Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617001253392
Ethics application status
Approved
Date submitted
8/08/2017
Date registered
28/08/2017
Date last updated
19/11/2020
Date data sharing statement initially provided
10/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Protective Vaccine Responses in Infants after Maternal Pertussis Vaccination
Scientific title
Protective Vaccine Responses in Infants after Maternal Pertussis Vaccination
Secondary ID [1] 292565 0
None
Universal Trial Number (UTN)
Trial acronym
PRIME
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Maternal and infant vaccination 304234 0
Pertussis 304316 0
Condition category
Condition code
Public Health 303583 303583 0 0
Other public health
Infection 303584 303584 0 0
Other infectious diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This study aims to determine the degree to which maternal diphtheria, tetanus and acellular pertussis vaccine (dTap) vaccine in pregnancy affects Australian infants’ humoral and cell-mediated immune responses to routine immunisations given at 6 weeks, 4, 6, 12 and 18 months of age.

We will document whether the mother has had the Pertussis vaccine in pregnancy and the date this occurred but we will not be giving this vaccine as part of this study.

All routine childhood vaccinations will be administered to the infant by immunisation certified nurses during the course of this study.

Blood samples will be taken as follows: maternal blood at visit 1 (6 to =10 weeks post-partum) and visit 2 (18 to <19 months post-partum). Infant blood at visit 1 (6 to =10 weeks of age), visit 4 (28 to 42 days post-visit 3), visit 6 (18 to <19 months) and visit 7 (28 to 42 days post-visit 6). Nasopharyngeal swabs will be collected from infants at visit 4 (28 to 42 days post-visit 3), visit 5 (12 to <14 months) and visit 7 (28 to 42 days post-visit 6).

In addition, with parental consent a sample from the infant participant’s newborn screening blood test (also known as the “Guthrie Test”) will be requested from the local newborn screening program laboratories and will be used to measure pertussis IgG levels at birth.
Intervention code [1] 298834 0
Not applicable
Comparator / control treatment
We will enrol a cohort of infants whose mothers have either received no vaccination or their first dTap vaccine or subsequent dTap boosters during pregnancy and compare their infants’ antibody responses, pneumococcal carriage as a marker of vaccine efficacy, persistence of antibody and cell-mediated immunity, and frequency of local reactions following their routine immunisations at 6 weeks, 4, 6, 12 and 18 months of age.

No adult dTpa within 5 years
(N=100 maternal participants)
1st adult dTpa booster vaccination during pregnancy (dTap3)
(N=100 maternal participants)
2nd or subsequent adult dTpa booster vaccination during pregnancy (dTap3 or dTap5)
(N=100 maternal participants)
1st adult dTpa booster vaccination during pregnancy (dTap5)
(N=100 maternal participants)
Control group
Active

