Pertussis, caused by Bordetella pertussis, is a highly contagious respiratory disease that poses a significant risk to young infants, resulting in both severe morbidity and mortality [1]. Among infants with pertussis, approximately 4% of cases are fatal. Dramatic decreases in pediatric pertussis cases and deaths have resulted from infant vaccination programs, which include whole-cell vaccines based on killed B. pertussis and acellular pertussis (aP) vaccines using highly purified B. pertussis antigens [1]. In countries with well-established childhood pertussis immunization programs, severe disease, and death predominantly occur in the first months of life in infants who are too young for vaccination.
Vaccination of pregnant women is an effective strategy to reduce disease burden in infants too young for immunization [2]. Active transfer of maternal IgG across the placenta after immunization during pregnancy provides protection to the infant during the early weeks to the first months of life [3,4]. Many countries have adopted policies for pertussis immunization in pregnancy in the second or third trimester of pregnancy [[5], [6], [7]]. Observational and randomized-controlled trials (RCTs) report significantly elevated blood antibody levels in both the mother and infant following pertussis vaccination during pregnancy, with no evidence of adverse pregnancy complications (e.g., preterm deliveries, stillbirth). In addition, the incidence of neonatal pertussis has declined in line with high maternal vaccination coverage [8,9]. A growing body of data confirms pertussis vaccination during pregnancy is highly effective in preventing infant pertussis, hospitalization, and death and has an overall positive benefit-risk ratio [10].
Combined tetanus toxoid, reduced diphtheria toxoid, and aP (Tdap) vaccines have been used for pertussis boosting in adolescents, adults, and pregnant women [1]. In these vaccines pertussis toxin (PT) is chemically inactivated (PTchem), which destroys conformational epitopes involved in toxin neutralization. This leads to an impaired functional antibody response [11], which is believed to contribute to the observed pertussis resurgence in some countries using aP vaccines [12,13]. The use of a genetically detoxified aP (aPgen) vaccine, which preserves the functionally active epitopes of PT, is proposed for the replacement of the chemically inactivated aP (aPchem) vaccine [14]. Genetic inactivation is obtained by changing two key amino acids in the S1 subunit of PT [15].
A recombinant pertussis vaccine containing genetically detoxified pertussis PT (PTgen) and filamentous hemagglutinin (FHA) is licensed as a pertussis standalone vaccine (PertagenⓇ, aPgen) and in combination with tetanus, reduced-dose diphtheria toxoids (PertagenⓇ-Td, TdaPgen) in Thailand and Singapore. In a pivotal phase 2/3 adolescent study, both aPgen and TdaPgen showed comparable safety and superior immunogenicity to Tdapchem and induced anti-PT antibodies that persisted at higher levels up to at least three years postvaccination [16,17]. In a subsequent phase 2 RCT, the immunogenicity of different doses of recombinant pertussis vaccine including licensed TdaPgen was studied in healthy nonpregnant and pregnant women and demonstrated to be safe and more immunogenic than Tdapchem [18,19]. Follow-up of infants born to pregnant women vaccinated with TdaPgen in this RCT demonstrated that compared to Tdapchem PT-IgG and PT-neutralizing antibodies were higher in infants at birth and continued to be higher at two months of age [20]. Licensed aPgen was not studied in this RCT. Postmarketing safety surveillance of aPgen and TdaPgen in Thailand, where both formulations are available for booster immunization of adolescents and adults including pregnant women, has confirmed the safety of both recombinant pertussis vaccines when given in the second or third trimester of pregnancy [21]. The use of these recombinant pertussis vaccines by pregnant women in Thailand offers the opportunity to study real-world data on infant antibody levels at birth, reflecting the placental transfer of pertussis antibodies from mothers to infants after receiving recombinant aPgen or TdaPgen in pregnancy. We conducted an observational study in which we recruited pregnant women who had opted to receive a dose of aPgen or TdaPgen vaccine during pregnancy, and measured PT neutralizing, PT-IgG, and FHA-IgG antibody levels in cord sera obtained postdelivery. This is the first study to report on the level of passive immunity against pertussis induced in infants following vaccination in pregnancy with recombinant aPgen or TdaPgen in a real-world setting and the first study overall to report such data for aPgen.
