants.
In Conclusion, the findings in our study showed that high levels of maternal poliovirus antibodies could attenuate the antibody responses to the Sabin and Salk IPVs. In addition, to the best of our knowledge, we for the first time used multivariable linear regression models to investigate the relationships between maternal antibody levels and the serologic responses of infants to Sabin IPVs with different potency of D-antigen units per dose. And our findings also suggested that altering the potency of the Sabin IPVs could alter the associations between maternal antibody levels and the serological responses of infants.
Materials and methods
Ethics statement
The study was approved by the institutional review board of Jiangsu Provincial Center for Disease Control and Prevention. Each participant of this clinical trial was requested to provide written informed consent by the legal guardians. The research protocol was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Study design and participants
This was a sub-study based on the phase Ⅱ, randomized, positive-controlled Sabin IPV clinical trial (Clinical Trials.gov identifier NCT02985320). The clinical trial was implemented at one site in Pizhou County, Jiangsu Province, China, between November 2016 and May 2017. Eligible participants were healthy infants, aged 60–90 days. Exclusion criteria included (1) prior vaccination of poliovirus, (2) allergy to any vaccine or any ingredient of the vaccine, (3) a history of seizure or mental disease, (4) a confirmed immunosuppressive condition, (5) major congenital defects, (6) acute febrile disease on the day of enrolment, and (7) receipt of any vaccine, research drug, blood product or immunosuppressant within a certain time prior to the study entry.
A total of 600 healthy infants were enrolled in the study and randomly assigned at a 1:1:1:1:1 ratio to 1 of the 5 different treatment groups. Participants in group A, B and C separately received the high-dose, the medium-dose and the low-dose of Sabin IPV at 2, 3 and 4 months of age. Participants in the two positive control groups, group D and E, received Salk IPV (wild-type IPV, manufactured by Sanofi Pasteur) and Sabin IPV (manufactured by the Institute of Medical Biology, the Chinese Academy of Medical Sciences in Kunming, CAMS), respectively, on the same schedule. Serum samples of the participants in five groups were collected prior to the first dose of the vaccines (Sabin IPVs or Salk IPV) and 30 days after the third dose of the vaccines in the phase Ⅱ trial. During the enrollment interview, basic demographic information of each child was also collected.
Vaccine
The investigational Sabin IPV was produced by the Sinovac Biotech Company (Beijing, China), containing the following 3 live attenuated poliovirus strains: type 1 (Sabin SO+3), type 2 (Sabin SO+3) and type 3 (Pfizer RSO3). In the phase Ⅱ trial, the Sinovac Biotech Company produced high, medium and low dose of Sabin IPV with a potency of 22.5:67.5:67.5 (type 1, 22.5 D-antigen units per dose [DU/dose]; type 2, 67.5 DU/dose; type 3, 67.5 DU/dose), 15:45:45 and 7.5:22.5:22.5 DU/dose, respectively. The control Sabin IPV with a potency of 30:32:45 DU/dose was manufactured by the Institute of Medical Biology, the Chinese Academy of Medical Biology. And the control Salk IPV with a potency of 40:8:32 DU/dose was manufactured by Sanofi Pasteur.
Determination of neutralizing titers
Serum samples were collected from all infants before the first vaccination and 30 days after the third vaccination to detect the levels of neutralizing antibody titers against poliovirus types 1, 2 and 3. The neutralization assay was performed by the National Institutes for Food and Drug Control, according to the method recommended by the WHO.Citation22 Briefly, 2-fold serial dilutions of serum samples (50 μl) were mixed with an equal amount of virus suspension containing 100 CCID50 of each poliovirus serotype and were incubated for 3 h at 35°C in a 96-well micro-cultured plate in a 5% CO2 atmosphere. Then, 100 μl of HEP-2 cell suspension (80,000–100,000 cells/mL) was added to each well and incubated for 7 days. Each serum sample was tested in duplicate. The reciprocal of the highest serum dilution that inhibited 50% of the viral cytopathic effect was taken as the neutralization antibody titer against relative poliovirus. A titer 1:8 was considered to be positive. Seroconversion was defined as an increase in antibody titer by a factor of at least 4 from pre- to post- vaccination values. If infants had an antibody titer <1:8 before vaccination, seroconversion was defined as an antibody titer ≥1:8 after vaccination.
Statistical analysis
Statistical analyses were performed using SPSS Statistics standard 23.0. Samples with virus-neutralizing antibody titers below the detection limit (1:8) were given an arbitrary value of 1:4 for the statistical calculations. The virus-neutralizing antibody titers were transformed into log10 titers for the calculation of the geometric mean titers (GMTs) and geometric mean increases (GMIs) with 95% confidence intervals (CIs). Geometric mean increase (GMI) was the geometric mean of the ratios of the titers after vaccination to the titers before vaccination. In order to study the effect of maternally derived antibody on the immunogenicity of IPVs in five different treatment groups, the subjects of each treatment group were categorized as <1:8, 1:8 to <1:32, 1:32 to <1:128 and ≥1:128 subgroups according to the antibody titers before vaccination. Then the GMTs and GMIs were compared among the four subgroups using one way ANOVA and Wilcoxon rank-sum tests, and the seroconversion rates were compared among the four subgroups using χ2 and Fisher’s exact tests. Meanwhile, associations of pre-immunization antibody levels (categorized as four grades) and post-immunization antibody titers (or fold increases) in each treatment group were also estimated using multivariable linear regression model to obtain the adjusted ß with 95% CI. We included the set of covariates in the regression models as follows: infant sex, age and BMI. Infant age and BMI were modeled as continuous variables, whereas infant sex was treated as binary variable. A p value of < 0.05 indicated statistical significance.
Disclosure of potential conflicts of interest
Yuansheng Hu, Jianfeng Wang, Qiang Gao are employed by Sinovac. Biotech Co., LTD. All other authors have no conflicts.
Author contributions
Y.H, and Q.G designed the trial and the study protocol, F.Z contributed to the critical review and revision of the report. R.T, K.C, Y.H, L.C, M.Z, S.L, H.M, J.W led and participated in the site work, including the recruitment, follow-up. R.T and K.C contributed to the data collection, data management, and statistical analysis and wrote the paper.
Abbreviations
| OPV | = | oral poliovirus vaccine |
| VAPP | = | vaccine-associated paralytic poliomyelitis |
| cVDPVs | = | circulating vaccine-derived polioviruses |
| iVDPVs | = | immunodeficiency-associated vaccine-derived polioviruses |
| GMTs | = | geometric mean titers |
| GMIs | = | geometric mean increases |
| CI | = | confidence intervals |
| BMI | = | body mass index |
| EPI | = | Expanded Program on Immunization |
| CAMS | = | Institute of Medical Biology, the Chinese Academy of Medical Sciences in Kunming |
Additional information
Funding
References
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