Outcomes
Primary outcome [1] 303019 0
Pertussis antibody responses and antibody responses to other routine infant immunisations tetanus and diphtheria toxoids, H. influenzae type b (Hib) and PCV13 at age 7 months.
Timepoint [1] 303019 0
Blood will be collected from the infant participant at 7 months of age (28 to 42 days after receiving the 6 month routine vaccinations) to measure antibody responses.
Primary outcome [2] 303121 0
Antibody persistence to tetanus and diphtheria toxoids, H. influenzae type b (Hib) and PCV13 at age 18 months and responses to DTaP booster.
Timepoint [2] 303121 0
Blood will be collected from the infant participant at 18 months of age and at 19 months of age (28 to 42 days after receiving the 18 month routine vaccinations) to measure antibody responses.
Primary outcome [3] 303122 0
Frequency of local reactions to routine infant and 18 month DTaP booster immunisation.
Timepoint [3] 303122 0
Location reactions (pain, erythema and induration/swelling) will be reported using a diary card that will be completed by the infant participant's parent for a period of 7 days post-vaccination.The diary card will be completed after the infant participant is vaccinated at 6 weeks, 4 months, 6 months and 18 months of age.
Secondary outcome [1] 337709 0
Correlate maternal pertussis, tetanus and diphtheria IgG levels with infant IgG responses to those antigens and other related vaccine antigens (pneumococcal vaccine serotypes, Hib) at 7 and 18 months of age.
Timepoint [1] 337709 0
Maternal participants will have blood collected at the same point that their infant receives their routine 6 week vaccinations (6 to less than or equal to 10 weeks post-partum) and again when their infant receives their routine 18 month vaccines (18 to less than 20 months post-partum) to measure IgG levels.
Infant participants will have blood collected at 7 months of age (28 to 42 days after receiving their routine 6 month vaccinations), and 18 months of age to measure IgG levels.
Secondary outcome [2] 337710 0
Assess the relationship between maternal post-partum vaccine specific B-cell and T-cell memory responses to infants’ antibody and cell-mediated immune responses
Timepoint [2] 337710 0
Maternal participants will have blood collected at the same point that their infant receives their routine 6 week vaccinations (6 to less than or equal to 10 weeks post-partum) and again when their infant receives their routine 18 month vaccines (18 to less than 20 months post-partum) to measure memory B-cell and T-cell responses.
Infant participants will have blood collected at 6 weeks of age (pre-vaccination), 7 months of age (28 to 42 days after receiving their routine 6 month vaccinations), 18 months of age and approximately 19 months of age (28 to 42 days after receiving their routine 18 month vaccinations) to measure antibody and cell-mediated immune responses.
Secondary outcome [3] 337711 0
Determine the frequency of systemic symptoms and fever (greater than or equal to 38 degrees celsius axillary) to routine infant and 18 month DTaP booster immunisation.
Timepoint [3] 337711 0
Systemic symptoms (vomiting, diarrhoea, decreased feeding, irritability, drowsiness and restlessness) and body temperature (axillary) will be reported using a diary card that will be completed by the infant participant's parent for a period of 7 days post-vaccination. The diary card will be completed post-vaccination at 6 weeks, 4 months, 6 months and 18 months of age.
Secondary outcome [4] 337939 0
Compare the density of the pneumococcus and presence of PCV13 serotypes in the nasopharynx of infants (with and without maternal dTaP immunisation) at 7, 12 and 19 months of age.
Timepoint [4] 337939 0
Infant participants will have a nasopharyngeal swab collected to assess pneumococcal carriage at 7, 12 and 19 months of age.
Secondary outcome [5] 338139 0
Generation of vaccine-specific B-cell memory and T-cell responses post-primary immunisations and pre- and post-DTaP booster.
Timepoint [5] 338139 0
Infant participants will have blood collected at 7 months of age (28 to 42 days after receiving their routine 6 month vaccinations), 18 months of age (immediately before receiving their 18 month routine vaccinations) and at approximately 19 months of age (28 to 42 days after receiving their routine 18 month vaccinations) to measure memory B cell and T cell responses.

Eligibility
Key inclusion criteria
Maternal Inclusion Criteria
Maternal participants must meet all of the following to be eligible to participate in the study:
1. Has provided written informed consent and is willing and able to comply with the scheduled visits and study procedures.
2. Generally well or any medical conditions are stable and well-controlled.
3. Aged 18 to less than or equal to 45 years.
4. English speaking with a good understanding of the English language.
5. Has received:
i) no adult dTap vaccination during their most recent pregnancy OR
ii) first adult dTap booster vaccination during their most recent pregnancy and at least 4 weeks prior to delivery OR
iii) second or subsequent adult dTap vaccination during their most recent pregnancy and at least 4 weeks prior to delivery.
Note: women who have received a dTap vaccination during the last 10 years, but not during their most recent pregnancy are eligible to participate as per inclusion criteria 5 i).
6. Their newborn infant is eligible to participate in the study (ie meets all of the infant inclusion criteria and none of the exclusion criteria).
7. Available for the entire study period.

Infant Inclusion Criteria
Infant participants must meet all of the following criteria to be eligible to participate in the study:
1. The infant’s parent has given written informed consent and is willing and able to comply with the scheduled visits and study procedures.
2. Is a healthy male or female infant born at term (equal to or greater than 37 weeks gestation)
3. Is available for the entire study period.
4. The infant’s mother is eligible to participate in the study (ie meets all of the maternal inclusion criteria and none of the exclusion criteria).
Minimum age
6 Weeks
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Infant participants presenting with any of the following will not be eligible to participate in the study:

1. Already received their 6 week vaccinations (as recommended by the national immunisation schedule) prior to study visit 1.

2. Has received or plans to receive a Meningococcal ACWY conjugate vaccine prior to completing study visit 4 (28-42 days post-visit 3).

3. Has a diagnosed or suspected major congenital anomaly, genetic disorders or serious chronic illness.

4. Has a confirmed or suspected immunosuppressive or immunodeficient condition.

5. Has received immunoglobulins or any blood products since birth or planned administration during the study period.

6. Chronic administration of immunosuppressants since birth, including high-dose oral or parenteral corticosteroid therapy > 2mg/kg per day prednisolone for more than 2 weeks. Inhaled and topical corticosteroids are permitted.

7. Any contraindications to vaccination as listed in the current edition of the NHMRC Australian Immunisation Handbook.

8. Parent/legal guardian does not agree for their infant to be vaccinated as per the current national immunisation schedule, with the only exception being receipt of a third dose of pneumococcal vaccine at 6 months of age and a booster dose at 18 months of age (instead of 12 months of age) or planned administration of additional vaccinations (e.g. influenza, meningococcal B) within 2 weeks of the routine vaccinations administered during the study
Note: an infant is eligible to participate if they have not received a birth dose of Hepatitis B vaccine.