Methods
Design
This was an investigator-initiated postmarketing observational study conducted between January 21, 2019, and May 30, 2020, in Thailand aimed at obtaining real-world data on the level of immune protection offered to newborns following immunization in pregnancy with a recombinant pertussis vaccine containing genetically detoxified PT (PTgen) that is licensed in Thailand for booster immunization of individuals aged 11 years and older including pregnant women. During the study period, pregnant women were offered tetanus and reduced-diphtheria toxoids (Td) vaccine in the first trimester of pregnancy as part of the Thai national immunization program. Additionally, they had the option to opt for pertussis vaccination in the second or third trimester of pregnancy as per recommendation by the Royal Thai College of Obstetricians and Gynaecologists. The pertussis vaccination history of the participating pregnant women was unknown, but women are likely to have received whole-cell pertussis vaccination or no pertussis vaccination in childhood, and no pertussis vaccination after childhood. The recombinant pertussis vaccine, which is produced by BioNet-Asia Ltd. (Bangkok, Thailand), is available both as a standalone pertussis vaccine (PertagenⓇ) or Td-combination (BoostagenⓇ, or PertagenⓇ-Td). Both formulations contain 5 µg PTgen and 5 µg FHA.
This study aimed to recruit 500 pregnant women who had received one dose of PertagenⓇ (aPgen) (n = 250) or PertagenⓇ-Td (TdaPgen) (n = 250) during pregnancy (exposed cohort), and 75 pregnant women who had only received a dose of Td vaccine during pregnancy as part of the national immunization program (unexposed cohort). All vaccinated pregnant women were recruited before delivery at King Chulalongkorn Memorial Hospital, Bangkok, Thailand between January 2019 and May 2020 (Thai Clinical Trial Registry: TCTR20200528006). The recruitment of women was carried out through posted flyers distributed at the antenatal clinic, and through healthcare providers who at the time of advising pregnant women on the potential benefits of pertussis vaccination during pregnancy provided information about the study and the option to participate. Written informed consent to collect cord blood postdelivery was obtained during the routine visit before planned delivery.
To be included, pregnant women had to be between 18 and 40-year-old; had an ultrasound at 18-22 weeks gestation showing no fetal structural abnormality, and had an uncomplicated singleton pregnancy at the time of screening; had received one dose of aPgen or Tdapgen or only Td vaccine during pregnancy; and were willing and able to provide written informed consent for cord blood collection. Subjects were excluded in the case of significant congenital abnormality confirmed by ultrasound during pregnancy; fetal abnormality, stillbirth, or neonatal death; or when women had received pertussis vaccine <1 year before the current pregnancy.
All participants provided informed consent. The study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice according to the International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines.
Objectives
The primary objective was to assess geometric mean titers (GMTs) of PT-neutralizing antibodies and geometric mean concentrations (GMCs) of anti-PT IgG and anti-FHA IgG in cord sera following aPgen or TdaPgen vaccination in pregnancy. Secondary objectives were to describe pregnancy and neonatal outcomes in mothers and infants after aPgen or TdaPgen compared to Td vaccination in pregnancy, and to assess the proportion of infants with an anti-PT IgG serostatus >30 IU/ml at birth in the exposed cohort (aPgen or TdaPgen): this serostatus cut-off value was selected based on published data that anti-PT IgG concentrations >30 IU/ml at birth are associated with seropositivity (>5 IU/ml) until three months of age [22]. As an exploratory objective, cord PT-neutralizing antibodies and cord anti-PT IgG and anti-FHA IgG were studied in the exposed cohort in relation to gestational age at the time of vaccination (<27, 27-36, or >36 weeks).
Assessment
Obstetric and birth outcomes were recorded at delivery. A 6-ml umbilical cord blood sample was collected after birth to obtain serum.
Anti-PT and anti-FHA IgG levels were analyzed using a commercial ELISA kit (EUROIMMUN, Lubeck, Germany) as described previously [23]. PT-neutralizing antibody titers were measured using a validated Chinese hamster ovary (CHO) neutralization assay as described previously [16]. Blood sample processing and immunoassays are described in more detail in Supplementary Materials.
Pregnancy and neonatal outcomes including complications during pregnancy and delivery were recorded. Data on pregnancy and neonatal birth outcomes were evaluated as part of the manufacturer’s (BioNet-Asia) active pharmacovigilance surveillance program of aPgen and TdaPgen vaccination in pregnant women in line with Thai Food and Drug Administration regulations, and have been partly published previously [21]. The collection of (serious) adverse events postvaccination was not part of this observational study.
Statistics
Data management and statistical analysis were performed by the Center of Excellence for Biomedical and Public Health Informatics (BIOPHICS; Bangkok, Thailand). The target sample size was 500 participants, with an estimated 400 participants in the exposed cohort (see Supplementary Material for determination of sample size and description of study populations).
Descriptive statistics included GMCs of anti-PT and anti-FHA IgG antibodies and GMTs of PT-neutralizing antibodies (and 95% confidence intervals [CI]), as well as serostatus cutoff rates of >30 IU/ml (and 95% CI), measured at birth (in cord blood) in each group. For continuous variables, statistical differences between groups were tested using ANOVA, or the Kruskal-Wallis test in post hoc analyses. For categorical variables, differences between groups were tested using the chi-square test. P-values (P) ≤ 0.05 were considered statistically significant.
Source: Sciencedirect
