Mucosal Immune Responses Against Neisseria Gonorrhoeae Following Meningococcal Immunization in Healthy Young Adults
Phase: PHASE2
Conditions: Gonorrhoea
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
1 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018
Mucosal immune responses against Neisseria gonorrhoeae following 
meningococcal immunization in healthy young adults 
DMID Protocol Number: 19-0015 
DMID Funding Mechanisms: Vaccine and Treatment Evaluation Unit (VTEU) (Protocol 
Development); Infectious Diseases Clinical Research Consortium (IDCRC) (Protocol 
Implementation, Analysis, and Closeout) 
IND Sponsor: Division of Microbiology and Infectious Diseases, NIAID, NIH, DHHS 
Lead Principal Investigator: Varun K. Phadke MD 
DMID Clinical Project Manager: Peter Wolff  
Version Number:  7.0 
14 August 2023 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
2 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018
STATEMENT OF ASSURANCE 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office of 
Human Research Protections (OHRP) for federally-funded human subjects research.  Each FWA 
will designate at least one Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) registered with OHRP, for which the research will be reviewed and approved by the 
IRB/IEC and will be subject to continuing review [45 CFR 46.103(b)]. The IRB/IEC designated 
under an FWA may include an institution’s IRB/IEC, an independent IRB/IEC, or an IRB/IEC of 
another institution after establishing a written agreement with that other institution. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
3 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018
STATEMENT OF COMPLIANCE 
The study trial will be carried out in accordance with Good Clinical Practice (GCP) and 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, 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

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
4 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
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 IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
Varun K. Phadke MD 
Associate Professor of Medicine, Division of 
Infectious Diseases 
Emory University Vaccine and Treatment Evaluation 
Unit (VTEU) 
The Hope Clinic of the Emory Vaccine Center 
 
 
 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
5 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................11 
LIST OF ABBREVIATIONS ........................................................................................................12 
PROTOCOL SUMMARY .............................................................................................................17 
1 
KEY ROLES.........................................................................................................................21 
2 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................23 
2.1 
Background .................................................................................................................23 
2.2 
Scientific Rationale .....................................................................................................24 
2.2.1 Purpose of Study ............................................................................................24 
2.2.2 Study Population ............................................................................................25 
2.3 
Potential Risks and Benefits .......................................................................................25 
2.3.1 Potential Risks ...............................................................................................25 
2.3.2 Potential Benefits ...........................................................................................29 
3 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES .....30 
3.1 
Study Design Description ...........................................................................................30 
3.2 
Study Objectives .........................................................................................................31 
3.2.1 Primary ...........................................................................................................31 
3.2.2 Secondary .......................................................................................................31 
3.2.3 Exploratory ....................................................................................................31 
3.3 
Study Endpoints or Outcome Measures .....................................................................32 
3.3.1 Primary ...........................................................................................................32 
3.3.2 Secondary .......................................................................................................32 
3.3.3 Exploratory ....................................................................................................32 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
6 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
4 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT .........................................35 
4.1 
Study Product Description ..........................................................................................35 
4.1.1 Formulation, Packaging, and Labeling ..........................................................35 
4.1.2 Product Storage and Stability .........................................................................36 
4.2 
Acquisition/Distribution .............................................................................................36 
4.3 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product.........................................................................36 
4.4 
Accountability Procedures for the Study Intervention/Investigational Product(s) .....37 
5 
SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL ....39 
5.1 
Eligibility Criteria .......................................................................................................39 
5.1.1 Subject Inclusion Criteria...............................................................................39 
5.1.2 Subject Exclusion Criteria .............................................................................40 
5.2 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination
 ..................................................................................................................................43 
5.2.1 Withdrawal from the Study or Discontinuation of the Study Product ...........43 
5.2.2 Subject Replacement ......................................................................................44 
5.2.3 Study Termination .........................................................................................44 
6 
STUDY PROCEDURES ......................................................................................................45 
6.1 
Screening ....................................................................................................................45 
6.1.1 Visit 00A, Day -56 to -1 for subjects in the no biopsy cohort / -56 to -28 for 
subjects in the biopsy cohort, 1st Screen, Clinic Visit ....................................45 
6.1.2 Visit 00B, Day -7 to -1 for subjects in the no biopsy cohort / -34 to -28 for 
subjects in the biopsy cohort, 2nd Screen, Clinic Visit (optional) .................46 
6.1.3 Visit 00C, Day -28 to -14, Baseline Rectal Mucosal Biopsy, Clinic Visit ....47 
6.1.4 Visit 00P, Day -27 to -12, Baseline Rectal Mucosal Biopsy, Telephone Visit
 ........................................................................................................................48 
6.2 
Enrollment ..................................................................................................................48 
6.2.1 Visit 01, Day 1, Randomization and First Vaccination, Clinic Visit .............48 
6.3 
Planned Study Visits ...................................................................................................50 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
7 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
6.3.1 Visit 02, Day 8 (±1 day), Clinic Visit ............................................................50 
6.3.2 Visit 03, Day 15 (±1 day), Clinic Visit ..........................................................51 
6.3.3 Visit 04, Day 29 (±1 day), Second Vaccination, Clinic Visit ........................51 
6.3.4 Visit 05, Day 36 (±1 day), Clinic Visit ..........................................................53 
6.3.5 Visit 06, Day 43 (±3 days), Rectal Mucosal Biopsy, Clinic Visit .................53 
6.3.6 Visit 06P, Day 44 (+1 day), Telephone Visit .................................................54 
6.3.7 Visit 07, Day 57 (±1 day), Clinic Visit ..........................................................55 
6.3.8 Visit 08, Final Study Visit, Day 181 (±7 days), Clinic Visit .........................56 
6.3.9 Early Termination Visit .................................................................................57 
6.4 
Unscheduled Study Visits ...........................................................................................57 
6.5 
Protocol Deviations ....................................................................................................58 
7 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................59 
7.1 
Clinical Evaluations ....................................................................................................59 
7.1.1 Research Procedures ......................................................................................60 
7.1.2 Assessment of Concomitant Medications/Treatments other than Study 
Product ...........................................................................................................61 
7.2 
Laboratory Evaluations ...............................................................................................62 
7.2.1 Clinical Laboratory Evaluations ....................................................................62 
7.2.2 Research Assays .............................................................................................63 
7.2.2.1 
Antibody assays ................................................................................63 
7.2.2.2 
Cell-mediated immunity assays ........................................................64 
7.2.2.3 
Bacterial adhesion assay ...................................................................64 
7.2.2.4 
Laboratory Specimen Preparation, Handling, and Storage ...............64 
7.2.2.5 
Laboratory Specimen Shipping ........................................................65 
8 
ASSESSMENT OF SAFETY ...............................................................................................66 
8.1 
Assessing and Recording Safety Parameters ..............................................................66 
8.1.1 Adverse Events ..............................................................................................66 
8.1.1.1 
Adverse Events Grading ...................................................................66 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
8 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
8.1.2 Reactogenicity ................................................................................................68 
8.1.3 Serious Adverse Events .................................................................................68 
8.2 
Specification of Safety Parameters .............................................................................69 
8.2.1 Solicited Events .............................................................................................69 
8.2.2 Unsolicited Events .........................................................................................70 
8.2.3 Medically-Attended Adverse Events (MAAEs) ............................................70 
8.3 
Reporting Procedures ..................................................................................................70 
8.3.1 Reporting Serious Adverse Events ................................................................70 
8.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND
 ........................................................................................................................71 
8.3.3 Reporting of Pregnancy .................................................................................72 
8.4 
Type and Duration of Follow-up of Subjects after Adverse Events ...........................72 
8.5 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings......................................................................................72 
8.6 
Halting Rules ..............................................................................................................73 
8.6.1 Study Halting Criteria ....................................................................................73 
8.6.2 Individual Halting Criteria .............................................................................73 
8.7 
Safety Oversight .........................................................................................................74 
8.7.1 Independent Safety Monitor (ISM) ................................................................74 
8.7.2 Safety Monitoring Committee (SMC) ...........................................................74 
9 
HUMAN SUBJECTS PROTECTION .................................................................................76 
9.1 
Institutional Review Board/Independent Ethics Committee ......................................76 
9.2 
Informed Consent Process ..........................................................................................76 
9.3 
Consent for Future Use of Stored Specimens and Data .............................................78 
9.4 
Exclusion of Women, Minorities, and Children (Special Populations) ......................79 
9.5 
Subject Confidentiality ...............................................................................................79 
9.6 
Certificate of Confidentiality ......................................................................................80 
9.7 
Costs, Subject Compensation, and Research Related Injuries ...................................80 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
9 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
10 
STATISTICAL CONSIDERATIONS .................................................................................82 
10.1 Study Hypotheses .......................................................................................................82 
10.2 Sample Size Considerations .......................................................................................82 
10.3 Treatment Assignment Procedures .............................................................................84 
10.3.1 Randomization Procedures ............................................................................84 
10.3.2 Masking Procedures .......................................................................................84 
10.4 Planned Interim Analyses ...........................................................................................85 
10.4.1 Interim Safety Review ...................................................................................85 
10.4.2 Interim Immunogenicity Review ...................................................................85 
10.5 Final Analysis Plan .....................................................................................................85 
10.5.1 Analysis Populations ......................................................................................86 
10.5.1.1 Immunogenicity Population ..............................................................86 
10.5.1.2 Safety Population ..............................................................................86 
10.5.2 Baseline Characteristics .................................................................................86 
10.5.3 Immunogenicity Analysis Plan ......................................................................86 
10.5.4 Safety Analysis Plan ......................................................................................87 
11 
ELECTRONIC CASE REPORT FORMS AND ACCESS TO SOURCE DATA ..............88 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................90 
13 
DATA HANDLING AND RECORD KEEPING ................................................................91 
13.1 Data Management Responsibilities ............................................................................91 
13.2 Data Coordinating Center/Biostatistician Responsibilities ........................................91 
13.3 Data Capture Methods ................................................................................................91 
13.4 Types of Data ..............................................................................................................92 
13.5 Study Records Retention ............................................................................................92 
14 
CLINICAL MONITORING .................................................................................................93 
15 
PUBLICATION POLICY ....................................................................................................94 
16 
LITERATURE REFERENCES ............................................................................................95 
17 
APPENDICES ......................................................................................................................99 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
10 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Appendix A. SCHEDULE OF EVENTS ...........................................................................100 
Appendix B. TABLE OF STUDY ASSAYS AND BLOOD VOLUME COLLECTION .104 
Appendix C. TOXICITY TABLE ......................................................................................107 
 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
11 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
LIST OF TABLES 
Table 1: 
Treatment Arm Goals* ...............................................................................................20 
Table 2: 
95% Confidence Intervals for GMTs and GMT Ratios across a range of 
Sample Sizes and Antigens .........................................................................................83 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
12 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
LIST OF ABBREVIATIONS 
4CMenB 
Bexsero® or multi-component meningococcal serogroup B 
vaccine 
ACIP 
Advisory Committee on Immunization Practices 
AE 
Adverse Event/Adverse Experience 
aPTT 
Activated Partial Thromboplastin Time 
BLA 
Biologics License Applications 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CMS 
Clinical Material Services 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease 2019 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CROMS 
Clinical Research Operations and Management Support 
CSR  
Clinical Study Report 
CT 
Chlamydia trachomatis 
DCC 
Data Coordinating Center 
DGI 
Disseminated Gonococcal Infection 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, 
NIH, DHHS 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
13 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EUA 
Emergency Use Authorization 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FHbp 
Factor H Binding Protein 
FWA 
Federal Wide Assurance 
GC 
Neisseria gonorrhoeae 
GCP 
Good Clinical Practice 
GMFR 
Geometric Mean Fold Rise  
GMT 
Geometric Mean Titer 
HEENT 
Head/Ear/Eyes/Nose/Throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICS 
Intracellular Cytokine Staining 
IDCRC 
Infectious Diseases Clinical Research Consortium  
IDE 
Investigational Device Exemption 
IDES  
Internet Data Entry System 
IEC 
Independent or Institutional Ethics Committee 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
14 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
IgA 
Immunoglobin A 
IgG 
Immunoglobin G  
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IUD 
Intrauterine Device  
JAMA 
Journal of the American Medical Association 
LLC 
Limited Liability Corporation 
MAAEs 
Medically-Attended Adverse Events  
MBC 
Memory B Cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MeNZB 
New Zealand Meningococcal Group B Vaccine 
mL 
Milliliter  
mm 
Millimeter   
MM 
Medical Monitor 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NAAT 
Nucleic Acid Amplification Test 
NadA 
Neisserial Adhesion A 
NDA 
New Drug Application 
NEJM 
New England Journal of Medicine 
NHBA 
Neisserial Heparin Binding Antigen 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
15 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OER 
Office of Extramural Research 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
OMV 
Outer Membrane Vesicle 
PBMC 
Peripheral Blood Mononuclear Cell 
PBS 
Phosphate-Buffered Saline 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PID 
Pelvic Inflammatory Disease 
PK 
Pharmacokinetics 
PLT 
Platelet Count 
PT 
Prothrombin Time 
QA 
Quality Assurance 
QC 
Quality Control 
RPR 
Rapid Plasma Reagin 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SBA 
Serum Bactericidal Antibody 
SDCC 
Statistical and Data Coordinating Center  
SMA 
Secondary Medical Assessor  

