A Phase II Double-Blind Trial to Evaluate the Safety, Immunogenicity and Effect on Infant Immune Responses of a Single Dose of Tdap in Pregnant Women in Mali
Phase: PHASE2
Conditions: Clostridium Difficile Immunisation, Diphtheria, Diphtheria Immunisation, Pertussis, Tetanus, Tetanus Immunisation
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol 16-0024 
Version 3.0 
Pertussis Vaccine in Pregnant Women 
24 July 2019 
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Abbreviated Title: Study on the safety and immunogenicity of 
Boostrix vaccine in pregnant Malian women and their infants 
A Phase II Double-blind Trial to Evaluate the Safety, 
Immunogenicity and Effect on Infant Immune Responses of a Single 
Dose of Tdap in Pregnant Women in Mali 
DMID Protocol Number: 16-0024 
DMID Funding Mechanism: Vaccine and Treatment Evaluation Units 
Pharmaceutical Support Provided by: DMID Clinical Materials Services Contract 
IND Sponsor: Division of Microbiology and Infectious Diseases, National Institute of 
Allergy and Infectious Diseases, National Institutes of Health 
Lead Principal Investigator: Kathleen M. Neuzil, MD, MPH; University of Maryland 
School of Medicine, Center for Vaccine Development 
Contract PI/Co-investigator:  Karen L. Kotloff, MD; University of Maryland School of 
Medicine, Center for Vaccine Development 
Site PIs : Milagritos Tapia, MD University of Maryland School of Medicine, Center for 
Vaccine Development 
Samba O. Sow MD., MSc., Centre pour le Développement des Vaccins – Mali, Bamako, 
Mali 
Site Investigators: Fadima Cheick Haidara MD., Fatoumata Diallo MD., Moussa Doumbia 
MD., Flanon Coulibaly MD., Djeneba Traoré MD., Ibrahima Téguété MD., Awa Traoré 
PharmD., Mamoudou Kodio PharmD., Uma Onwuchekwa, Centre pour le Développement 
des Vaccins – Mali, Bamako, Mali 
DMID Clinical Project Manager: Wendy Buchanan, BSN, MS 
DMID Scientific Lead: Kristina T. Lu, PhD 
DMID Medical Officer: Francisco Jose Leyva, MD, PhD, ScM 
DMID Medical Monitor: Mohamed M. Elsafy, MD 
Draft or Version Number: 3.0 
24 July 2019 
 
 

DMID Protocol 16-0024 
Version 3.0 
Pertussis Vaccine in Pregnant Women 
24 July 2019 
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STATEMENT OF COMPLIANCE 
This trial will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of 
Human Subjects 
• Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 
(Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical 
Investigators), 21 CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 
CFR Part 312 (Investigational New Drug Application), 21 CFR 812 (Investigational 
Device Exemptions) 
• International Conference on Harmonisation: Good Clinical Practice (ICH E6); 62 
Federal Register 25691 (1997); and future revisions 
• Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research, Report of the National Commission for the Protection of 
Human Subjects of Biomedical and Behavioral Research 
• National Institutes of Health (NIH) Office of Extramural Research (OER), Research 
Involving Human Subjects, as applicable 
• National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of 
Award, as applicable 
• Applicable Federal, State, and Local Regulations and Guidance 
Compliance with these standards provides public assurance that the rights, safety, and well-being 
of trial subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Subjects Protections Training. 
 
 

DMID Protocol 16-0024 
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24 July 2019 
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SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 Good Clinical Practice (GCP) guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and Institutional Review Board 
(IRB)/Institutional Ethics Committee (IEC) approval, except when necessary to protect the 
safety, rights, or welfare of subjects. 
 
Lead Principal Investigator (CVD Baltimore):  
Signed: 
 
 
Date: 
 
 
Name 
Title 
 
 
 
Site Principal Investigator (CVD Mali):  
Signed: 
 
 
Date: 
 
 
Name 
Title 
 
 
 
 

DMID Protocol 16-0024 
Version 3.0 
Pertussis Vaccine in Pregnant Women 
24 July 2019 
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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .................................................................................................2 
SIGNATURE PAGE .......................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................10 
LIST OF ABBREVIATIONS ........................................................................................................11 
PROTOCOL SUMMARY .............................................................................................................15 
1. 
KEY ROLES ..............................................................................................................24 
2. 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................27 
2.1. 
Background Information .............................................................................................27 
2.1.1. 
Disease Caused by Bordetella Pertussis .....................................................................27 
2.1.2. 
Burden of Illness .........................................................................................................27 
2.1.3. 
Prevention of Pertussis in Young Infants through Maternal Vaccination in 
Developed Countries ..................................................................................................28 
2.1.4. 
Interference of Maternal Antibody with Infant Immune Responses ..........................28 
2.1.5. 
Cytokines Produced in Response to Vaccine Antigens ..............................................29 
2.1.6. 
Role of Breastfeeding .................................................................................................30 
2.1.7. 
Pertussis Vaccines in Pregnant Women .....................................................................30 
2.1.8. 
Timing of Maternal Immunization .............................................................................31 
2.2. 
Rationale .....................................................................................................................31 
2.3. 
Potential Risks and Benefits .......................................................................................32 
2.3.1. 
Potential Risks and Discomforts .................................................................................32 
2.3.2. 
Potential Benefits ........................................................................................................35 
3. 
OBJECTIVES AND OUTCOME MEASURES ........................................................37 
3.1. 
Study Objectives .........................................................................................................37 
3.1.1. 
Primary .......................................................................................................................37 
3.1.2. 
Secondary ...................................................................................................................37 
3.1.3. 
Exploratory .................................................................................................................38 
3.2. 
Study Outcome Measures ...........................................................................................38 

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3.2.1. 
Primary .......................................................................................................................38 
3.2.2. 
Secondary ...................................................................................................................39 
3.2.3. 
Exploratory .................................................................................................................40 
4. 
STUDY DESIGN .......................................................................................................41 
5. 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................43 
5.1. 
Subject Inclusion Criteria ...........................................................................................43 
5.2. 
Subject Exclusion Criteria ..........................................................................................44 
5.3. 
Treatment Assignment Procedures .............................................................................46 
5.3.1. 
Randomization Procedures .........................................................................................46 
5.3.2. 
Masking Procedures ....................................................................................................47 
5.3.3. 
Reasons for Withdrawal and Discontinuation of Study Product 
Administration ............................................................................................................47 
5.3.4. 
Handling of Withdrawals and Discontinuation of Administration .............................48 
5.3.5. 
Subject Replacement ..................................................................................................49 
5.3.6. 
Termination of Study ..................................................................................................49 
6. 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT ...............................50 
6.1. 
Study Product Description ..........................................................................................50 
6.1.1. 
Acquisition ..................................................................................................................50 
6.1.2. 
Formulation, Packaging, and Labeling .......................................................................51 
6.1.3. 
Product Storage and Stability .....................................................................................52 
6.2. 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product ..........................................................................52 
6.2.1. 
BOOSTRIX ................................................................................................................53 
6.2.2. 
Td Control Vaccine .....................................................................................................53 
6.2.3. 
Administration ............................................................................................................54 
6.3. 
Modification of Study Intervention/Investigational Product for a Subject ................54 
6.4. 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) ....................................................................................................................54 
6.5. 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product/Investigational Device ...................................................................................55 
6.6. 
Concomitant Medications/Treatments ........................................................................55 
7. 
STUDY SCHEDULE .................................................................................................56 

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7.1. 
Recruitment .................................................................................................................56 
7.2. 
Screening ....................................................................................................................56 
7.3. 
Enrollment/Baseline ...................................................................................................57 
7.4. 
Follow-up ....................................................................................................................58 
7.4.1. 
Clinic or Home Visits .................................................................................................59 
7.4.1.1. 
Post Study Vaccination Follow-up Visit, Day 4 (±1 d): Home Visit, Pregnant 
Women (Visit 02 or V02) ...........................................................................................59 
7.4.1.2. 
Post Study Vaccination Follow-up Visit, Day 8 (+3 d): Home Visit, Pregnant 
Women (Visit 03 or V03) ...........................................................................................59 
7.4.2. 
Clinic Visits ................................................................................................................60 
7.4.2.1. 
Immunology and Safety Follow-up Visit, 30 Days Post Study Vaccination 
Visit, Day 31 (±4 d): Clinic Visit, Pregnant Women (Visit 04 or V04) .....................60 
7.4.2.2. 
Subsequent Follow-up Visits ......................................................................................60 
7.4.2.2.1. 
Labor and Delivery Visit, Birth (+3 d): Clinic Visit, Pregnant Women and 
Infants (Visit 05 or V05) .............................................................................................60 
7.4.2.2.2. 
6 Weeks Postpartum Safety Follow-up Visit, Birth + Day 42 (±5 d): Clinic 
Visit, Postpartum Women and Infants (Visit 06 or V06) ...........................................62 
7.4.2.2.3. 
10 or 18 Weeks Postpartum Safety Follow-up Visit, Birth + Day 70 (±5 d) or 
Birth + Day 130 (±5 d): Clinic Visit, Postpartum Women and Infants (Visit 
07 or V07) ...................................................................................................................62 
7.5. 
Final Study Visit .........................................................................................................63 
7.6. 
Early Termination Visit (if needed) ............................................................................63 
7.7. 
Unscheduled Visit (if needed) ....................................................................................64 
8. 
STUDY PROCEDURES/EVALUATIONS ...............................................................66 
8.1. 
Clinical Evaluations ....................................................................................................66 
8.2. 
Laboratory Evaluations ...............................................................................................67 
8.2.1. 
Clinical Laboratory Evaluations .................................................................................67 
8.2.2. 
Special Assays or Procedures .....................................................................................68 
8.2.3. 
Specimen Preparation, Handling, and Shipping .........................................................70 
8.2.3.1. 
Instructions for Specimen Preparation, Handling, and Storage ..................................70 
8.2.3.2. 
Specimen Shipment ....................................................................................................70 
9. 
ASSESSMENT OF SAFETY .....................................................................................71 

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9.1. 
Specification of Safety Parameters .............................................................................71 
9.2. 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ...................................................................................................................72 
9.2.1. 
Adverse Events ...........................................................................................................72 
9.2.2. 
Reactogenicity (for Vaccine Studies and Some Therapeutic Trials) ..........................74 
9.2.3. 
Additional Adverse Event Severity Grading ..............................................................77 
9.2.4. 
Grading of Specific Adverse Events in the Pregnant Women and their 
Infants .........................................................................................................................78 
9.2.5. 
Serious Adverse Events ..............................................................................................82 
9.2.6. 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values 
or Abnormal Clinical Findings ...................................................................................83 
9.3. 
Reporting Procedures ..................................................................................................83 
9.3.1. 
Serious Adverse Events ..............................................................................................84 
9.3.2. 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND ............84 
9.4. 
Type and Duration of Follow-up of Subjects after Adverse Events ...........................85 
9.5. 
Halting Rules ..............................................................................................................85 
9.6. 
Safety Oversight (ISM plus SMC or DSMB) .............................................................86 
9.6.1. 
Independent Safety Monitor (ISM) ............................................................................86 
9.6.2. 
Data and Safety Monitoring Board (DSMB) ..............................................................87 
10. 
CLINICAL MONITORING .......................................................................................89 
10.1. 
Site Monitoring Plan ...................................................................................................89 
11. 
STATISTICAL CONSIDERATIONS .......................................................................90 
11.1. 
Study Hypotheses .......................................................................................................90 
11.2. 
Sample Size Considerations .......................................................................................90 
11.2.1. 
Study Design ...............................................................................................................90 
11.2.2. 
Study Population .........................................................................................................90 
11.2.3. 
Sample Size ................................................................................................................91 
11.3. 
Planned Interim Analyses ...........................................................................................93 
11.3.1. 
Interim Safety Review ................................................................................................93 
11.3.2. 
Interim Immunogenicity or Efficacy Review .............................................................93 
11.4. 
Final Analysis Plan .....................................................................................................94 

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11.4.1. 
Analysis Populations ..................................................................................................94 
11.4.2. 
Safety Data ..................................................................................................................95 
11.4.3. 
Immunogenicity Data (ELISA) ..................................................................................95 
11.4.4. 
Missing Values and Outliers .......................................................................................96 
12. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................97 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................98 
14. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ..................................................99 
14.1. 
Ethical Standard ..........................................................................................................99 
14.2. 
Institutional Review Board .........................................................................................99 
14.3. 
Informed Consent Process ..........................................................................................99 
14.3.1. 
Informed Consent/Assent Process (in Case of a Minor) ..........................................101 
14.4. 
Exclusion of Women, Minorities, and Children (Special Populations) ....................102 
14.5. 
Subject Confidentiality .............................................................................................102 
14.6. 
Study Discontinuation ..............................................................................................103 
14.7. 
Costs, Subject Compensation, and Research Related Injuries .................................103 
14.8. 
Future Use of Stored Specimens and Data ...............................................................104 
15. 
DATA HANDLING AND RECORD KEEPING ....................................................105 
15.1. 
Data Management Responsibilities ..........................................................................105 
15.2. 
Data Capture Methods ..............................................................................................105 
15.3. 
Types of Data ............................................................................................................105 
15.4. 
Timing/Reports .........................................................................................................106 
15.5. 
Study Records Retention ..........................................................................................106 
15.6. 
Protocol Deviations ..................................................................................................106 
16. 
PUBLICATION POLICY ........................................................................................108 
17. 
LITERATURE REFERENCES................................................................................109 
APPENDIX A ..............................................................................................................................112 
 
 

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LIST OF TABLES 
Table 1: Treatment Arms and Study Vaccine to be Administered ................................................22 
Table 2: Specimen Volumes (mL) for Pregnant Women and Infants ...........................................69 
Table 3: Local (Injection Site) Reactogenicity Grading ................................................................74 
Table 4: Local (Injection Site) Reactogenicity Measurements ......................................................75 
Table 5: Subjective Systemic Reactogenicity Grading ..................................................................76 
Table 6: Quantitative Systemic Reactogenicity Grading ...............................................................77 
Table 7: Pulse and Blood Pressure Severity Grading ....................................................................77 
Table 8: Maternal and Infant Adverse Events ...............................................................................78 
Table 9: Power (%) to Detect Safety Events .................................................................................91 
Table 10: Precision for Estimating GMC of ELISA Antibody Response .....................................92 
Table 11: Minimum Detectable Difference in Infant PT Antibody GMC at Birth 
Comparing Infants Born to Mothers Vaccinated with BOOSTRIX versus Td ..........93 
 
 

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LIST OF FIGURES 
Figure 1: Schematic of Study Design ............................................................................................23 
 
 

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24 July 2019 
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LIST OF ABBREVIATIONS 
ACIP 
Advisory Committee on Immunization Practices, CDC 
ACOG 
American College of Obstetrics and Gynecology 
AE 
Adverse Event/Adverse Experience 
AGA 
Appropriate for Gestational Age 
ASQ-3 
Ages and Stages Questionnaire-3 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats per Minute 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
cm 
Centimeter 
CMS 
Clinical Materials Services 
CNAM 
Centre Nationale à la lutte contre la Maladie 
CRM197 
a form of diphtheria toxoid 
CROMS 
Clinical Research Operations and Management Support 
CSR 
Clinical Study Report 
CVD 
Center for Vaccine Development 
CVD-Mali 
Center for Vaccine Development- Mali 
°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
D 
Day(s) 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
DTwP 
Diptheria, Tetanus, and whole-cell Pertussis Vaccine 
eClinicalSM 
Electronic Data Capture System 
eCRF 
electronic Case Report Form 
e.g. 
for example 
EGA 
Estimated Gestational Age 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EPI 
Expanded Program on Immunization 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 

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FHA 
Filamentous Hemagglutinin 
FIM 2 
Fimbriae 2 
FIM 3 
Fimbriae 3 
FW 
Field Worker 
FWA 
Federalwide Assurance 
g/dL 
Grams per Deciliter 
GA 
Gestational Age 
GBS 
Guillain-Barré Syndrome 
GCP 
Good Clinical Practices 
gDM 
Gestational Diabetes Mellitus 
GMC 
Geometric Mean Concentration 
GMR 
Geometric Mean Ratio 
GMT 
Geometric Mean Titer 
GSK 
GlaxoSmithKline Biologicals 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IATA 
International Air Transport Association 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
i.e. 
that is 
IEC 
Independent or Institutional Ethics Committee 
IFN 
Interferon 
IgA 
Immunoglobulin A 
IL 
Interleukin 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intent-to-Treat 
LGA 
Large for Gestational Age 
LMP 
Last Menstrual Period 
MAPT 
Multicenter Acellular Pertussis Trial 
mcg or µg 
Microgram(s) 
MD 
Doctor of Medicine 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 

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mg/dL 
Milligram(s) per Deciliter 
mL 
Milliliter(s) 
mm 
Millimeter(s) 
mm Hg 
Millimeters of Mercury 
MOP 
Manual of Procedures 
MPH 
Master of Public Health 
MS or MSc 
Master of Science 
MSD 
Meso Scale Diagnostic 
N 
Number of Subjects 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OER 
Office of Extramural Research (NIH) 
OHRP 
Office for Human Research Protections 
PBMC 
Peripheral Blood Mononuclear Cells 
PERCH 
Pneumonia Etiology Research for Child Health 
PHI 
Personal/Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
PRN 
Pertactin 
PRR 
Proportional Reporting Ratio 
PT 
Pertussis Toxin 
QA 
Quality Assurance 
QC 
Quality Control 
Rh(D) 
Rhesus Antigen D (a red blood cell surface protein) 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SBA 
Serum Bactericidal Antibody 
SGA 
Small for Gestational Age 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
Td 
Tetanus Diphtheria Toxoid 
Tdap 
Tetanus Diphtheria Acellular Pertussis Vaccine 
Th 
T Helper Cell 
TNF 
Tumor Necrosis Factor 
TT 
Tetanus Toxoid 
UK 
United Kingdom 
US 
United States 
USP 
United States Pharmacopeial Convention 
V 
Visit 

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VAERS 
Vaccine Adverse Event Reporting System 
vs.  
Versus 
VTEU 
Vaccine and Treatment Evaluation Unit 
VVM 
Vaccine Vial Monitor 
WBC 
White Blood Cells 
WFI 
Water for Injection 
WHO 
World Health Organization 
 
 

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PROTOCOL SUMMARY 
Title: 
A Phase II Double-Blind Trial to Evaluate the Safety, 
Immunogenicity, and Effect on Infant Immune Responses of a 
Single Dose of Tdap in Pregnant Women in Mali 
Phase: 
2 
Population: 
200 healthy pregnant women, ages 18 through 39 years, 
inclusive, who meet all eligibility criteria, and their infants 
Number of Sites: 
 
 
Study Site: 
At least one Vaccine and Treatment Evaluation Unit (VTEU)-
subcontracted site 
 
Referral Health Center of Commune I (CSREF I) of the district 
of Bamako, Mali 
 
Study Duration: 
21 months: Approximately 2 months in the start-up period, 6 
months enrolling subjects, and 13 months (3-7 months while 
pregnant and 6 months postpartum) from last subject vaccinated 
until she and her infant complete follow-up 
Subject Participation 
Duration: 
Pregnant subjects: Approximately 10-13 months; infants: 
approximately 6 months 
Description of Agent or 
Intervention: 
Test agent: A single dose of Tetanus, diphtheria, acellular 
pertussis (Tdap) (BOOSTRIX) manufactured by 
GlaxoSmithKline Biologicals (GSK) and administered 
intramuscularly at a volume of 0.5 milliliter (mL) or Control 
agent: a single dose of Tetanus diphtheria toxoid (Td) 
intramuscularly at a volume of 0.5 mL. 
Objectives: 
 
Primary: 
Safety and Tolerability: 
• To assess the safety and tolerability of a single 0.5 mL 
intramuscular injection of BOOSTRIX in pregnant 
women. 
• To assess the safety of a single maternal BOOSTRIX 
vaccination on the fetus and infant. 

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Immunogenicity: 
• To assess the level of PT antibody at birth among infants 
whose mothers received a single dose of BOOSTRIX or 
Td while pregnant. 
 
Secondary: 
Immunogenicity: 
• To assess the antibody response to BOOSTRIX vaccine 
antigens in pregnant women one month after receipt of 
BOOSTRIX, at the time of delivery, and at 6 months 
after delivery. 
• To compare the antibody levels of BOOSTRIX vaccine 
antigens at birth (cord blood) and 6 weeks of age (before 
receiving any infant doses of Diphtheria, Tetanus, and 
whole-cell Pertussis (DTwP)) in infants whose mothers 
received BOOSTRIX or Td during pregnancy. 
• To assess placental antibody transfer by determining the 
ratio of maternal and infant BOOSTRIX -specific 
antibody responses at delivery. 
• To assess interference with infant antibody responses to 
DTwP either prior to the second dose of the primary 
DTwP series, at approximately 10 weeks of age (in ½ of 
subjects), or approximately one month after the third 
dose of the primary DTwP series, at approximately 18 
weeks of age (in ½ of subjects), and at 6 months of age 
(all subjects). 
 
Exploratory: 
Immunogenicity: 
• To assess the effects of maternal age, parity, gestational 
age (GA) at which the vaccine is given, GA at delivery, 
and infant birthweight on antibody responses to 
BOOSTRIX in pregnant women at time of delivery, and 
in their newborn infants at birth. 

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• To assess maternal secretory immunity through 
measurement of breast milk antibodies to Tdap vaccine 
antigens in women at the time of delivery, at 6 weeks 
postpartum, at 10 weeks (in ½ of women) or 18 weeks (in 
½ of women) postpartum, and at 6 months after delivery. 
• To assess the cytokine profile after stimulation in vitro 
with diphtheria, tetanus and pertussis antigens of 
peripheral blood mononuclear cells (PBMC) obtained 
from women before and one month after receiving 
BOOSTRIX or Td. 
• To assess the cytokine profile after stimulation in vitro 
with diphtheria, tetanus, and pertussis antigens of PBMC 
obtained from infants before the first dose of DTwP 
(approximately 6 weeks of age) in all subjects, one month 
after the first dose of DTwP (approximately 10 weeks of 
age) in ½ of infants, one month after the last dose of 
DTwP (approximately 18 weeks of age) in ½ of infants, 
and at 6 months of age in all infants. 
 
Outcome Measures: 
 
 
 
 
 
 
 
 
Primary: 
Safety and Tolerability: 
• 
Safety in pregnant women: Frequency and severity of 
study vaccine-related serious adverse events (SAEs), and 
all SAEs in pregnant women from study vaccination 
through 6 months postpartum, description and 
comparison between those receiving BOOSTRIX and Td. 
• 
Safety in pregnant women and fetuses/infants: Frequency 
and severity of adverse events specific to pregnancy, in 
pregnant women and their infants (as delineated in 
Section 9.2.4), description and comparison between those 
receiving BOOSTRIX and Td. 
• 
Tolerability in pregnant women: Frequency and severity 
of solicited injection site and systemic reactogenicity 
events from study vaccination until 7 days following 
vaccination (Day 8). 

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• 
Tolerability in pregnant women: Frequency and severity 
of all unsolicited non-serious AEs from day of study 
vaccination to Day 31, description and comparison 
between those receiving BOOSTRIX and Td. 
• 
Safety in the infants: Frequency and severity of study 
vaccine-related serious adverse events, and all SAEs in 
infants from birth through 6 months of age, description 
and comparison between infants born to women 
vaccinated with BOOSTRIX and Td. 
Immunogenicity: 
• 
Infant humoral immunity: Geometric Mean 
Concentration (GMC) of serum IgG antibodies to PT as 
measured by Enzyme-Linked Immunosorbent Assay 
(ELISA) at birth between infants born to women 
vaccinated with BOOSTRIX and Td. 
 
