Maternal Pertussis Wholecell Responses

Study Overview
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Brief Summary
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Pertussis is resurging worldwide. In Africa alone it is estimated that there are 2.1 million cases and 542,000 deaths from pertussis in infants under 1 year with the highest rates of morbidity and mortality in infants <3 months old, before possible prevention via the infant immunization programme1. To protect these most vulnerable infants, the World Health Organisation (WHO) recommends Tdap vaccination as safe in pregnancy and recommends the use of wP vaccines within the EPI. Maternal antibody following aP vaccination can interfere with infant anti-pertussis antibody responses post infant EPI vaccination, which is of concern in high burden settings such as Uganda. There are therefore multiple factors in this population which may influence the effect of pertussis immunization in pregnancy, and which have not been studied, most notably HIV infection and interference with wP vaccines in infants. The immunogenicity of Tdap in HIV-infected pregnant women has not yet been examined. In addition, to date, the effect of maternal vaccination, placental transfer and infant antibody responses in HEU infants have not been studied at all. There are no studies examining the immune response to wP vaccine administered to infants (EPI recommendation) whose mothers received aP in pregnancy.

Official Title
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The Safety and imMunogeNicity of Combined Pertussis-cOntaining Vaccine (Tdap) for HIV-infected Pregnant WomEn and Their newboRns - A Randomized Clinical Trial