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
16 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
STI 
Sexually Transmitted Infection 
SUSAR 
Suspected Unexpected Serious Adverse Event 
US 
United States 
USP 
United States Pharmacopeial Convention 
VTEU 
Vaccine and Treatment Evaluation Unit 
WBC 
White Blood Count 
WFI 
Water For Injection 
WHO 
World Health Organization 
 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
17 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
PROTOCOL SUMMARY 
 
Title: 
Mucosal immune responses against Neisseria gonorrhoeae 
following meningococcal immunization in healthy young adults 
Design of the Study: 
 
This is a mechanistic clinical trial to assess the systemic and 
mucosal immunogenicity of the multicomponent meningococcal 
serogroup B vaccine (4CMenB or Bexsero®) (group 1, 
approximately 40 subjects) against N. gonorrhoeae (GC), using a 
placebo vaccine (normal saline) as a comparator (group 2, 
approximately 10 subjects). 
Study Phase: 
2 
Study Population: 
This trial will enroll approximately 50 (maximum of 60 subjects) 
healthy male and non-pregnant female subjects aged 18 to 49 
years, and will be conducted in the US 
Number of Sites: 
1 (Emory University VTEU)  
Description of Study 
Product or Intervention: 
The active product will be Bexsero® (4CMenB), a FDA-
approved multi-component meningococcal serogroup B vaccine 
that contains outer membrane vesicles (OMVs) containing PorA 
serosubtype P1.4, as well as three recombinant protein antigens 
(neisserial adhesion A [NadA], factor H binding protein [FHbp] 
fusion protein, and neisserial heparin binding antigen [NHBA] 
fusion protein). 4CMenB is presented as a single-dose prefilled 
syringe that is administered intramuscularly on a 2 dose (0.5-
Milliliter (mL) each) schedule, with the second dose to be given 
1 month apart from the first. 
The comparator product will be a normal saline placebo. 
Study Objectives: 
 
Primary: 
• To characterize the rectal mucosal Immunoglobin G 
(IgG) antibody response to GC elicited by the 4CMenB 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
18 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
vaccine as compared with the placebo vaccine in healthy 
adult subjects. 
Secondary: 
• To characterize the serum IgG antibody response to GC 
elicited by the 4CMenB vaccine as compared with the 
placebo vaccine in healthy adult subjects. 
• To assess the safety and reactogenicity of 4CMenB in 
healthy adult subjects. 
• Exploratory: 
• To characterize the vaginal mucosal IgG antibody 
response to GC elicited by the 4CMenB vaccine as 
compared with the placebo vaccine in healthy adult 
subjects. 
• To characterize the oropharyngeal mucosal IgG antibody 
response to GC elicited by the 4CMenB vaccine as 
compared with the placebo vaccine in healthy adult 
subjects. 
• To characterize the serum Immunoglobin A (IgA) 
antibody response to GC elicited by the 4CMenB vaccine 
as compared with the placebo vaccine in healthy adult 
subjects. 
• To characterize the mucosal IgA antibody response to 
GC elicited by the 4CMenB vaccine as compared with 
the placebo vaccine in healthy adult subjects. 
• To characterize the systemic B cell responses to GC 
antigens elicited by 4CMenB vaccine as compared with 
the placebo vaccine in healthy adult subjects. 
• To characterize the systemic T cell responses to GC 
antigens elicited by 4CMenB vaccine as compared with 
the placebo vaccine in healthy adult subjects. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
19 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• To characterize the mucosal T cell responses to GC 
antigens elicited by 4CMenB vaccine as compared with 
the placebo vaccine in healthy adult subjects. 
• To characterize the serum bactericidal antibody responses 
to GC elicited by 4CMenB vaccine as compared with the 
placebo vaccine in healthy adult subjects. 
• To evaluate the impact of 4CMenB vaccine-induced 
antibodies on gonococcal adhesion to human cervical 
cells. 
• To characterize immune responses to N. meningitidis 
elicited by the 4CMenB vaccine as compared with the 
placebo vaccine in healthy adult subjects for use as 
controls. 
Duration of Individual 
Subject Participation: 
The duration of each subject’s participation is approximately 8 
months, from recruitment through the last study visit. 
Estimated Time to Last 
Subject/Last Study Day: 
Approximately 14 months. The enrollment period will be 
approximately 6 months and subjects will be followed through 6 
months after their first vaccination. 
 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
20 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Table 1: 
Treatment Arm Goals* 
 
Rectal Mucosal Biopsy Cohort 
(N=20) 
No Rectal Mucosal Biopsy Cohort 
(N=30) 
Total 
Vaccine 
Male 
Non-pregnant 
Female 
Male 
Non-Pregnant 
Female 
 
4CMenB 
8 
8 
12 
12 
40 
Placebo 
2 
2 
3 
3 
10 
 
*As noted in the study design, this trial will enroll approximately 50 (maximum of 60 subjects) 
healthy male and non-pregnant female subjects aged 18 to 49 years, randomized in a ratio of 4 to 
1 4CMenB to placebo 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
21 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
1 
KEY ROLES 
Lead Principal 
Investigator:                           
 
 
 
 
 
 
 
 
Varun K. Phadke, MD 
Associate Professor of Medicine, Division of Infectious 
Diseases 
Emory University Vaccine and Treatment Evaluation Unit 
(VTEU) 
The Hope Clinic of the Emory Vaccine Center 
500 Irvin Court, 
 
Decatur, GA 30030 
Phone: 
 
Fax: 
 
Email: 
 
DMID Clinical Project 
Manager: 
Peter A. Wolff, MHA 
DMID, NIAID, NIH 
5601 Fishers Lane 
Bethesda, MD, 20892 
Email: 
 
 
 
Statistical and Data 
Coordinating Center: 
 
The Emmes Company, LLC 
401 North Washington Street, 
 
Rockville, MD 20850 
Phone: 
 
Email: 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
22 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
IDCRC Protocol 
Management: 
 
FHI 360 
359 Blackwell Street, 
 
Durham, NC 27701 
Phone: 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
23 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
2 
BACKGROUND AND SCIENTIFIC RATIONALE 
2.1 
Background  
Gonorrhea is a sexually transmitted infection (STI) caused by the gram-negative diplococcus 
GC. It causes urethritis and cervicitis in sexually active men and women respectively, and in 
women can lead to upper genital tract disease (i.e., pelvic inflammatory disease (PID)), which is 
a risk factor for ectopic pregnancy and infertility. Extragenital infections of other mucosal sites 
(e.g., rectum and pharynx) are also possible, as are invasive infections (i.e., disseminated 
gonococcal infection, or DGI) such as gonococcal arthritis/dermatitis syndrome, septic arthritis, 
and endocarditis. Finally, perinatally acquired infection – which typically occurs among 
newborns of asymptomatic women – can cause sight-threatening conjunctivitis (ophthalmia 
neonatorum). 
In 2012 the World Health Organization estimated approximately 78 million new cases of 
gonorrhea globally.1 In the United States, gonorrhea is the second most commonly reported 
notifiable disease, with more than 550,000 cases reported in 2017. Rates of gonococcal disease 
have been steadily increasing since 2009 irrespective of age, sex, ethnic group, or geographic 
region.2 
Though gonococcal infections are curable with antibiotic therapy, antimicrobial resistance has 
become a global public health problem. The prevalence of resistance to multiple antibiotic 
classes has increased gradually since the 1940s2, and GC isolates with reduced susceptibility to 
current first-line therapy – ceftriaxone and azithromycin – have emerged.3 Given the large and 
growing burden of disease, and the threat of untreatable gonococcal infections due to 
antimicrobial resistance, a safe and effective vaccine is urgently needed. Unfortunately, previous 
efforts to develop a gonorrhea vaccine have been largely unsuccessful. 
Recently, a retrospective case-control study in New Zealand demonstrated 31% (95% confidence 
interval (CI), 21-39) effectiveness of an OMV meningococcal group B vaccine (MeNZB) against 
incident gonorrhea.4 The same group of investigators also reported 24% (95% CI, 1-42) vaccine 
effectiveness against hospitalization caused by gonorrhea.5 Previous ecological studies had 
suggested a possible protective effect of OMV vaccines against gonorrhea in Norway6 and 
Cuba.7 Meningococcal OMV vaccines have been used successfully to control epidemic strains of 
N. meningitidis serogroup B.8 These vaccines elicit serum bactericidal antibody (SBA) responses 
directed primarily against meningococcal strain-specific porin protein, PorA.9 The precise 
mechanism of cross-protection conferred by meningococcal OMV vaccines against GC remains 
unknown. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
24 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
A four component meningococcal serogroup B vaccine (Bexsero® or 4CMenB) was recently 
licensed for use in the United States and was given a category B recommendation by the 
Advisory Committee on Immunization Practices (ACIP) for use in adolescents and young adults 
up to 25 years of age.10 Bexsero includes OMVs containing PorA serosubtype P1.4, as well as 
three recombinant protein antigens (neisserial adhesion A [NadA], factor H binding protein 
[FHbp] fusion protein, and neisserial heparin binding antigen [NHBA] fusion protein).11 An 
analysis of gonococcal incidence following a 4CMenB vaccination campaign in one region of 
Quebec, Canada found a non-significant reduction in gonorrhea cases in the post-vaccination 
period12, supporting the findings from New Zealand, and suggesting that 4CMenB vaccine could 
protect against gonorrhea. 
A recent study found a high level of amino acid sequence identity between the 4CMenB OMV 
antigens and those in the MeNZB OMV in the vaccine studied in New Zealand, and with OMV 
homologues in a laboratory strain of GC. The same study found that rabbits vaccinated either 
with MeNZB or the OMV component of 4CMenB raised antibodies against GC, and that 
4CMenB vaccination in humans elicited serum antibodies against GC.13 In contrast, another 
study found vaccination with a native OMV vaccine raised SBA responses against GC in mice, 
but 4CMenB vaccination did not elicit similar SBA responses in humans.14  
Given the potential public health impact of an effective vaccine against gonorrhea, a better 
understanding of the immunologic responses to GC following 4CMenB vaccination is needed. 
Specifically, although two studies have characterized antibody responses against GC following 
4CMenB in serum, gonorrhea is a mucosal disease. While there are studies looking at the ability 
of meningococcal serogroup B vaccines to modulate human nasopharyngeal mucosal immunity 
to N. meningitidis, there are no data on the impact of 4CMenB on immunologic responses at the 
human mucosal surfaces where GC is typically encountered (urethra, rectum, cervix, and 
pharynx). 
2.2 
Scientific Rationale 
2.2.1 
Purpose of Study 
This is a mechanistic clinical trial to assess the systemic and mucosal immunogenicity of the 
multicomponent meningococcal serogroup B vaccine (4CMenB or Bexsero®) against GC, using 
a placebo vaccine (normal saline) as a comparator, in healthy young adults. 
4CMenB is licensed for use in those aged 10-25 years and is administered intramuscularly as a 
two dose-series, with the second dose given at least one month after the first dose. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
25 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
2.2.2 
Study Population 
The study population will include approximately 50 males and non-pregnant females, 18 to 49 
years of age, inclusive, who are in good health and meet all eligibility criteria. 
Subjects will be recruited from the community at large and enrolled at 1 VTEU site (Hope 
Clinic, Emory VTEU). 
This age range was selected to represent the population with the highest incidence of gonorrhea2 
therefore children are excluded from this study. There are no plans currently to include children 
in future studies of mucosal immune responses to GC after meningococcal immunization. 
2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
The potential risks of participating in this trial are those related to having venous blood drawn, 
the intramuscular injections, possible reactions to the 4CMenB or placebo vaccines, undergoing 
oropharyngeal, vaginal and rectal mucosal sampling, and breach of confidentiality. 
Blood draw and Intramuscular (IM) injection 
Drawing blood may cause transient discomfort and fainting and lead to or exacerbate iron 
deficiency in those who are not anemic. Fainting is usually transient and managed by having the 
subject lie down and elevating his/her legs. Bruising at the blood draw site may occur but can be 
prevented or lessened by applying pressure to the blood draw site for a few minutes after the 
blood is taken. 
 