Secondary: 
Immunogenicity: 
• 
Maternal humoral immunity: GMC of serum IgG 
antibodies to Tdap vaccine antigens (PT (Pertussis 
Toxin), FHA (Filamentous Hemagglutinin), PRN 
(Pertactin), tetanus, diphtheria) as measured by ELISA in 
pregnant women one month after receipt of BOOSTRIX 
or Td, at the time of delivery, and 6 months after 
delivery. 
• 
Infant humoral immunity: GMC of serum IgG antibodies 
to Tdap vaccine antigens (PT, FHA, PRN, tetanus, 
diphtheria) as measured by ELISA at birth and prior to 
receipt of first DTwP (approximately 6 weeks of age) 
among infants born to women vaccinated with 
BOOSTRIX compared to Td. 
• 
Placental antibody transfer: The geometric mean ratio 
(GMR) of maternal and infant-specific Tdap-specific 
antibodies (PT, FHA, PRN, tetanus, diphtheria) as 

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measured by ELISA at delivery after intrapartum receipt 
of BOOSTRIX versus Td. 
• 
Interference with infant responses among infants whose 
mothers received intrapartum BOOSTRIX compared to 
Td: GMC of antibodies to DTwP vaccine antigens (PT, 
FHA, PRN, Fimbriae 2 (FIM2), Fimbriae 3 (FIM3), 
tetanus, diphtheria) as measured by ELISA one month 
after the first dose of DTwP (~10 weeks of age, ½ of 
infants), one month after the third dose of DTwP vaccine 
(~18 weeks of age, ½ of infants), and at 6 months of age. 
 
Exploratory: 
Immunogenicity: 
• 
Maternal immunogenicity cofactors for maternal and 
neonatal anti-PT antibody responses following 
intrapartum BOOSTRIX: Maternal age (18-29, 30-39 
years old), parity (primiparous vs. multiparous), GA at 
time of vaccination (14-17, 18-21, 22-26 weeks), GA at 
time of delivery (28-32, 33-36, 37 or more weeks), and 
infant birthweight as potential independent associations 
with PT GMC.  
• 
Maternal secretory immunity: GMC of breast milk IgG 
and IgA antibodies to Tdap vaccine antigens (PT, FHA, 
PRN, tetanus, diphtheria) as measured by ELISA in 
women at the time of delivery, at 6 weeks after deliver, at 
10 weeks (in ½ of women) or 18 weeks (in ½ of women) 
after delivery, and 6 months after delivery after 
intrapartum receipt of BOOSTRIX versus Td. 
• 
Maternal cytokine responses: Cytokines produced by 
peripheral blood cells stimulated with DTwP vaccine 
antigens, as measured by multiplex assays, in women 
before and one month after receiving Tdap. Cytokines 
measured will include: Interferon (IFN)-γ, Inerleukin 
(IL)-10, IL-12p70, IL-12/IL-23p40, IL-13, IL-15, IL-16, 
IL-17A, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, 
Tumor Necrosis Factor (TNF)-α, and TNF-β. 

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• 
Infant cytokine responses: Cytokines produced by infant 
peripheral blood cells stimulated with DTwP antigens 
from infants whose mothers received intrapartum 
BOOSTRIX versus Td, measured by multiplex assays 
before the first dose (or umbilical cord blood), one month 
after the first dose of DTwP (~10 weeks of age, ½ of 
subjects), one month after the last dose of study vaccine 
(approximately 18 weeks, ½ of subjects), and at 6 months 
of age. Cytokines measured will include: IFN-γ, IL-10, 
IL-12p70, IL-12/IL-23p40, IL-13, IL-15, IL-16, IL-17A, 
IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, TNF-α, 
and TNF-β. 
 
Description of Study Design: This is a phase II, single center, randomized, double-blind, 
active-controlled study in which 200 healthy pregnant women, 
ages 18 through 39 years, inclusive, will be randomly allocated 
in a 2:1 ratio to receive either Tdap (BOOSTRIX) or Td at 14 
0/7 weeks through 26 6/7 weeks estimated GA. After signing an 
informed consent form (ICF), all subjects will undergo a review 
of current and past medical history, current and prior medication 
use, and recent and relevant vaccination history. A physical 
examination performed as part of routine antenatal care or a 
study-specific focused exam may be used to determine 
eligibility. For the fetuses of pregnant subjects, GA will be 
established by ultrasound, whenever possible, in combination 
with date of last menstrual period (LMP), when available, and 
fundal height. 
Eligibility will be confirmed, and the subject will be enrolled in 
the study. Each subject will receive prenatal care consistent with 
national guidelines and with local standards as practiced by 
clinicians caring for pregnant women and delivering neonates in 
the study area. In Mali, this includes hemoglobin, sickle cell test, 
Rh group, HIV, syphilis, toxoplasmosis, and rubella serology 
and urine glucose and protein at the first presentation for 
antenatal care, urine albumin and glucose at each subsequent 
visit and ultrasound at 22 and 32 weeks gestation. 

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At the time of randomization to vaccine allocation, women will 
also be randomized to a schedule of postpartum visits for 
specimen collection. All women-infant pairs will have specimens 
collected at birth, at 6 weeks after delivery, and at 6 months after 
delivery. In addition, women-infant pairs will be allocated in a 
1:1 ratio to have specimen collections at one month following 
the first dose of DTwP (approximately 10 weeks of age), or at 
one month following the third dose of DTwP (approximately 18 
weeks of age). Thus, pregnant subjects will typically have 7 
clinic visits (only 6 if delivery occurs before the first visit after 
vaccination, on Day 31): 3 antenatal visits (Screening Visit, 
Study Day 1, and Study Day 31, unless delivery occurs first), 1 
visit at the time of delivery, and 3 postpartum visits – at 6 weeks, 
at 10 or 18 weeks postpartum, and a final visit 6 months 
postpartum. The maternal subject will also undergo 2 home visits 
after vaccination to assess her health status (Days 4 and 8).  
Infants born to the pregnant subjects will have 4 study visits: at 
birth, at approximately 6 weeks of age (day of first DTwP), at 
approximately 10 or 18 weeks of age (one month after first or 
third dose of DTwP, respectively), and at 6 months of age. 
Blood and colostrum/breast milk samples for immunologic 
assessments will be collected as described below: 
• 
Pregnant subjects: approximately 30 mL of whole blood 
will be collected by venipuncture on Study Day 1 (prior 
to vaccination), Study Day 31 (one month after 
vaccination), at delivery, and at 6 months postpartum in 
all women. 
• 
Infants: up to 30 mL of umbilical cord blood will be 
collected at delivery and 5 mL peripheral blood will be 
collected by venipuncture at 6 weeks (prior to first dose 
of DTwP), either the 10-week or 18-week (per 
randomized study schedule), and 6 months of age in all 
infants. If cord blood cannot be obtained, 2-5 mL of 
peripheral blood will be collected by venipuncture within 
72 hours of birth when possible. Cord blood is preferred 
over venipuncture. 

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• 
At delivery, and at the 6-week, either the 10-week or 18-
week (per randomized study schedule), and the 6-month 
postpartum visit, a 10-20mL sample of colostrum or 
breast milk will be collected. When possible, the first 
breast milk or colostrum collection will occur while the 
mother and baby are admitted for delivery and 
postpartum care. When not possible, it may be collected 
any time within the first 4 days of life. 
Safety will be monitored from the time of signing of the ICF 
until trial termination. 
Estimated Time to Complete 
Enrollment: 
Approximately 6 months from the first vaccinated subject 
 
Table 1: Treatment Arms and Study Vaccine to be Administered 
 
Treatment Arm 
Subject Group 
BOOSTRIX 
Td 
Total 
Pregnant women 
133 
67 
200 
 
 

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2. 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1. 
Background Information 
2.1.1. 
Disease Caused by Bordetella Pertussis 
Pertussis, or whooping cough, is a disease of the upper and lower respiratory tract caused by 
Bordetella pertussis (B. pertussis), a Gram-negative bacterium that lives in the upper respiratory 
tract. Pertussis is highly contagious. The bacteria attach to the cilia that line part of the upper 
respiratory system, and release toxins which damage the cilia and inflame the airways. While 
disease usually starts with cold-like symptoms and maybe a mild cough or fever, it may progress 
to paroxysms of coughing, post-tussive vomiting, and exhaustion. Pertussis is particularly 
dangerous in young infants, in whom it may lead to pneumonia, pulmonary hypertension, 
convulsions, apnea, encephalopathy, and death. 
2.1.2. 
Burden of Illness 
The introduction of pertussis vaccination in the past century has led to dramatic decreases in 
pertussis disease throughout the world. Nevertheless, pertussis burden remains high globally, as 
an estimated 16 million cases of pertussis occurred worldwide as recently as 2008.[1] Moreover, 
there has been a resurgence in pertussis disease in industrialized countries in recent years, with 
over 48,000 cases reported in the US alone for 2012. [2] This rise is likely due to a combination 
of factors, including improved diagnostics, heightened awareness of the disease, a decrease in 
natural immunity due to low circulation, and decreased duration of protection from acellular 
pertussis vaccines.[3] 
Even in settings where vaccination coverage is high, the highest incidence of serious disease and 
mortality occurs in infants under two months of age, as they are too young to receive protection 
through current pertussis vaccines. In the US, this age group accounts for 57% of all infant 
pertussis hospitalizations. [4, 5] 
Less is known about pertussis in low resource settings.  A modeling study estimated there were 
16 million cases of pertussis and over 160,000 deaths in children younger than 5 years due to 
pertussis worldwide in 2014, with most deaths occurring in developing countries. [1, 2, 6] Recent 
data from the Pneumonia Etiology Research for Child Health (PERCH) study, a case-control 
study of pneumonia etiology conducted in 7 low and middle resource countries, identified 
pertussis in 2.2% of severe pneumonia hospitalizations and 2.9% of pneumonia deaths. Younger, 
unimmunized, and HIV-exposed infants, and those in Africa, were most at risk. The case-fatality 
rate among infants 1-5 months of age at the 5 African sites where cases were detected was 
12.5%. As PERCH excluded children younger than 1 month of age, these are undoubtedly 
underestimates.[7] 

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2.1.3. 
Prevention of Pertussis in Young Infants through Maternal Vaccination in 
Developed Countries 
Serious disease and death due to pertussis overwhelmingly occur in infants under two months of 
age, including in settings with excellent access to medical care and high vaccination coverage. 
[3] The rising incidence of pertussis in industrialized countries among infants too young to 
complete their primary vaccination series has prompted recommendations for pertussis 
vaccination during pregnancy in the US, UK, New Zealand, and several Latin American and 
European countries. [1-4, 8]The goal of these recommendations is to achieve protection of young 
infants through transplacental transfer of maternal immunoglobulin G antibodies until active 
immunization of the infant can occur. The US Advisory Committee on Immunization Practices 
(ACIP) first recommended antenatal pertussis immunization in 2011 for women who had not 
previously received Tdap vaccine, [9]and expanded this recommendation to all pregnant women 
during every pregnancy, regardless of prior receipt of Tdap. [10] In support of this policy, both 
observational [11, 12] and interventional [13] studies have shown that antenatal Tdap 
immunization results in increased infant antibody levels. The benefits of this intervention were 
further supported through an evaluation of the national antenatal pertussis immunization program 
in the UK begun in 2012, in which a case-control study design demonstrated a vaccine 
effectiveness of 91% against laboratory-confirmed clinical pertussis among children younger 
than 3 months of age. [14] In the US, a case control study estimated that maternal Tdap vaccine 
given in the third trimester of pregnancy was 77.7% effective against the outcome of pertussis in 
infants younger than 2 months of age. This estimate rose to 90.5% against hospitalized cases of 
pertussis in infants. [15] 
2.1.4. 
Interference of Maternal Antibody with Infant Immune Responses 
The beneficial effects of maternal antibody early in life must be balanced with any detrimental 
effects on primary infant responses to pertussis vaccines. In the maternal pertussis immunization 
studies from the 1930s and 1940s in the US, infant agglutinin antibody responses to whole-cell 
pertussis vaccine were lower in infants born to mothers who received whole-cell pertussis 
vaccine as compared to mothers who received no vaccine. Subsequent studies in the 1990s 
examining the effect of pre-existing antibodies in unvaccinated pregnant women showed that 
infant responses to whole-cell vaccines were suppressed by pre-existing maternal antibody, while 
responses to acellular vaccines were not affected, or at least were suppressed to a lesser degree. 
[16-18] One of these studies [18]evaluated this issue within the NIAID-funded Multicenter 
Acellular Pertussis Trial (MAPT), which allowed direct comparison between whole-cell and 
multiple acellular pertussis vaccines. In this evaluation, pre-existing anti-PT antibodies had a 
strongly negative effect on PT responses for the two whole-cell DTwP vaccines, but only a 
minimal reduction for the acellular DTaP vaccines. 
Several recent studies in in the US, Europe, and Vietnam have described the immunogenicity of 
acellular pertussis vaccines in pregnancy, and in all cases the infants also received acellular 

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pertussis vaccines. [10, 19-22] In all studies, the first dose of infant vaccine was given at or after 
2 months of age. An NIAID-sponsored study of Tdap vs. placebo in 48 women in the US found 
that Tdap was immunogenic in pregnant women and that infants born to such women had 
statistically higher concentrations of pertussis antibodies at delivery and 2 months of age. 
Antibody titers for FHA at age 7 months were significantly lower in infants whose mothers 
received Tdap, although the difference was no longer significant at 13 months of age following a 
Tdap booster dose. [10] In a nonrandomized study in Belgium, pregnant women who received 
Tdap and their infants through 2 months of life had higher concentrations of all antigens included 
in the vaccine. Blunting was reported for infant diphtheria and PT responses one month after the 
third dose of infant vaccine, and a minor blunting effect persisted for PT responses after the 
booster dose. [20] In Vietnam, women and infants up to 2 months of age had significantly higher 
GMCs for PT, PRN, and FHA.  One month after completion of the primary infant vaccination 
schedule, anti-PRN GMC was significantly lower in the vaccinated group. [19] In the US, the 
blunting of infant responses to FHA was overcome by the booster dose in the second year of life; 
studies in Vietnam are on-going to determine the effect of the booster dose on infant responses. 
[10, 19, 20] 
The clinical significance of any blunting effect of maternal antibody on infant primary responses 
is complicated by the lack of an agreed correlate of protection for pertussis. High concentrations 
of antibodies to PT, FHA, PRN, Fim 2, and Fim 3 are known to be protective against disease. 
Small amounts of antibody to the A subunit of PT will prevent death in infants although it will 
not prevent infection. [22] Therefore, while all responses may be clinically important, the 
postulated critical role of anti-PT antibodies in protection against severe infant pertussis justifies 
an emphasis on this response in the first months of life. 
2.1.5. 
Cytokines Produced in Response to Vaccine Antigens 
The development of robust antibody responses relies on the stimulation of T cells, which 
supports antibody development through direct interactions with B lymphocytes and the secretion 
of cytokines. Th1 and Th17 cytokines have been shown to contribute to protection against 
pertussis in mice, following infection or vaccination. [23] Most recently, IL-17 induced by 
DTwP has been associated with enhanced pertussis clearance in the baboon model. [24] There is 
limited information on cytokine T cell responses to Tdap during pregnancy. A recent study 
reported transient and impaired IFN-γ responses in pregnant women who received Tdap, [25] but 
these results were derived from a very small number of subjects and using whole blood (as 
opposed to purified cells) stimulated with polyclonal, not pertussis-specific antigens. It is 
possible that the passive transfer of maternal antibodies might interfere with the ability of 
pertussis antigens to elicit protective cellular responses. Cytokine measurements in vaccinated 
infants would allow assessment of the potential impact of maternal immunization on the infant’s 
T cell responses following vaccination. 

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2.1.6. 
Role of Breastfeeding 
Breast feeding has been associated with reduced risk of respiratory illnesses early in life. [26, 27] 
Pertussis-specific IgA and IgG have been detected in breast milk from women who had received 
DTwP during childhood [28]as well as IgA in colostrum of Tdap vaccinated pregnant 
women[29, 30], and it has been proposed that breastfeeding may have a protective role against 
infection. [28, 29] Investigating antibodies in breast milk of Tdap vaccinated women will 
provide a more comprehensive evaluation of immunogenicity and test the hypothesis that women 
vaccinated during pregnancy develop mucosal antibodies that are also available for protection of 
the offspring. Studies that have examined the effect of maternal antibodies on infant responses to 
acellular pertussis vaccines have not investigated antibodies in maternal milk. [9, 10] 
2.1.7. 
Pertussis Vaccines in Pregnant Women 
In Mali, there are no recommendations for vaccinating pregnant women routinely with a 
pertussis-containing vaccine. In the US, the UK, and elsewhere, both Adacel and BOOSTRIX 
are licensed. Adacel is a pregnancy category C and BOOSTRIX is a pregnancy category B. The 
US and UK recommend that either vaccine be given to pregnant women. Only BOOSTRIX is 
pre-qualified by the WHO, and therefore is the vaccine of choice for developing countries, and 
the vaccine that will be used for this study. [14] Standard of care in Mali is to administer to 
pregnant women at the first prenatal visit a dose of Td vaccine manufactured by Biological E. 
Limited and prequalified by the WHO.  The whole-cell vaccines received by infants varies by 
country, with most low-income countries using a pentavalent vaccine (DTwP-HepB-Hib) 
manufactured by one of 8 different WHO-prequalified manufacturers. [14] 
In the United States, post licensure surveillance data of Tdap during pregnancy, including studies 
looking at repeated doses, have revealed no association with medically attended acute adverse 
events during pregnancy or adverse birth outcomes. [1-4] A recent review of 392 reports to the 
Vaccine Adverse Event Reporting System (VAERS) of AEs in pregnant women who received 
Tdap vaccine after the routine recommendation (11/01/2011–6/30/2015) was compared to 
published data before the routine Tdap recommendation (01/01/2005–06/30/2010). An increase 
in proportion of reports for stillbirths (1.5–2.8%) and injection site reactions/arm pain (4.5–
11.9%) and a decrease in reports of spontaneous abortion (16.7–1%) occurred after the 
recommendation compared to the period before the routine recommendation for Tdap during 
pregnancy. In most recent reports, vaccination (79%) occurred during the third trimester. 
Overall, no new or unexpected AEs were noted among pregnant women who received Tdap after 
routine recommendations for maternal Tdap vaccination. Changes in reporting patterns would be 
expected, given the broader use of Tdap in pregnant women in the third trimester after the 
routine recommendation as compared to before. 

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2.1.8. 
Timing of Maternal Immunization 
In the US, the ACIP states that the optimal timing for Tdap administration is between 27 and 36 
weeks gestation although Tdap may be given at any time during pregnancy. [10] Two recent 
studies support that earlier vaccination may be more beneficial. In Israel, a prospective study that 
included women in their 20th week of pregnancy or later demonstrated that IgG GMCs to PT 
were higher in newborn cord sera when women were immunized at 27-30 weeks compared with 
31-36 weeks of gestation. [20] Likewise, in a prospective observation cohort study in Geneva, 
Switzerland, early second-trimester maternal Tdap immunization significantly increased neonatal 
antibodies compared to later dosing. [21] 
In Mali, and elsewhere in Africa, tetanus-containing vaccines are recommended to be given at 
the first pregnancy encounter. The rationale for this recommendation is that many women in 
Mali will not present for multiple, regular prenatal visits, as is done in the United States. Thus, 
the recommendation for first encounter vaccination ensures that a woman receives the vaccine 
and has adequate time to develop immunity and transfer antibody to her unborn child. Delaying 
the administration of tetanus-containing vaccines until the third trimester of pregnancy would be 
a deviation from standard of care, and would likely be unacceptable to the community. 
Therefore, second trimester vaccination may be the best option in this trial for consistency with 
local practices. Any pregnant women who presents in the first trimester and wishes to participate 
in the study will be asked to return during the second trimester for randomization and receipt of a 
tetanus-containing vaccine. 
2.2. 
Rationale 
Unfortunately, the positive impact of maternal pertussis vaccination cannot be assumed to be 
generalizable to low resource settings, where most pertussis deaths occur. Maternal antibody 
transfer in low resource settings may be adversely affected by malnutrition, HIV, malaria, and 
other factors. [12] In addition any diminution of primary infant antibody responses by the 
presence of maternal antibody may be more pronounced in low resource countries for two main 
reasons. First, infants in Africa and many low resource countries in Asia receive their primary 
pertussis-containing vaccines at earlier time points – 6, 10, and, 14 weeks as compared to 2, 4, 
and 6 months in industrialized settings. It might be expected that any interference would be 
greater at younger ages, when maternal antibody concentrations are higher. While booster doses 
may overcome any deleterious effect of maternal antibody on infant primary responses to 
pertussis vaccines in developed countries, most low resource countries do not include a pertussis 
booster in the second year of life. [1, 10] The second reason that interference with infant 
immunization may be more pronounced in developing countries is that they continue to use 
whole-cell vaccines in the primary infant series. As above, prior studies suggest that higher 
levels of maternal antibodies were associated with lower infant responses to whole-cell pertussis 

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vaccines, with less of an effect seen in infants given acellular pertussis vaccines. [13] These two 
factors highlight the need for context-specific data on maternal pertussis immunization. 
Maternal pertussis vaccination would be feasible in low resource countries. Existing antenatal 
tetanus immunization programs have been successful worldwide and may serve as a platform for 
pertussis vaccine introduction as Tdap combinations could be substituted for Td or tetanus toxoid 
(TT). In Mali, standard of care is to administer Td to pregnant women during their first contact 
with the health care system, which for most women is in the second trimester. 
Realizing the importance of pertussis prevention in infants too young to receive vaccine, and the 
lack of data on the impact of maternal vaccination on infant responses in developing country 
settings where whole-cell vaccines are used, a study is necessary to examine the safety, 
immunogenicity, and effect on infant antibody responses of a Tdap vaccine administered during 
pregnancy among women in Mali. 
2.3. 
Potential Risks and Benefits 
2.3.1. 
Potential Risks and Discomforts 
The potential risks of participating in this study are those associated with having blood drawn, 
intramuscular (IM) injection of and possible reactions to the study vaccine, accompanying risks 
to the fetus and infant of the vaccinated mother, risks of breast milk collection, and breach of 
confidentiality. 
Ultrasound: All women will have an ultrasound to date the pregnancy. This procedure is not 
harmful to the mother or fetus, but it may feel uncomfortable. Mothers will be informed if the 
ultrasound reveals any implications for the pregnancy or the health of the child. It is possible this 
news may cause emotional distress; there may also be additional costs to women who choose to 
perform further testing based on this information. 
Phlebotomy:  Drawing blood is typically well tolerated and uneventful. However, it often causes 
transient mild discomfort. Some subjects may have near syncope (2%) or true syncope (fainting). 
Fainting is a transient autonomic (vasovagal) response to phlebotomy that occurs in 
approximately 1% of blood donors and less than 1% of those having diagnostic phlebotomy. [24] 
It is managed by having the subject lie down, loosening his or her clothes, monitoring vital signs, 
reassuring the subject, and giving fluids. Minor bruising (up to 12%) or a hematoma (2-3%) may 
occur at the blood draw site. It can be prevented or decreased in frequency by employing 
experienced phlebotomists and can be ameliorated, when it occurs, by applying pressure to the 
draw site for several minutes. Rarely, following phlebotomy, persons may have nerve injury 
(typically lateral antebrachial nerve) causing pain, paresthesias, and motor or sensory loss. This 
phenomenon is uncommon and typically resolves quickly with watchful waiting only. [25] 
Infection at the site of the blood draw is rare, and can be avoided by using antiseptics and other 
appropriate techniques. In a study of over 4000 persons undergoing routine venipuncture for 
insurance application, there were no serious local reactions such as cellulitis or phlebitis. [24] 