Conditions
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Pertussis

Intervention / Treatment
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* Biological: Standard of care vaccines
* Biological: Boostagen, (BioNet-Asia)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be a woman aged 18 years or older, inclusive at day of signing the ICF; Pregnant woman at >16 and <26 weeks gestation, verified by ultrasound scan; Documented HIV test during pregnancy taken by rapid test at the screening visit; Low risk, singleton pregnancy, as assessed by the study physician based on ultrasound scan and previous obstetric history; and The woman is willing to comply with the study procedures, including giving birth at Kawempe National Referral Hospital, remaining in the study area until the infant is 1 year old and is able to provide informed consent for herself and on behalf of the infant Exclusion Criteria: Any of the following: Previous anaphylaxis to any component of Td or Tdap vaccines; vaccination is otherwise contraindicated (per product monographs); Documented to have received four or more previous tetanus toxoid vaccine doses (as this would prevent randomisation to Tdap group and receipt of two additional tetanus toxoid containing vaccines); History of pre-eclampsia or eclampsia in previous pregnancies; Gestational diabetes in current pregnancy; Rhesus negative mothers; Multigravida; Previous late stillbirth (defined as loss of pregnancy at any time after 28 weeks gestation); Previous low birth weight baby of less than 2.0 kilograms or premature delivery (defined as a delivery before 37 weeks gestation); Previous neonatal death (defined as death of an infant within the first 28 days of life); Previous delivery of an infant with a known or suspected genetic or chromosomal abnormality; History of other significant pregnancy related complications judged likely to affect the safety of the mother or infant or to significantly compromise the endpoint data collected; History of other significant neonatal complications judged likely to affect the safety of the mother or infant or to significantly compromise the endpoint data collected; Significant maternal chronic illness including but not limited to hypertension requiring treatment, heart disease, lung disease, neurological disorders including a history of epilepsy or recurrent afebrile seizures, kidney disease, liver disease, anaemia and other haematological disorders (including sickle cell), endocrine disorders including known diabetes mellitus, autoimmunity; Severe anaemia (less than 7.0g/dL); Known Syphilis or hepatitis B (HBV) virus positive or found to be Syphilis or HBV positive during screening; Any other condition judged to significantly increase the risks to either the mother or the infant within the current pregnancy (including relevant history from previous pregnancies); Receipt of any blood product including human immunoglobulins at any stage during the current pregnancy or plan to receive any blood products during the period or trial participation (receipt of blood products in an emergency or for obstetric reasons will not represent a protocol deviation given such situations are unplanned); Clinically suspected or confirmed congenital or acquired clotting or bleeding disorders or the current receipt of medications known to alter clotting or bleeding; Any clinically significant signs or symptoms of acute illness, significant abnormalities in vital signs, an axillary temperature of greater than 38.0°C or any recorded fever (greater than 38.0°C) in the preceding 24 hours; Two or more symptoms (nausea/vomiting, diarrhoea, headaches, fatigue and myalgia) rated as grade 2 and clinically significant on the maternal systemic reactogenicity scale present at baseline on the day of vaccination; Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily; Participation in the 4 weeks preceding the trial vaccination or planned participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure; History of being treated for pertussis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: The study will take a 2x2 formation, with four groups: HIV-uninfected women, standard of care vaccines in pregnancy; HIV-uninfected women, Tdap vaccine in pregnancy; HIV-infected women, standard of care vaccines in pregnancy; HIV-infected women, Tdap vaccine in pregnancy.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pregnant women not living with HIV, Td vaccine<br> | Biological: Standard of care vaccines<br>* Visit 1: Check tetanus immunisation status. Vaccination up to 25+ 6 weeks of pregnancy with Td; Visit 2: vaccination at least 4 weeks after visit 2 with either Tdap or Td (per randomisation and according to WHO guidance)<br>|
| Experimental: Pregnant women not living with HIV, Tdap vaccine<br> | Biological: Boostagen, (BioNet-Asia)<br>* Visit 1: Check tetanus immunisation status. Vaccination up to 25+ 6 weeks of pregnancy with Td; Visit 2: vaccination at least 4 weeks after visit 2 with either Tdap or Td (per randomisation and according to WHO guidance);<br>|
| Active Comparator: Pregnant women living with HIV, Td vaccine<br> | Biological: Standard of care vaccines<br>* Visit 1: Check tetanus immunisation status. Vaccination up to 25+ 6 weeks of pregnancy with Td; Visit 2: vaccination at least 4 weeks after visit 2 with either Tdap or Td (per randomisation and according to WHO guidance)<br>|
| Experimental: Pregnant women living with HIV, Tdap vaccine<br> | Biological: Boostagen, (BioNet-Asia)<br>* Visit 1: Check tetanus immunisation status. Vaccination up to 25+ 6 weeks of pregnancy with Td; Visit 2: vaccination at least 4 weeks after visit 2 with either Tdap or Td (per randomisation and according to WHO guidance);<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-pertussis toxin (PT) and anti-FHA IgG concentrations in cord blood of Tdap-vaccinated HIV-infected vs HIV-uninfected pregnant women. |  | At delivery | 
| Anti-pertussis toxin (PT) and anti-FHA IgG concentrations in cord blood of Tdap -vaccinated vs Tdap -unvaccinated pregnant women and whether this differs by maternal HIV status. |  | At delivery | 
| Anti-PT and anti-FHA IgG concentrations in infants born to Tdap vaccinated vs Tdap -unvaccinated pregnant women 4 weeks after the completion of a series of primary vaccination with 3 doses of wP vaccine, and whether this differs by maternal HIV status. |  | 18 weeks of pregnancy | 
| Safety Outcome: Safety assessment of Tdap vaccine vs Td vaccine in HIV-infected vs HIV-uninfected pregnant women - Pregnant Women | Percentage of maternal Subjects With Solicited Local and Solicited Systemic AEs and percentage with any Unsolocited AEs; Percentage of Maternal Subjects With Serious Adverse Events (SAEs), Unsolicited Medically Attended AEs (MAEs) and Unsolicited AEs Leading to Study Withdrawal | First vaccination visits | 
| Safety Outcome: Safety assessment of Tdap vaccine vs Td vaccine in HIV-infected vs HIV-uninfected pregnant women - Pregnant Women | Percentage of maternal Subjects With Solicited Local and Solicited Systemic AEs and percentage with any Unsolocited AEs; Percentage of Maternal Subjects With Serious Adverse Events (SAEs), Unsolicited Medically Attended AEs (MAEs) and Unsolicited AEs Leading to Study Withdrawal | At 12 months of age of infants | 
| Safety Outcome: Safety assessment of Tdap vaccine vs Td vaccine in HIV-infected vs HIV-uninfected pregnant women - Infants | Percentage of Infants With SAEs, Unsolicited AEs and AEs Leading to Study Withdrawal by a clinical examination | At birth | 
| Safety Outcome: Safety assessment of Tdap vaccine vs Td vaccine in HIV-infected vs HIV-uninfected pregnant women - Infants | Percentage of Infants With SAEs, Unsolicited AEs and AEs Leading to Study Withdrawal by a clinical examination | At 18 weeks of age | 
| Safety Outcome: Safety assessment of Tdap vaccine vs Td vaccine in HIV-infected vs HIV-uninfected pregnant women - Infants | Percentage of Infants With SAEs, Unsolicited AEs and AEs Leading to Study Withdrawal by a clinical examination | At 6 months of age to assess health of the infant (phone call) | 
| Safety Outcome: Safety assessment of Tdap vaccine vs Td vaccine in HIV-infected vs HIV-uninfected pregnant women - Infants | Percentage of Infants With SAEs, Unsolicited AEs and AEs Leading to Study Withdrawal by a clinical examination | At 9 months of age to assess health of the infant (phone call) | 
| Safety Outcome: Safety assessment of Tdap vaccine vs Td vaccine in HIV-infected vs HIV-uninfected pregnant women - Infants | Percentage of Infants With SAEs, Unsolicited AEs and AEs Leading to Study Withdrawal by a clinical examination | At 12 months of age to assess health of the infant (phone call) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-PT and anti-FHA IgG concentrations in HIV-infected and HIV-uninfected pregnant women following Tdap vs Td vaccination during pregnancy (4 weeks post-vaccine & at delivery) |  | 4 weeks post-vaccine & at delivery | 
| Anti-PT IgG antibody avidity in HIV-infected and HIV-uninfected pregnant women following Tdap vs Td vaccination during pregnancy |  | 18 weeks of pregnancy, 4 weeks post-vaccine, at delivery | 
| Serum bactericidal activity in HIV-infected and HIV-uninfected pregnant women following Tdap vs Td vaccination during pregnancy |  | 18 weeks of pregnancy, 4 weeks post-vaccine, at delivery | 
| Anti-PT IgG and anti-FHA placental transfer ratios in HIV-infected and HIV-uninfected pregnant women following Tdap vs Td vaccination during pregnancy |  | 18 weeks of pregnancy, 4 weeks post-vaccine, at delivery | 
| Tetanus Toxoid antibody responses in HIV-infected and HIV-uninfected pregnant women following Tdap vs Td vaccination during pregnancy |  | 18 weeks of pregnancy, 4 weeks post-vaccine, at delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Whooping Cough, Pertussis, Vaccination, Pregnancy, Infant, Newborn, HIV