IM injection may also cause transient discomfort and fainting. Drawing blood and 
IM injection may cause infection. The use of aseptic (sterile) technique will make infection at the 
site where blood will be drawn or where the study vaccination will be given extremely unlikely. 
Bexsero® (4CMenB) 
Bexsero® was licensed by the FDA for active immunization to prevent invasive disease caused 
by Neisseria meningitidis serogroup B in 2005 and is approved for use in individuals aged 10 
through 25 years. 
A comprehensive description of the risks of adverse events (AEs) are described in the package 
insert.11 The most common (frequency ≥10%) solicited adverse reactions observed in clinical 
trials were pain at the injection site (≥83%), myalgia (≥48%), erythema (≥45%), fatigue (≥35%), 
headache (≥33%), induration (≥28%), nausea (≥18%), and arthralgia (≥13%). 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
26 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
From post marketing experience, lymphadenopathy been reported after receiving Bexsero.  Since 
this was voluntarily reported from a population of uncertain size, the incidence rate cannot be 
estimated. 
There are limited safety data for 4CMenB in adults over age 25 years. Although the vaccine is 
licensed for use in individuals aged 10 through 25 years, the ACIP has noted that there are no 
theoretical differences in safety for persons aged >25 years compared with those aged 10–25 
years, thus the ACIP supports the routine use of MenB vaccines in persons aged ≥10 years who 
are at increased risk for serogroup B meningococcal disease.15 
An analysis of two mass vaccination campaigns that used 4CMenB in response to two university 
outbreaks of MenB included safety data from 16,974 individuals who received at least one dose 
of 4CMenB with a median age of 20 years (range 16-65 years).16 In this analysis, 8.4% of 
vaccinated individuals reported any AE, with the most common AEs being pain in the injected 
arm (10%), fever (9%), headache (5%), nausea (4%), and fatigue (4%). A total of 54 individuals 
(0.3%) experienced a Serious Adverse Event (SAE), only three of which were suspected to be 
related to the 4CMenB. In one phase 1 study of healthy adults aged 18-40 years17 and three phase 
2 studies of laboratory workers (age range 18-65 years)18-20 receiving 4CMenB vaccination, the 
vaccine was well-tolerated and there were no SAEs.   
Oropharyngeal mucosal secretion sampling 
Oropharyngeal secretion sampling may cause transient discomfort. Participants will be asked to 
stop some activities before these samples are collected, including oral sex, or use of certain oral 
or inhaled immunomodulatory agents – such as corticosteroids – which may be inconvenient. 
Vaginal mucosal secretion sampling 
Vaginal mucosal secretion sampling may cause anxiety, transient discomfort, and 
embarrassment. Participants will be asked to stop some activities before these samples are 
collected, including vaginal sex, or use of anything in or around their vagina – such as tampons, 
spermicide, lubricants, or medications (e.g., topical yeast treatments) – which may be 
inconvenient. 
Rectal mucosal secretion sampling 
Rectal mucosal secretion sampling may cause anxiety, transient discomfort, and embarrassment. 
Participants will be asked to stop some activities before these samples are collected, including 
receptive anal intercourse, or insertion of anything into their anus – such as cleaning products, 
lubricant, enemas, or douches (including water) – which may be inconvenient. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
27 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Rectal mucosal biopsy 
Risks associated with lower gastrointestinal endoscopy include colitis from chemicals for 
endoscope sterilization, bowel perforation, bleeding, diverticulitis, and infection. All procedures 
will be performed by Dr. Kelley or a nurse practitioner trained by Dr. Kelley. Non-physician 
medical providers have performed endoscopic procedures for diagnostic and therapeutic 
procedures for years. Many of these require mastery of flexible sigmoidoscopes, detailed 
anatomy of the full colon, and familiarity with sedation procedures.21, 22 Procedures utilizing 
flexible instruments that access a deeper area of the colon and may or may not require sedation 
are more complicated and risky than the procedure detailed in this protocol which utilizes a rigid 
sigmoidoscope and only accesses the sigmoid colon a maximum of 15 cm from the anal verge.  
Therefore, it is appropriate for a trained, licensed mid-level provider to perform the procedure. 
Dr. Kelley’s team has performed >300 similar procedures for other IRB approved protocols with 
zero complications.   
All procedures will utilize disposable rigid sigmoidoscopes, forceps, and guides to reduce risk of 
infection and obviate the need for instrument sterilization between participants.  To minimize 
risks, rigid proctoscopy, rather than flexible sigmoidoscopy or full colonoscopy, will be used in 
this study and the number of biopsies taken will be limited to 12.  Colonoscopy has been shown 
to be associated with a still low, but significantly greater risk of complications than 
rectosigmoidoscopy.23 The frequency of serious complications after flexible sigmoidoscopy is 
extremely low and complications from rigid sigmoidoscopy are presumably even lower, but 
unknown.  In two large studies including a combined 144,832 clinically indicated procedures, the 
incidence of serious complications ranged from 0.06 to 0.8% utilizing flexible sigmoidoscopy.23, 
24 Obtaining biopsies may be associated with an increased risk of complications. The best 
available data on the risk of multiple biopsies comes from studies of dysplasia surveillance 
among patients with long-standing inflammatory bowel disease, in whom large numbers of 
“blind” biopsies are obtained throughout the colon for early detection of malignant 
transformation. In two such studies including a combined 3,011 procedures and a median of 
eight and 17 biopsies, respectively, there was only one serious complication, for an incidence of 
approximately 0.33%.25, 26 In a study of subjects undergoing endoscopic procedures exclusively 
for research purposes, including 64 flexible sigmoidoscopies with a mean of 25 biopsies obtained 
from the rectosigmoid, there were no major complications. Thirteen subjects experienced minor 
symptoms (self-limited bleeding and pain), which were not related to the number of biopsies.27  
A summary of procedures across several Microbicide Trial Network (an NIH-funded, 
international network designed to develop topical agents for Human Immunodeficiency Virus 
(HIV) prevention) was published in 2017.28 This manuscript reported on the safety of 1,004 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
28 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
sigmoidscopy procedures with >15,000 biopsy collection from 278 research participants. Many 
participants underwent multiple procedures (median 3 procedures). There were no SAEs, and an 
AE related to sigmoidoscopy was reported in 1.6% of procedures. Eight of the 16 related AEs 
reported were abdominal pain, flatulence, bleeding, diarrhea, and bloating. Fourteen of the 16 
related AEs were grade 1 and 2/16 were grade 2; median time to resolution was 1 day. The 
authors concluded that repeated intestinal mucosal biopsies for research purposes are safe. Thus, 
based on the available data, the risk of serious complications from the proposed study 
procedures, even with up to 10 biopsy specimens, is expected to be very low (<1:5000).  
There is theoretical risk of increased acquisition of HIV or other infection if a study participant is 
exposed soon after the rectal biopsy procedure (i.e. while the mucosal surface is damaged).  
Therefore, study subjects will be counseled not to engage in anal intercourse for 1 week after the 
rectal biopsy procedure.  
Biologic samples will be coded with a unique identifier prior to processing and storage for 
immunologic assays.  Therefore, lab personnel will be unable to link specimens with 
participants.  Only the PI and designated co-investigators/study personnel will be able to access 
information to identify specimens of individual participants. 
Breach of Confidentiality 
Subjects will be asked to provide protected health information (PHI). All attempts will be made 
to keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see a subject’s PHI. All records will be kept in a locked file cabinet or 
maintained in a locked room at the site. Electronic files will be password protected. Only people 
who are involved in the conduct, oversight, monitoring, or auditing of this trial will be allowed 
access to this PHI. Any publications from this trial will not use information that will identify 
subjects by name. Organizations that may inspect and/or copy research records maintained at the 
site for quality assurance (QA) and data analysis include groups such as NIAID (or its designee) 
and FDA. 
A description of this 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. 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
29 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
2.3.2 
Potential Benefits 
For subjects assigned to the Bexsero® group of the study, this meningococcal vaccine is known 
to elicit protective antibodies against N. meningitidis serogroup B in adults aged 10-25 years of 
age. There may also be benefits to society through the improvement of our understanding of 
mucosal immune responses to GC following 4CMenB vaccination. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
30 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
3 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
3.1 
Study Design Description 
This is a single-center phase 2 double blinded mechanistic clinical trial to assess the systemic 
and mucosal immunogenicity of the multicomponent meningococcal serogroup B vaccine 
(4CMenB or Bexsero®) against GC, using a placebo vaccine (normal saline) as a comparator. 
This trial will enroll approximately 50 healthy male and non-pregnant female subjects aged 18 to 
49 years, inclusive, who meet all eligibility criteria. Subjects will be randomized 4:1 to one of 
two treatment groups. Group 1 (approximate N=40) will receive two doses of 4CMenB on Day 1 
and Day 29. Group 2 (approximate N=10) will receive two placebo injections on Day 1 and Day 
29. The goal will be to ensure adequate representation of subjects by sex in both groups 
(Table 1) 
Vaccine preparation and administration will be unblinded. Only pharmacy personnel, the Emmes 
unblinded team and an unblinded vaccinator will have access to the study codes, and all other 
study personnel will be blinded. Subjects will be followed through 6 months after their first 
vaccination (Day 181). 
All subjects will undergo sampling of mucosal secretions for testing for antibodies against GC. 
Male subjects will undergo oropharyngeal and rectal mucosal sampling, and female subjects will 
undergo oropharyngeal, vaginal and rectal mucosal sampling. A subset of subjects in each 
treatment group (N=16 in Group 1, N=4 in Group 2) will undergo rectal mucosal biopsy at two 
time points (baseline and following the second vaccination) for assessment of tissue GC specific 
cellular responses. The goal will be to ensure adequate representation of subjects by sex in both 
groups in the rectal mucosal biopsy cohort (Table 1). 
This trial is expected to take approximately 14 months to complete, from initiation through 
availability of a final report on the primary outcomes of mucosal antibody responses and the 
secondary outcomes of serum antibody responses and safety outcomes related to mucosal 
sampling procedures and 4CMenB vaccination. For additional details on study procedures and 
evaluations and study schedule by study visits/days, see Sections 6, 7, and 8 and well as 
Appendices Appendix A and Appendix B. 
Schematic of Study Design: See Table 1. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
31 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
3.2 
Study Objectives 
3.2.1 
Primary  
• To characterize the rectal mucosal IgG antibody response to GC elicited by the 4CMenB 
vaccine as compared with the placebo vaccine (normal saline) in healthy adult subjects. 
3.2.2 
Secondary 
• To characterize the serum IgG antibody response to GC elicited by the 4CMenB vaccine 
as compared with the placebo vaccine in healthy adult subjects. 
• To assess the safety and reactogenicity of 4CMenB in healthy adult subjects. 
3.2.3 
Exploratory  
• To characterize the vaginal mucosal IgG antibody response to GC elicited by the 
4CMenB vaccine as compared with the placebo vaccine in healthy adult subjects. 
• To characterize the oropharyngeal mucosal IgG antibody response to GC elicited by the 
4CMenB vaccine as compared with the placebo vaccine in healthy adult subjects. 
• To characterize the serum IgA antibody response to GC elicited by the 4CMenB vaccine 
as compared with the placebo vaccine in healthy adult subjects. 
• To characterize the mucosal IgA antibody response to GC elicited by the 4CMenB 
vaccine as compared with the placebo vaccine in healthy adult subjects. 
• To characterize the systemic B cell responses to GC antigens elicited by 4CMenB 
vaccine as compared with the placebo vaccine in healthy adult subjects. 
• To characterize the systemic T cell responses to GC antigens elicited by 4CMenB 
vaccine as compared with placebo vaccine in healthy adult subjects. 
• To characterize the mucosal T cell responses to GC antigens elicited by 4CMenB vaccine 
as compared with the placebo vaccine in healthy adult subjects. 
• To characterize the serum bactericidal antibody responses to GC elicited by 4CMenB 
vaccine as compared with the placebo vaccine in healthy adult subjects. 
• To evaluate the impact of 4CMenB vaccine-induced antibodies on gonococcal adhesion 
to human cervical cells. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
32 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• To characterize immune responses to N. meningitidis elicited by the 4CMenB vaccine as 
compared with the placebo vaccine in healthy adult subjects for use as controls. 
3.3 
Study Endpoints or Outcome Measures 
3.3.1 
Primary  
• Rectal mucosal IgG concentrations (geometric mean titers, GMT) against GC OMV 
antigens at Day 1, 29, 43, 57, and 181 in each treatment group 
3.3.2 
Secondary  
• Serum IgG concentrations (GMT) against GC OMV antigens at Day 1, 29, 43, 57, and 
181 in each treatment group 
• Frequency and severity of any AE related to 4CMenB immunization through the end of 
the study. 
• Frequency of SAEs through the end of the study. 
3.3.3 
Exploratory  
• Rectal mucosal IgG concentrations (GMT) against GC antigens before and after 
vaccination in each treatment group 
• Serum IgG concentrations (GMT) against GC antigens before and after vaccination in 
each treatment group 
• Vaginal mucosal IgG concentrations geometric mean titer (GMT) against GC antigens 
before and after vaccination in female subjects in each treatment group 
• Oropharyngeal mucosal IgG concentrations (GMT) against GC antigens before and after 
vaccination in each treatment groupSerum IgA concentrations (GMT) against GC 
antigens before and after vaccination in each treatment group 
• Rectal mucosal IgA concentrations (GMT) against GC antigens before and after 
vaccination in each treatment group 
• Vaginal mucosal IgA concentrations (GMT) against GC antigens before and after 
vaccination in female subjects in each treatment group 
• Oropharyngeal mucosal IgA concentrations (GMT) against GC antigens before and after 
vaccination in each treatment group 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
33 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Frequencies and function of memory B cells specific for antigens from GC before and 
after vaccination by ELISpot in each treatment group. 
• Frequencies and function of peripheral blood T cells specific for antigens from GC before 
and after vaccination by ELISpot in each treatment group.  
• Frequencies, phenotype, and function of peripheral blood CD4+ T cells specific for 
antigens from GC based on cytokine profile before and after vaccination by intracellular 
cytokine staining in each treatment group. 
• Frequencies, phenotype, and function of peripheral blood CD8+ T cells specific for 
antigens from GC based on cytokine profile before and after vaccination by intracellular 
cytokine staining in each treatment group. 
• Frequencies, phenotype, and function of rectal mucosal CD4+ T cells specific for 
antigens from GC based on cytokine profile before and after vaccination by intracellular 
cytokine staining in each treatment group. 
• Frequencies, phenotype, and function of rectal mucosal CD8+ T cells specific for 
antigens from GC based on cytokine profile before and after vaccination by intracellular 
cytokine staining in each treatment group. 
• Serum bactericidal antibody titers against GC  before and after vaccination in each 
treatment group. 
• Percent inhibition of gonococcal adhesion to human cervical cell line (ME180) by 
mucosal antibodies at Day 43 in each treatment group. 
• Serum IgG concentrations (GMT) against N. meningitidis antigens before and after 
vaccination in each treatment group 
• Frequencies and function of memory B cells specific for antigens from N. meningitidis 
before and after vaccination by ELISpot in each treatment group. 
• Frequencies and function of peripheral blood T cells specific for antigens from N. 
meningitidis before and after vaccination by ELISpot in each treatment group.  
• Frequencies, phenotype, and function of peripheral blood CD4+ T cells specific for 
antigens from N. meningitidis based on cytokine profile before and after vaccination by 
intracellular cytokine staining in each treatment group. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
34 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Frequencies, phenotype, and function of peripheral blood CD8+ T cells specific for 
antigens from N. meningitidis based on cytokine profile before and after vaccination by 
intracellular cytokine staining in each treatment group. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
35 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
4 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
4.1 
Study Product Description 
Bexsero®11: Active Product 
Each 0.5-mL dose of Bexsero® (4CMenB) is formulated to contain 50 micrograms each of 
recombinant proteins NadA, NHBA, and fHbp, 25 micrograms of OMV, 1.5 mg aluminum 
hydroxide (0.519 mg of Al3+), 3.125 mg sodium chloride, 0.776 mg histidine, and 10 mg 
sucrose at pH 6.4 – 6.7. The NadA component is a fragment of the full-length protein derived 
from N. meningitidis strain 2996 (peptide 8 variant 2/3). The NHBA component is a recombinant 
fusion protein comprised of NHBA (peptide 2) and accessory protein 953 derived from N. 
meningitidis strains NZ98/254 and 2996, respectively. The fHbp component is a recombinant 
fusion protein comprised of fHbp (variant 1.1) and the accessory protein 936 derived from N. 
meningitidis strains MC58 and 2996, respectively. These 3 recombinant proteins are individually 
produced in Escherichia coli and purified through a series of column chromatography steps. The 
OMV antigenic component is produced by fermentation of N. meningitidis strain NZ98/254 
(expressing outer membrane protein PorA serosubtype P1.4), followed by inactivation of the 
bacteria by deoxycholate, which also mediates vesicle formation. The antigens are adsorbed onto 
aluminum hydroxide. Each dose contains less than 0.01 micrograms kanamycin (by calculation) 
Placebo 
The placebo is 0.9% Sodium Chloride, USP injection. 
 