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Intramuscular Injection:  The injection of a vaccine into the deltoid muscle, as will be done in 
this study, is typically well tolerated. However, it often causes transient discomfort. As with 
phlebotomy, although less commonly, it can cause near syncope or syncope. It can also cause an 
abscess, a hematoma, injury to blood vessels and peripheral nerves, or tingling or numbness. 
Proper technique reduces the risks of infection, bleeding, and injury. 
The Vaccine:  BOOSTRIX manufactured by GSK, is indicated for active booster immunization 
against tetanus, diphtheria, and pertussis. BOOSTRIX is approved for use as a single 
intramuscular injection for persons aged 10 years of age and older in the US.  [31] 
The safety of BOOSTRIX has been evaluated in multiple studies in adolescents and adults. The 
most relevant to this age group was a study in US adults 19 to 64 years of age that compared 
BOOSTRIX (n=1,522) to Adacel (Sanofi Pasteur) (n=762). Solicited local and systemic 
reactions were monitored for 14 days after vaccination, and medically significant AEs and SAEs 
for 6 months. Solicited adverse reactions (any/severe), reported by adult BOOSTRIX recipients 
were pain at the injection site (61%/1.6%), erythema (21%/1.6%), induration (17.6%/1.4%), 
headache (30%/2.2%), fatigue (28.1%/2.5%), any gastrointestinal symptoms (15.9%/1.2%), and 
fever (5.5% >99.5oF/0.1% >102.2oF). The reactogenicity profile closely mirrored that of Adacel, 
the other US licensed Tdap.  [31] 
The incidence of unsolicited adverse events reported in the 31 days after vaccination was 
comparable in the 2 groups (17.8% and 22.2% for BOOSTRIX and Adacel).  Serious adverse 
events were reported to occur during the entire study period (0-6 months) by 1.4% and 1.7% of 
subjects who received BOOSTRIX and Adacel. During the 6-month extended safety period, no 
serious adverse events of a neuroinflammatory nature or with information suggesting an 
autoimmune etiology were reported in subjects who received BOOSTRIX. [31] 
Since licensure, additional events have been voluntarily reported, but none have prompted 
concern for common or severe events caused by the vaccine. 
Rare or uncommon reactions include anaphylaxis or other acute allergic reactions and syncope. 
Acute and potentially life-threatening allergic reactions (i.e., anaphylaxis) are also possible. 
These reactions occur in about 1 in 4 million people given a vaccination. These reactions can 
manifest as skin rash (urticaria), swelling around the mouth, throat or eyes (angioedema), 
difficulty breathing (bronchospasm), a fast pulse (tachycardia), or decrease in blood pressure 
(hypotension). If these reactions occur, they can usually be stopped by the administration of 
emergency medications by the study personnel. As with any vaccine or medication, there is a 
very small chance of a fatal reaction (death), although researchers do not expect this to occur. 
[31] 
If Guillain-Barré syndrome (GBS) occurred within 6 weeks of receipt of a prior vaccine 
containing tetanus toxoid, the risk of Guillain-Barré syndrome may be increased following a 
subsequent dose of tetanus toxoid-containing vaccine, including BOOSTRIX. A review by the 

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Institute of Medicine (IOM) found evidence for a causal relationship between receipt of tetanus 
toxoid and both brachial neuritis and Guillain-Barré syndrome. [31] 
Progressive or unstable neurologic conditions (e.g., cerebrovascular events and acute 
encephalopathic conditions) are reasons to defer vaccination with a pertussis-containing vaccine, 
including BOOSTRIX. It is not known whether administration of BOOSTRIX to persons with an 
unstable or progressive neurologic disorder might hasten manifestations of the disorder or affect 
the prognosis. Administration of BOOSTRIX to persons with an unstable or progressive 
neurologic disorder may result in diagnostic confusion between manifestations of the underlying 
illness and possible adverse effects of vaccination. [31] 
The vaccine manufacturer maintains a surveillance registry to collect data on pregnancy 
outcomes and newborn health status outcomes following vaccination with BOOSTRIX during 
pregnancy. In the event of an observed safety signal from that registry, the manufacturer would 
share that information with the sponsor and appropriate actions for trial subjects would be taken. 
It is unknown if the vaccine to be used in this study poses any risks to an unborn child or to 
children born to mothers who are vaccinated during pregnancy. The vaccine is currently deemed 
as pregnancy category B. A developmental toxicity study has been performed in female rats at a 
dose approximately 40 times the human dose (on a mL/kg basis) and revealed no evidence of 
harm to the fetus due to BOOSTRIX. Animal fertility studies have not been conducted with 
BOOSTRIX. 
The effects of the vaccine on lactation and nursing, as well as the effects on the breastfed infant 
of a woman vaccinated with BOOSTRIX during pregnancy, are unknown. 
Breast Milk Collection:  Women will provide breast milk within the 4 days following delivery 
and at 3 time points postpartum (at 6 weeks, either 10 or 18 weeks, and 6 months postpartum). 
There is no significant risk of this collection. Some women may experience mild tenderness from 
milk expression. 
Potential Risks to Infants:  As with the risks to pregnant women, there is a possibility that 
obtaining a blood sample from your infant may cause some pain, swelling, bruising, or infection 
at the site of the blood draw. To avoid infection, a qualified and trained staff member will collect 
the blood from the infant.   
The standard of care in Mali is to vaccinate infants with the pentavalent Diphtheria and Tetanus 
and Pertussis and Haemophilus influenzae and Hepatitis B vaccine at 6, 10, and 14 weeks of age; 
this vaccination should provide protection. There is a possibility that the infant’s response to the 
pertussis vaccine could be lower after the usual infant vaccinations because of the mother’s study 
vaccine. 
Privacy and Confidentiality:  Subjects will be asked to provide and allow research team 
members access to personal/protected health information (PHI) of the woman and her infant. All 
attempts will be made to keep this PHI confidential within the limits of the law. However, there 
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locked file cabinet or maintained in a locked room at each participating VTEU site. Electronic 
files will be password protected. Only people who are involved in the conduct, oversight, 
monitoring, or auditing of this study will be allowed access to the PHI that is collected. Any 
publications from this study will not use information that will identify subjects by name. 
Organizations that may inspect and/or copy research records maintained at the participating site 
for quality assurance and data analysis include groups such as the National Institute of Allergy 
and Infectious Diseases (NIAID) and/or its representatives and the US Food and Drug 
Administration (FDA). They also include the Malian Research Ethics Committee of the School 
of Medicine, Pharmacy, and Dentistry and the Malian National Drug Authority. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by US law. This web site will not include information that can identify subjects. At most, this 
web site will include a summary of the results. 
There may be other unknown risks, discomforts, or side effects. 
2.3.2. 
Potential Benefits 
BOOSTRIX is licensed in the US for use in persons 10 years old and older and per WHO pre-
qualification guidelines for persons 4 years and older, and therefore includes the age range of 
young adult women who are eligible for this trial. Although not routinely recommended for 
pregnant women in Mali, BOOSTRIX is not contra-indicated in pregnancy. Therefore, a 
potential benefit of participation is protection against pertussis in the women and the infants. Td 
recipients will not accrue any treatment-related benefits while enrolled.  
For pregnant subjects, their infants may receive the benefit of transplacental pertussis antibody 
transfer and/or breast milk antibodies. These antibodies could potentially provide complete or 
partial protection against pertussis. Contacts of subjects, including infants, could benefit by herd 
immunity whereby the subjects are protected from pertussis disease and as a result cannot spread 
pertussis to their contacts. In summary, the prospect of direct benefit due to participation in this 
study exists for pregnant subjects and their fetuses/infants.   
There may be no direct personal benefit of participation. There is potential that BOOSTRIX 
administered to pregnant women may cause harm in the infants if primary responses to pertussis-
containing vaccines are adversely affected. The potential societal benefit is that BOOSTRIX may 
be found to be safe, well tolerated, and immunogenic in pregnant women and lead to levels of 
antibodies in infants thought to protect them, thus informing scientists and policymakers on the 
benefits of Tdap for pregnant women and their babies in Mali and other African countries.  
Close follow-up of pregnant subjects, and infants will potentially afford them additional benefit 
due to frequent access to experts in obstetrics, pediatrics, and immunizations. Pregnant women 
enrolled in this study will receive an ultrasound, which is standard of care in Mali, but 
unaffordable to the majority. Likewise, pregnant women will receive the recommended set of 
pregnancy blood tests (glucose, syphilis, toxoplasmosis, HIV serologies) in Mali at no additional 

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charge. While these are recommended in Mali, they are unaffordable to many women who must 
forego these tests. 

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3. 
OBJECTIVES AND OUTCOME MEASURES  
3.1. 
Study Objectives 
3.1.1. 
Primary 
Safety and Tolerability: 
• To assess the safety and tolerability of a single 0.5 mL intramuscular injection of 
BOOSTRIX in pregnant women. 
• To assess the safety of a single maternal BOOSTRIX vaccination on the fetus and infant. 
Immunogenicity: 
• To assess the level of PT antibody at birth among infants whose mothers received a 
single dose of BOOSTRIX or Td while pregnant. 
3.1.2. 
Secondary 
Immunogenicity: 
• To assess the antibody response to BOOSTRIX vaccine antigens in pregnant women one 
month after receipt of BOOSTRIX, at the time of delivery, and at 6 months after delivery. 
• To compare the antibody levels of BOOSTRIX vaccine antigens at birth (cord blood) and 
6 weeks of age (before receiving any infant doses of Diphtheria, Tetanus, and whole-cell 
Pertussis (DTwP)) in infants whose mothers received BOOSTRIX or Td during 
pregnancy. 
• To assess placental antibody transfer by determining the ratio of maternal and infant 
BOOSTRIX -specific antibody responses at delivery. 
• To assess interference with infant antibody responses to DTwP either prior to the second 
dose of the primary DTwP series, at approximately 10 weeks of age (in ½ of subjects), or 
approximately one month after the third dose of the primary DTwP series, at 
approximately 18 weeks of age (in ½ of subjects), and at 6 months of age (all subjects). 
 
 

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3.1.3. 
Exploratory 
Immunogenicity: 
• To assess the effects of maternal age, parity, gestational age (GA) at which the vaccine is 
given, GA at delivery, and infant birthweight on antibody responses to BOOSTRIX in 
pregnant women at time of delivery, and in their newborn infants at birth. 
• To assess maternal secretory immunity through measurement of breast milk antibodies to 
Tdap vaccine antigens in women at the time of delivery, at 6 weeks postpartum, at 10 
weeks (in ½ of women) or 18 weeks (in ½ of women) postpartum, and at 6 months after 
delivery. 
• To assess the cytokine profile after stimulation in vitro with diphtheria, tetanus and 
pertussis antigens of peripheral blood mononuclear cells (PBMC) obtained from women 
before and one month after receiving Tdap or Td. 
• To assess the cytokine profile after stimulation in vitro with diphtheria, tetanus, and 
pertussis antigens of PBMC obtained from infants before the first dose of DTwP 
(approximately 6 weeks of age) in all subjects, one month after the first dose of DTwP 
(approximately 10 weeks of age) in ½ of infants, one month after the last dose of DTwP 
(approximately 18 weeks of age) in ½ of infants, and at 6 months of age in all infants. 
3.2. 
Study Outcome Measures 
3.2.1. 
Primary 
Safety and Tolerability: 
• Safety in pregnant women: Frequency and severity of study vaccine-related serious 
adverse events (SAEs), and all SAEs in pregnant women from study vaccination through 
6 months postpartum, description and comparison between those receiving BOOSTRIX 
and Td. 
• Safety in pregnant women and fetuses/infants: Frequency and severity of adverse events 
specific to pregnancy, in pregnant women and their infants (as delineated in Section 
9.2.4), description and comparison between those receiving BOOSTRIX and Td. 
• Tolerability in pregnant women: Frequency and severity of solicited injection site and 
systemic reactogenicity events from study vaccination until 7 days following vaccination 
(Day 8). 
• Tolerability in pregnant women: Frequency and severity of all unsolicited non-
seriousAEs from day of study vaccination to Day 31, description and comparison 
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• Safety in the infants: Frequency and severity of study vaccine-related serious adverse 
events, and all SAEs in infants from birth through 6 months of age, description and 
comparison between infants born to women vaccinated with BOOSTRIX and Td. 
Immunogenicity: 
• Infant humoral immunity: Geometric Mean Concentration (GMC) of serum IgG 
antibodies to PT as measured by Enzyme-Linked Immunosorbent Assay (ELISA) at birth 
between infants born to women vaccinated with BOOSTRIX and Td. 
3.2.2. 
Secondary 
Immunogenicity: 
• Maternal humoral immunity: GMC of serum IgG antibodies to Tdap vaccine antigens 
(PT (Pertussis Toxin), FHA (Filamentous Hemagglutinin), PRN (Pertactin), tetanus, 
diphtheria) as measured by ELISA in pregnant women one month after receipt of 
BOOSTRIX or Td, at the time of delivery, and 6 months after delivery. 
• Infant humoral immunity: GMC of serum IgG antibodies to Tdap vaccine antigens (PT, 
FHA, PRN, tetanus, diphtheria) as measured by ELISA at birth and prior to receipt of 
first DTwP (approximately 6 weeks of age) among infants born to women vaccinated 
with BOOSTRIX compared to Td. 
• Placental antibody transfer: The geometric mean ratio (GMR) of maternal and infant-
specific Tdap-specific antibodies (PT, FHA, PRN, tetanus, diphtheria) as measured by 
ELISA at delivery after intrapartum receipt of BOOSTRIX versus Td. 
• Interference with infant responses among infants whose mothers received intrapartum 
BOOSTRIX compared to Td: GMC of antibodies to DTwP vaccine antigens (PT, FHA, 
PRN, Fimbriae 2 (FIM2), Fimbriae 3 (FIM3), tetanus, diphtheria) as measured by ELISA 
one month after the first dose of DTwP (~10 weeks of age, ½ of infants), one month after 
the third dose of DTwP vaccine (~18 weeks of age, ½ of infants), and at 6 months of age. 
 
 

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3.2.3. 
Exploratory 
Immunogenicity: 
• Maternal immunogenicity cofactors for maternal and neonatal anti-PT antibody responses 
following intrapartum BOOSTRIX: Maternal age (18-29, 30-39 years old), parity 
(primiparous vs. multiparous), GA at time of vaccination (14-17, 18-21, 22-26 weeks), 
GA at time of delivery (28-32, 33-36, 37 or more weeks), and infant birthweight as 
potential independent associations with PT GMC. 
• Maternal secretory immunity: GMC of breast milk IgG and IgA antibodies to Tdap 
vaccine antigens (PT, FHA, PRN, tetanus, diphtheria) as measured by ELISA in women 
at the time of delivery, at 6 weeks after deliver, at 10 weeks (in ½ of women) or 18 weeks 
(in ½ of women) after delivery, and 6 months after delivery after intrapartum receipt of 
BOOSTRIX versus Td. 
• Maternal cytokine responses: Cytokines produced by peripheral blood cells stimulated 
with DTwP vaccine antigens, as measured by multiplex assays, in women before and one 
month after receiving Tdap. Cytokines measured will include: Interferon (IFN)-γ, 
Inerleukin (IL)-10, IL-12p70, IL-12/IL-23p40, IL-13, IL-15, IL-16, IL-17A, IL-1α, IL-
1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, Tumor Necrosis Factor (TNF)-α, and TNF-β. 
• Infant cytokine responses: Cytokines produced by infant peripheral blood cells stimulated 
with DTwP antigens from infants whose mothers received intrapartum BOOSTRIX 
versus Td, measured by multiplex assays before the first dose (or umbilical cord blood), 
one month after the first dose of DTwP (~10 weeks of age, ½ of subjects), one month 
after the last dose of study vaccine (approximately 18 weeks, ½ of subjects), and at 6 
months of age. Cytokines measured will include: IFN-γ, IL-10, IL-12p70, IL-12/IL-
23p40, IL-13, IL-15, IL-16, IL-17A, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, 
TNF-α, and TNF-β. 

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4. 
STUDY DESIGN 
This is a phase II, single center, randomized, double-blind, active-controlled study in which 200 
healthy pregnant women, ages 18 through 39 years, inclusive, will be randomly allocated in a 2:1 
ratio to receive either Tdap (BOOSTRIX) or Td at 14 0/7 weeks through 26 6/7 weeks estimated 
GA. After signing an informed consent form (ICF), all subjects will undergo a review of current 
and past medical history, current and prior medication use, and recent vaccination history. A 
physical examination performed as part of routine antenatal care or a study-specific brief exam 
may be used to determine eligibility. For the fetuses of pregnant subjects, GA will be established 
by ultrasound, whenever possible, in combination with date of last menstrual period (LMP), 
when available, and fundal height. 
Eligibility will be confirmed, and the subject will be enrolled in the study. Each subject will 
receive prenatal care consistent with national guidelines and with local standards as practiced by 
clinicians caring for pregnant women and delivering neonates in the study area. In Mali, this 
includes hemoglobin, sickle cell test, Rh group, HIV, syphilis, toxoplasmosis, and rubella 
serology and urine glucose and protein at the first presentation for antenatal care, urine albumin 
and glucose at each subsequent visit and ultrasound at 22 and 32 weeks gestation. 
At the time of randomization to vaccine allocation, women will also be randomized to a schedule 
of postpartum visits for specimen collection. All women-infant pairs will have specimens 
collected at birth, at 6 weeks after delivery, and at 6 months after delivery.  In addition, women-
infant pairs will be allocated in a 1:1 ratio to have specimen collections at one month following 
the first dose of DTwP (approximately 10 weeks of age), or at one month following the third 
dose of DTwP (approximately 18 weeks of age). Thus, pregnant subjects will typically have 7 
clinic visits (only 6 if delivery occurs before the first visit after vaccination, on Day 31): 3 
antenatal visits (Screening Visit, Study Day 1 and Study Day 31, unless delivery occurs first), 1 
visit at the time of delivery, and 3 postpartum visits – at 6 weeks, at 10 or 18 weeks postpartum, 
and a final visit 6 months postpartum. The maternal subject will also undergo 2 home visits after 
vaccination to assess her health status (Days 4 and 8). 
Infants born to the pregnant subjects will have 4 study visits: at birth, at approximately 6 weeks 
of age (day of first DTwP), at approximately 10 or 18 weeks of age (one month after first or third 
dose of DTwP, respectively), and at 6 months of age. 
Blood and colostrum/breast milk samples for immunologic assessments will be collected as 
described below: 
• 
Pregnant subject: approximately 30 mL of blood will be collected on Study Day 1 (prior 
to vaccination), Study Day 31 (one month after vaccination), at delivery, and at 6 months 
postpartum in all women. 
• 
Infants: up to 30 mL of umbilical cord blood will be collected at delivery and 5 mL 
peripheral blood will be collected at 6 weeks (prior to first dose of DTwP), either the 10-

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week or 18-week (per randomized study schedule), and 6 months of age in all infants. If 
cord blood cannot be obtained, 2-5 mL of peripheral blood will be collected by 
venipuncture within 72 hours of birth, before discharge, when possible. Cord blood is 
preferred over venipuncture. 
• 
At delivery, and at the 6-week, either the 10-week or 18-week (per randomized study 
schedule), and the 6-month postpartum visit, a 10-20mL sample of colostrum or breast 
milk will be collected. When possible, the first breast milk or colostrum collection will 
occur while the mother and baby are admitted for delivery and postpartum care. When 
not possible, it may be collected any time within the first 4 days of life. 
Safety will be monitored from the time of signing of the ICF until trial termination. 
For additional details on study procedures and evaluations and study schedule by type of visit or 
study visits/days, see Sections 7 and 8 and Appendix A. 

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5. 
STUDY ENROLLMENT AND WITHDRAWAL 
Subject Inclusion and Exclusion Criteria must be confirmed by a study clinician licensed to make 
medical diagnoses. 
No exemptions are granted on Subject Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Questions about eligibility will be directed toward the DMID Medical Officer. 
5.1. 
Subject Inclusion Criteria 
Prospective subjects must meet all of the following inclusion criteria to be considered eligible for 
enrollment: 
1. Healthy pregnant woman 18-39 years of age, inclusive. 
2. Singleton fetus, with estimated gestational age of 14 0/7 through 26 6/7 weeks gestation, 
inclusive, on the day of study vaccination. 
3. Provide written consent after the nature of the study has been explained according to local 
regulatory requirements and prior to any study procedures.1 
4. In good health as determined by medical history, targeted physical examination2,3, vital 
signs4,5,6, and clinical judgment of the investigator.  
                                                 
1 Prior to obtaining individual informed consent for each subject, the investigators will obtain community consent by discussing 
the trial with all the appropriate local groups, as necessary, to obtain permission to approach the subjects. Written, informed 
consent for participation in the trial will be obtained by the investigators from all individual subjects. The consent forms will be 
written in French, the official language of Mali, and will be translated into Bambara, the most prevalent of the local languages, 
and recorded on audiotape. 
2 if indicated based on medical history, to evaluate acute or currently ongoing chronic medical diagnoses or conditions that would 
affect the assessment of eligibility and safety of subjects. Chronic medical diagnoses or conditions being actively managed must 
be within acceptable limits in the last 180 days. Any prescription change that is due to change of health care provider, insurance 
company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be considered a deviation 
of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome, as determined by the 
site principal investigator or appropriate sub-investigator, will not be considered a deviation of this inclusion criterion. Subjects 
may be on chronic or as needed (prn) medications if, in the opinion of the site principal investigator or appropriate sub-
investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not 
indicate a worsening of medical diagnosis or condition. Similarly, medication changes subsequent to enrollment and the study 
vaccination are acceptable provided the subject is asymptomatic, condition stable, and there is no additional risk to the subject or 
interference with the evaluation of responses to the study vaccination.   
3 Physical examination performed as part of routine antenatal care of a study-specific brief exam may be used to determine 
eligibility.                                                                                                                 
4 Oral temperature less than 37.8°C.                                                                                                                         
5 Pulse 55 to 100 bpm, inclusive.                                                                                                                        
6 Systolic blood pressure 90 to 140 mm Hg, inclusive. Diastolic blood pressure 55 to 90 mm Hg, inclusive. 
 

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5. Ability to comprehend and comply with all study procedures, as determined by the 
investigator determining eligibility, and availability for follow-up. 
6. Willing to allow study staff to gather pertinent medical information, including pregnancy 
outcome data and medical information about her infant. 
5.2. 
Subject Exclusion Criteria 
Prospective subjects must not meet any of the following exclusion criteria to be considered 
eligible for enrollment: 
1. History of illness or an ongoing illness that, in the opinion of the investigator, may pose 
additional risk to the subject or her fetus if she participates in the study. 
2. Infection requiring systemic antibiotics or antiviral treatment within the 7 days prior to study 
vaccination. 
3. Fever (oral temperature ≥ 37.8°C/100.0°F) or other acute illness within 3 days prior to study 
vaccination.7  
4. Known active neoplastic disease8, anticancer chemotherapy, or radiation therapy (cytotoxic) 
within 3 years prior to study vaccination.  
5. History of any hematologic malignancy at any time.  
6. A history of a serious adverse event following previous immunizations (e.g., Bell’s Palsy, 
Guillain-Barre Syndrome, encephalopathy), or history of progressive neurologic disorders. 
7. Known or suspected disease that impairs the immune system including known or suspected 
HIV infection or HIV-related disease. 
8. Receipt of immunosuppressive therapy.9 
9. Known hepatitis B or hepatitis C infection, by history or medical record. 
                                                 
7 An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site 
principal investigator or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety 
parameters as required by the protocol. 
8 excluding non-melanoma skin cancer. 
9 including long-term use of glucocorticoids: oral, inhaled, intranasal or parenteral prednisone ≥ 20 mg/day or equivalent for 
more than 2 weeks within the 30 days prior to enrollment. Use of topical corticosteroids is allowed. 
 

