Maternal Immunization With Tetanus Toxoid, Reduced Diphtheria Toxoid, Reduced-dose (2 µg) Recombinant Pertussis Vaccine (TdaP2gen) and Its Effect on the Immune Response in Thai Infants up to 15-18 Months Old

Maternal Immunization With Tetanus Toxoid, Reduced Diphtheria Toxoid, Reduced-dose (2 µg) Recombinant Pertussis Vaccine (TdaP2gen) and Its Effect on the Immune Response to Tetanus, Diphtheria and Pertussis in Thai Infants up to 15-18 Months Old: An Open-label, Randomized Controlled Trial

Pertussis remains a major global public health problem. In Thailand, pertussis vaccination is recommended during pregnancy at 20-32 weeks' gestation, together with routine childhood diphtheria-tetanus-pertussis vaccination administered as a primary series at 2, 4, and 6 months and booster doses at 18 months and 4-6 years of age.

TdaP2gen, a newly developed combined tetanus, diphtheria, and recombinant genetically detoxified acellular pertussis vaccine containing 2 µg pertussis antigen, has shown favorable safety and non-inferior immunogenicity compared with existing pertussis vaccines. However, data on its use in pregnant women, transplacental antibody transfer, and potential immune interference in infants remain limited.

This study aims to evaluate the safety and immunogenicity of TdaP2gen in pregnant women, assess antibody transfer to newborns, and investigate immune responses to tetanus, diphtheria, and pertussis following primary and booster pertussis-containing vaccinations in infants and toddlers, including comparisons between whole-cell and acellular pertussis-containing vaccine schedules.

Pertussis remains a major global public health problem. In Thailand, pertussis vaccination is recommended for all pregnant women at 20-32 weeks' gestation to protect newborns and young infants against pertussis during early life. In addition, combined diphtheria-tetanus-pertussis vaccination is routinely administered as a primary series at 2, 4, and 6 months of age, followed by booster doses at 18 months and 4-6 years of age.

TdaP2gen is a combined tetanus, diphtheria, and recombinant genetically detoxified acellular pertussis vaccine, containing 2 µg pertussis antigen, which has been recently developed. Previous clinical studies have demonstrated that TdaP2gen is safe and elicits non-inferior immune responses against pertussis compared with the 5 µg recombinant acellular pertussis vaccine (TdaP5gen) and the chemically inactivated Tdap vaccine. However, as TdaP2gen is a newly licensed vaccine in Thailand, data on its safety, immunogenicity in pregnant women, placental antibody transfer to infants, and potential immune interference with infant responses to routine pertussis-containing vaccines remain limited.

Therefore, this study aims to evaluate the safety and immunogenicity of TdaP2gen in pregnant women, assess transplacental antibody transfer to newborns, and investigate its impact on immune responses to diphtheria, tetanus, and pertussis following primary series and booster vaccination up to 15-18 months of age in infants and young children.

This study is divided into 3 phases as follows:

Phase 1 - Maternal and fetal phase: This phase will evaluate the immunogenicity and safety of TdaP2gen vaccination in pregnant women, including immune responses against tetanus, diphtheria, and pertussis, as well as the transplacental transfer of antibodies to newborns.

Phase 2 - Infant phase: This phase will assess immune responses to tetanus, diphtheria, and pertussis in infants following completion of the primary pertussis-containing vaccine series at 2, 4, and 6 months of age, comparing infants who receive whole-cell pertussis-containing vaccines (wP-containing vaccines) with those who receive acellular pertussis-containing vaccines (aP-containing vaccines).

Phase 3 - Toddler phase: This phase will evaluate immune responses to tetanus, diphtheria, and pertussis in toddlers after receiving a pertussis-containing booster vaccination at 15-18 months of age, comparing children who receive whole-cell pertussis-containing vaccines (wP-containing vaccines) with those who receive acellular pertussis-containing vaccines (aP-containing vaccines).