4.1.1 
Formulation, Packaging, and Labeling 
Bexsero®: Active Product 
Bexsero® (4CMenB) is a sterile, white, opalescent, suspension for intramuscular injection. 
4CMenB is supplied as a 0.5-mL suspension in a glass prefilled syringe (packaged without 
needles). 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 or regulatory specifications and 
include the statement “Caution: New Drug – Limited by Federal Law to Investigational Use.” 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
36 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Placebo 
Placebo will be supplied as 0.9% Sodium Chloride Injection, USP which is a colorless, sterile, 
nonpyrogenic, isotonic solution of sodium chloride and water for injection (WFI). Each mL 
contains supplied chloride 9 mg. It contains no bacteriostatic, antimicrobial agent, or added 
buffer and is supplied only in single-dose containers. The placebo, 0.9% Sodium Chloride, 
contains no preservatives. The solution may contain hydrochloric acid and/or sodium hydroxide 
for pH adjustment (pH 5.3 [4.5 to 7.0]). 
 
4.1.2 
Product Storage and Stability 
Bexsero®: Active Product 
Bexsero® (4CMenB) must be stored between 2°C to 8°C (36°F to 46°F). Do not freeze. Do not 
use if the vaccine has been frozen. Protect from light. 
Placebo 
0.9% Sodium Chloride, USP injection must be stored at 20ºC to 25ºC (68°F to 77ºF) [See USP 
Controlled Room Temperature; excursions between 15°C and 30°C (59°F and 86°F) are 
permitted]. See protocol-specific manual of procedures (MOP) for further instructions. 
4.2 
Acquisition/Distribution 
Bexsero®: Active Product 
4CMenB will be provided by DMID Clinical Materials Services (CMS, Fisher BioServices). 
Placebo 
Normal saline will be used as the placebo and will be provided by DMID CMS (Fisher 
BioServices). 
4.3 
Dosage/Regimen, Preparation, Dispensing and Administration of 
Study Intervention/Investigational Product 
Bexsero® (4CMenB): Active Product 
Bexsero® (4CMenB) will be administered as a 2 dose series (0.5-mL each) with the second dose 
given 1 month after the first dose (Day 1 and Day 29) in participants randomized to Group 1. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
37 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Shake the syringe immediately before use to form a homogeneous suspension. Do not use the 
vaccine if it cannot be resuspended. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and container 
permit. Do not use if particulate matter or discoloration is found. 
Bexsero® will be administered as a 0.5-mL intramuscular injection into the deltoid muscle of the 
upper arm. The vaccine dose will be administered within 30 minutes following removal from the 
refrigerator. 
Placebo 
The placebo will be administered as a 2-dose series (0.5-mL each) with the second dose given 1 
month after the first dose (Day 1 and Day 29) in participants randomized to Group 2.  
Gently invert the normal saline vial 5 to 7 times. Using aseptic technique, puncture the septum 
top of the saline vial with a 1-inch, 23- or 25-gauge disposable, sterile needle attached to a 1-mL 
disposable, sterile syringe. Withdraw 0.5 mL from the saline vial. The prepared saline dose in the 
syringe will be allowed to store at room temperature and administered within 30 minutes. The 
dose will be administered IM over the deltoid region of the preferred arm. 
Syringes for both Bexsero and placebo will be overlayed with a blinding tape and flagged 
(wrapped) with a prescription label. Labeling specifics will be referenced in the MOP.  Labeled 
syringes will be provided to the unblinded vaccine administrator. The unblinded vaccine 
administrator will be credentialed to administer vaccines but will not be involved in study-related 
assessments, subject contact, or data collection following vaccination. 
4.4 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
Study vaccines will be stored and shipped from the DMID contract CMS to the Clinical Sites. 
Once received, vaccines will be stored in and dispensed by the Investigational Pharmacy. DMID 
will determine the disposition of unused product.  
The FDA requires accounting for the disposition of all investigational products. The Investigator 
is responsible for ensuring that a current record of product disposition is maintained and product 
is dispensed only at an official study site by authorized personnel as required by applicable 
regulations and guidelines. Records of product disposition, as required by federal law, consist of 
the date received, date administered, quantity administered, and the subject number to whom the 
drug was administered.  

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
38 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
The Investigational Pharmacist will be responsible for maintaining accurate records of the 
shipment and dispensing of the investigational product. The pharmacy records must be available 
for inspection by the DMID monitoring contractors, and is subject to inspection by a regulatory 
agency (e.g., FDA) at any time. An assigned Study Monitor will review the pharmacy records. 
Unused investigational product syringes will be stored at 2oC-8oC in the Investigational 
Pharmacy until clinical trial accountability is completed. At study termination, all unused 
investigational product will be disposed in accordance with the MOP following complete drug 
accountability and monitoring. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
39 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
5 
SELECTION OF SUBJECTS AND STUDY 
ENROLLMENT AND WITHDRAWAL 
Subjects will be recruited through: posting of IRB-approved flyers on the Emory University 
campus; use of social media, list serves (such as CDC, Emory University, Emory Vaccine 
Center, and Vaccine Dinner Club), and clinical trial recruitment websites; a HIPAA-compliant 
clinical trials database to identify subjects of previous studies at the Hope Clinic who have 
agreed to future contact; presentations by Hope Clinic faculty at various University and 
community venues; and volunteer word-of-mouth. 
If subjects are agreeable and interested, they will be screened initially over the phone for general 
eligibility criteria and their PHI will be saved in a locked cabinet in a secure office of the study 
coordinator/recruiter. When appropriate, an appointment at the Hope Clinic is then scheduled for 
an in-person clinic visit. Research staff will then obtain written consent per the standard 
informed consent process before conducting protocol-specific screening activities. 
This study will enroll both male and non-pregnant female subjects. The goal will be to ensure 
approximately adequate representation of subjects by sex in both treatment groups (Table 1). 
To facilitate this, enrollment will be stratified by both sex and treatment arm. Enrollment of 
subjects by sex and “cohort” (either “biopsy” or “no biopsy”) will be based on the numbers listed 
in Table 1, and all subjects will be randomized 4:1 to either 4CMenB or placebo. 
Subject Inclusion and Exclusion Criteria must be confirmed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator (PI) or sub-
investigator. 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 
Eligibility Criteria 
5.1.1 
Subject Inclusion Criteria 
Subjects must meet all the following inclusion criteria to be eligible for this trial: 
1. Must be aged 18-49 years old (inclusive) at the time of vaccination. 
2. Must be able to provide written informed consent. 
3. Must have a body mass index (BMI) ≥18.5 and <35.0 kg/m2 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
40 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
4. Must be in good health based on physical examination, vital signs*, medical history, 
safety labs** (as applicable to the rectal biopsy and no biopsy cohorts) and the 
investigator’s clinical judgment. 
*Vital signs must be within the normal ranges in Appendix C If a subject has elevated 
systolic or diastolic blood pressure, subject may rest for 10 minutes in a quiet room and the 
blood pressure may be retaken. 
**Safety labs must be within the normal ranges in Appendix C, and the normal ranges will 
be those used by the reference clinical lab. 
5. For female subjects only: If a female participant is of childbearing potential*, she must 
use contraception** from 30 days before study product administration through the end of 
study participation. 
*A woman is considered of childbearing potential unless post-menopausal (defined as history of 
≥1 year of spontaneous amenorrhea), or permanently surgically sterilized (bilateral 
oophorectomy, salpingectomy, hysterectomy). 
**Acceptable methods of contraception include: abstinence or no sex with a male, monogamous 
relationship with a man who had a vasectomy at least 6 months before the 1st study vaccine, 
prescription oral contraceptives, intrauterine device (IUD), birth control implants or 
injections, contraceptive patch, vaginal ring, condoms and diaphragms/cervical cap with 
spermicide (“double barrier” method) 
6. Must be available and willing to participate for the duration of this trial.  
7. Willing to provide mucosal samples: vaginal secretions for women and oropharyngeal 
and rectal secretions for men and women. 
8. For the rectal biopsy cohort only, willing to provide rectal biopsies. 
 