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10. Behavioral or cognitive impairment or psychiatric disease10 that, in the opinion of the 
investigator, may interfere with the subject’s ability to participate in the trial.  
11. Have a history of alcohol or drug abuse within 5 years prior to study vaccination.11 
12. Known hypersensitivity or allergy to any component of the study vaccine (formaldehyde, 
alum).  
13. History of severe allergic reaction (e.g., anaphylaxis) after a previous dose of BOOSTRIX or 
any other vaccine directed against tetanus, diphtheria, or pertussis. 
14. Receipt or planned receipt of any live licensed vaccine within 30 days before or after 
vaccination or any inactivated licensed vaccine within 14 days before or after vaccination. 
15. Receipt of immunoglobulin (except RhoGAM, which is allowed) or other blood products 
within 90 days prior to study vaccination. 
16. Receipt of an experimental agent or device within 30 days prior to vaccination, or the 
expected receipt of an experimental agent12 (other than BOOSTRIX) during this trial-
reporting period.  
17. High risk for serious obstetrical complication (refer to ACOG Practice Bulletins for 
definitions, as necessary).13 
18. Pregnant with a fetus with a known or suspected major congenital14 anomaly or genetic 
abnormality.  
19. Study personnel or immediate family members (brother, sister, child, parent) or the spouse of 
study personnel. 
                                                 
10 includes hospitalization for psychiatric illness, suicide attempt, or confinement for danger to self or others within 10 years prior 
to study vaccination. 
11 that is believed by the site investigator to potentially interfere with the subject’s ability to participate in the study. 
12 Experimental agents include vaccines, drugs, biologics, devices, blood products, and medications. Subjects who have received 
a licensed product, as a subject in a clinical trial, within 30 days prior to vaccination or who are expecting to enroll in such a trial 
during the study period will also be excluded. Observational studies, surveys, and other studies that do not involve experimental 
agents or devices are allowed. 
13 including the following: (a)gestational hypertension (well controlled history of essential or gestational hypertension, as 
evidenced by normal BPs as defined above, is allowed), (b)gestational diabetes not controlled by diet and exercise (the use of 
insulin or glyburide to control gDM, at the time of enrollment, is exclusionary), (c)current pre-eclampsia or eclampsia, (d)known 
current multiple gestation, (e)history of preterm delivery before EGA 35 weeks 0 days or current preterm labor, and/or (f)known 
intrauterine fetal growth restriction (defined as ultrasound confirmation of an estimated fetal weight that is less than the 10th 
percentile for gestational age). 
14 Congenital anomalies and definitions of major congenital anomalies are discussed in detail in Section 9.1 under Assessment of 
Safety. 

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5.3. 
Treatment Assignment Procedures 
5.3.1. 
Randomization Procedures 
Per International Council for Harmonisation (ICH) guideline E6: Good Clinical Practice (GCP), 
screening records will be kept at each participating VTEU site to document the reason why an 
individual was screened, but failed trial entry criteria. The reasons why individuals failed 
screening will be recorded in the Data Coordinating Center’s (DCC) Advantage eClinicalSM 
(Electronic Data Capture System). 
Once consented and upon entry of demographic data and confirmation of eligibility for this trial, 
the subject will be enrolled. Pregnant subjects will be randomly allocated to 1 of 2 treatment 
arms; 133 will be assigned to receive BOOSTRIX and 67 will be assigned to receive Td. No 
subject will receive more than one vaccination as part of enrollment in this study. All doses will 
be administered intramuscularly in the arm chosen by the subject. 
At the time of enrollment subjects will also be assigned a study schedule. Women will be 
randomized in a 1:1 ratio for the third specimen collection after delivery/birth for mother/infant 
pairs at either one month following the first dose of DTwP (approximately 10 weeks of age) or 
one month following the third dose of DTwP (approximately 18 weeks of age). 
When internet access allows, enrollment and randomization of subjects will be done online using 
the enrollment module of Advantage eClinical. A back-up randomization process will be in place 
in the event internet access is unavailable. The randomization schemes for assignment to 
treatment arm and assignment to study schedule will be prepared by statisticians at the DCC and 
included in the enrollment module for this trial. Advantage eClinical will assign each subject to a 
treatment arm and study schedule after the demographic and eligibility data have been entered 
into the system. Instructions for use of the enrollment module are included in the Advantage 
eClinical User’s Guide. A designated individual or individuals at each participating VTEU site 
will be provided with a treatment code list for emergency unblinding purposes, which will be 
kept in a secure place. 
Subjects who sign the informed consent form and are randomized but do not receive study 
vaccine may be replaced. Subjects who sign the informed consent form and are randomized and 
vaccinated, and subsequently withdraw or are withdrawn or terminated from this trial or are lost 
to follow-up, will not be replaced. 
 
 

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The randomization scheme for this trial is presented in Table 1. 
Table 1: Treatment Arms and Study Vaccine to be Administered 
 
Treatment Arm 
 
Subject Group 
 
BOOSTRIX 
Td 
 
Total 
Pregnant women 
133 
67 
200 
5.3.2. 
Masking Procedures 
This is a double-blind study. Pregnant subjects, investigators, study personnel performing any 
study-related assessments following study vaccine administration, and laboratory personnel 
performing antibody assays will be blinded to treatment assignments. 
The randomization scheme will be generated by the DCC and provided to unblinded study 
personnel (i.e., research pharmacists or other trained/delegated personnel performing study 
vaccination preparations and unblinded study vaccine administrators) at each participating 
VTEU site or subcontracted site. 
The unblinded study vaccine administrator is a study personnel member credentialed to 
administer vaccines and may also participate in dose preparation but will not be involved in 
study-related assessments or have subject contact for data collection following study vaccine 
administration, for pregnant women or their infants. 
Data and Safety Monitoring Board (DSMB) may receive data in aggregate and presented by 
treatment arm (pregnant women, infants). The DSMB may also be provided with expected and 
observed rates of the solicited AEs in an unblinded fashion and may request the treatment 
assignment be unblinded for an individual subject if required for safety assessment. In the open 
session the DSMB may review data by subject group (pregnant women, infants) with all 
summaries for pregnant women and infants presented in aggregate over the treatment arms. In 
the closed session the DSMB may review unblinded data for the pregnant women and infant 
subject groups. 
5.3.3. 
Reasons for Withdrawal and Discontinuation of Study Product Administration 
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled. 
An investigator may also withdraw a subject from receiving the study product for any reason. 
Follow-up safety evaluations will be conducted, if the subject agrees.  If a subject withdraws or 
is withdrawn prior to completion of the study, the reason for this decision must be recorded in 
the data collection forms.  
The reasons, might include, but are not limited to the following: 

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• 
Subject no longer meets eligibility criteria 
• 
Subject meets individual halting criteria (reference to Section 9.5) 
• 
Subject becomes noncompliant 
• 
Medical disease or condition, or new clinical finding(s) for which continued 
participation, in the opinion of the investigator might compromise the safety of the 
subject, interfere with the subject's successful completion of this study, or interfere with 
the evaluation of responses 
• 
Subject lost to follow-up 
• 
Determined by a physician’s discretion to require additional therapy not indicated in the 
protocol to ensure subject’s health and well-being (or treatment failure, if applicable) 
• 
New information becomes available that makes further participation unsafe or 
unwarranted. 
• 
Termination of this trial 
• 
Subject withdrawal of consent 
The investigator should be explicit regarding study follow-up (e.g. safety follow-up) that might 
be carried out despite the fact the subject will not receive further study product.  If the subject 
consents, every attempt will be made to follow all AEs through resolution.  The procedures that 
collect safety data for the purposes of research must be inclusive in the original informed consent 
or the investigator may seek subsequent informed consent using an IRB/IEC-approved consent 
form with the revised procedures. 
The investigator will inform the subject that already collected data will be retained and analyzed 
even if the subject withdraws from this study.  
5.3.4. 
Handling of Withdrawals and Discontinuation of Administration 
The primary reason for withdrawal from this trial will be recorded on the Study Status data 
collection form. Subjects will be encouraged to complete the Early Termination Visit. The Early 
Termination Visit procedures are listed in Section 7.6. 
Every attempt will be made to follow all adverse events, including solicited injection site and 
systemic reactions, unsolicited non-serious adverse events, serious adverse events, and 
pregnancy outcomes, ongoing at the time of early withdrawal, through resolution as per 
applicable collection times defined for the specific type of adverse event. 
In the case of subjects who fail to appear for a safety follow-up assessment, extensive effort (i.e., 
three documented contact attempts via phone calls, e-mails, home visits, etc., made on separate 
occasions) will be made to locate or recall them, or at least to determine their health status. These 
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Subjects who withdraw, or are withdrawn or terminated from this trial, or are lost to follow-up 
after signing the informed consent form, randomization, and receipt of study vaccine will not be 
replaced. Subjects who withdraw, or are withdrawn or terminated from this trial, or are lost to 
follow-up after signing the informed consent form and randomization but before receipt of study 
vaccine may be replaced. 
5.3.5. 
Subject Replacement 
Subjects who sign the informed consent form and are randomized but do not receive study 
vaccine may be replaced. Subjects who sign the informed consent form and are randomized and 
vaccinated, and subsequently withdraw or are withdrawn or terminated from this study or are lost 
to follow-up, will not be replaced. The proposed sample size for the trial accounts for a 15% rate 
of subject loss.  
5.3.6. 
Termination of Study  
Although the sponsor has every intention of completing this trial, it reserves the right to 
terminate this trial at any time for clinical or administrative reasons. Reasons for termination 
include, but are not limited to, study closure due to DSMB review and recommendation and at 
the discretion of DMID. 
If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary. The investigator will provide a 
detailed written explanation of the termination to the IRB/IEC. 

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6. 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
6.1. 
Study Product Description 
BOOSTRIX 
BOOSTRIX (Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccine, 
Adsorbed) is a noninfectious, sterile, vaccine for intramuscular administration. It contains tetanus 
toxoid, diphtheria toxoid, and pertussis antigens (inactivated PT, formaldehyde-treated FHA, and 
PRN). The antigens are the same as those in INFANRIX, but BOOSTRIX is formulated with 
reduced quantities of these antigens. 
Tetanus toxin is produced by growing Clostridium tetani in a modified Latham medium derived 
from bovine casein. The diphtheria toxin is produced by growing Corynebacterium diphtheriae 
in Fenton medium containing a bovine extract. The bovine materials used in these extracts are 
sourced from countries which the United States Department of Agriculture (USDA) has 
determined neither have nor are at risk of bovine spongiform encephalopathy (BSE). Both toxins 
are detoxified with formaldehyde, concentrated by ultrafiltration, and purified by precipitation, 
dialysis, and sterile filtration. 
The acellular pertussis antigens (PT, FHA, and PRN) are isolated from Bordetella pertussis 
culture grown in modified Stainer-Scholte liquid medium. PT and FHA are isolated from the 
fermentation broth; PRN is extracted from the cells by heat treatment and flocculation. The 
antigens are purified in successive chromatographic and precipitation steps. PT is detoxified 
using glutaraldehyde and formaldehyde. FHA and PRN are treated with formaldehyde. 
Tetanus and diphtheria toxoid potency is determined by measuring the amount of neutralizing 
antitoxin in previously immunized guinea pigs. The potency of the acellular pertussis 
components (inactivated PT, formaldehyde-treated FHA, and PRN) is determined by ELISA on 
sera from previously immunized mice. 
BOOSTRIX is manufactured by GSK and is approved for use in the US in persons 10 years and 
old and by the WHO for persons 4 years and older. In Mali, the vaccine is not approved by the 
national drug authority. 
Tetanus and Diphtheria Toxoids Adsorbed (Td) Control Vaccine 
The Td control vaccine is prequalified by WHO and will be provided by the Ministry of Health 
in Mali, as per standard of care.  It is indicated for the active immunization of adults and children 
7 years of age and older against diphtheria and tetanus.  Vaccine manufacturer details will be 
provided in the protocol-specific Manual of Procedures (MOP). 
6.1.1. 
Acquisition 
BOOSTRIX will be provided by GSK Biologicals. Upon request by DMID, BOOSTRIX will be 
shipped to the following address: 

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DMID Clinical Materials Services (CMS) 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350 
Fax: 240-477-1360 
Email: DMID.CMS@ThermoFisher.com 
Study vaccine (BOOSTRIX) will be provided through the DMID CMS to the each VTEU 
participating subcontracted VTEU site prior to the start of this trial upon request and with prior 
approval from DMID. Should the site principal investigator require additional BOOSTRIX 
during this trial, further instructions on requesting study vaccine will be provided in the protocol-
specific MOP. 
Td control vaccine will be provided by Malian Expanded Program on Immunization (EPI) as per 
standard recommendations for vaccination of pregnant women. 
6.1.2. 
Formulation, Packaging, and Labeling 
BOOSTRIX 
Formulation 
Each 0.5-mL dose of vaccine is formulated to contain 5 Lf of tetanus toxoid, 2.5 Lf of diphtheria 
toxoid, 8 mcg of inactivated PT, 8 mcg of FHA, and 2.5 mcg of PRN (69 kiloDalton outer 
membrane protein). Each 0.5-mL dose contains aluminum hydroxide as adjuvant (not more than 
0.39 mg aluminum by assay), 4.4 mg of sodium chloride, ≤100 mcg of residual formaldehyde, 
and ≤100 mcg of polysorbate 80 (Tween 80).   
Storage 
The vaccine must be stored at 2°C to 8°C (35°F to 46°F). Do not freeze. 
Packaging and Labeling 
The vaccine is supplied as 0.5 mL single-dose prefilled syringes. The tip caps of the prefilled 
syringes contain natural rubber latex; the plungers are not made with natural rubber latex. 
The study product will be labeled according to manufacturer specifications and include the 
statement “Caution: New Drug – Limited by Federal Law to Investigational Use.” 
Td Control Vaccine 
Formulation 
The vaccine contains purified tetanus and diphtheria toxoids, with a reduced dose of the 
diphtheria component. One dose of 0.5 mL has a potency of less than 30 IU of diphtheria toxoid, 
and not less than 40 IU of tetanus toxoid. The toxoids are adsorbed onto at least 1.5 mg 
aluminum phosphate. Thimerosal 0.1 mg/ml is used as a preservative. 
 
 

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Storage 
The vaccine should be protected from light and must be stored at 2°C to 8°C (36°F to 46°F). Do 
not freeze. 
Packaging  
The vaccine is supplied as 10-dose vials of 5 mL.  
Multi-dose vials of Td control vaccine from which one or more doses of vaccine have been 
removed during an immunization session may be used in subsequent immunization sessions for 
up to a maximum of 4 weeks, provided that all of the following conditions are met: 
• The expiry date has not passed; 
• The vaccines are stored under appropriate cold chain conditions; 
• The vaccine vial septum has not been submerged in water; 
• Aseptic technique has been used to withdraw all doses; 
• The vaccine vial monitor, if attached, has not reached the discard point. 
6.1.3. 
Product Storage and Stability 
The temperature of the storage unit will be recorded manually daily (excluding non-business 
days and holidays as applicable), continuously monitored during the duration of this trial per 
each participating VTEU site’s standard operating procedures, and documentation will be 
maintained. If the temperature fluctuates outside of the required range, the affected study 
product(s) will be quarantined at the correct storage temperature and labeled as ‘Do Not Use’ 
until further notice. The research pharmacist or other study staff member designated to oversee 
the storage of the study product, will alert the site principal investigator and study coordinator if 
the temperature fluctuates outside of the required range. In the event the temperature fluctuates 
outside of the required range, including accidental freezing or disruption of the cold chain, the 
affected study product(s) will not be administered without review and specific instructions from 
DMID. The site principal investigator or responsible person will notify the protocol principal 
investigator and immediately contact the DMID Product Support Team at 
DMIDProductSupportTeam@niaid.nih.gov for further instructions before any additional study 
vaccinations are administered. Based on the information collected, DMID and/or the 
manufacturer will determine whether the affected study product(s) can be used. If it cannot be 
used, the site will receive specific instructions on how to return the affected study product(s) to 
the DMID CMS or destroy it on site. Additional instructions for quarantine will be provided in 
the protocol-specific MOP. 
6.2. 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
See the Prescribing Information and protocol-specific MOP for detailed information on the 
preparation, labeling, storage, and administration of study vaccine for each treatment arm. Study 

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vaccine preparation will be performed by the participating VTEU site’s (or subcontracted site’s) 
research pharmacist or designee on the same day of study vaccine administration. 
Visually inspect the study vaccines upon receipt and prior to use. If the study product(s) 
appear(s) to have been damaged, contaminated or discolored, contain visible particulate matter, 
or if there are any concerns regarding its integrity, do NOT use the affected study product(s). The 
affected study product(s) must be quarantined at 2°C to 8°C (35.6°F to 46.4°F) and labeled as 
‘Do Not Use’ (until further notice). The site principal investigator or responsible person should 
immediately contact the DMID Product Support Team at 
DMIDProductSupportTeam@niaid.nih.gov and DMID Clinical Project Manager for further 
instructions before any additional study vaccinations are administered. Based on the information 
collected, DMID and/or the manufacturer will determine whether the affected study product(s) 
can be used. If it cannot be used, the site will receive specific instructions on how to return the 
affected study product(s) to the DMID CMS or destroy it on site. If the study vaccines are 
unusable, study personnel will use another from the study supply. Replacement study vaccine 
(BOOSTRIX only) may be requested by contacting DMID. Additional instructions for 
quarantine and DMID contact information are provided in the protocol-specific MOP. 
6.2.1. 
BOOSTRIX 
Dosage 
BOOSTRIX will be administered intramuscularly as a single 0.5 mL dose. 
Preparation 
Visually inspect the BOOSTRIX vaccine upon receipt and prior to use. If the study product(s) 
appear(s) to have been damaged, contaminated or discolored, contain visible particulate matter, 
or if there are any concerns regarding its integrity, do NOT use the affected study product(s). The 
affected study product(s) must be quarantined at 2°C to 8°C (35.6°F to 46.4°F) and labeled as 
‘Do Not Use’ (until further notice). The site principal investigator or responsible person should 
immediately contact the DMID Product Support Team at 
DMIDProductSupportTeam@niaid.nih.gov and DMID Clinical Project Manager for further 
instructions before any additional study vaccinations are administered. 
No study vaccine preparation is required for the BOOSTRIX vaccine as it is contained in a 
prefilled syringe and the entire contents will be administered to subjects’ pretreatment 
assignment. Prior to administration, shake vigorously to obtain a homogeneous, turbid, white 
suspension. Ensure that the plunger rod is firmly attached to the rubber stopper by turning the 
plunger clockwise until slight resistance is felt. Do not over tighten. Remove syringe LUER Tip-
cap and needle cap. Attach needle by pressing and twisting in a clockwise rotation until secured 
to the syringe. 
6.2.2. 
Td Control Vaccine 
Dosage 

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Td control vaccine will be administered intramuscularly as a single 0.5 mL dose. 
Preparation 
The Td control vaccine vial should be shaken before use to homogenize the suspension. The Td 
control vaccine will be prepared by withdrawing sufficient volume of Td from multidose vial to 
administer a 0.5 mL dose. Further details on the handling of the multi-dose vials will be 
described in the protocol-specific MOP. 
6.2.3. 
Administration 
Study vaccine will be administered as a single 0.5 mL intramuscular (IM) injection into the 
deltoid muscle of the subject’s preferred arm. The vaccine must NOT be administered 
intravenously, subcutaneously, or intradermally. The protocol-specific MOP contains additional 
information on how to administer IM injections. 
Each dose of study vaccine will be administered as soon as possible, but no longer than 30 
minutes after preparation. The prepared syringe must remain at room temperature until 
administered. 
6.3. 
Modification of Study Intervention/Investigational Product for a 
Subject 
There will be no dose modifications. All subjects will receive a single 0.5 mL dose of 
BOOSTRIX or Td control vaccine. For pregnant women, the dose will be administered between 
14 0/7 weeks gestation and 26 6/7 weeks gestation. 
6.4. 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
After receipt of the study vaccine, the site principal investigator is responsible for its distribution 
and disposition and has ultimate responsibility for study vaccine accountability. The site 
principal investigator may delegate distribution and disposition authority to each participating 
VTEU site’s (or subcontracted site’s) research pharmacist or designee. Each participating VTEU 
site’s research pharmacist or other qualified delegated research staff member will be responsible 
for maintaining complete records and documentation of study vaccine receipt, accountability, 
dispensing, temperature and storage conditions, and final disposition of the study vaccine. All 
study vaccine, whether administered or not, will be documented on the appropriate study product 
accountability record or dispensing log. The sponsor's monitoring staff will verify each 
participating VTEU site’s study product accountability records and dispensing logs per the site 
monitoring plan. 
Used and unused study vaccine will be retained until monitored and released for disposition as 
applicable. This may occur on an ongoing basis for used study vaccine. Final disposition of the 
unused study vaccine will be determined by DMID and communicated to the subcontracted sites 
by the DMID Clinical Project Manager. 

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6.5. 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product/Investigational Device  
Subject compliance is not anticipated to be an issue. The study vaccine is given as one dose at a 
single visit according to treatment assignment, administered by an unblinded study vaccine 
administrator via IM injection. Administration will be documented on the appropriate data 
collection form and entered into the electronic Case Report Form (eCRF). 
6.6. 
Concomitant Medications/Treatments 
Subject receipt of any medications, therapies, or vaccines will be recorded on the appropriate 
data collection form. Concomitant medications will include all current medications and 
medications taken within the 90 days prior to signing the informed consent form until discharge 
after delivery for pregnant women. For infants, concomitant medications will be recorded from 
birth until the day of life 180 visit. 
Medications/vaccinations reported in the eCRF are limited to those taken within 30 days prior to 
study vaccination through discharge after delivery for pregnant women and the day of life 180 
visit for infants. Participants cannot plan to receive a live vaccine within 30 days following study 
vaccination, nor should they plan to receive an inactivated vaccine within 14 days following 
study vaccination. Prescription medications, vaccinations, over-the-counter drugs, herbals, 
vitamins, and supplements will be recorded. Use of any new post-study vaccination medication 
that is not considered standard of care for conditions associated with pregnancy should prompt 
evaluation for the presence of a new diagnosis or condition. 
Medications that might interfere with the evaluation of the investigational product should be 
avoided unless necessary. Medications in this category include the prohibited medications per 
the Subject Exclusion Criteria (see Section 5.2). In addition, the site principal investigator or 
sub-investigator may identify other medications that should not be used due to a risk to subject 
safety or assessment of reactogenicity and immunogenicity. 