Phase 1: Pregnant women

Inclusion Criteria:

• Pregnant women aged 20 to 45 years
• Healthy women in good general health
• Gestational age between 20 and 32 weeks at enrollment
• Singleton pregnancy
• Low-risk, uncomplicated pregnancy as assessed by an obstetrician
• No evidence of congenital anomalies identified on prenatal ultrasonographic screening
• Willing to receive TdaP2gen vaccination and comply with collection of biological specimens as specified in the study protocol
• Willing to allow their infant to receive either whole-cell pertussis-containing or acellular pertussis-containing combination vaccines according to the study randomization process, and to allow collection of biological specimens from the infant as specified in the study protocol
• Able and willing to provide written informed consent prior to study participation

Exclusion Criteria:

• Receipt of a tetanus-, diphtheria-, and chemical-detoxified pertussis-containing vaccine within 1 year prior to enrollment, or receipt of a tetanus-, diphtheria-, and genetic-detoxified pertussis-containing vaccine (TdaPgen) or genetic-detoxified acellular pertussis vaccine (aPgen) within 2 years prior to enrollment, including during the current pregnancy
• History of laboratory-confirmed or clinically diagnosed pertussis infection within 1 year prior to enrollment
• Presence of underlying medical conditions that may affect study outcomes, including but not limited to malignancy, autoimmune disease, immunodeficiency, epilepsy, hypertension, renal disease, or liver disease, as determined by the investigators
• Pregnancy complications including hypertension (blood pressure >140/90 mmHg with proteinuria, or >150/100 mmHg regardless of proteinuria), current antihypertensive treatment, or preeclampsia
• Endocrine disorders including hyperthyroidism, untreated hypothyroidism, or impaired glucose tolerance (e.g., type 1 or type 2 diabetes mellitus) diagnosed before or during pregnancy requiring treatment beyond dietary control
• Severe or progressive neurological disorders, including epilepsy or a history of Guillain-Barré syndrome
• Receipt of immunosuppressive agents, immunomodulatory agents, or high-dose systemic corticosteroids (>2 mg/kg/day, >20 mg/day, or equivalent) for more than 14 consecutive days within 6 months prior to enrollment
• History of stillbirth, neonatal death, or recurrent spontaneous abortion (≥3 episodes).
• Current medical or surgical treatment for prevention of preterm labor during the current pregnancy
• Receipt of blood products, blood components, or immunoglobulins within 6 months prior to enrollment
• Receipt of live attenuated vaccines within 3 months or any other vaccines within 28 days prior to enrollment
• History of hypersensitivity or adverse reactions to study vaccines or vaccine components, or history of severe allergic reactions such as anaphylaxis to any vaccine
• Behavioral, cognitive, or psychiatric conditions that, in the opinion of the investigator, may interfere with study participation or protocol compliance
• History of smoking, alcohol abuse, or intravenous drug use that, in the opinion of the investigator, may interfere with study assessments or outcomes
• Fever (body temperature ≥38.0°C or equivalent) within 72 hours prior to enrollment
• Acute illness within 4 weeks prior to enrollment
• Contraindications to intramuscular vaccination, including thrombocytopenia, coagulation disorders, hemophilia A or B, or use of anticoagulant therapy during pregnancy
• Concurrent participation in another clinical study involving investigational vaccines or medications during participation in this study
• Any medical or obstetric condition that, in the opinion of the study investigator, may interfere with study assessments or increase the risk to the mother or infant associated with study participation

Phase 2: Infants

Inclusion Criteria:

- All infants born to pregnant women enrolled in Phase 1 who received TdaP2gen vaccination during pregnancy will be eligible for enrollment to Phase 2 study

Exclusion Criteria:

• Gestational age <32 weeks (very preterm birth)
• Birth weight <1,500 grams (very low birth weight)
• Presence of major congenital anomalies identified after birth, including congenital abnormalities associated with genetic disorders, congenital infections, or severe structural abnormalities involving major organ systems such as the central nervous system, cardiovascular system, respiratory system, hepatobiliary and gastrointestinal system, or genitourinary system
• Presence of severe neonatal medical conditions that may affect immune responses to study vaccines, including but not limited to severe respiratory distress, severe bronchopulmonary dysplasia, hypoxic ischemic encephalopathy (HIE), severe intraventricular hemorrhage (IVH), severe sepsis, non-physiologic jaundice, neonatal autoimmune thrombocytopenia, neurological disorders such as neonatal convulsions, necrotizing enterocolitis, or intracranial hemorrhage
• Presence of conditions associated with increased risk of serious adverse reactions to study vaccines
• Any medical condition or circumstance that, in the opinion of the study investigator, may interfere with study assessments or increase the risk to the participant associated with study participation