5.1.2 
Subject Exclusion Criteria 
Subjects meeting any of the following exclusion criteria at baseline will be excluded from study 
participation: 
1. Has ever been diagnosed with meningococcal infection or gonococcal infection at any 
anatomic site. 
2. Has ever received any serogroup B meningococcal vaccine. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
41 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
3. Any positive test result for STI (including GC/Chlamydia trachomatis (CT), Rapid 
Plasma Reagin (RPR) and HIV) at screening*. 
*Female subjects will also be tested for Trichomonas at screening. 
4. Any history of Chlamydia trachomatis or syphilis infection at any body site in the 
preceding 12 months. 
5. Has known allergy or history of anaphylaxis or other serious adverse reaction to a 
vaccine or vaccine products. 
6. Has severe allergy or anaphylaxis to latex. 
7. Has an acute illness or temperature ≥38.0°C on Day 1*. 
*Subjects with fever or acute illness on the day of vaccination may be re-assessed and enrolled if 
healthy or only minor residual symptoms remain within 3 days. 
8. Has a history of a bleeding disorder, or is taking chronic anti-coagulant (e.g. warfarin, 
direct thrombin inhibitors, heparin products, etc.), anti-platelet, or Non-Steroidal Anti-
Inflammatory Drug (NSAID) therapy. 
9. Has history of autoimmune disease, or clinically significant cardiac, pulmonary, 
gastrointestinal, hepatic, rheumatologic, or renal disease by history or physical 
examination. 
10. Has history of active malignancy other than squamous cell or basal cell skin cancer, 
unless there has been surgical excision that is considered to have achieved cure*. 
*Subjects with a history of skin cancer must not be vaccinated at the previous tumor site. 
11. Has known or suspected congenital or acquired immunodeficiency, or recent history or 
current use of immunosuppressive therapy*. 
*Anti-cancer chemotherapy or radiation therapy within the preceding 3 years, or long-term (≥2 
weeks within the previous 3 months) systemic corticosteroid therapy (at a dosage of ≥0.5 
mg/kg/day). Intranasal or topical prednisone (or equivalent) are allowed. 
12. Is post-organ and/or stem cell transplant, whether or not on chronic immunosuppressive 
therapy. 
13. Had major surgery (per the investigator’s judgment) within 4 weeks before study entry or 
planned major surgery during this trial. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
42 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
14. Has history of diabetes* mellitus type 1 or type 2, including cases controlled with diet 
alone*. 
*History of isolated gestational diabetes is not an exclusion criterion. 
15. Received live attenuated vaccines from 30 days before first vaccination until 30 days 
after second vaccination. 
16. Received killed or inactivated vaccines* from 14 days before first vaccination until 14 
days after second vaccination. 
*For inactivated influenza vaccine, from 7 days before either vaccination until 7 days after 
either vaccination 
17. Received mRNA, viral vector, or any other technology platform COVID-19 vaccine 
within 14 days prior to first dose of the study product.* 
 
*COVID-19 vaccination should take priority over administration of the study product.  
18. Received experimental therapeutic agents within 12 months before first vaccination or 
plans to receive any experimental therapeutic agents during this trial except for EUA 
COVID-19 therapy.* 
*Only exclusionary if, in the opinion of the investigator, they would interfere with safety or 
endpoint assessment. 
19. Is currently participating or plans to participate in another clinical study which would 
involve receipt of an investigational product or undergoing a procedure*. 
*Only exclusionary if, in the opinion of the investigator, they would interfere with safety or 
endpoint assessment. 
20. Received blood products or immunoglobulin in the 3 months before study entry or 
planned use during this trial. 
21. Has major psychiatric illness in the past 12 months that in the opinion of the investigator 
would preclude participation. 
22. Has current alcohol use or current or past abuse of recreational or narcotic drugs by 
history as judged by the investigator to potentially interfere with study adherence. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
43 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
23. In the opinion of the investigator cannot communicate reliably, is unlikely to adhere to 
the requirements of this trial, or has any condition which would limit the ability to 
complete this trial. 
24. Is pregnant or breast feeding. 
 
5.2 
Withdrawal from the Study, Discontinuation of Study Product, or 
Study Termination  
5.2.1 
Withdrawal from the Study or Discontinuation of the Study Product  
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 discontinue a subject from receiving the study product for any reason. 
Follow-up safety and immunogenicity 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 case report forms (CRFs).  
The reasons for subject withdrawal or discontinuation of study product, might include, but are 
not limited to the following: 
• Subject no longer meets eligibility criteria 
• Subject meets individual halting criteria (reference to section 8.6.2) 
• 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 
• Subject becomes pregnant, if applicable 
• 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) 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
44 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
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.  
5.2.2 
Subject Replacement 
Subjects who withdraw, or are withdrawn from this study, or are lost to follow-up after signing 
the informed consent form (ICF) and administration of the study product may be replaced at the 
investigator’s discretion.  Subjects who withdraw, or are withdrawn from this study, or are lost to 
follow-up after signing the ICF but before administration of the study product may be replaced at 
the investigator’s discretion.   
5.2.3 
Study Termination  
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. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
45 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
6 
STUDY PROCEDURES 
6.1 
Screening  
6.1.1 
Visit 00A, Day -56 to -1 for subjects in the no biopsy cohort / -56 to -28 for 
subjects in the biopsy cohort, 1st Screen, Clinic Visit 
Potential subjects will be screened for eligibility up to 56 days before the first study vaccination. 
The following activities will be performed at the 1st screening visit. 
• Begin the informed consent process. Provide subjects with a description of this trial 
(purpose and study procedures) and ask them to read the ICF. Provide an opportunity to 
the potential subject to ask questions. If she/he wishes to proceed with participation, the 
ICF should be signed before performing any screening procedures 
• Review eligibility criteria. 
• Interview subjects to collect demographics, medical history, sexual history, vaccination 
history, and pre-study medication use. Interview of subjects is sufficient for obtaining 
medical history. Solicitation of medical records from the subject’s primary care provider 
is not required. 
• Review subjects’ concomitant medications taken within 30 days before signing the ICF. 
• Obtain vital signs, including oral temperature, pulse, and blood pressure to assure 
eligibility. 
• Measure height and weight and calculate BMI. 
• Perform a physical examination including the following organs and organ systems: 
general appearance, head/eyes/ears/nose/throat (HEENT), neck, lungs, heart, abdomen, 
extremities, musculoskeletal, lymph nodes, skin, and nervous system. Genital and rectal 
exams will be performed at the investigator’s discretion. All physical exams will be done 
by a clinician licensed to make medical diagnoses and listed on Form FDA 1572 as site 
PI or sub-investigator 
• Collect venous blood for RPR and HIV-1/2 antibody testing. 
• During screening for the rectal biopsy cohort only, collect venous blood for complete 
blood count (White Blood Count (WBC), hemoglobin, Platelet Count (PLT)), 
prothrombin time (PT) and activated partial thromboplastin time (aPTT) 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
46 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Collect urine for pregnancy test from all female subjects of childbearing potential. 
• Collect pharyngeal and rectal swabs for nucleic acid amplification testing (NAAT) for 
GC and CT 
• Collect urine for NAAT for GC/CT from male subjects 
• Collect a self-collected vaginal swab for NAAT for GC/CT/Trichomonas from female 
subjects 
• The overall eligibility of the subject to participate in this trial will be assessed once all 
screening test values and results of any other required evaluations are available. Subjects 
who qualify for inclusion will be contacted and scheduled for baseline rectal mucosal 
biopsy or first vaccination within 28 days. 
• Subjects who qualify for inclusion in the rectal biopsy cohort will be instructed to abstain 
from receptive anal intercourse or insertion of anything into their anus, for at least 2 days 
prior to the baseline rectal mucosal biopsy visit 
• Subjects who qualify for inclusion will be instructed to abstain from receptive anal and/or 
vaginal intercourse, insertion of anything into their vagina and/or anus, or oral sex for at 
least 2 days prior to the enrollment/first vaccination visit 
 
6.1.2 
Visit 00B, Day -7 to -1 for subjects in the no biopsy cohort / -34 to -28 for 
subjects in the biopsy cohort, 2nd Screen, Clinic Visit (optional) 
This screening visit will only occur to repeat a screening assessment whose initial result is 
thought to be temporary). The following activities will be performed at the 2nd screening visit if 
it occurs. 
• Review eligibility criteria, including results of available clinical screening lab 
evaluations. 
• Review medical history and any updates obtained by interview of subjects since the 
screening visit (Visit 00A) to assure continued eligibility. 
• Review interim sexual history to identify any new sexual partners since the last screening 
visit 
• Review all concomitant medications recorded on the appropriate Electronic Case Report 
Form (eCRF). 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
47 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Obtain vital signs including oral temperature, blood pressure, and pulse, if needed. 
• Measure height and weight and calculate BMI, if needed. 
• Perform a targeted physical examination, if needed. 
• Collect blood and urine for safety labs, if needed 
• Subjects who qualify for inclusion in the rectal biopsy cohort will be instructed to abstain 
from receptive anal intercourse or insertion of anything into their anus, for at least 2 days 
prior to the baseline rectal mucosal biopsy visit 
 
6.1.3 
Visit 00C, Day -28 to -14, Baseline Rectal Mucosal Biopsy, Clinic Visit 
This visit will only take place for subjects being enrolled in the rectal biopsy cohort. The 
following activities will be performed at Visit 00C. 
• Ensure participant is safe to proceed with biopsy procedure, including results of all 
clinical screening lab evaluations*. 
 
*If the initial safety labs are >28 days old, these tests will need to be repeated and results 
obtained before rectal mucosal biopsy (see Section 7.2). 
• Review medical history and any updates obtained by interview of subjects since the last 
screening visit (Visit 00A or, if performed, Visit 00B) to assure the participant is safe to 
proceed with biopsy procedure. 
• Review interim sexual history to identify any new sexual partners since the last screening 
visit 
• Review all concomitant medications and recent (within 28 days) vaccinations with 
subjects before the first vaccination for accuracy and completeness. Any new medications 
taken since the last screening visit (Visit 00A or, if performed, Visit 00B) will be 
recorded on the appropriate eCRF and reviewed to assure the participant is safe to 
proceed with biopsy procedure. 
• Assess all AE/SAEs from the biopsy procedure and record them on the appropriate 
Electronic Case Report Form (eCRF). 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
48 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Obtain vital signs including oral temperature, blood pressure, and pulse to assure the 
participant is safe to proceed with biopsy procedure. Vital signs obtained on the day of 
biopsy will not be considered "screening", nor used for determining eligibility. 
• Perform a targeted physical examination as needed before the biopsy procedure, if 
indicated based on review of complete medical history and updates obtained by interview 
of subjects since the last screening visit (Visit 00A or, if performed, Visit 00B). 
• Perform rigid sigmoidoscopy and collect rectal mucosal biopsy samples for immunologic 
assays as described in the Schedule of Events (Appendix A) (for subjects in the mucosal 
biopsy subgroup). 
• Subjects will be counseled not to engage in anal intercourse for 1 week after the rectal 
biopsy procedure. 
• Subjects will be reminded to abstain from receptive anal and/or vaginal intercourse, 
insertion of anything into their vagina and/or anus, or oral sex for at least 2 days prior to 
the enrollment/first vaccination visit. 
 