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7. 
STUDY SCHEDULE 
Complete study schedule details listed by type of visit are described below. Refer also to 
Sections 4, 5, and 8 and Appendix A. 
7.1. 
Recruitment 
We will enroll 200 pregnant women in their first and second trimesters, 18 to 39 years old, 
inclusive. The infants of the pregnant subjects will be followed from birth to 6 months of age. 
Subjects must be in good health and meet all eligibility criteria. They will be enrolled at a 
referral health center of Commune I with prenatal and labor/delivery capabilities in Bamako, 
Mali. The target population will reflect the community at large. Estimated time to complete 
enrollment in this study is approximately 2 months of startup activities and 6 months of 
enrollment from first to last enrollee joining. Means of recruitment may include flyers, word of 
mouth, and discussions about the study in the clinics, community, and health care clinic 
outreach. The Malian research team may also use group meetings to explain the nature of the 
study to prospective subjects, prior to engaging in the individual informed consent process. The 
local IRB will approve all materials prior to use. 
Subject Inclusion and Exclusion Criteria will be assessed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572. This clinician will either be the site 
principal investigator or be delegated by the site principal investigator to perform this role. 
No exemptions are granted on Subject Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Questions about eligibility should be directed toward the DMID Medical Officer. 
7.2. 
Screening 
Screening Visit, Day -30 to Day 1: Clinic Visit, Pregnant Women (Visit 00 or V00) 
Potential subjects will be screened for eligibility within 30 days prior to the administration of the 
study vaccination. The following activities will be performed: 
• 
If not performed at the time of recruitment, subjects will be provided with a description 
of the study (purpose and study procedures) and asked to read and sign the informed 
consent form. The informed consent form will be signed prior to performing any study 
procedures, including any screening procedures. 
• 
Eligibility criteria will be reviewed with prospective subjects. 
• 
Complete medical history, including vaccination history, will be obtained by chart review 
and supplemented by interview of the subject to evaluate for eligibility. 
• 
All concomitant medications and vaccinations, as determined by chart review and subject 
interview, taken within 90 days prior to signing the informed consent form, will be 

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reviewed with subjects. Medications/vaccinations reported in the eCRF are limited to 
those taken within 30 days prior to study vaccination. 
• 
Obtain vital signs (oral temperature, pulse, blood pressure), height, and weight. Subjects 
will be asked not to eat or drink anything hot or cold, or smoke within 10 minutes prior to 
taking an oral temperature. 
• 
A targeted physical examination may be performed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or 
sub-investigator, if indicated based on review of complete medical history. For pregnant 
women, an examination performed by her own obstetrical clinician may also provide data 
when a targeted exam is called for. 
• 
An ultrasound will be performed to date the pregnancy. 
• 
Subjects will be given a research identification card that includes a photograph. 
7.3. 
Enrollment/Baseline 
Enrollment and Vaccination Visit, Day 1: Clinic Visit, Pregnant Women (Visit 01 or V01) 
• 
Reconfirm subject’s willingness to participate prior to performing any study procedures, 
including administration of the study vaccination. 
• 
Obtain informed consent (if screening and enrollment visits have been combined). 
• 
Review eligibility criteria with subjects prior to the study vaccination to ensure 
eligibility. 
• 
Complete medical history and any updates obtained by interview and/or review of 
medical charts of subjects since the screening visit will be reviewed with subjects prior to 
the study vaccination to ensure eligibility. 
• 
All concomitant medications and vaccinations will be reviewed with subjects prior to the 
study vaccination for accuracy and completeness. Any new concomitant 
medications/vaccinations taken since the screening visit will be reviewed with subjects 
and used in the assessment for eligibility, prior to the study vaccination. Medications 
reported in the eCRF are limited to those taken within 30 days prior to the study 
vaccination. Subjects will be reminded they should not plan to receive any live or 
inactivated vaccine within 30 or 14 days, respectively, after study vaccination. 
• 
Vital signs, namely oral temperature, pulse, and blood pressure, will be obtained prior to 
the study vaccination. Vital signs assessed on Day 1 prior to the study vaccination will be 
considered as baseline. Subjects will be asked not to eat or drink anything hot or cold, or 
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• 
Height and weight will be obtained, if not done on screening visit. 
• 
A targeted physical examination may be performed prior to the study vaccination by a 
study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator, if indicated based on review of 
complete medical history and any updates obtained by interview of subjects or medical 
chart review since the screening visit. For pregnant women, an examination performed by 
her own obstetrical clinician may also provide data when a targeted exam is called for. 
• 
Approximately 30 mL of venous blood will be collected immediately prior to the study 
vaccination for baseline serology and cytokine assays. 
• 
Subjects will be enrolled in Advantage eClinical and assigned to treatment arm 
(BOOSTRIX or Td) and post-partum study schedule. 
• 
Pre-administration solicited event assessments will be performed prior to study 
vaccination to establish baseline. Subjects will then receive a single dose of study vaccine 
via IM injection into the deltoid muscle of the subject preferred arm. The site of injection 
(right or left arm) and time of administration will be recorded on the appropriate data 
collection form. Subjects will be observed in the clinic for at least 30 minutes after the 
study vaccination. The study vaccination site will be examined, post-administration 
solicited event assessments will be performed, and any AE/SAEs will be assessed and 
recorded on the appropriate data collection form prior to discharge from the clinic. 
• 
Subjects’ home addresses will be recorded so study personnel may complete follow-up 
home visits. 
• 
Subjects will be instructed to notify the study center if they develop any severe reactions 
after the study vaccination. If the site principal investigator or appropriate sub-
investigator deems the reaction severe enough, s/he will give further instructions on the 
proper course of action, including a return to the clinic for immediate evaluation if 
appropriate. 
• 
It is possible the screening and enrollment visits may occur at the same time. 
7.4. 
Follow-up 
Follow-up visits are scheduled in reference to the study vaccination date (Day 1) as indicated for 
each visit window. The types of follow-up visits are described below as home visits, and clinic 
visits. See Appendix A for specific study visits/days and study procedures and evaluations to be 
conducted at each follow-up visit. At any time during the follow-up period of pregnant women, 
study personnel may review her medical chart to gather information about the current pregnancy 
that is relevant to the conduct of this study.  If a woman experiences a stillbirth, all specimen 

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collection will stop, however the mother will be followed for safety until 6 months after the 
stillbirth. 
7.4.1. 
Clinic or Home Visits 
These visits will occur in person at the clinic or may be conducted by trained field officers at the 
participants’ homes. 
7.4.1.1. 
Post Study Vaccination Follow-up Visit, Day 4 (±1 d): Home Visit, Pregnant 
Women (Visit 02 or V02) 
• 
This visit will take place in the clinic or alternatively by trained field workers (FWs). 
• 
Study personnel will obtain interim medical history, including an assessment for new 
medical conditions by interview of subjects and note any changes since the previous visit. 
• 
Study personnel will review solicited AEs with subjects and assess and record all 
solicited data, AE/SAEs, unsolicited AEs, and concomitant medications/vaccinations on 
the appropriate data collection forms. FWs will be trained on the assessment of local and 
systemic reactogenicity. If the subject reports an AE that is either not included among the 
solicited AEs or is a grade 3 solicited AE, then the FW will contact a study clinician. The 
study clinician will either visit the participant at home or the participant will be referred 
to the study health center based on the FW’s assessment. 
7.4.1.2. 
Post Study Vaccination Follow-up Visit, Day 8 (+3 d): Home Visit, Pregnant 
Women (Visit 03 or V03) 
• 
This visit will take place in the clinic or alternatively by trained FWs. 
• 
Study personnel will obtain interim medical history, including an assessment for new 
medical conditions, by interview of subjects and note any changes since the previous 
visit.  
• 
Study personnel will review solicited AEs with subjects and assess and record all 
solicited data, AE/SAEs, unsolicited AEs, and concomitant medications/vaccinations on 
the appropriate data collection forms. FWs will be trained on the assessment of local and 
systemic reactogenicity. If the subject reports an AE that is either not included among the 
solicited AEs or is a grade 3 solicited AE, then the FW will contact a study clinician. The 
study clinician will either visit the participant at home or the participant will be referred 
to the study health center based on the FW’s assessment. 

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7.4.2. 
Clinic Visits 
7.4.2.1. 
Immunology and Safety Follow-up Visit, 30 Days Post Study Vaccination Visit, 
Day 31 (±4 d): Clinic Visit, Pregnant Women (Visit 04 or V04) 
• 
Study personnel will reconfirm subject’s willingness to participate prior to performing 
any study procedures. They will also obtain an interim medical history, including an 
assessment for new medical conditions by interview of subjects and note any changes 
since the previous clinic visit, home visit, or phone call. Study personnel will confirm 
that all eligibility criteria continue to be met. 
• 
Study personnel will review the solicited AEs with subjects, if not already reviewed and 
recorded during previous visits, and assess and record all new AE/unsolicited AEs/SAEs 
and concomitant medications/vaccinations on the appropriate data collection forms. 
• 
Vital signs, namely oral temperature, pulse, and blood pressure will be obtained. Subjects 
will be asked not to eat or drink anything hot or cold, or smoke within 10 minutes prior to 
taking an oral temperature. 
• 
A targeted physical examination may be performed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or 
sub-investigator, if indicated based on review of interim medical history. An examination 
performed by subject’s own obstetrical clinician may also provide data when a targeted 
exam is called for. 
• 
The study vaccination site will be examined. 
• 
Approximately 30 mL of venous blood will be collected for post-vaccination serology 
and cytokine assays. 
7.4.2.2. 
Subsequent Follow-up Visits 
7.4.2.2.1. Labor and Delivery Visit, Birth (+3 d): Clinic Visit, Pregnant Women and 
Infants (Visit 05 or V05) 
• 
Obtain interim medical history, including an assessment for new medical conditions by 
interview of subjects and note any changes since the previous clinic visit. Study 
personnel will solicit and record all new SAEs (as well as AEs (solicited and unsolicited)) 
and concomitant medications/vaccinations if less than 30 days post vaccination) on the 
appropriate data collection form. 
• 
Vital signs, namely oral temperature, pulse, and blood pressure, will be obtained. 
Subjects will be asked not to eat or drink anything hot or cold, or smoke within 10 
minutes prior to taking an oral temperature. Vital signs recorded for the mother as part of 

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her delivery record may be used in lieu of study personnel performing vital sign 
measurements. 
• 
A targeted physical examination may be performed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or 
sub-investigator, if indicated based on review of interim medical history. An examination 
performed by the subject’s own obstetrical clinician may also provide data when a 
targeted exam is called for. 
• 
On admission for parturition, 30 mL of blood will be drawn from the pregnant woman for 
serology. When possible, this blood will be drawn at the time of admission labs.  
• 
After delivery, study personnel will review the study procedures required for the infant 
going forward, add the infant’s name to the informed consent form, and ask the woman to 
acknowledge her infant’s participation as well as her continuing participation by signing 
and dating the form again. 
• 
If possible, 20- 30 mL of cord blood will be collected at the time of delivery. If cord 
blood cannot be obtained, 2-5 mL of peripheral blood will be collected by venipuncture 
within 72 hours of birth, before discharge, when possible. Cord blood is preferred over 
venipuncture. 
• 
Study personnel will record birth outcomes on the appropriate data collection form. 
• 
Colostrum or breast milk, 10-20 mL, will be collected from the mother for serology. In 
Mali, women are often discharged on the same day as delivery and lactation is not always 
established. Thus, the first collection may occur on any of the first 4 days of life of the 
infant.  
• 
The newborn infant will be enrolled into the study at the time of birth. A targeted 
physical examination may be performed by a study clinician licensed to make medical 
diagnoses and listed on the Form FDA 1572 as the site principal investigator or sub-
investigator, if indicated based on review of interim medical history. A physical exam 
performed by the infant’s doctor may also provide information, if required, for 
documentation. 
• 
Axillary temperature, heart rate, respiratory rate, head circumference, length, and weight 
will be collected from the medical chart of the infant. If not performed as part of routine 
care, these measurements, except weight may be taken by qualified members of the 
research team within 7 days of life. Weights will only be recorded when obtained at birth. 
• 
For infants, study personnel will solicit and record on the appropriate data collection form 
infant AEs, SAEs, and concomitant medications/vaccinations until the day of life 180 

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visit. Only medically attended AEs will be recorded. Events associated with routine 
newborn care and health maintenance visits will not be recorded. 
• 
To collect cord blood and to perform physical examination of the mother and newborn at 
delivery, an on-call team comprised of a study physician and nurse will be posted at the 
recruitment site close to the delivery room. This team will collaborate with the local on-
call team. The team will refer to the study ID or consent form to confirm the 
identification of the participant. 
7.4.2.2.2. 6 Weeks Postpartum Safety Follow-up Visit, Birth + Day 42 (±5 d): Clinic Visit, 
Postpartum Women and Infants (Visit 06 or V06) 
• 
Obtain interim medical history of mother and infant, including an assessment for new 
medical conditions by interview of subjects and note any changes since the previous 
clinic visit. Study personnel will solicit and record all new congenital anomalies and 
SAEs on the appropriate data collection form. 
• 
Study personnel will record infant concomitant medications on the appropriate data 
collection form. 
• 
A targeted physical examination may be performed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or 
sub-investigator, if indicated based on review of interim medical history. A targeted 
physical exam may be performed on the mother, infant, or both. 
• 
5 mL of infant venous blood will be collected for serology and cytokine assessments. 
• 
10-20 mL breast milk will be collected from the mother for antibody measurements. 
• 
Study personnel will collect infant length, weight, and head circumference as well as 
birth outcomes on the appropriate data collection form. 
7.4.2.2.3. 10 or 18 Weeks Postpartum Safety Follow-up Visit, Birth + Day 70 (±5 d) or 
Birth + Day 130 (±5 d): Clinic Visit, Postpartum Women and Infants (Visit 07 or 
V07) 
• 
Obtain interim medical history of mother and infant, including an assessment for new 
medical conditions by interview of subjects and note any changes since the previous 
clinic visit. Study personnel will solicit and record all new congenital anomalies and 
SAEs on the appropriate data collection form. 
• 
Study personnel will record infant concomitant medications on the appropriate data 
collection form. 

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• 
A targeted physical examination may be performed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or 
sub-investigator, if indicated based on review of interim medical history. A targeted 
physical exam may be performed on the mother, infant, or both. 
• 
5 mL of infant venous blood will be collected for serology and cytokine assessments 
prior to receipt of DTwP.  
• 
10-20 mL breast milk will be collected from the mother for antibody measurements. 
• 
Study personnel will collect infant length, weight, and head circumference as well as 
birth outcomes on the appropriate data collection form. 
7.5. 
Final Study Visit 
6 months Postpartum Safety Follow-up Visit, Birth + Day 180 (±7 d): Clinic Visit, 
Postpartum Women and Infants (Visit 08 or V08) 
• 
Obtain interim medical history of mother and infant. Study personnel will solicit and 
record all new congenital anomalies and SAEs on the appropriate data collection form. 
• 
Study personnel will record infant concomitant medications on the appropriate data 
collection form. 
• 
A targeted physical examination may be performed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or 
sub-investigator, if indicated based on review of interim medical history. A targeted 
physical exam may be performed on the mother, infant, or both. 
• 
5 mL of infant venous blood will be collected for serology assessments. 
• 
Approximately 30 mL of venous blood will be collected from the mother for post-
vaccination serology and cytokine assays. 
• 
10-20 mL breast milk will be collected from the mother for antibody measurements. 
• 
Study personnel will collect infant length, weight, and head circumference as well as 
birth outcomes on the appropriate data collection form. 
• 
Study personnel will discharge mother and infant from study. 
7.6. 
Early Termination Visit (if needed) 
The following activities will be performed at the early termination visit for subjects who 
withdraw, or are withdrawn or terminated from this study: 
• 
Obtain interim medical history, including an assessment for new medical conditions by 
interview of subjects and review of medical charts, if applicable, and note any changes 
since the previous clinic visit or phone call. 

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• 
Obtain vital signs: heart rate, blood pressure, and temperature. Subjects will be asked not 
to eat or drink anything hot or cold, or smoke within 10 minutes prior to taking an oral 
temperature. 
• 
Study personnel will collect infant length, weight, and head circumference as well as 
birth outcomes on the appropriate data collection form. 
• 
Review solicited AEs (if within 8 days after the study vaccination or if after the 8-day 
period but the AE information had not previously been collected). 
• 
All concomitant medications/vaccinations will be recorded on the appropriate data 
collection form (if within the period of collection of concomitant medications). 
• 
Review adverse events (if within the collection period for AEs). 
• 
Review serious adverse events, if within the collection period for SAEs. 
• 
A targeted physical examination may be performed on the mother and/or infant by a 
study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator, if indicated based on review of interim 
medical history. 
• 
Examine study vaccination site (if within 30 days after the study vaccination). 
• 
Record birth outcomes, if applicable. 
7.7. 
Unscheduled Visit (if needed) 
Unscheduled visits may occur at any time during this study. Any of the following activities may 
be performed: 
• 
Obtain interim medical history, including an assessment for new medical conditions by 
interview of subjects and review of medical charts, if applicable, and note any changes 
since the previous clinic visit or phone call. 
• 
Obtain vital signs: heart rate, blood pressure, and temperature. Subjects will be asked not 
to eat or drink anything hot or cold, or smoke within 10 minutes prior to taking an oral 
temperature. 
• 
Study personnel will collect infant length, weight, and head circumference as well as 
birth outcomes on the appropriate data collection form. 
• 
Review solicited AEs (if within 8 days after the study vaccination or if after the 8-day 
period but the AEs had not previously been collected). 
• 
Review concomitant medications/vaccinations (if within the collection period for 
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• 
Review adverse events (if within the collection period for AEs). 
• 
Review serious adverse events, if within the collection period for SAEs.  
• 
A targeted physical examination may be performed on the mother and/or infant by a 
study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator, if indicated based on review of interim 
medical history. 
• 
Examine study vaccination site (if within 30 days after the study vaccination). 
• 
Record birth outcomes, if relevant. 

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8. 
STUDY PROCEDURES/EVALUATIONS 
8.1. 
Clinical Evaluations 
Complete medical history to determine eligibility will be obtained by review of the medical 
record supplemented by interview for pregnant women. The information will be obtained at the 
screening visit and will be updated on Day 1, prior to study vaccination. Subjects and records, 
when available, will be queried regarding a history of significant medical disorders of the head, 
eyes, ears, nose, throat, mouth, cardiovascular system, lungs, gastrointestinal tract, liver, 
pancreas, kidney, urologic system, nervous system, blood, lymph nodes, endocrine system, 
musculoskeletal system, skin, and genital/reproductive tract. A history of any allergies, cancer, 
immunodeficiency, psychiatric illness, substance abuse, and autoimmune disease will be 
solicited. At follow-up visits, an interim medical history will be obtained by interview of the 
subjects and review of the medical chart of pregnant women when needed, noting any changes 
since the previous clinic visit or phone call. The interim medical history will include an 
assessment for new medical conditions and symptoms. 
Medications history (concomitant medications) will include a review of all current medications 
through the intervals described in Section 6.6 (Concomitant Medications/Treatments). 
Prescription and over-the-counter drugs will be included as well as vaccines, herbals, vitamins, 
and supplements. Use of any new medication should prompt evaluation for the presence of a new 
diagnosis, unless the medication is an expected medication in the care of a pregnant woman. 
Examples of medications used in the care of pregnant women that would not prompt evaluation 
for a new diagnosis would be prenatal vitamins for all women and RhoGAM for Rh(D)-negative 
women. Assessment of eligibility will include a review of all permitted and prohibited 
medications per the Subject Inclusion and Exclusion Criteria. In addition, the site principal 
investigator or appropriate sub-investigator may identify other medications that should not be 
used due to a risk to subject safety or assessment of reactogenicity and immunogenicity. 
At the screening visit, a targeted physical examination, if indicated based on subject’s complete 
medical history, may be performed by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site principal investigator or sub-investigator. For pregnant 
women, information from a physical exam performed by the subject’s clinician may also be 
used. On Day 1, prior to the vaccination, and as needed at follow-up visits after vaccination, a 
targeted physical examination may be performed by a study clinician licensed to make medical 
diagnoses and listed on the Form FDA 1572 as the site principal investigator or sub-investigator, 
if indicated based on the subject’s interim medical history. Targeted physical examinations are 
performed to investigate further symptoms reported by the subject that may have relevance to the 
study. 
Vital signs (oral temperature, pulse, and blood pressure) will be collected on Day 1 prior to the 
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Vital signs assessed on Day 1 prior to study vaccination will be considered as baseline. Subjects 
will be asked to not eat or drink anything hot or cold, or smoke within the 10 minutes prior to 
taking an oral temperature. 
Solicited event assessments will include an assessment of solicited adverse events occurring 
from the time of vaccination (Day 1) through Day 8. These assessments include injection site 
(local) reactions of ecchymosis (bruising), erythema (redness), induration (hardness)/edema 
(swelling), pain, and tenderness as well as systemic reactions including fever, feverishness 
(chills/shivering/sweating), fatigue (tiredness), malaise (general unwell feeling), myalgia (body 
aches/muscular pain exclusive of the injection site), arthralgia (joint pain exclusive of the 
injection site), headache, nausea, and allergic reaction (pruritus/urticaria). Pre-administration 
solicited systemic event assessments will be performed prior to study vaccination to establish 
baseline, then the study vaccination will be given. 
Subjects will be observed in the clinic for at least 30 minutes after the study vaccination. The 
study vaccination site will be examined, post-administration solicited event assessments will be 
performed, and any AE/SAEs will be assessed and recorded on the appropriate data collection 
form prior to discharge from the clinic. A field worker will visit all subjects on Days 4 and 8 to 
collect information on solicited adverse events and any AE/SAEs. The study vaccination site will 
also be examined on Day 31. 
8.2. 
Laboratory Evaluations 
8.2.1. 
Clinical Laboratory Evaluations 
Clinical screening laboratory parameters are not included in the routine evaluation for eligibility. 
If the medical record or history reveals laboratory abnormalities that might preclude eligibility or 
affect subject safety or the investigator’s ability to assess the safety, tolerability, or 
immunogenicity of the vaccine, the investigator may use that information to determine 
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8.2.2. 
Special Assays or Procedures 
Immunogenicity 
Laboratory assays to determine serum antibody concentrations to Tdap antigens will be 
performed at VTEU site laboratories using qualified ELISAs. Cytokines produced by peripheral 
blood cells from vaccinated mothers and infants stimulated with DTwP antigens will be 
measured using commercial and validated multiplex technology.  Subjects who withdraw early 
will have assays run on available samples. 
Breast Milk and Colostrum:  The exploratory measurement of antibody to Tdap antigens in 
colostrum/breast milk will be performed at VTEU site laboratories using qualified ELISAs. 
These assays have not been validated for colostrum/ breast milk. 
Laboratory personnel performing all assays will be blinded as to the allocation arm of pregnant 
subjects (Tdap vs. Td), study visit number, and whether the samples are from adult or infant 
subjects. The volume of venous blood and colostrum/breast milk to be collected for assays is 
presented in Table 2. 
 

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8.2.3. 
Specimen Preparation, Handling, and Shipping 
8.2.3.1. 
Instructions for Specimen Preparation, Handling, and Storage 
Instructions for specimen preparation, handling, and storage are included in the protocol-specific 
MOP, as appropriate. 
8.2.3.2. 
Specimen Shipment 
Specimen shipment will occur at intervals during the course of this trial following all applicable 
International Air Transport Association (IATA) requirements and according to the specifics for 
storage temperature and documentation as detailed in the protocol-specific MOP, as appropriate. 
Further instructions for specimen shipment will be included in the protocol-specific MOP, as 
appropriate. 

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9. 
ASSESSMENT OF SAFETY 
9.1. 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of the following: 
1) Study vaccine-related Serious Adverse Events occurring from the time of the study 
vaccination through the visit 6 months postpartum (180 days of life for the infant visit) 
for pregnant subjects and infants. All SAEs during this timeframe will be assessed and 
documented. 
2) Adverse Events related to pregnancy and the infant as delineated below in Section 9.2.4. 
For the pregnant woman/mother: pregnancy loss, vaginal bleeding (antepartum or 
postpartum), post-abortal endometritis/salpingitis, preterm rupture of membranes, 
preterm contractions/labor/delivery, poor fetal growth, hypertension/pre-
eclampsia/eclampsia, chorioamnionitis, postpartum endometritis, gestational diabetes 
mellitus. For the infant: preterm birth, low birth weight, neonatal complications, and 
congenital anomalies. 
3) Solicited Adverse Events – reactogenicity events occurring from the time of study 
vaccination through 7 days after study vaccination (Day 8) or until resolution. 
a. Injection site reactions including ecchymosis (bruising), erythema (redness), 
induration (hardness)/edema(swelling), pain, and tenderness. 
b. Systemic reactions including fever (days 4 and 8 only during home visits), 
feverishness (chills/shivering/sweating), fatigue (tiredness), malaise (general 
unwell feeling), myalgia (body aches/muscular pain exclusive of the injection 
site), arthralgia (joint pain exclusive of the injection site), headache, nausea, and 
allergic reaction (pruritus/urticaria). 
4) Unsolicited Non-Serious Adverse Events – all non-serious unsolicited adverse events will 
be assessed and documented, and all study vaccine-related non-serious adverse events 
occurring from the time of study vaccination through approximately 30 days after study 
vaccination (the Day 31 visit). For pregnant women who deliver before Day 31, 
unsolicited adverse events will be recorded until delivery. 
5) Major Congenital Anomalies 
Congenital Anomalies: In this study, we will report as SAEs all major congenital 
anomalies known prior to a mother/infant dyad completing the study. These outcomes 
must occur following maternal vaccination during gestation or the perinatal period 
(within the first 5 days after delivery) but the diagnosis may be confirmed anytime during 
participation. We define “major congenital anomaly” as “defects that are present at birth 
and that have surgical, medical, or serious cosmetic significance.” [33] 
The following list of problems are among the conditions reported in the US National 
Birth Defects registry and would be deemed as examples of major congenital anomalies: 

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anencephaly, spina bifida, encephalocele, anophthalmia, microphthalmia, cyanotic 
congenital heart diseases, cleft lip or palate, tracheoesophageal fistula, rectal stenosis, 
major limb deformities including shortening, gastroschisis, omphalocele, and 
diaphragmatic hernia. Some problems that are congenital anomalies but would be 
considered minor include most simple birthmarks, single transverse palmar creases, 
clinodactyly, umbilical hernias, post-axial polydactyly, ankyloglossia, and epicanthal 
folds. 
Positional deformations, such as molding or overriding cranial sutures, metatarsus 
adductus, tibial torsion, and genu varum are not to be recorded as major congenital 
anomalies. Normal variants, such as minor anomalies of the pinna, supernumerary 
nipples, and penile torsion are also not major congenital anomalies. If major congenital 
anomalies are found prenatally, before enrollment, women will be excluded from 
participation. Many minor congenital anomalies will typically only be noted at or soon 
after birth. 
9.2. 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
9.2.1. 
Adverse Events 
Adverse Event: 
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product regardless of its causal relationship to the study 
treatment. FDA defines an AE as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product. The occurrence of an AE may come to the attention of study personnel during study 
visits and interviews of a study recipient presenting for medical care, or upon review by a study 
monitor. 
AEs, including solicited local (injection site) and systemic (subjective and quantitative) 
reactions, will be captured on the appropriate data collection form and eCRF. Information to be 
collected for unsolicited non-serious AEs includes event description, date of onset, assessment of 
severity, relationship to study product and alternate etiology (assessed only by those with the 
training and authority to make a diagnosis and listed on the Form FDA 1572 as an investigator), 
date of resolution, seriousness and outcome. FWs will be trained on the assessment of local and 
systemic reactogenicity. If the subject reports an AE that is either not included among the 
solicited AEs or is a grade 3 solicited AE, then the FW will contact a study clinician. The study 

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clinician will either visit the participant at home or the participant will be referred to the study 
health center based on the FW’s assessment. AEs occurring during the trial collection and 
reporting period will be documented appropriately regardless of relationship. AEs will be 
followed through resolution. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the severity of any pre-existing medical 
condition increases, it should be recorded as an AE. 
All AEs must be graded for severity and relationship to study product (see definitions). Adverse 
events characterized as intermittent require documentation of onset and duration of each episode. 
The start and stop date of each reported AE will be recorded on the appropriate data collection 
form and eCRF. 
Severity of Event: AEs will be assessed by the investigator using a protocol-defined grading 
system (toxicity table included as an appendix). For events not included in the protocol-defined 
grading system, the following guidelines will be used to quantify severity: 
• 
Mild (Grade 1):  Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• 
Moderate (Grade 2):  Events result in a low level of inconvenience or concern with 
therapeutic measures.  Moderate events may cause some interference with functioning 
and daily activities. 
• 
Severe (Grade 3):  Events interrupt the subject’s daily activities and may require systemic 
drug therapy or other treatment.  Severe events are usually incapacitating. 
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent require documentation of onset and duration of each episode. 
Relationship to Study Products: The assessment of the relationship of an AE to the 
administration of study product is made only by those with the training and authority to make a 
diagnosis and listed on the Form FDA 1572 as an investigator based on all available information 
at the time of the completion of the eCRF. Whether the AE is related or not, is not a factor in 
determining what is or is not reported in this trial. If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. 
In a clinical trial, the study product must always be suspect. To help assess, the following 
guidelines are used. 