9. Current or planned participation in an investigational study (participation in observational studies is permitted) during the study period.

10. Has received any investigational or non-registered drugs, vaccines or devices since birth or planned during the study period.

11. Any other significant acute or chronic medical condition that in the opinion of the investigator may interfere with the interpretation of study results or place the participant at increased risk if they participate in the study.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
In order to have 80% power to detect (at p<0.05) a reduction of 20% in post-vaccination pertussis toxin GMC from 47.9 µg/ml (previously observed where there was no maternal immunisation), a sample size of 96 per group is required (please note there will be 4 groups of mother and infant pairs). This assumes a log antibody concentration standard deviation of 0.55 µg/ml, which was observed in the previous study. Reductions associated with maternal immunisation of >25% in pertussis antigen GMCs were observed previously, so a group size of N=96 in the current study will be more than adequately powered to detect effects of a similar size. To allow for participant drop-outs, we will recruit 100 subjects /group. Overall, as we are recruiting 4 groups, there will be 400 healthy term infants and their mothers enrolled in the study.

Antibody titres will be log transformed and Geometric mean concentrations/ titres calculated with 95% confidence intervals. The principal analyses of immunogenicity will be based on t-tests (GMCs/GMTs) and chi-square tests (% seroprotected; % large local reactions) where appropriate between maternally vaccinated and unvaccinated groups. Further analyses examining the association of different factors such as type of vaccine, site, maternal gestation at time of vaccination, parity, gender, age with antibody responses will use multiple regression methods: linear when IgG response, logistic model when proportions of infants with protective titres is the response. Maternal antibody responses will be correlated with infant antibody responses using Spearman’s rank correlation co-efficient.

The analysis of safety data will be primarily descriptive in nature.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/10/2017
Actual
27/10/2017
Date of last participant enrolment
Anticipated
23/12/2021
Actual
Date of last data collection
Anticipated
30/06/2023
Actual
Sample size
Target
400
Accrual to date
139
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA
Recruitment hospital [1] 8714 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [2] 8716 0
St John of God Hospital, Murdoch - Murdoch
Recruitment hospital [3] 8717 0
St John of God Hospital, Mt Lawtley - Mt Lawley
Recruitment hospital [4] 8718 0
Osborne Park Hospital - Stirling
Recruitment postcode(s) [1] 16835 0
6008 - Subiaco
Recruitment postcode(s) [2] 16837 0
6150 - Murdoch
Recruitment postcode(s) [3] 16838 0
6050 - Mt Lawley
Recruitment postcode(s) [4] 16839 0
6021 - Stirling

Funding & Sponsors
Funding source category [1] 297145 0
Government body
Name [1] 297145 0
Telethon- Perth Children's Hospital Research Fund
Country [1] 297145 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Telethon Kids Institute
Address
10 Roberts Road
SUBIACO WA 6008
Country
Australia
Secondary sponsor category [1] 296157 0
None
Name [1] 296157 0
Address [1] 296157 0
Country [1] 296157 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298314 0
Child and Adolescent Health Service Human Research Ethics Committee
Ethics committee address [1] 298314 0
Ethics committee country [1] 298314 0
Australia
Date submitted for ethics approval [1] 298314 0
17/01/2017
Approval date [1] 298314 0
16/02/2017
Ethics approval number [1] 298314 0
RGS: 0000000036
Ethics committee name [2] 298366 0
St John of God Health Care Human Research Ethics Committee
Ethics committee address [2] 298366 0
Ethics committee country [2] 298366 0
Australia
Date submitted for ethics approval [2] 298366 0
02/05/2017
Approval date [2] 298366 0
10/05/2017
Ethics approval number [2] 298366 0
#1155

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76682 0
Prof Peter Richmond
Address 76682 0
Telethon Kids Institute
Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 76682 0
Australia
Phone 76682 0
+61 8 6456 5604
Fax 76682 0
+61 8 6456 2314
Email 76682 0
[email protected]
Contact person for public queries
Name 76683 0
Jennifer Kent
Address 76683 0
Telethon Kids Institute
Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 76683 0
Australia
Phone 76683 0
+61 8 6319 1850
Fax 76683 0
+61 8 6456 2314
Email 76683 0
[email protected]
Contact person for scientific queries
Name 76684 0
Peter Richmond
Address 76684 0
Telethon Kids Institute
Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 76684 0
Australia
Phone 76684 0
+61 8 6456 5604
Fax 76684 0
+61 8 6456 2314
Email 76684 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The de-identified data collected in this study will be published in peer-reviewed journals or presented at conferences


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.