6.1.4 
Visit 00P, Day -27 to -12, Baseline Rectal Mucosal Biopsy, Telephone Visit 
This visit will take place 24-48 hours after the baseline rectal biopsy procedure only for subjects 
enrolled in the rectal biopsy cohort. The following activities will be performed at Visit 00P. 
• Assess all AE/SAEs from the biopsy procedure and record them on the appropriate 
eCRF. 
• Subjects will be reminded not to engage in anal intercourse for 1 week after the rectal 
biopsy procedure. 
• Subjects will be reminded to abstain from receptive anal and/or vaginal intercourse, 
insertion of anything into their vagina and/or anus, or oral sex for at least 2 days prior to 
the enrollment/first vaccination visit. 
 
6.2 
Enrollment 
6.2.1 
Visit 01, Day 1, Randomization and First Vaccination, Clinic Visit 
The following activities will be performed at the first vaccination visit. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
49 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Reconfirm the subject’s willingness to participate before performing any study 
procedures, including their first vaccination. 
• Review eligibility criteria, including results of HIV, RPR, and STI screening lab 
evaluations, with subjects before the first vaccination to assure continued eligibility. 
• Review interim sexual history to identify any new sexual partners since the last screening 
visit. Subjects that report new sexual exposures should undergo repeat STI screening and 
enrollment should be deferred until results are available and assure continued eligibility. 
• Review medical history and any updates obtained by interview of subjects since the last 
screening visit (Visit 00A or, if performed, Visits 00B and/or 00C) to assure continued 
eligibility. 
• Review all concomitant medications and recent (within 28 days) vaccinations with 
subjects before the first vaccination for accuracy and completeness. Any new medications 
taken since the last screening visit (Visit 00A or, if performed, Visits 00B and/or 00C) 
will be recorded on the appropriate eCRF and assessed for continued eligibility. 
• Review COVID-19 vaccine history to ensure the subject is at least 14 days out from any 
COVID-19 vaccine before receiving study vaccine. 
• Assess all AE/SAEs and record them on the appropriate eCRF. 
• Obtain vital signs including oral temperature, blood pressure, and pulse before the first 
vaccination. Perform a targeted physical examination as needed before the first 
vaccination, if indicated based on review of complete medical history and updates 
obtained by interview of subjects since the last screening visit (Visit 00A or, if 
performed, Visits 00B and/or 00C). 
• Perform a urine pregnancy test within 24 hours before first vaccination on all female 
subjects of childbearing potential. Results must be negative and known before first 
vaccination. 
• Collect blood samples for baseline immunologic assays as described in the Schedule of 
Events (Appendix A) 
• Collect rectal and oropharyngeal mucosal secretion samples for immunologic assays as 
described in the Schedule of Events (Appendix A) 
• From female subjects, collect vaginal mucosal secretion samples for immunologic assays 
as described in the Schedule of Events (Appendix A) 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
50 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Subjects will be enrolled in Advantage eClinical and randomly assigned before the first 
vaccination. 
• Perform pre-administration reactogenicity assessments before the first vaccination to 
establish baseline. Subjects will then receive a single dose of vaccine via IM injection 
into the deltoid muscle of the preferred arm. The site of injection (right or left arm) and 
time of administration will be recorded on the appropriate eCRF. 
• Observe subjects in the clinic for ≥15 minutes after vaccination to monitor for any acute 
reactions. 
• Evaluate the vaccination site and assess for reactogenicity and AE/SAEs for ≥15 minutes 
after vaccination and before discharge from clinic and record on the appropriate CRF. 
• Subjects will enter their reactogenicity information in an electronic memory aid (with a 
paper back up). Subjects will be provided a thermometer and ruler and will record daily 
oral temperature, solicited injection site and systemic reactions, any unsolicited AEs, and 
concomitant medications. Subjects will have their electronic memory aid reviewed with 
them at their next study visit. 
 
6.3 
Planned Study Visits 
6.3.1 
Visit 02, Day 8 (±1 day), Clinic Visit 
The following activities will be performed at Visit 02. 
• Obtain interim medical history by interview of subjects and note any changes since the 
previous clinic visit. 
• Record all concomitant medications on the appropriate eCRF. 
• Assess all AE/SAEs and record them on the appropriate eCRF. 
• Obtain vital signs including oral temperature, blood pressure, and pulse, if indicated 
based on review of complete medical history. 
• A targeted physical examination will be performed, if needed, by a study clinician 
licensed to make medical diagnoses and listed on Form FDA 1572 as the site PI or sub-
investigator, if indicated based on review of complete medical history. 
• Assess for reactogenicity phenomena through subject interview and review memory aid. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
51 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Examine vaccination site for local reactions. 
• Collect blood samples for immunologic assays as described in the Schedule of Events 
(Appendix A). 
 
6.3.2 
Visit 03, Day 15 (±1 day), Clinic Visit 
The following activities will be performed at Visit 03. 
• Obtain interim medical history by interview of subjects and note any changes since the 
previous clinic visit. 
• Record all concomitant medications on the appropriate eCRF. 
• Assess all AE/SAEs and record them on the appropriate eCRF. 
• Obtain vital signs including oral temperature, blood pressure, and pulse, if indicated 
based on review of complete medical history. 
• A targeted physical examination will be performed, if needed, by a study clinician 
licensed to make medical diagnoses and listed on Form FDA 1572 as the site PI or sub-
investigator, if indicated based on review of complete medical history. 
• Collect blood samples for immunologic assays as described in the Schedule of Events 
(Appendix A) 
• Subjects will be instructed to abstain from receptive anal and/or vaginal intercourse, 
insertion of anything into their vagina and/or anus, or oral sex for at least 2 days prior to 
the next study visit 
 
6.3.3 
Visit 04, Day 29 (±1 day), Second Vaccination, Clinic Visit 
The following activities will be performed at Visit 04. 
• Obtain interim medical history by interview of subjects and note any changes since the 
previous clinic visit. 
• Review interim sexual history to identify any new sexual partners since the last screening 
visit 
• Record all concomitant medications on the appropriate eCRF. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
52 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Review COVID-19 vaccine history to ensure the subject is at least 14 days out from any 
COVID-19 vaccine before receiving study vaccine. 
• Assess all AE/SAEs and record them on the appropriate eCRF. 
• Obtain vital signs including oral temperature, blood pressure, and pulse. 
• A targeted physical examination will be performed, if needed, by a study clinician 
licensed to make medical diagnoses and listed on Form FDA 1572 as the site PI or sub-
investigator, if indicated based on review of complete medical history. 
• Collect venous blood for RPR testing 
• Collect pharyngeal and rectal swabs for nucleic acid amplification testing (NAAT) for 
GC and CT 
• Collect urine for NAAT for GC/CT from male subjects 
• Collect a self-collected vaginal swab for NAAT for GC/CT from female subjects 
• Collect blood samples for immunologic assays as described in the Schedule of Events 
(Appendix A) 
• Collect rectal and oropharyngeal mucosal secretion samples for immunologic assays as 
described in the Schedule of Events (Appendix A) 
• From female subjects, collect vaginal mucosal secretion samples for immunologic assays 
as described in the Schedule of Events (Appendix A) 
• Perform a urine pregnancy test within 24 hours before second vaccination on all female 
subjects of childbearing potential. Results must be negative and known before second 
vaccination. 
• Perform pre-administration reactogenicity assessments before the second vaccination to 
establish baseline. Subjects will then receive a single dose of vaccine via IM injection 
into the deltoid muscle of the preferred arm. The site of injection (right or left arm) and 
time of administration will be recorded on the appropriate eCRF. 
• Observe subjects in the clinic for ≥15 minutes after vaccination to monitor for any acute 
reactions. 
• Evaluate the vaccination site and assess for reactogenicity and AE/SAEs for ≥15 minutes 
after vaccination and before discharge from clinic and record on the appropriate CRF. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
53 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Subjects will enter their reactogenicity information in an electronic memory aid (with 
paper back up). Subjects will be provided a thermometer and ruler (if needed) and will 
record daily oral temperature, solicited injection site and systemic reactions, any 
unsolicited AEs, and concomitant medications. Subjects will have their electronic 
memory aid reviewed with them at their next study visit. 
 
6.3.4 
Visit 05, Day 36 (±1 day), Clinic Visit 
The following activities will be performed at Visit 05. 
• Obtain interim medical history by interview of subjects and note any changes since the 
previous clinic visit. 
• Record all concomitant medications on the appropriate eCRF. 
• Assess all AE/SAEs and record them on the appropriate eCRF. 
• Obtain vital signs including oral temperature, blood pressure, and pulse, if indicated 
based on review of complete medical history. 
• A targeted physical examination will be performed, if needed, by a study clinician 
licensed to make medical diagnoses and listed on Form FDA 1572 as the site PI or sub-
investigator, if indicated based on review of complete medical history. 
• Assess for reactogenicity phenomena through subject interview and review memory aid 
• Examine vaccination site for local reactions 
• Collect blood samples for immunologic assays as described in the Schedule of Events (0) 
• Subjects will be instructed to abstain from receptive anal and/or vaginal intercourse, 
insertion of anything into their vagina and/or anus, or oral sex for at least 2 days prior to 
the next study visit 
 
6.3.5 
Visit 06, Day 43 (±3 days), Rectal Mucosal Biopsy, Clinic Visit 
The following activities will be performed at Visit 06. 
• Obtain interim medical history by interview of subjects and note any changes since the 
previous clinic visit. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
54 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Obtain interim sexual history to identify any new sexual partners since the start of the 
study and the second vaccination visit 
• Record all concomitant medications on the appropriate eCRF. 
• Assess all AE/SAEs and record them on the appropriate eCRF. 
• Obtain vital signs including oral temperature, blood pressure, and pulse. 
• A targeted physical examination will be performed, if needed, by a study clinician 
licensed to make medical diagnoses and listed on Form FDA 1572 as the site PI or sub-
investigator, if indicated based on review of complete medical history. 
• If indicated based on the subject’s interim sexual history: Collect pharyngeal and rectal 
swabs for NAAT for GC and CT, collect urine for NAAT for GC/CT from male subjects, 
and collect a self-collected vaginal swab for NAAT for GC/CT from female subjects 
• Collect blood samples for immunologic assays as described in the Schedule of Events 
(Appendix A) 
• Collect rectal and oropharyngeal mucosal secretion samples for immunologic assays as 
described in the Schedule of Events (Appendix A) 
• From female subjects, collect vaginal mucosal secretion samples for immunologic assays 
as described in the Schedule of Events (Appendix A) 
• Perform rigid sigmoidoscopy and collect rectal mucosal biopsy samples for immunologic 
assays as described in the Schedule of Events (Appendix A) (for subjects in the mucosal 
biopsy subgroup) 
• Subjects will be counseled not to engage in anal intercourse for 1 week after the rectal 
biopsy procedure. 
• Subjects will be instructed to abstain from receptive anal and/or vaginal intercourse, 
insertion of anything into their vagina and/or anus, or oral sex for at least 2 days prior to 
the next study visit 
 
6.3.6 
Visit 06P, Day 44 (+1 day), Telephone Visit 
This visit will take place 24-48 hours after the baseline rectal biopsy procedure only for subjects 
enrolled in the rectal biopsy cohort. The following activities will be performed at Visit 06P. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
55 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Assess all AE/SAEs from the biopsy procedure and record them on the appropriate 
eCRF. 
• Subjects will be reminded not to engage in anal intercourse for 1 week after the rectal 
biopsy procedure. 
• Subjects will be reminded to abstain from receptive anal and/or vaginal intercourse, 
insertion of anything into their vagina and/or anus, or oral sex for at least 2 days prior to 
the next study visit. 
 