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• 
Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
9.2.2. 
Reactogenicity (for Vaccine Studies and Some Therapeutic Trials) 
Reactogenicity events are AEs that are common and known to occur following administration of 
this type of study vaccine. The following Toxicity Grading Scales will be used to grade solicited 
local (injection site) and systemic (subjective and quantitative) reactions: 
Table 3: Local (Injection Site) Reactogenicity Grading 
Local (Injection Site) 
Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain  
Does not interfere with 
daily activity 
Repeated use of non-
narcotic pain reliever > 24 
hours or interferes with 
daily activity 
Any use of narcotic pain 
reliever or prevents daily 
activity 
Tenderness  
Discomfort only to deep 
palpation 
Discomfort to light 
palpation or movement 
Significant discomfort to 
any touch or movement  
Ecchymosis (Bruising)* 
No interference with daily 
activity 
Some interference with 
daily activity not requiring 
medical intervention 
Prevents daily activity and 
requires medical 
intervention 
Erythema (Redness)* 
  Does not interfere with 
daily activity 
  Interferes with daily 
activity 
Prevents daily activity  
Induration 
(Hardness)/Edema 
(Swelling)* 
  Does not interfere with 
daily activity 
  Interferes with daily 
activity 
Prevents daily activity 
 
 
 

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Ecchymosis (bruising), erythema (redness), and induration (hardness)/edema (swelling) as 
analyzed by measurement will be graded as follows: 
 
Table 4: Local (Injection Site) Reactogenicity Measurements 
Local (Injection Site) Reaction 
Small 
Medium 
Large 
Ecchymosis (Bruising)* 
1-50 mm 
51-100 mm 
> 100 mm 
Erythema (Redness)* 
1-50 mm 
51-100 mm 
> 100 mm 
Induration (Hardness)/Edema 
(Swelling)* 
1-50 mm 
51-100 mm 
> 100 mm 
  *Will not be used as halting criteria. 
 
In addition to grading the measured local reactions at the greatest single diameter, the 
measurements will be recorded as continuous variables. 
 
 

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Table 5: Subjective Systemic Reactogenicity Grading 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Feverishness 
(Chills/Shivering/Sweating) 
No interference 
with daily activity 
Some interference with 
daily activity not 
requiring medical 
intervention 
Prevents daily activity and 
requires medical 
intervention 
Fatigue (Tiredness) 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant; prevents daily 
activity 
Malaise (General Unwell 
Feeling) 
No interference 
with daily activity 
Some interference with 
daily activity not 
requiring medical 
intervention 
Prevents daily activity and 
requires medical 
intervention 
Myalgia (Body 
Aches/Muscular Pain)* 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant; prevents daily 
activity 
Arthralgia (Joint Pain)* 
No interference 
with daily activity 
Some interference with 
daily activity not 
requiring medical 
intervention 
Prevents daily activity and 
requires medical 
intervention 
Headache 
No interference 
with daily activity 
Repeated use of non-
narcotic pain reliever > 
24 hours or some 
interference with daily 
activity 
Significant; any use of 
narcotic pain reliever or 
prevents daily activity 
Nausea 
No interference 
with daily activity 
Some interference with 
daily activity 
Prevents daily activities 
Allergic Reaction  
Pruritus without 
rash  
Localized urticaria OR 
requires oral therapy 
Generalized urticaria; 
angioedema OR 
anaphylaxis OR requires 
epinephrine 
  *Not at injection site. 
 
 

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Oral temperature# will be graded as follows: 
 
Table 6: Quantitative Systemic Reactogenicity Grading 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever* - oral† 
38.0 – 38.4°C 
100.4 – 101.1°F 
38.5 – 38.9°C 
101.2 – 102.0°F 
> 38.9°C 
> 102.1°F 
#Oral temperature assessed on Day 1 prior to study vaccination will be considered as baseline. 
*A fever can be considered not related to the study product if an alternative etiology can be documented. 
†Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
9.2.3. 
Additional Adverse Event Severity Grading 
Pulse and blood pressure# will be graded as follows: 
Table 7: Pulse and Blood Pressure Severity Grading 
Physiologic Parameter 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Bradycardia - beats per minute 
50 – 54 or 45-50 if 
baseline <60 bpm 
45 – 49 or 40-44 if 
baseline <60 bpm 
< 45 or <40 if baseline 
<60 bpm 
Tachycardia - beats per minute 
101 – 115 
116 – 130 
> 130 or ventricular 
dysrhythmias 
Hypotension (systolic) mm Hg 
85-89 
80-84 
< 80 
Hypertension (systolic) mm Hg 
141-150 
151-160 
> 160 
Hypertension (diastolic) mm Hg 
91-95 
96-109 
> 109 
#Pulse and blood pressure assessed on Day 1 prior to the study vaccination will be considered as baseline. 
 
 

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9.2.4. 
Grading of Specific Adverse Events in the Pregnant Women and their Infants 
Table 8: Maternal and Infant Adverse Events 
Maternal Adverse Events 
(Adverse Events during Pregnancy) 
Parameter  
Normal 
Grade 1 
Grade 2 
Grade 3 
 
Pregnancy loss (Pregnancy 
does not result in a live 
birth) 
Spontaneous abortion or 
miscarriage in the first or 
second trimester of 
gestation 
   
 
Fetal death at or after 20 
weeks of gestation 
(stillbirth) 
None 
N/A 
N/A 
Spontaneous 
abortion or 
miscarriage  
 
Bleeding (vaginal) during 
pregnancy prior to the 
onset of labor 
None 
Spotting or 
bleeding less than 
menses 
Bleeding like 
menses or heavier, 
no intervention 
indicated 
Profuse bleeding 
with dizziness or 
orthostatic 
hypotension, 
transfusion 
indicated 
 
Postpartum hemorrhage  
 
EBLc ≤500 cc for 
vaginal delivery 
or  
≤1000 cc after CS 
or reported as 
normal  
 
EBL 501-1000 for 
vaginal delivery or 
1001-1500 for CS 
or reported as 
slightly increased  
 
EBL >1000 for 
vaginal delivery or  
>1500 for CS, with 
or without mild 
dizziness, no 
transfusion required  
 
Hemorrhage at a 
level for which 
transfusion of 
packed cells or 
any amount of 
other blood 
components is 
indicated 
 
Postabortal 
endometritis/salpingitis  
 
None 
Low grade fever 
and uterine 
tenderness, 
resolved with oral 
antibiotics  
 
Moderate 
symptoms, 
requiring ≤3 days 
of parenteral 
antibiotics  
 
Severe symptoms 
requiring >3 days 
of IV antibiotics 
or development 
of TOA 
 
Preterm rupture of 
membranes  
 
None 
N/A 
Preterm rupture but 
not resulting in 
delivery before 37 
weeks gestation  
Preterm rupture 
resulting in 
delivery before  
37 weeks 
gestation  
 

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Preterm contractions 
/labor/deliverye 
 
 
None 
Braxton Hicks 
contractions 
(as early as 
second trimester) 
Preterm 
contractions which 
resolve without 
medical 
intervention  
 
Preterm 
contractions with 
cervical change 
which result in 
medical 
intervention but not 
resulting in preterm 
delivery  
Delivery before 
37 weeks 
gestation  
 
Poor fetal growth 
If infant is small for 
gestational age on newborn 
exam: report as 
NEONATAL OUTCOME 
based on birth weight 
(see below) 
At or above 10th 
percentile  
 
Fetal growth <10th 
percentile but ≥3rd 
percentile for 
gestational age by 
ultrasound   
 
N/A 
Fetal growth <3rd 
percentile for 
gestational age by 
ultrasound  
 
Hypertension, 
preeclampsia/eclampsia 
None 
Pregnancy induced 
hypertension 
Preeclampsia 
HELLP 
syndrome, or 
eclampsia, 
 
Chorioamnionitis  
 
None 
Fever (38°C–
38.4°C or 
100.4°F–100.9°F) 
with two or more: 
FHRe >160 BPMf, 
maternal HR 
>120, uterine 
tenderness 
between 
contractions or 
purulent AF or 
preterm labor  
Same as Grade 1 
plus fever 38.5°C–
40°C or 101°F–
104°F  
 
Criteria for Grade 
2 plus fetal 
distress or fever 
>40°C or 104°F 
 
Postpartum endometritis 
 
None 
Low grade fever 
and uterine 
tenderness, 
resolved with oral 
antibiotics  
Moderate 
symptoms, treated 
by ≤3 days of 
parenteral 
antibiotics  
 
Severe symptoms 
treated with >3 
days of IV 
antibiotics, 
addition of 
heparin, or 
operative 
intervention 
 
Gestational diabetes 
mellitus  
N/A  
New onset 
controlled by diet  
New onset with 
initiation of 
medical therapy 
Uncontrolled 
despite treatment 
modification 
 
Clinical AE, pregnancy-
related, NOT identified 
elsewhere in this AE 
Grading Table  
None 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
 
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities 
 
 
 
 

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Mode of deliveryf 
(normal spontaneous vaginal 
delivery, induced delivery, 
assisted vaginal delivery, 
Caesarean Section) 
Not reported as AE/SAE. Mode of delivery is a procedure and should not be reported or 
graded as an AE/SAE. The reason for selecting the mode of delivery (for example: Caesarean 
Section for severe preeclampsia) should be reported and graded as appropriate.    
 
 
 
 

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Infant Adverse Events 
(Neonatal and Infant Events) 
Parameter 
Normal 
 Grade 1 
 Grade 2 
 Grade 3 
 
Preterm birthg 
 
 
Born after 36 6/7 
weeks gestation 
 
Late preterm: 
34 to 36 6/7 weeks 
gestation 
 
Early preterm: 
32 to 33 6/7 weeks 
gestation  
 
Very or 
extremely 
preterm: 
< 31 6/7 weeks 
gestation  
 
Birth weight (grams)g  
(Small, appropriate, large for 
gestational age) 
 
Report separately poor fetal 
growth 
(as above) 
Birth weight 
>2500  
 
Low birth weight: 
1501-2500  
Very low birth 
weight ≤1500  
 
Neonatal complications 
in a term infant 
Normal term 
infant discharged 
home with mother 
after 
uncomplicated 
delivery and 
nursery course 
 
Transient signs 
and symptoms 
requiring  no 
intervention, and 
resolved 
spontaneouslyh 
Signs/symptoms 
requiring 
interventioni but 
discharged home 
with mother (± 2 
days), or close to it 
Required NICU 
for more than 1 
week, and/or 
interventions 
(including 
surgery) leading 
to prolonged 
hospitalization 
(report SAE)j 
 
Clinical AE in the newborn 
NOT identified elsewhere 
in this AE Grading Table  
(postmaturityl) 
None 
Symptoms causing 
no or minimal 
interference with 
usual functional 
activities 
 
Symptoms causing 
greater than 
minimal 
interference with 
function and 
activities 
 
Symptoms 
causing inability 
to perform 
functions  or 
activities 
 
 
 
Congenital anomalies/ 
birth defectsm 
Variants of 
normal and minor 
anomalies are 
NOT reported, 
graded or 
followed as AE, 
or SAEs. They 
are collected in 
the database as 
part of the 
medical 
examination and 
reported in the 
Final Study 
Report. 
N/A 
N/A 
Major congenital 
anomalies are 
reported as SAEs. 
 
Abbreviations and definitions:  
a Please refer to ‘Definitions of Safety Parameters’ for regulatory definition of ‘life threatening’ that requires reporting of SAE.   
b Even if pregnancy loss does not require obstetrical care, and is a natural outcome of non-viable conception, psychological 
events around the event require recognition especially in research subjects.  
c EBL:  Estimated blood loss. 
d TOA:  Tubo-ovarian abscess. 
e For preterm delivery, report two AEs: one for mother and one for infant. Unless specified otherwise in the protocol, only one 
neonatal AE will be reported for all preterm birth-related problems. Additional AEs will be reported only if infant has unexpected 
AEs: surgery, congenital anomalies, etc.   

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f Examples of complications of delivery that would meet AE/SAE reporting are: maternal death, stillbirth, bleeding placenta 
previa or abruption that required emergency delivery, etc.  
g Preterm birth and low birth weight carry different risks and will be reported separately (or twice if an infant is both preterm and 
low birth weight). If gestational age is not known, only birth weight will be reported. Infants will be plotted on the appropriate 
growth scale for the population being studied and percentage of ‘appropriate’, ‘large’, or ’small for gestational age’ infants will 
be reported in the final study report.  
h Examples: transient tachypnea, hypothermia, cephalo-hematoma, bruising. Admitted to normal nursery or observed for less than 
one day in NICU/SCN.  
i Examples: admission to NICU/SCN for physiological causes like hyperbilirubinemia requiring phototherapy, hypoglycemia, 
suspected but ruled out congenial infection, oxygen via nasal cannula, or NCPAP. 
j Examples: confirmed neonatal infection:  bacterial, viral, fungal sepsis, meconium aspiration syndrome on respirator, severe 
laboratory, or/and clinical signs and symptoms.  
k Examples: perinatal asphyxia: 10 min Apgar scores below 5, shock, critical neonatal laboratory values, etc. 
l Post maturity carries unique, but still not clearly defined risks. Currently, this category should be used to evaluate signs and 
symptoms related to post-maturity. 
m Investigators should consult the protocol and/or the MOP for a list of ‘major congenital anomalies’ and report them as SAE. 
Minor anomalies (also listed in the protocol and/or MOP) are structural findings that do not have surgical, medical or cosmetic 
importance. Minor physical features that typically occur in more than 4% of newborn infants are considered ‘variants’ of normal, 
while ‘minor anomalies’ occur in less than 4% of infants. If in doubt: review referenced articles in Rasmussen et al Clin Infect 
Dis 2014 p S 428ff29  and/or consult DMID.  
AE:  Adverse Events 
CS:  Cesarean Section 
HELLP syndrome:  Group of symptoms that occur in pregnant women who have: hemolysis (H); elevated liver enzymes (EL); 
low platelet count (LP). 
9.2.5. 
Serious Adverse Events 
Serious Adverse Event (SAE):  An adverse event or suspected adverse reaction is considered 
“serious” if, in the view of either the site principal investigator or sponsor, it results in any of the 
following outcomes: 
• 
Death, 
• 
a life-threatening adverse event*, 
• 
inpatient hospitalization or prolongation of existing hospitalization, 
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• 
a congenital anomaly/birth defect¥. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 

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*Life-threatening adverse event. An adverse event is considered “life-threatening” if, in the view 
of either the site principal investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death. 
 
¥Congenital anomalies will be reported as described under Section 9.1. 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. FWs will be trained on the assessment 
of local and systemic reactogenicity. If the subject reports an AE that is either not 
included among the solicited AEs or is a grade 3 solicited AE, then the FW will contact a 
study clinician. The study clinician will either visit the participant at home or the 
participant will be referred to the study health center based on the FW’s assessment. 
• 
Recorded on the appropriate SAE data collection form and eCRF. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
• 
Reviewed and evaluated by an Independent Safety Monitor (ISM) (as deemed necessary 
per Section 9.6.1), the DSMB (periodic review unless related), DMID, and the IRB, as 
required by local reporting guidelines. 
9.2.6. 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
The site principal investigator or appropriate sub-investigator is responsible for recording all 
AE/SAEs that are observed or reported during this trial, as described in this protocol, regardless 
of the relationship to study product. AE/SAEs, or abnormal clinical findings will be collected, 
assessed, documented, reported, and followed appropriately. 
9.3. 
Reporting Procedures 
Solicited injection site and systemic reactogenicity events for pregnant women will be 
documented and reported from the time of each study vaccination through 7 days after the study 
vaccination. 
Unsolicited non-serious AEs for pregnant women will be documented and reported from the time 
of study vaccination through approximately 30 days after the study vaccination (Day 31 or 
delivery, whichever occurs first, for pregnant women). 

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SAEs among pregnant women will be documented and reported from the time of study 
vaccination through 6 months postpartum. 
For infants, there are no solicited events. AEs and SAEs will be recorded from birth until the 180 
days of life for the infant visit. Events that are not medically attended, or that are a part of routine 
infant health maintenance, will not be reported. 
9.3.1. 
Serious Adverse Events 
SAEs will be followed until resolution even if this extends beyond the study-reporting period.  
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
Any AE that meets a protocol-defined serious criterion must be submitted immediately 
(within 24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance 
Group, at the following address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, select SAE data fields must also be entered into the DCC’s 
Advantage eClinical. Please see the protocol-specific MOP for details regarding this procedure. 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. 
The site will send a copy of the SAE report(s) to the ISM (as deemed necessary per Section 
9.6.1) when they are provided to the DMID Pharmacovigilance Group. The DMID Medical 
Monitor and DMID Clinical Project Manager will be notified of the SAE by the DMID 
Pharmacovigilance Group. The DMID Medical Monitor will review and assess the SAE for 
regulatory reporting and potential impact on study subject safety and protocol conduct. 
At any time after completion of the study, if the site principal investigator or appropriate sub-
investigator becomes aware of an SAE that is suspected to be related to study product, the site 
principal investigator or appropriate sub-investigator will report the event to the DMID 
Pharmacovigilance Group. 
9.3.2. 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the investigator, DMID, the Investigational New Drug (IND) 
sponsor, will report any suspected adverse reaction that is both serious and unexpected. DMID 
will report an adverse event as a suspected adverse reaction only if there is evidence to suggest a 

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causal relationship between the drug and the adverse event. DMID will notify FDA and all 
participating investigators (i.e., all investigators to whom the sponsor is providing drug under its 
IND(s) or under any principal investigator’s IND(s)) in an IND safety report of potential serious 
risks from clinical trials or any other source, as soon as possible, but in no case later than 15 
calendar days after the sponsor determines that the information qualifies for reporting as 
specified in 21 CFR Part 312.32. DMID will also notify FDA of any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible, but in no case later than 7 calendar 
days after the sponsor’s initial receipt of the information. Relevant follow up information to an 
IND safety report will be submitted as soon as the information is available. Upon request from 
FDA, DMID will submit to FDA any additional data or information that the agency deems 
necessary, as soon as possible, but in no case later than 15 calendar days after receiving the 
request. 
All serious events designated as “not related” to study product(s), will be reported to the FDA at 
least annually in a summary format. 
9.4. 
Type and Duration of Follow-up of Subjects after Adverse Events 
Non-serious AEs will be collected, assessed, and followed through resolution from the time of 
study vaccination through approximately 30 days after study vaccination. For pregnant women, 
this period extends from vaccination until Day 31 or delivery, whichever occurs earlier. All 
unresolved non-serious AEs will be followed through resolution even if this extends beyond the 
study-reporting period. 
SAEs and new-onset chronic medical conditions will be collected, assessed, and followed from 
the time of study vaccination through resolution even if this extends beyond the study-reporting 
period. The reporting period extends from vaccination until 6 months postpartum (180 days of 
life for the infant visit) for pregnant women. 
Resolution of an AE/SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
Follow-up procedures, evaluations, and outcomes will be recorded on the appropriate data 
collection form. 
9.5. 
Halting Rules 
For pregnant women, further enrollment and study vaccinations will be halted for DSMB 
review/recommendation if any of the following are reported: 
• 
Any subject experiences ulceration, abscess, or necrosis at the injection site related to 
study product administration. 
• 
Any subject experiences laryngospasm, bronchospasm, or anaphylaxis within 1 day after 
administration of study product that is considered related to study product. 

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• 
Two or more subjects experience generalized urticaria within 3 days after administration 
of study product that is considered related to study product. 
• 
Any subject experiences a study vaccine-related SAE from the time of study vaccination 
through subject’s last study visit. 
• 
Any subject experiences acute weakness of limbs and/or cranial nerve innervated muscles 
(description of potential signal of GBS) after administration of study vaccine. 
For pregnant women, this study will also be halted for DSMB review/recommendation if, within 
7 days after administration of the study vaccination, any of the following occurs: 
• 
5% or more of subjects (with a minimum of 5 subjects) who received study vaccine 
experience the same severe (Grade 3) study vaccine-related injection site reaction. 
• 
5% or more of subjects (with a minimum of 5 subjects) who received study vaccine 
experience the same severe (Grade 3) study vaccine-related subjective systemic reaction 
with the exception of allergic reaction, for which the severity (grade) is corroborated by 
study personnel. 
• 
5% or more of subjects (with a minimum of 5 subjects) who received study vaccine 
experience the same severe (Grade 3) study vaccine-related quantitative systemic 
reaction. 
• 
5% or more of subjects (with a minimum of 5 subjects) who received study vaccine 
experience the same severe (Grade 3) pregnancy-related AEs, as found in Section 9.2.4, 
that are deemed study-vaccine related. 
Grading scales for solicited local (injection site) and systemic (subjective and quantitative) 
reactions are included in Section 9.2.2. Solicited injection site measurements will not be used to 
halt the study. 
If any of the halting rules are met following any subject receipt of study vaccination, then this 
study will not continue with the remaining enrollments or study vaccinations without a review by 
and recommendation from the DSMB to proceed. 
DMID retains the authority to suspend additional enrollment and study interventions/ 
administration of study product during the entire study, as applicable. 
9.6. 
Safety Oversight (ISM plus SMC or DSMB) 
9.6.1. 
Independent Safety Monitor (ISM) 
The ISM is a physician with relevant expertise whose primary responsibility is to provide 
independent safety monitoring in a timely fashion. Participation is for the duration of the trial 
and is a voluntary position that does not receive payment. The ISM must meet the requirements 
of the NIAID conflict of interest policy. 