6.3.7 
Visit 07, Day 57 (±1 day), Clinic Visit 
The following activities will be performed at Visit 07. 
• Obtain interim medical history by interview of subjects and note any changes since the 
previous clinic visit. 
• Review interim sexual history to identify any new sexual partners since the last screening 
visit 
• Record all concomitant medications on the appropriate eCRF. 
• Assess all AE/SAEs and record them on the appropriate eCRF. 
• Obtain vital signs including oral temperature, blood pressure, and pulse, if indicated 
based on review of complete medical history. 
• A targeted physical examination will be performed, if needed, by a study clinician 
licensed to make medical diagnoses and listed on Form FDA 1572 as the site PI or sub-
investigator, if indicated based on review of complete medical history. 
• Collect blood samples for immunologic assays as described in the Schedule of Events 
(Appendix A) 
• Collect rectal and oropharyngeal mucosal secretion samples for immunologic assays as 
described in the Schedule of Events (Appendix A) 
• From female subjects, collect vaginal mucosal secretion samples for immunologic assays 
as described in the Schedule of Events (Appendix A) 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
56 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Subjects will be instructed to abstain from receptive anal and/or vaginal intercourse, 
insertion of anything into their vagina and/or anus, or oral sex for at least 2 days prior to 
the next study visit 
 
6.3.8 
Visit 08, Final Study Visit, Day 181 (±7 days), Clinic Visit 
The following activities will be performed at Visit 08. 
• Obtain interim medical history by interview of subjects and note any changes since the 
previous clinic visit. 
• Obtain interim sexual history to identify any new sexual partners since the last study visit 
• Record all concomitant medications on the appropriate eCRF. 
• Assess all AE/SAEs and record them on the appropriate eCRF. 
• Obtain vital signs including oral temperature, blood pressure, and pulse, if indicated 
based on review of complete medical history. 
• A targeted physical examination will be performed, if needed, by a study clinician 
licensed to make medical diagnoses and listed on Form FDA 1572 as the site PI or sub-
investigator, if indicated based on review of complete medical history. 
• Collect venous blood for RPR and HIV-1/2 antibody testing 
• Collect pharyngeal and rectal swabs for NAAT for GC and CT 
• Collect urine for NAAT for GC/CT from male subjects 
• Collect a self-collected vaginal swab for NAAT for GC/CT from female subjects 
• Collect blood samples for immunologic assays as described in the Schedule of Events 
(Appendix A) 
• Collect rectal and oropharyngeal mucosal secretion samples for immunologic assays as 
described in the Schedule of Events (Appendix A) 
• From female subjects, collect vaginal mucosal secretion samples for immunologic assays 
as described in the Schedule of Events (Appendix A) 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
57 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
6.3.9 
Early Termination Visit  
The following activities will be performed at the early termination visit for subjects who 
withdraw, or are withdrawn or terminated from this trial: 
• Obtain interim medical history by interview of subjects and note any changes since the 
last study visit. 
• Obtain interim sexual history to identify any new sexual partners since the last study visit 
• Record all concomitant medications on the appropriate eCRF. 
• Assess all AE/SAEs and record them on the appropriate eCRF. 
• Obtain vital signs including oral temperature, blood pressure, and pulse, if needed. 
• Perform a targeted physical examination, if indicated based on review of complete 
medical history. 
• Examine vaccination site for local reactions if visit occurs ≤7 days after last injection. 
• Assess for reactogenicity phenomena through subject interview and review memory aid if 
visit occurs ≤7 days after last injection. 
• Perform a urine pregnancy test on all female subjects of childbearing potential (if 
indicated) 
• If subject allows, obtain blood samples for immunologic assays appropriate to that visit if 
visit occurs within window of a regular study visit as described in the Schedule of Events 
(Appendix A). 
• If subject allows, collect rectal and oropharyngeal mucosal secretion samples for 
immunologic assays appropriate to that visit if visit occurs within window of a regular 
study visit as described in the Schedule of Events (Appendix A). 
• If subject allows, from female subjects, collect vaginal mucosal secretion samples for 
immunologic assays appropriate to that visit if visit occurs within window of a regular 
study visit as described in the Schedule of Events (Appendix A). 
6.4 
Unscheduled Study Visits  
Unscheduled visits may occur at any time during this trial. Labs may be drawn at PI discretion. 
Any of the following activities may be performed: 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
58 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Obtain interim medical history by interview of subjects and note any changes since the 
last study visit. 
• Record all concomitant medications on the appropriate eCRF. 
• Obtain vital signs including oral temperature, blood pressure, and pulse, if indicated. 
• Perform a targeted physical examination, if indicated based on review of complete 
medical history. 
• Examine vaccination site for local reactions if visit occurs ≤7 days after study vaccination 
• Assess for reactogenicity phenomena through subject interview if visit occurs ≤7 days 
after last injection. 
• Obtain blood for safety if needed. 
• Perform a urine pregnancy test on all female subjects of childbearing potential (if 
indicated). 
• Assess all AE/SAEs and record them on the appropriate eCRF. 
6.5 
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 
investigator, or the study site staff.  As a result of deviations, corrective actions should be 
developed by the site and implemented promptly.  It is the responsibility of the site PI and other 
study personnel to use continuous vigilance to identify and report protocol deviations. All 
individual protocol deviations will be addressed in subject study records. All protocol deviations, 
either individual, product, or site-specific will be collected and the record stored at the study site. 
Protocol deviations must be sent to the local IRB/IEC per its guidelines and will be reported to 
the sponsor. The site PI and other study personnel are responsible for knowing and adhering to 
their IRB/IEC requirements. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
59 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
7 
DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
7.1 
Clinical Evaluations 
• Complete medical history will be obtained by interviewing the subjects at the first study 
visit. Subjects 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 subsequent follow-up visits, an interim medical 
history will be obtained by interview of the subjects noting any changes since the 
previous clinic visit. 
• Concomitant medications will be collected as described in Section 7.1.2. 
• At the first screening visit (Visit 00A), a physical examination will be performed by a 
study clinician licensed to make medical diagnoses and listed on Form FDA 1572 as the 
site PI or sub-investigator. For all subsequent visits, a targeted physical examination may 
be performed by a study clinician licensed to make medical diagnoses and listed on Form 
FDA 1572 as the site PI or sub-investigator, if indicated based on subject’s interim 
medical history. 
• Vital signs (oral temperature, pulse, and blood pressure) will be collected at each study 
visit if indicated. Vital signs assessed on the screening visits (V00A and V00B) will be 
considered as baseline. Subjects must not eat or drink anything hot or cold, or smoke 
within 10 minutes before taking oral temperature. In the event of an abnormal heart rate 
or blood pressure due to physiological variation or activity, the subject may rest for 10 
minutes in a quiet room, and then blood pressure and/or heart rate may be re-measured. 
The repeated measurement may be used to determine eligibility per the judgement of the 
investigator. 
• Height and weight will be collected on the screening visit to determine BMI. 
• Pre-administration reactogenicity assessments will be performed before each vaccination. 
A subject with mild (Grade 1) pre-administration reactogenicity which is transient, 
resolving, or clinically insignificant may be vaccinated at the investigator’s discretion. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
60 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Subjects will be observed in the clinic for ≥15 minutes after each vaccination. The 
vaccination site will be examined, post-administration reactogenicity assessments will be 
performed, and any AE/SAEs will be assessed and recorded on the appropriate eCRF 
before discharge from the clinic. 
• All subjects will complete an electronic memory aid (with paper back up) on the day of 
each vaccination through seven days following each vaccination. Subject memory aids 
will be reviewed with the subjects for AEs (solicited injection site and systemic reactions, 
and unsolicited AEs). In addition, after each vaccination, whenever the subject is seen in 
the clinic, solicited and unsolicited reactogenicity and AEs will be reviewed. 
• Reactogenicity assessments will include an assessment of solicited AEs occurring from 
the time of each vaccination through seven days following each vaccination, which 
include injection site reactions (pruritus, erythema, ecchymosis, induration/swelling, 
pain, and tenderness) and systemic reactions (fever, chills/shivering/sweating, fatigue, 
malaise, myalgia and arthralgia (exclusive of the injection site), headache, and nausea). 
 
7.1.1 
Research Procedures  
Oropharyngeal mucosal secretion sampling 
Trained, delegated study staff will be performing all oropharyngeal secretion (saliva) sampling 
procedures. Saliva will be collected and stored in the appropriate container. Instructions for 
saliva collection, handling, and storage are included in the MOP. 
Vaginal mucosal secretion sampling 
A trained, delegated clinician will be performing all vaginal mucosal sampling procedures with 
the assistance of a study coordinator utilizing a lubricated speculum and light source. Vaginal 
mucosal secretion samples will be collected and stored in the appropriate container. Instructions 
for vaginal secretion sample collection, handling, and storage are included in the MOP. 
Rectal mucosal secretion sampling and biopsy 
A trained, delegated clinician will be performing all rectal mucosal sampling procedures with the 
assistance of the study coordinator. 
All subjects will have rectal mucosal secretions sampled utilizing a disposable anoscope and a 
light source. A lubricated anoscope will be inserted into the anus and 2-3 swabs or wicks will be 
used to collect secretions from the bowel wall for antibody measurements. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
61 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
For subjects in the rectal mucosal biopsy cohort, a rigid sigmoidoscope, light source, and jumbo 
biopsy forceps will be utilized. Following rectal mucosal secretion sampling, without the 
administration of any previous enemas or other preparation, a rigid sigmoidoscope will be 
inserted and 8-12 adequate ~1.0 millimeter (mm) thick biopsy specimens will be taken from 
normal-appearing rectal mucosa approximately 10 cm above the external anal aperture using 
flexible sigmoidoscopic forceps mounted on a semi-flexible rod.  All biopsy specimens will be 
coded with a unique numeric identifier such that the laboratories that receive the specimens will 
be unable to link them back to the study participants. The biopsy specimens will be placed in 
phosphate-buffered saline (PBS) and transported to a lab where the specimens will be processed 
for flow cytometry. 
Twenty-four to forty-eight hours after the procedure, study personnel will call the participants 
who donated rectal biopsy samples and inquire about symptoms, complications, or adverse 
events related to study procedures. Participants who report symptoms suggestive of any 
significant complications will receive advice on seeking care and will be given referrals to 
appropriate healthcare professionals as needed. This follow-up may be completed over the phone 
or through electronic communication.   
 
7.1.2 
Assessment of Concomitant Medications/Treatments other than Study Product 
Administration of any medications, therapies, or vaccines will be documented on the appropriate 
eCRF. Concomitant medications will include all current medications and non-study vaccinations 
taken within 30 days before signing the ICF through approximately 28 days after the last study 
vaccination, and for new-onset chronic medical conditions through the final study visit for each 
subject. Subjects who do not receive all vaccinations will have concomitant medications 
collected through approximately 28 days after the last vaccination, or early termination, 
whichever occurs first. Prescription and over-the-counter drugs will be included as well as 
herbals, vitamins, and supplements. 
Use of new medication should prompt evaluation for the presence of a new diagnosis of chronic 
medical disease or condition. 
Medications that might interfere with the evaluation of the study vaccines should not be used 
during the trial unless absolutely necessary. Medications in this category include the prohibited 
medications per the subject exclusion criteria (see Section 5.1.2). In addition, the site PI 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. Use of medications as 
prophylaxis before study vaccination is prohibited. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
62 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
To the sponsor’s knowledge, there are no known drug-vaccine interactions with the study 
vaccines and subjects are not being asked to discontinue current medications not listed in the 
exclusion criteria. In the event medical conditions dictate use of medications, subjects are 
encouraged to obtain adequate care, comply with the course of therapy as prescribed by their 
physician, and inform the Investigator as soon as practicable. Details of all medications taken 
during this trial (date, brand or generic name) will be recorded. 
7.2 
Laboratory Evaluations 
Laboratory assays and blood volumes are detailed in Appendix B. 
7.2.1 
Clinical Laboratory Evaluations 
Screening 
To be eligible for participation in this trial and receipt of the first vaccine, the subject’s clinical 
screening lab evaluations (Visit 00A) must be confirmed to meet the subject inclusion criteria 
(see Section 5.1). All subjects will be screened for GC and CT infection at all relevant mucosal 
sites with NAAT. Female subjects will also be screened for Trichomonas vaginalis vaginal 
infection by NAAT. NAAT will be performed as follows: 
• Rectal and pharyngeal swabs, and urine specimens will be obtained from male subjects 
• Rectal and pharyngeal swabs, and self-collected vaginal swabs will be obtained from 
female subjects 
Subjects will be screened for RPR and HIV-1/2 antibody. If a positive result on any of these 
screening tests occurs, the subject will be referred for appropriate follow-up and results reported 
as required by state law. These screening tests must be negative for the subject to be eligible to 
participate. 
Urine pregnancy tests will be performed by the site laboratory at the screening visit (Visit 00A) 
and within 24 hours before initial vaccination (Day 1 (Visit 01)) on all female subjects of 
childbearing potential. Results must be negative and known before randomization on Day 1 
(Visit 01) and before receipt of vaccination. 
In the subset of participants who will undergo rectal mucosal biopsy, additional laboratory tests 
at the screening visit (Visit 00A) will include complete blood count (WBC, hemoglobin, PLT), 
PT and aPTT. 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
63 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Follow-Up 
Urine pregnancy tests will be performed by the site laboratory within 24 hours before second 
vaccination (Day 29 (Visit 04)) on all female subjects of childbearing potential. Results must be 
negative and known before receipt of vaccination. 
Subjects will be re-screened for GC and CT infection at all relevant mucosal sites with NAAT 
prior to the second vaccination at Day 29 (Visit 04) and at the final study visit (Day 181 (Visit 
08)) as follows: 
• Rectal and pharyngeal swabs, and urine specimens will be obtained from male subjects 
• Rectal and pharyngeal swabs, and self-collected vaginal swabs will be obtained from 
female subjects 
Subjects will also be re-screened for RPR at Day 29 (Visit 04) and Day 181 (Visit 08). If a 
positive result on any of these screening tests occurs, the subject will be referred for appropriate 
follow-up and results reported as required by state law. 
 