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The ISM: 
• 
Will have experience in obstetrics. 
• 
Is in close proximity to the study site and has the authority and ability to readily access 
subject records in real time. 
• 
May be a member of the participating institution’s staff but preferably be from a different 
organizational group within the institution. 
• 
Should not be in a direct supervisory relationship with the investigator. 
• 
Should have no direct involvement in the conduct of the study. 
The ISM will: 
• 
Sign a Conflict of Interest (COI) certification at the time they are asked to participate and 
provide updates to this information as needed. 
• 
Receive reports of Serious Adverse Events (SAEs) deemed related to the study from the 
site investigator and will be notified by email when DMID is notified of the SAE. 
• 
Receive reports from the site investigator of any subject who experiences acute weakness 
of limbs and/or cranial nerve innervated muscles (description of potential signal of GBS) 
after administration of study vaccine. 
• 
Evaluate the SAE and report their clinical assessment to DMID, through DMID-CROMS 
SOCS in a timely manner using the attached report form and email the report to DMID-
CROMS SOCS. 
• 
Communicate with the investigator at the participating site as needed. 
• 
Review additional safety related events at the request of DMID. 
• 
Provide additional information to DMID and/or the DSMB by teleconference as 
requested. 
9.6.2. 
Data and Safety Monitoring Board (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises DMID. The DSMB members will be separate and 
independent of study personnel participating in this trial and should not have scientific, financial, 
or other conflicts of interest related to this trial. The DSMB will consist of members with 
appropriate expertise to contribute to the interpretation of the data from this trial. 
The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. Procedures for DSMB reviews/meetings will be defined in 
the charter. Reports may include enrollment and demographic information, medical history, 
concomitant medications, physical assessments, clinical laboratory values, dosing compliance, 

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and solicited and unsolicited AE/SAEs. The DSMB will review SAEs on a regular basis and ad 
hoc during this trial. The DMID Medical Monitor and the ISM (as deemed necessary per Section 
9.6.1) will be responsible for reviewing SAEs in real time. 
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and 
presented by treatment arm (pregnant women, infants). The DSMB may also be provided with 
expected and observed rates of the solicited AEs in an unblinded fashion and may request the 
treatment assignment be unblinded for an individual subject if required for safety assessment. 
The DSMB will review grouped and unblinded data in the closed session only. As an outcome of 
each review/meeting, the DSMB will make a recommendation as to the advisability of 
proceeding with study vaccinations (as applicable), and to continue, modify, or terminate this 
trial. 
The DSMB will conduct the following reviews: 
• 
When safety data collected through Day 8 is available for 25% of pregnant study 
subjects. 
• 
Ad hoc when a halting rule is met or DMID/DSMB chair may convene an ad hoc meeting 
if there are immediate concerns regarding observations during this trial. 
• 
Final review meeting: 6 to 8 months after clinical database lock to review the cumulative 
unblinded data for this trial. The data will be provided in a standard summary format. The 
DSMB may be asked to provide recommendations in response to questions posed by 
DMID. 

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10. 
CLINICAL MONITORING 
10.1. 
Site Monitoring Plan 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines, and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP, and applicable sponsor 
standard operating procedures. DMID, the sponsoring agency, or its designee will conduct site-
monitoring visits as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID. Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, eCRFs, informed consent forms, medical and laboratory 
reports, and protocol and GCP compliance. Site monitors will have access to each participating 
VTEU site, study personnel, and all study documentation according to the DMID-approved site 
monitoring plan. Study monitors will meet with site principal investigators to discuss any 
problems and actions to be taken and document visit findings and discussions. 

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11. 
STATISTICAL CONSIDERATIONS 
The primary goals of this study are to assess the safety and tolerability of BOOSTRIX when 
administered to pregnant women, as well as to determine the maternal and infant immune 
response. Additional goals include evaluating the effect of maternal antibody on primary infant 
immune responses to DTwP, identifying cofactors associated with infant and maternal immune 
responses and determining immune responses in colostrum/breast milk. 
11.1. 
Study Hypotheses 
BOOSTRIX will be safe and well tolerated in pregnant women and will lead to PT levels that are 
higher in the pregnant women and their infants as compared to pregnant women vaccinated with 
a Td vaccine and their infants. This is one of the first studies of maternal Tdap vaccination in a 
low resource setting in Africa, and where infants received whole cell, rather than acellular 
pertussis vaccinations. Thus, this study is intended to obtain preliminary estimates of immune 
response in this setting; it is not designed to test a formal hypothesis. 
11.2. 
Sample Size Considerations 
11.2.1. 
Study Design 
This is a phase II, randomized, double-blind, active-controlled study in which 200 healthy 
pregnant women, ages 18 through 39 years, inclusive, will be randomly allocated in a 2:1 ratio to 
receive either Tdap (BOOSTRIX) or Td at 14 0/7 weeks through 26 6/7 weeks estimated GA. 
After signing an ICF, all subjects will undergo a review of current and past medical history, 
current and prior medication use, and recent and relevant vaccination history. All pregnant 
subjects will have a physical examination as part of routine antenatal care. For the fetuses of 
pregnant subjects, GA will be established by ultrasound, whenever possible, in combination with 
date of LMP, when available, and fundal height. Subjects will be enrolled, vaccinated, and 
followed for safety, tolerability, and immune responses as described in this protocol.  
11.2.2. 
Study Population 
200 healthy pregnant women, ages 18 through 39 years, inclusive, who meet all eligibility 
criteria, and their infants. 
Based on the accrual rate for similar studies, it seems reasonable to expect that the sites will be 
able to enroll this study in a timely fashion. Prior experience suggests up to 15% of subjects may 
be excluded from the per protocol analysis for the primary immunogenicity outcome either 
because they were lost-to-follow-up or otherwise do not have data available following the study 
vaccination, or because they had a protocol deviation requiring their exclusion from the per 
protocol analysis. 

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11.2.3. 
Sample Size 
The study is planned to enroll 200 pregnant women (133 BOOSTRIX, 67 Td). 
This will be one of the first studies of maternal Tdap vaccination in an African, low resource 
setting, and where infants received whole cell, rather than acellular pertussis vaccinations. Thus, 
this study is intended to obtain preliminary estimates of immune response in this setting; it is not 
designed to test a specific null hypothesis. The tables below describe the power to detect safety 
events and the precision available for estimating immune response for the planned sample size. 
Table 9 indicates the probability of observing one or more safety event, such as solicited 
injection site or systemic symptom, or an unsolicited adverse event of a particular type within a 
treatment arm. 
Table 9: Power (%) to Detect Safety Events 
Event 
Frequency 
N = 133 
N = 67 
≥0.01% 
Rare 
1.3 
<1 
≥0.1% 
Uncommon 
12.5 
6.5 
 ≥1% 
Common 
73.7 
49.0 
≥10% 
Very 
Common 
100.0 
99.9 
In addition to safety, as a co-primary objective, the study will assess serum PT antibody at birth 
among infants whose mothers received a single dose of BOOSTRIX, and as secondary and 
exploratory objectives, the study will assess maternal and infant humoral response to all vaccine 
antigens. Immune response will be measured by ELISA. Table 10 presents the precision (95% 
CI) available for estimating GMC of ELISA titers against the vaccine component using 
assumptions for GMC and standard deviation (SD) for maternal and infant response to Tdap 
from Munoz et al. [13] and infant response post third dose of primary DTwP vaccine series from 
Ladhani et al. [34] 
 
 

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Table 10: Precision for Estimating GMC of ELISA Antibody Response 
GMC 
 
SD 
(log-scale) 
95% CI Estimate 
N = 133 
N=67 
Maternal ELISA Antibodies at Delivery following maternal Tdap 
PT 
51 
0.90 
43.7 
59.5 
41.0 
63.5 
FHA 
184.8 
0.73 
163.1 
209.3 
154.8 
220.6 
PRN 
184.5 
1.45 
143.8 
236.7 
129.5 
262.9 
FIM 
1485.7 
1.17 
1214.8 1817.0 
1115.8 
1978.2 
Infant ELISA Antibodies at Birth following maternal Tdap 
PT 
68.8 
0.78 
60.2 
78.7 
56.8 
83.3 
FHA 
234.2 
0.67 
208.7 
262.8 
198.8 
276.0 
PRN 
219 
1.38 
172.9 
277.4 
156.5 
306.5 
FIM 
1867 
1.22 
1514.7 2301.3 
1386.7 
2513.7 
Infant Response post 3rd Dose DTwP following maternal Tdap 
PT 
28.8 
0.68 
25.6 
32.3 
24.4 
34.0 
FHA 
25.5 
0.60 
23.0 
28.3 
22.0 
29.5 
FIM 
113.9 
0.81 
99.1 
130.9 
93.5 
138.8 
Infant Response post 3rd Dose DTwP (no maternal vaccination) 
PT 
43.2 
0.65 
38.6 
48.3 
36.9 
50.6 
FHA 
41.1 
0.66 
36.7 
46.1 
35.0 
48.3 
FIM 
224.9 
0.97 
190.2 
265.9 
177.2 
285.4 
Table 11 presents the minimum difference in infant PT antibody GMC at birth between the Td 
and Tdap (BOOSTRIX) vaccination arms that would be detectable with 80% power. The 
assumed GMC and SD used for these calculations are based on the PT antibody GMC and SD 
observed at birth in infants whose mother received either Tdap or placebo vaccination during 
pregnancy, reported in Munoz et al. [13]. The calculations are based on a two-sided two sample 
T-test to compare means, with alpha = 0.05. 
 
 

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Table 11: Minimum Detectable Difference in Infant PT Antibody GMC at Birth 
Comparing Infants Born to Mothers Vaccinated with BOOSTRIX versus Td 
Td 
Tdap 
(BOOSTRIX) 
Assumed GMC  
(BOOSTRIX) 
Maximum GMC 
Detectable with Power = 
0.8 
(Td) 
Minimum Detectable 
Difference 
(BOOSTRIX - Td) 
N=67 
N=133 
50.0 
33.1 
16.9 
60.0 
40.4 
19.6 
70.0 
44.7 
25.3 
80.0 
49.4 
30.6 
90.0 
60.3 
29.7 
11.3. 
Planned Interim Analyses 
Interim analyses would only be used to terminate this trial in the event that unanticipated safety 
events deemed to be of sufficient concern to require such action by the sponsor. A DSMB will be 
convened by DMID to review study progress and subject, clinical, safety, and reactogenicity 
data. 
Cumulative safety information, study status, and primary endpoint results may be presented at a 
public forum in a blinded manner or presented as summaries aggregated by study arm at the 
discretion of the sponsor while the primary study is ongoing. While the primary study is ongoing 
no data will be released that is unblinding at an individual subject level, and caution will be taken 
to ensure that data summarized by treatment arm does not identify the treatment assignment of 
any individual subject. Any ad-hoc analyses, jointly developed by the SDCC and/or University 
of Maryland, will be executed by the SDCC as needed. 
None of the interim analyses will include any formal statistical hypothesis testing; therefore, p-
value adjustment will not be made to any analyses. 
11.3.1. 
Interim Safety Review 
An interim safety review will occur when safety data collected through Day 8 is available for 
25% of pregnant study subjects. Reports for interim safety reviews will include data for pregnant 
participants, and any infants born at the time of data cutoff. Summaries may include enrollment 
and demographic information, medical history, concomitant medications, physical assessments, 
and solicited and unsolicited AE/SAEs. Additional data may be requested by the DSMB as 
described in Section 9.6.2. 
This trial will be monitored to determine if any of the halting rules described in Section 9.5 are 
met. 
11.3.2. 
Interim Immunogenicity or Efficacy Review 
An interim immunogenicity review is not planned. 

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11.4. 
Final Analysis Plan 
A formal statistical analysis plan will be developed and finalized prior to database lock. 
11.4.1. 
Analysis Populations 
The Safety Analysis population includes all pregnant women who received the study 
vaccination, and all infants born during the study. 
The maternal intent-to-treat (ITT) population for immunogenicity analyses includes all pregnant 
women who received the study vaccination. 
The maternal per-protocol (PP) population for immunogenicity analyses includes all subjects in 
the ITT subset with the following exclusions: 
• 
Data from all available visits for subjects: 
• 
Found to be ineligible at baseline. 
• 
Without results from the baseline visits. 
• 
Without results from at least one post-vaccination visit. 
• 
Data from all visits subsequent to major protocol deviations, such as: 
• 
Receipt of non-study licensed vaccine within the pre-specified exclusion windows 
(Section 5.2). 
• 
Receipt of immunosuppressive therapy (e.g., corticosteroids) within 30 days prior to 
or after study vaccination. 
• 
Data from any visit that occurs substantially out of window. 
The infant ITT population for immunogenicity analyses includes all infants born to women who 
received the study vaccination. 
The infant PP population for primary and secondary immunogenicity analyses includes all 
infants in the ITT subset who have a blood sample from the perinatal period (cord blood or 
drawn blood within the 72 hours after birth). 
The infant PP population for exploratory immunogenicity analyses includes all infants in the ITT 
subset with the following exclusions: 
• 
Infants who did not receive DTwP within appropriate window. 
• 
Infants who received any product that would impact immune response. 
• 
Infants with blood samples captured substantially out of window. 
In the case of mis-randomization, subjects will be analyzed according to the study product 
actually received for all analysis populations. 

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11.4.2. 
Safety Data 
Maternal safety and tolerability, and fetal/infant outcomes will be summarized for the Safety 
Analysis Population. 
Solicited AEs will be summarized by severity on days 4 and 8 after the study vaccination and as 
the maximum severity over the 8 days. Additionally, solicited AEs will be analyzed by taking the 
most severe response over the follow-up period, dichotomizing into a binary variable (none 
versus mild, moderate, or severe) and using standard techniques, such as exact confidence 
intervals, to summarize the proportion of subjects reporting each symptom, any injection site 
symptom, and any systemic symptom. 
Unsolicited AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA) for 
preferred term and system organ class (SOC). The number of SAEs is expected to be small in 
this trial, so these events will be reported by detailed listings showing the event description, 
MedDRA preferred term and SOC, date of study vaccination, event date, severity, relatedness, 
and outcome for each event. Non-serious unsolicited AEs will be summarized as number and 
percentage of subjects reporting at least one event in each MedDRA preferred term and SOC, 
tabulated by severity and relationship to study product. Additionally, the proportion of subjects 
and exact 95% confidence intervals of AEs in aggregate and by MedDRA categories will be 
computed. 
The proportion of subjects reporting solicited or unsolicited AEs may be compared between 
treatment arms using Fisher’s exact test. The number of untoward fetal outcomes, perinatal 
complications, and major congenital abnormalities is expected to be small and so these events 
will be reported by a detailed listing including the event description, MedDRA preferred term 
and SOC, relevant dates (study vaccination and AEs), severity, relatedness, and outcome for 
each event. If more than 5% of pregnant women experience untoward fetal outcomes, perinatal 
complications, or infants born with major congenital abnormalities, the proportion of subjects 
with such events will be compared between the BOOSTRIX and Td treatment arms using 
Fisher’s Exact test. 
11.4.3. 
Immunogenicity Data (ELISA) 
Immunogenicity data summaries and analysis for pregnant women will be presented for the ITT 
and the PP populations. Immunogenicity data summaries and analysis for infants will be 
presented for the infant ITT and infant PP populations. 
Immune responses will be reported for antibodies against each of the antigens in the vaccine and 
at each time point for each subject group- pregnant women receiving BOOSTRIX, pregnant 
women receiving Td, and the infants of women who received BOOSTRIX or Td while pregnant. 
GMC and corresponding 95% confidence intervals will be reported. 
For each antigen, GMC will be compared between treatment arms using a t-test on log-
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The level of antibody transplacentally transferred will be summarized as the Geometric Mean 
Ratio (GMR), with corresponding 95% confidence interval, of mother’s concentration to infant’s 
concentration for all mother-infant pairs for which both the mother and infant have data at the 
applicable time point (delivery/birth). 
Graphical presentations of immune response may include reverse cumulative distribution (RCD) 
curves, and longitudinal presentations of GMTs. 
To evaluate the association with of maternal immunogenicity cofactors, Maternal and Infant anti-
PT ELISA response will be summarized stratified by maternal age (18-29, 30-39 years old), 
parity (primiparous vs. multiparous), GA at time of vaccination (14-17, 18-21, 22-26 weeks), GA 
at time of delivery (28-32, 33-36, 37 or more weeks), and infant birthweight, and these cofactors 
will be evaluated in regression modeling. 
Antibody responses in breast milk/colostrum will be evaluated in a similar way to above. 
Additional exploratory analyses, including analysis of cytokine response will be described in the 
statistical analysis plan. 
11.4.4. 
Missing Values and Outliers 
All attempts will be made to collect all data per protocol. As missing data are expected to be 
minimal, no imputation will be performed for missing values. Any data point that appears to be 
erroneous or inexplicable based on clinical judgment will be investigated as a possible outlier. If 
data points are identified as outliers, sensitivity analyses will be performed to examine the 
impact of including or excluding the outliers. Any substantive differences in these analyses will 
be reported. 

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12. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating VTEU site (or subcontracted site) will maintain appropriate medical and 
research records for this trial, in compliance with ICH E6, Section 4.9, and regulatory and 
institutional requirements for the protection of confidentiality of subjects. Each participating 
VTEU site will permit authorized representatives of the DMID, its designees, and appropriate 
regulatory agencies to examine (and when required by applicable law) to copy clinical trial 
records for the purposes of quality assurance reviews, audits, monitoring and evaluation of the 
trial safety and progress. These representatives will be permitted access to all source data, which 
include, but are not limited to, hospital records, clinical and office charts, laboratory notes, 
memoranda, evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files and 
records kept at the pharmacy, at the laboratories, and medico-technical departments involved in 
this clinical trial. Source data are all information, original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation 
of the trial. 
Interview of subjects is sufficient for obtaining medical history. For pregnant women, it is 
expected that certain source data, such as gestational age and diagnosis of high risk obstetrical 
conditions, will be extracted from the antenatal record. In the event of the need to obtain 
information for the evaluation of eligibility or safety, the research team may, with the permission 
of the subject via the consent process, obtain that information from the medical chart. 

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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, each participating VTEU site 
and its subcontractors are responsible for conducting routine quality assurance (QA) and quality 
control (QC) activities to internally monitor study progress and protocol compliance. The site 
principal investigator will provide direct access to all study-related sites, source data/data 
collection forms, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. The site principal investigator will ensure all study 
personnel are appropriately trained and applicable documentations are maintained on site. 
The DCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for clarification and resolution. 
DMID-designated clinical monitors will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, ICH/GCP 
guidelines, and the applicable regulatory requirements. Clinical monitoring reports will be 
submitted to DMID. 

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14. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1. 
Ethical Standard 
The site principal investigator will ensure that this trial is conducted in full conformity with the 
principles of the Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research (National Commission for the Protection of Human Subjects of Biomedical 
and Behavioral Research [April 18, 1979]) and codified in 45 CFR 46, 21 CFR 50 and 56, as 
applicable. The site principal investigator will also ensure conformity with ICH E6 Good 
Clinical Practice, and applicable federal regulations, guidance, and guidelines for Good Clinical 
Practice and Clinical Trials with humans. 
14.2. 
Institutional Review Board 
Each site principal investigator will obtain IRB approval for this protocol to be conducted at 
his/her research site(s) and send supporting documentation to the DMID before initiating 
recruitment of subjects. The investigator will submit applicable information to the IRB/IEC on 
which it relies for the review, to conduct the review in accordance with 45 CFR 46, ICH E6 
GCP, and as applicable, 21 CFR 56 (Institutional Review Boards) and 21 CFR 50 (Protection of 
Human Subjects), other federal, state, and local regulations. The IRB/IEC must be registered 
with the Office for Human Research Protections (OHRP) [OHRP-only or OHRP/FDA] as 
applicable to the research. DMID must receive the documentation that verifies IRB/IEC-approval 
for this protocol, associated informed consent documents, and upon request any recruitment 
material and handouts or surveys intended for the subjects, prior to the recruitment and 
enrollment of subjects. 
Any amendments to the protocol or consent materials will be approved by the IRB/IEC before 
they are implemented. IRB/IEC review and approval will occur at least annually throughout the 
enrollment and follow-up of subjects and may cease if annual review is no longer required by 
applicable regulations. The investigator will notify the IRB/IEC of deviations from the protocol 
and reportable SAEs, as applicable to the IRB/IEC policy. 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) 
issued by OHRP for federally funded research. 
14.3. 
Informed Consent Process 
Specifically, prior to obtaining individual informed consent for each subject, the investigators 
will discuss the trial with all the appropriate community associations and leaders, as necessary, to 
obtain permission to approach the prospective subjects. After community permission is granted, 
written, informed consent for participation in the trial will be obtained by the investigators from 
all individual subjects. The consent forms will be written in English; French, the official 

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language of Mali; and Bambara, the most prevalent of the local Malian languages. The consent 
documents will be recorded on audiotape, in order to allow Malian prospective subjects who may 
not be able to read English, French, or Bambara to hear the consent document verbatim in the 
language of their choice. 
The site principal investigator will choose subjects in accordance with the eligibility criteria 
detailed in Section 5. Before any study procedures are performed, subjects must sign (or, as is 
customary in Mali, consent may be indicated using a fingerprint) an informed consent form that 
complies with the requirements of 21 CFR Part 50 and 45 CFR 46 and the local IRB. 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continues throughout the individual’s trial participation. Before any study procedures 
are performed, including screening of subjects for eligibility, subjects will receive a 
comprehensive explanation of the proposed study procedures and study interventions/products, 
including the nature and risks of this trial, alternate therapies, any known AEs, the 
investigational status of the components, and the other elements that are part of obtaining proper 
informed consent. Subjects will also receive a detailed explanation of the proposed use and 
disclosure of their protected health information, including specifically their serum samples. 
Subjects will be allowed sufficient time to consider participation in this trial, after having the 
nature and risks of this trial explained to them and have the opportunity to discuss this trial with 
their family, friends, or others or think about it prior to agreeing to participate. 
The consent process of the pregnant subject will also include permission for inclusion of the 
infant in the postpartum phase of the study. After participants have given birth, study personnel 
will review the infant participation with them. After this review, participants will reaffirm their 
consent for their infants to take part in the post-partum phase of the study by signing the 
applicable page on the consent form. If this page is not signed, it is assumed that consent is not 
given and the infant will not participate in the post-partum phase of the study. Separate 
permission from the father of the infant will not be required, unless individual IRBs or Research 
Ethics Committees require it. Subject understanding of the study is determined by the research 
team member who is performing the informed consent process by asking the subject questions 
and by discussing the study with the subject. No formal Evaluation to Sign Consent or 
Comprehension Questionnaire will be used. 
For illiterate subjects, the consent document will be provided on audiotape with verbatim reading 
of the consent document in the language understandable to the subject. For illiterate pregnant 
women, even if the father of the baby is literate, the pregnant woman will provide permission. 
Whenever possible, the father of the baby will be involved in the decision, but his 

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signature/fingerprint to confirm permission for the infant participation will not be required, 
unless the local IRB/Research Ethics Committee requires it. 
The consent process for illiterate subjects will require that an impartial witness is present during 
the consent process and that the witness signs and dates the consent form. The witness must 
speak the language in which consent is obtained and must not be a key personnel member in the 
study. 
Informed consent forms describing in detail the study interventions/products, study procedures, 
risks, and possible benefits will be given to subjects. The informed consent form will not include 
any exculpatory statements. Informed consent forms will be IRB-approved and prospective 
subjects will be asked to read and review the appropriate document. Upon reviewing the 
appropriate document, the site principal investigator (or designee) will explain the research study 
to prospective subjects and answer any questions that may arise. Prospective subjects, if willing 
to join the study, will sign or fingerprint the informed consent form. Written documentation of 
the informed consent process will occur prior to starting any study procedures or interventions, 
including administering study product. 
DMID will provide the site principal investigator, in writing, any new information that 
significantly impacts subject risk of receiving the investigational product. This new information 
will be communicated by the site principal investigator to subjects who consent to participate in 
this trial in accordance with IRB requirements. The informed consent document will be updated, 
and subjects will be re-consented per IRB requirements, if necessary. 
Study personnel may employ IRB-approved recruitment efforts prior to obtaining subject 
consent; however, before any study procedures are performed to determine protocol eligibility, 
an informed consent form must be signed or fingerprinted. Subjects will be given a copy of all 
their signed or fingerprinted informed consent forms. 
The process of confirming on-going willingness to participate in the study will be documented 
on templated source documentation records. Subjects will be asked at visits through the study 
about their willingness to continue to provide consent for participation. 
The rights and welfare of subjects will be protected by emphasizing to subjects that the quality of 
their medical care will not be adversely affected if they decline to participate in or withdraw 
from this trial. 
14.3.1. 
Informed Consent/Assent Process (in Case of a Minor) 
N/A 

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14.4. 
Exclusion of Women, Minorities, and Children (Special Populations) 
This trial will be inclusive of all persons who meet the Subject Inclusion and Exclusion Criteria, 
regardless of religion, or ethnic background. Men are excluded because the study involves the 
evaluation of a vaccine for pregnant women. Given that this is the first formal study of 
BOOSTRIX in pregnant women in Mali, adolescent women who are pregnant will not be 
enrolled, only women 18 to 39 years old. In addition, women over age 39 years are being 
excluded because of the small increased risk of adverse pregnancy and fetal/infant outcomes in 
older women. 
14.5. 
Subject Confidentiality 
Subjects will have code numbers and will not be identified by name. Subject confidentiality is 
strictly held in trust by each participating VTEU site principal investigator, their study personnel, 
the sponsor(s), and their agents. This confidentiality is extended to cover testing of biological 
samples, in addition to the clinical information relating to subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning this trial or the data will be released to any 
unauthorized third party without prior written approval of the DMID and the subject. Subject 
confidentiality will be maintained when study results are published or discussed in conferences.   
All information provided by the sponsor and all data and information generated by each 
participating VTEU site as part of this trial (other than a subject’s medical records) will be kept 
confidential by the site principal investigator and other study personnel to the extent permitted by 
law. This information and data will not be used by the site principal investigator or other study 
personnel for any purpose other than conducting this trial. These restrictions do not apply to the 
following: (1) information which becomes publicly available through no fault of the site 
principal investigator or other study personnel; (2) information which is necessary to disclose in 
confidence to an IRB solely for the evaluation of this trial; (3) information which is necessary to 
disclose in order to provide appropriate medical care to a trial subject; or (4) study results which 
may be published as described in Section 16. 
The study monitor, applicable regulatory authorities, such as the FDA, or other authorized 
representatives of the sponsor may inspect all documents and records required to be maintained 
by the site principal investigator. This includes, but is not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the subjects in this trial. Each participating VTEU 
site will permit access to such records. 
To protect privacy, we have received a Certificate of Confidentiality.  With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings.  The researchers will use the Certificate to resist any demands for information 
that would identify the subject, except as explained below. 

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The Certificate cannot be used to resist a demand for information from personnel of the United 
States (US) Government that is used for auditing or evaluation of federally funded projects, like 
this study, or for information that must be released in order to meet the requirements of the US 
Food and Drug Administration (FDA). 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research.  If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information. 
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including: child and elder abuse, sexual 
abuse, or wanting to harm themselves or others. 
The Certificate of Confidentiality applies only under US law and does not apply to Malian 
courts. 
14.6. 
Study Discontinuation 
If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary. The investigator will provide a 
detailed written explanation of the termination to the IRB/IEC. If any subject’s private 
information will continue to be collected for this study, the IRB/IEC must approve a consent 
form with the study procedures, any risks and discomforts, and applicable elements, and the 
investigator or designee will re-consent the subjects as approved by the IRB/IEC. 
If this trial is discontinued, subjects who sign the informed consent form, and are randomized 
and vaccinated will continue to be followed for safety assessments. No further study vaccinations 
will be administered. 
14.7. 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for taking part in this trial. 
Subjects may be compensated for their participation in this trial. Compensation will be in 
accordance with the local IRB’s policies and procedures, and subject to IRB approval. 
If it is determined by a participating VTEU site and the site principal investigator that an injury 
occurred to a subject as a direct result of the tests or treatments that are done for this trial, then 
referrals to appropriate health care facilities will be provided to the subject. Study personnel will 
try to reduce, control, and treat any complications from this trial. Immediate medical treatment 
may be provided by a participating VTEU site, such as giving emergency medications to stop 
immediate allergic reactions to the study vaccine. No financial compensation will be provided to 

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the subject by a participating VTEU site or the sponsor for any injury suffered due to 
participation in this trial. 
14.8. 
Future Use of Stored Specimens and Data 
Subjects will be asked for their permission/refusal to allow storage of their remaining samples 
for possible use in future research studies, such as examining additional immunological 
assessments or testing for antibodies against other viruses or bacteria. This permission is 
recorded on the consent document but separate from the consent for inclusion in the trial itself. 
These residual samples will be stored for 15 years at a central clinical storage facility and may be 
shared with investigators at each participating VTEU site and with other investigators at other 
institutions. The samples will not be sold or used directly for production of any commercial 
product. No human genetic tests will be performed on samples. Each sample will be encoded 
(labeled) only with a barcode and a unique tracking number to protect subject confidentiality. If 
agreements regarding specimen transfer between institutions are required, such as Materials 
Transfer Agreements, the terms of those agreements will not contradict this protocol or the 
consent documents, and investigators will comply with the agreements. 
There are no benefits to subjects in the collection, storage, and subsequent use of their specimens 
for future research. Reports about future research done with subject’s samples will NOT be kept 
in their health records. 
Subjects may be given the option to decide if they want their samples to be used for future 
research or have their samples destroyed at the end of this trial. The subject’s decision can be 
changed at any time prior to the end of this trial by notifying the study doctors or nurses. 
However, if the subject originally consents to future use and subsequently changes her decision, 
any data from a previously collected sample may still be used for this research. 

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15. 
DATA HANDLING AND RECORD KEEPING 
The site principal investigator is responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported. 
Data collection forms will be derived from the eCRF and provided by the DCC to record and 
maintain data for each subject enrolled in this trial. All data collection forms will be completed 
in a neat, legible manner to ensure accurate interpretation of data. Black or blue ink will be used 
to ensure clarity of reproduced copies. When making a change or correction, study staff members 
will cross out the original entry with a single line and initial and date the change. Study staff 
members will not erase, overwrite, or use correction fluid or tape on the original. 
Data reported in the eCRF derived from the data collection forms will be consistent with the data 
collection forms or the discrepancies will be explained. 
The sponsor and/or its designee will provide guidance to site principal investigators and other 
study personnel on making corrections to the data collection forms and eCRF. 
15.1. 
Data Management Responsibilities 
All data collection forms and laboratory reports will be reviewed by the clinical team and data 
entry personnel, who will ensure that they are accurate and complete.  Adverse events will be 
recorded on the appropriate data collection form, assessed for severity and relationship, and 
reviewed by the site principal investigator or appropriate sub-investigator. 
Data collection is the responsibility of the study personnel at each participating VTEU site under 
the supervision of the respective site principal investigator. During this trial, the site principal 
investigator will maintain complete and accurate documentation for this trial. 
The DCC for this trial will be responsible for data management, quality review, analysis, and 
reporting of the trial data. 
15.2. 
Data Capture Methods 
Clinical (including, but not limited to, AE/SAEs, concomitant medications, medical history, and 
physical assessments), reactogenicity, and immunogenicity data will be entered into a 21 CFR 
11-compliant Internet Data Entry System provided by the DCC. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data 
that appear inconsistent, incomplete, or inaccurate. Clinical and reactogenicity data will be 
entered directly from the data collection forms completed by the study personnel. 
15.3. 
Types of Data 
Data for this trial will include clinical, safety, and outcome measures (e.g., clinical laboratory 
values, reactogenicity, and immunogenicity data). 

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15.4. 
Timing/Reports 
Clinical, safety, reactogenicity and immunogenicity data will be analyzed once the last subject 
and last infant born to a pregnant subject completes the final visit. Analyses will occur after all 
data have been entered, cleaned, and monitored, and the database locked. These analyses will be 
made available to the sponsor for planning subsequent trials and to the clinical investigators for 
publication. These analyses will not be used to make any decisions concerning the conduct of 
this trial. 
The clinical study report (CSR) will be completed when all primary safety endpoint data and all 
primary immunogenicity endpoint data are available. Any available data from the secondary and 
exploratory immunogenicity endpoints may also be included. The CSR will be amended as 
additional secondary and exploratory immunogenicity endpoint data become available. 
Interim statistical reports may be generated as deemed necessary and appropriate by DMID. 
Safety and immunogenicity summary reports may be generated for the DSMB. 
Cumulative safety information, study status, and primary endpoint results may be presented at a 
public forum in a blinded manner or presented as summaries aggregated by study arm at the 
discretion of the sponsor while the primary study is ongoing. While the primary study is ongoing 
no data will be released that is unblinding at an individual subject level, and caution will be taken 
to ensure that data summarized by treatment arm does not identify the treatment assignment of 
any individual subject. Any ad-hoc analyses, jointly developed by the SDCC and/or University 
of Maryland, will be executed by the SDCC as needed. Publication of manuscripts may occur at 
the discretion of the sponsor in accordance with DMID’s Expanded Distribution of Clinical 
Research Endpoint Data Policy. 
15.5. 
Study Records Retention 
Study documents will be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents will be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without the 
written consent of the sponsor. It is the responsibility of the sponsor to inform the investigator 
when these documents no longer need to be retained. 
The participating VTEU site must contact DMID for authorization prior to the destruction of any 
study records. Informed consent forms that include future use sections will be maintained as long 
as the sample exists. 
15.6. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or protocol-
specific MOP requirements. The noncompliance may be either on the part of the subject, the site 

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principal investigator, or other study personnel. As a result of deviations, corrective actions are 
to be developed by the site and implemented promptly. 
These practices are consistent with the following sections of ICH E6- 4.5: Compliance with 
Protocol, Sections 4.5.1, 4.5.2, and 4.5.3; 5.1: Quality Assurance and Quality Control, Section 
5.1.1; 5.20: Noncompliance, Sections 5.20.1, and 5.20.2. 
It is the responsibility of the site principal investigator and other trial personnel to use continuous 
vigilance to identify and report deviations within five working days of identification of the 
protocol deviation, or within five working days of the scheduled protocol-required activity. All 
deviations will be promptly reported to DMID, via the DCC’s Advantage eClinical. 
All protocol deviations, as defined above, will be addressed in study subject data collection 
forms. A completed copy of the DMID Protocol Deviation Form will be maintained in the 
Regulatory File as well as in the subject's chart. Protocol deviations will be sent to the local 
IRB/IEC per its guidelines. The site principal investigator and other study personnel are 
responsible for knowing and adhering to their IRB requirements. 

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16. 
PUBLICATION POLICY 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) an electronic 
version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made 
publicly available no later than 12 months after the official date of publication. The NIH Public 
Access Policy ensures the public has access to the published results of NIH-funded research. It 
requires investigators to submit final peer-reviewed journal manuscripts that arise from NIH 
funds to the digital archive PubMed Central upon acceptance for publication. Further, the policy 
stipulates that these papers must be accessible to the public on PubMed Central no later than 12 
months after publication. 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov, no later than 21 days after the enrollment of the first subject. Results of all 
clinical trials supported by the NIH, generally, need to be submitted no later than 12 months 
following the primary completion date. A delay of up to 2 years is available for trials that meet 
certain criteria and have applied for certification of delayed posting. 
As part of the result posting a copy of this protocol (and its amendments) and a copy of the 
Statistical Analysis Plan will be posted on ClincialTrials.gov. 
For this trial the responsible party is DMID which will register the trial and post results. 
The responsible party does not plan to request certification of delayed posting. 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 
• 
NIH NOT-OD-16-149 

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17. 
LITERATURE REFERENCES 
1. 
Pertussis vaccines: WHO position paper. Wkly Epidemiol Rec 2010; 85(40): 385-400. 
2. 
2012 Final Pertussis Surveillance Report. In: (U.S.) CfDCaP. Atlanta, GA: CDC, 2013. 
3. 
Burns DL, Meade BD, Messionnier NE. Pertussis resurgence: perspectives from the 
Working Group Meeting on pertussis on the causes, possible paths forward, and gaps in 
our knowledge. J Infect Dis 2014; 209 Suppl 1: S32-5. 
4. 
Clark TA. Changing pertussis epidemiology: everything old is new again. J Infect Dis 
2014; 209(7): 978-81. 
5. 
Tanaka M, Vitek CR, Pascual FB, Bisgard KM, Tate JE, Murphy TV. Trends in pertussis 
among infants in the United States, 1980-1999. JAMA 2003; 290(22): 2968-75. 
6. 
Yeung KHT, Duclos P, Nelson EAS, Hutubessy RCW. An update of the global burden of 
pertussis in children younger than 5 years: a modelling study. Lancet Infect Dis 2017; 
17(9): 974-80. 
7. 
Barger-Kamate B, Deloria Knoll M, Kagucia EW, et al. Pertussis-Associated Pneumonia 
in Infants and Children From Low- and Middle-Income Countries Participating in the 
PERCH Study. Clin Infect Dis 2016; 63(suppl 4): S187-s96. 
8. 
Gkentzi D, Katsakiori P, Marangos M, et al. Maternal vaccination against pertussis: a 
systematic review of the recent literature. Archives of disease in childhood Fetal and 
neonatal edition 2017; 102(5): F456-f63. 
9. 
Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and 
acellular pertussis vaccine (Tdap) in pregnant women and persons who have or anticipate 
having close contact with an infant aged <12 months --- Advisory Committee on 
Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep 2011; 60(41): 
1424-6. 
10. 
Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and 
acellular pertussis vaccine (Tdap) in pregnant women--Advisory Committee on 
Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep 2013; 62(7): 
131-5. 
11. 
Gall SA, Myers J, Pichichero M. Maternal immunization with tetanus-diphtheria-
pertussis vaccine: effect on maternal and neonatal serum antibody levels. American 
journal of obstetrics and gynecology 2011; 204(4): 334.e1-5. 
12. 
Hardy-Fairbanks AJ, Pan SJ, Decker MD, et al. Immune responses in infants whose 
mothers received Tdap vaccine during pregnancy. Pediatr Infect Dis J 2013; 32(11): 
1257-60. 
13. 
Munoz FM, Bond NH, Maccato M, et al. Safety and immunogenicity of tetanus 
diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and 
infants: a randomized clinical trial. JAMA 2014; 311(17): 1760-9. 
14. 
Amirthalingam G, Andrews N, Campbell H, et al. Effectiveness of maternal pertussis 
vaccination in England: an observational study. Lancet 2014; 384(9953): 1521-8. 
15. 
Skoff TH, Blain AE, Watt J, et al. Impact of the US Maternal Tetanus, Diphtheria, and 
Acellular Pertussis Vaccination Program on Preventing Pertussis in Infants <2 Months of 
Age: A Case-Control Evaluation. Clin Infect Dis 2017. 

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16. 
Van Savage J, Decker MD, Edwards KM, Sell SH, Karzon DT. Natural history of 
pertussis antibody in the infant and effect on vaccine response. J Infect Dis 1990; 161(3): 
487-92. 
17. 
Heininger U, Cherry JD, Christenson PD, et al. Comparative study of Lederle/Takeda 
acellular and Lederle whole-cell pertussis-component diphtheria-tetanus-pertussis 
vaccines in infants in Germany. Vaccine 1994; 12(1): 81-6. 
18. 
Englund JA, Anderson EL, Reed GF, et al. The effect of maternal antibody on the 
serologic response and the incidence of adverse reactions after primary immunization 
with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus 
toxoids. Pediatrics 1995; 96(3 Pt 2): 580-4. 
19. 
Maertens K, Cabore RN, Huygen K, et al. Pertussis vaccination during pregnancy in 
Belgium: Follow-up of infants until 1 month after the fourth infant pertussis vaccination 
at 15 months of age. Vaccine 2016; 34(31): 3613-9. 
20. 
Abu Raya B, Srugo I, Kessel A, et al. The effect of timing of maternal tetanus, diphtheria, 
and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis 
antibody levels - a prospective study. Vaccine 2014; 32(44): 5787-93. 
21. 
Eberhardt CS, Blanchard-Rohner G, Lemaitre B, et al. Maternal Immunization Earlier in 
Pregnancy Maximizes Antibody Transfer and Expected Infant Seropositivity Against 
Pertussis. Clin Infect Dis 2016; 62(7): 829-36. 
22. 
Cherry JD. Editorial commentary: the effect of Tdap vaccination of pregnant women on 
the subsequent antibody responses of their infants. Clin Infect Dis 2015; 61(11): 1645-7. 
23. 
Cushing AH, Samet JM, Lambert WE, et al. Breastfeeding reduces risk of respiratory 
illness in infants. Am J Epidemiol 1998; 147(9): 863-70. 
24. 
Yamakawa M, Yorifuji T, Kato T, et al. Long-Term Effects of Breastfeeding on 
Children's Hospitalization for Respiratory Tract Infections and Diarrhea in Early 
Childhood in Japan. Matern Child Health J 2015; 19(9): 1956-65. 
25. 
Kassim OO, Raphael DH, Ako-Nai AK, Taiwo O, Torimiro SE, Afolabi OO. Class-
specific antibodies to Bordetella pertussis, Haemophilus influenzae type b, Streptococcus 
pneumoniae and Neisseria meningitidis in human breast-milk and maternal-infant sera. 
Ann Trop Paediatr 1989; 9(4): 226-32. 
26. 
Abu Raya B, Srugo I, Kessel A, et al. The induction of breast milk pertussis specific 
antibodies following gestational tetanus-diphtheria-acellular pertussis vaccination. 
Vaccine 2014; 32(43): 5632-7. 
27. 
De Schutter S, Maertens K, Baerts L, De Meester I, Van Damme P, Leuridan E. 
Quantification of vaccine-induced antipertussis toxin secretory IgA antibodies in breast 
milk: comparison of different vaccination strategies in women. Pediatr Infect Dis J 2015; 
34(6): e149-52. 
28. 
Fedele G, Cassone A, Ausiello CM. T-cell immune responses to Bordetella pertussis 
infection and vaccination. Pathog Dis 2015; 73(7). 
29. 
Warfel JM, Zimmerman LI, Merkel TJ. Comparison of Three Whole-Cell Pertussis 
Vaccines in the Baboon Model of Pertussis. Clin Vaccine Immunol 2015; 23(1): 47-54. 

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30. 
Huygen K, Cabore RN, Maertens K, Van Damme P, Leuridan E. Humoral and cell 
mediated immune responses to a pertussis containing vaccine in pregnant and 
nonpregnant women. Vaccine 2015; 33(33): 4117-23. 
31. 
Pharmaceuticals G. BOOSTRIX package insert. Available at: 
https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_In
formation/Boostrix/pdf/BOOSTRIX.PDF.  
32. 
Limited BE. Diphtheria and Tetanus Vaccine (Adsorbed, Reduced Antigen(s) Content). 
Available at: 
https://extranet.who.int/gavi/PQ_Web/PreviewVaccine.aspx?nav=0&ID=280. Accessed 
12/18/2017. 
33. 
Rasmussen SA, Hernandez-Diaz S, Abdul-Rahman OA, et al. Assessment of congenital 
anomalies in infants born to pregnant women enrolled in clinical trials. Clin Infect Dis 
2014; 59 Suppl 7: S428-36. 
34. 
Ladhani SN, Andrews NJ, Southern J, et al. Antibody responses after primary 
immunization in infants born to women receiving a pertussis-containing vaccine during 
pregnancy: single arm observational study with a historical comparator. Clin Infect Dis 
2015; 61(11): 1637-44. 
 
 
 

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Appendix A 
Study Visit Type 
Recruitment 
Screening 
Enrollment/ 
Vaccination 
Clinic or 
Home Visit 
Clinic or 
Home Visit 
Follow-up 
Follow-up 
Follow-up 
Follow-up 
Follow-up 
Early Termination 
Unscheduled 
Study Visit 
Number 
R˜ 
VOO 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
 
Study Day 
 
1st & 2nd 
Trimesters 
-30 to 1 
D1 
D4+1 
D8+3d 
D31±4d 
Birth + 3d 
Birth + 
42d±5d 
Birth + 
70d±5d or 
130d±5d 
Birth + 
180d±7d 
 
 
EGA or Infant 
Age 
10-26 
weeks 
14-26 
weeks 
14-26 
weeks 
15-27 
weeks 
15-27 
weeks 
19-31 
weeks
Birth 
1.5 
months 
2 5 or 4.5 
months 
6 months 
 
 
Introduction to Study, 
Recruiting 
X 
Xm 
Xm 
 
 
 
 
 
 
 
 
 
Obtain Informed 
Consent∞ 
 
X 
Xm¬ 
 
 
 
 
 
 
 
 
 
Review Eligibility 
Criteria 
 
X 
Xm¬ 
 
 
X¬ 
 
 
 
 
 
 
Medical History@ 
 
X 
Xm¬ 
X¬ 
X¬ 
X¬ 
X¬ 
X¬˜ 
X¬˜ 
X¬˜ 
X¬ 
X¬ 
Concomitant 
Medications√@ 
 
X 
Xm¬ 
X¬ 
X¬ 
X¬ 
X! 
X˜ 
X˜ 
X˜ 
X! 
X! 
Vaccination History@ 
 
X 
Xm¬ 
X¬ 
X¬ 
X¬ 
X! 
 
 
 
 
 
Vital Signs$ (Oral 
Temperature%, Pulse, 
and BP) 
 
X 
X† 
 
 
X 
X 
 
 
 
X 
X 
Height and Weight 
 
X 
Xm 
 
 
 
 
 
 
 
 
 
Targeted Physical 
Exam {} 
 
X 
X m¬†# 
 
 
X 
X 
X 
X 
X 
X 
X 
Ultrasound to Date 
Pregnancy 
 
X 
 
 
 
 
 
 
 
 
 
 
Venous Blood 
Collection from 
Mother (30 mL) 
 
 
X† 
 
 
X 
X 
 
 
X 
 
 
Cord Blood (up to 30 
mL) 
 
 
 
 
 
 
X 
 
 
 
 
 
Venous Blood from 
Infant (5 mL) 
 
 
 
 
 
 
X& 
X 
X 
X 
 
 
Obtain Breastmilk 
Sample from Mother 
(10-20 mL) 
 
 
 
 
 
 
Xψ 
X 
X 
X 
 
 
Pre-Administration 
Solicited Event 
Assessments 
 
 
X† 
 
 
 
 
 
 
 
 
 
Randomize and 
Vaccinate Mother 
 
 
X 
 
 
 
 
 
 
 
 
 
30-minute Evaluation 
After Study 
Vaccination 
 
 
X 
 
 
 
 
 
 
 
 
 

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{}Targeted physical examination, if indicated based on review of complete or interim medical history. An 
examination performed by a pregnant woman’s own obstetrical clinician may also provide data when a targeted 
exam is called for. An exam should be performed for both the mother and infant if indicated for pregnant women on 
and after birth. 
$Vital signs assessed on Day 1 (Visit 01) prior to the study vaccination will be considered as baseline and used to 
determine eligibility. For the birth visit, vital signs recorded for the mother as part of her delivery record may be 
used in lieu of study personnel performing vital sign measurements. 
#A physical examination performed as part of routine antenatal care or a study-specific brief exam may be used. 
!If within 30 days post vaccination.  
˟ If within 8 days post vaccination.  
*SAEs and new-chronic onset medical conditions only after Day 31 or delivery, whichever occurs earlier. 
+Only medically attended AEs will be recorded. 
ψ The first colostrum collection may occur within the first 4 days of life of the infant.  
˚ Infant vital signs will include axillary temperature, heart rate, and respiratory rate. 
ˠ If not performed as routine care, these measurements, except for weight, may be taken by qualified members of the 
research team within 7 days of infant life. Weights will only be recorded when obtained at birth.  
˜ Procedures will be performed on both mother and infant. 
Ω Only infant height, weight, and head circumference will be recorded at these visits.