7.2.2 
Research Assays 
 
7.2.2.1 
Antibody assays 
Antibody assays will be performed at the study site (Stephens laboratory) and will include: 
• Measurement of IgG concentrations against GC antigens at mucosal sites (rectum, 
vagina, oropharynx) and in serum as described in the Schedule of Events (Appendix A) 
by enzyme-linked immunosorbent assay (ELISA) 
• Measurement of IgA concentrations against GC antigens at mucosal sites (rectum, 
vagina, oropharynx) and in serum as described in the Schedule of Events (Appendix A) 
by ELISA 
• Measurement of serum bactericidal antibody titers as described in the Schedule of Events 
(Appendix A) 
• Measurement of IgG concentrations against N. meningitidis antigens in serum as 
described in the Schedule of Events (Appendix A) by ELISA 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
64 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
7.2.2.2 
Cell-mediated immunity assays 
Cell-mediated immunity assays will be performed at the study site (Hope Clinic) and will 
include: 
• Frequencies and function of memory B cells (MBC) specific for antigens from GC and N. 
meningitidis as described in the Schedule of Events (Appendix A) by ELISpot 
• Frequencies and function of peripheral blood T cells specific for antigens from GC and 
N. meningitidis as described in the Schedule of Events (Appendix A) by ELISpot 
• Frequencies, phenotype, and function of peripheral blood CD4+ and CD8+ T cells 
specific for antigens from GC and N. meningitidis as described in the Schedule of Events 
(Appendix A) by intracellular cytokine staining (ICS) 
• Frequencies, phenotype, and function of rectal mucosal CD4+ and CD8+ T cells specific 
for antigens from GC as described in the Schedule of Events (Appendix A) by ICS 
 
7.2.2.3 
Bacterial adhesion assay 
Serum for bacterial adhesion assays will be collected as described in the Schedule of Events 
(Appendix A). For samples scheduled to be collected during vaccination visits, samples will be 
collected before vaccination. 
The bacterial adhesion assay will be performed at the study site (Stephens laboratory). 
Instructions for specimen preparation, handling, storage, and labeling are included in the MOP. 
 
7.2.2.4 
Laboratory Specimen Preparation, Handling, and Storage 
Serum for antibody assays will be collected as described in the Schedule of Events (Appendix 
A). For samples scheduled to be collected during vaccination visits, samples will be collected 
before vaccination. 
Peripheral blood mononuclear cell (PBMC) samples for MBC and T-cell assays will be collected 
as described in the Schedule of Events (Appendix A). For samples scheduled to be collected 
during vaccination visits, samples will be collected before vaccination. Plasma from the PBMC 
separations will be saved as described in the MOP. 
Instructions for specimen preparation, handling, storage, and labeling are included in the MOP. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
65 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
7.2.2.5 
Laboratory Specimen Shipping 
Specimen shipment will occur at intervals during 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 MOP. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
66 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
8 
ASSESSMENT OF SAFETY 
8.1 
Assessing and Recording Safety Parameters 
Safety will be assessed by the frequency and severity of:  
• Any AE related to 4CMenB immunization through the end of the study. 
• Any AE related to rectal mucosal sampling procedures through the end of the study. 
• Any SAEs through the end of the study. 
 
8.1.1 
Adverse Events  
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. In addition, AEs specific to the rectal mucosal biopsy cohort will be collected prior to 
study drug administration and are defined as any unfavorable and unintended sign, symptom, or 
disease temporally associated with the rectal mucosal biopsy procedure. 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.  
All AEs, including solicited local (injection site) and systemic (subjective and quantitative) 
reactions, will be captured on the appropriate eCRF.  Information to be collected for 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.  AEs occurring during the trial collection and reporting period will be documented 
appropriately regardless of relationship.  AEs will be followed through resolution. 
8.1.1.1 
Adverse Events Grading 
All AEs (clinical symptoms) will be graded for severity and assessed for relationship to study 
product (see definitions). AEs 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 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
67 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
appropriate eCRF. Changes in the severity of an AE will be documented to allow an assessment 
of the duration of the event at each level of intensity. 
 
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 that are usually transient and may require only minimal or no 
treatment or therapeutic intervention and generally do not interfere with the subject’s 
usual activities of daily living. 
• Moderate (Grade 2):  Events that are usually alleviated with additional specific 
therapeutic intervention.  The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research participant. 
• Severe (Grade 3):  Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.  Severe events are 
usually incapacitating. 
 
Relationship to Study Product: The assessment of the AE’s relationship to study product will 
be done by the licensed study physician indicated on the Form FDA 1572 and the assessment 
will be part of the documentation process.  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.  The relationship to study product 
will be assessed for AEs using the terms related or not related: 
• Related – There is a reasonable possibility that the study product caused the AE. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
68 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
8.1.2 
Reactogenicity  
Reactogenicity events are AEs that are common and known to occur following administration of 
this type of study vaccine. The Toxicity Grading Scale (Appendix C) will be used to grade 
solicited local (injection site) and systemic (subjective and quantitative) reactions. 
8.1.3 
Serious Adverse Events  
An AE or suspected adverse reaction is considered a SAE if, in the view of either the site PI or 
sponsor, it results in any of the following outcomes:  
• Death, 
• a life-threatening adverse event1,  
• 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. 
1 Life-threatening adverse event. An AE 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 AE that, had it occurred in a more severe form, might have 
caused death. 
SAEs will be: 
• Assessed for severity and relationship to study product or procedure and alternate 
etiology (if not related to study product) by a licensed study physician listed on the Form 
FDA 1572 or by the Institution as the site PI or Sub-Investigator. 
• Recorded on the appropriate SAE eCRF. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
69 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
• Followed through resolution by a licensed study physician (for investigational new drug 
application (IND) studies, a physician listed on the Form FDA 1572 as the site PI or Sub-
Investigator). 
• Reviewed and evaluated by DMID, an Independent Safety Monitor (ISM) (as deemed 
necessary), or Safety Monitoring Committee (SMC) (periodic review unless related), and 
the IRB/IEC. 
8.2 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of: 
• Any AE related to 4CMenB immunization through the end of the study. 
• Any AE related to rectal mucosal sampling procedures through the end of the study. 
• Any SAEs through the end of the study. 
 
8.2.1 
Solicited Events 
Solicited events are AEs that are common and known to occur following administration of study 
product. The Toxicity Grading Scale (Appendix C) will be used to grade solicited local (injection 
site) and systemic (subjective and quantitative) reactions. All subjects will complete a subject 
memory aid on the day of each vaccination through 7 days after each vaccination (i.e. Day 8 and 
Day 36 visits). Subject memory aids will be reviewed with the subjects for AEs (solicited 
injection site and systemic reactions, and unsolicited AEs). In addition, after each vaccination, 
whenever the subject is seen in the clinic or a phone call occurs (i.e., at all opportunities), 
solicited and unsolicited reactogenicity and AEs will be reviewed. Reactogenicity assessments 
will include an assessment of solicited AEs occurring from the time of each vaccination through 
seven days following each vaccination, which include injection site reactions (pruritus, erythema, 
ecchymosis, induration/swelling, pain, and tenderness) and systemic reactions (fever, 
chills/shivering/sweating, fatigue, malaise, myalgia and arthralgia (exclusive of the injection 
site), headache, and nausea). 
Solicited injection site and systemic reactogenicity events will be documented and reported from 
Day 1 through Day 8 and Day 29 through Day 36, 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
70 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
8.2.2 
Unsolicited Events 
Unsolicited events are any other AEs that occur following rectal biopsy procedures or 
administration of study product. Unsolicited AEs will be collected and assessed through the end 
of the protocol-defined follow up period. Unsolicited AEs are followed through resolution or 
stabilization even if this extends beyond the reporting period. 
8.2.3 
Medically-Attended Adverse Events (MAAEs)  
For each AE experienced, the subject will be asked if he/she had received medical attention, 
defined as hospitalization, an ER visit, or an otherwise unscheduled visit to or from medical 
personnel for any reason. AEs characterized by such unscheduled medical care will be 
designated as MAAEs. 
8.3 
Reporting Procedures 
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 or frequency of any pre-existing 
medical condition worsens, it should be recorded as an AE. 
If an event meets both the criteria of a study endpoint and an AE, the event will be reported 
either as a study endpoint or as an AE (not both). 
For the rectal biopsy cohort, SAEs will be documented and reported from the time of the 
baseline rectal mucosal biopsy through approximately 6 months after the first study vaccination. 
For the non-rectal biopsy cohort, SAEs will be documented and reported from the first study 
vaccination through approximately 6 months after the first study vaccination.  
8.3.1 
Reporting 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. 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
71 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Bethesda, MD 20817, USA 
SAE Hot Line: 
 
SAE FAX Number: 
 
SAE Email Address: 
 
In addition to the SAE form, select SAE data fields must also be entered into the data 
coordinating center (DCC) system. 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 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 PI 
or appropriate sub-investigator will report the event to the DMID Pharmacovigilance Group. 
 
8.3.2 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the site PI or appropriate sub-investigator, DMID, as the IND 
sponsor, will report any suspected unexpected serious adverse event (SUSAR) as an IND safety 
report to the FDA and will notify all participating site PIs (i.e., all PIs to whom the sponsor is 
providing drug under its IND(s) or under any PI’s IND(s)) of potential serious risks from clinical 
studies or any other source, as soon as possible. DMID will report to the FDA 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.  If the event is not fatal or life-
threatening the IND safety report will be submitted within 15 calendar days after the sponsor 
determines that the information qualifies for reporting as specified in 21 CFR Part 312.32.  
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 the 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.   

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
72 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
All SAEs that are not SUSARs will be reported to the FDA at least annually in a summary 
format. 
 
8.3.3 
Reporting of Pregnancy 
Upon awareness, pregnancies occurring in subjects will be recorded on the Pregnancy Report 
eCRF. Subjects who become pregnant will be discontinued from further study procedures, but 
will be followed and recorded for safety until pregnancy outcome as per the protocol. 
8.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
AEs will be assessed, and followed from initial recognition of the AE through end of the 
protocol defined follow-up period.   
SAEs will be followed up through resolution even if duration of follow-up goes beyond the 
protocol-defined follow-up period. 
Resolution of an AE is defined as the return to pre-treatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
8.5 
Procedures to be Followed in the Event of Abnormal Laboratory 
Test Values or Abnormal Clinical Findings 
The site PI or appropriate sub-investigator is responsible for recording all AE/SAEs that are 
observed or reported during this trial, regardless of the relationship to the vaccine. AE/SAEs or 
abnormal clinical findings will be collected, assessed, documented, reported, and followed 
appropriately. 
All subjects will be screened for GC and CT infection at all relevant mucosal sites with NAAT at 
screening (Visit 00A) and prior to rectal mucosal sampling procedures at Day 29 (Visit 04) and 
at the final study visit (Day 181 (Visit 08)). Female subjects will also be screened for 
Trichomonas vaginalis infection with NAAT at screening (Visit 00A). Subjects will also be 
screened for RPR at screening (Visit 00A), Day 29 (Visit 04) and Day 181 (Visit 08), as well as 
HIV-1/2 antibody (Visit 00A and 08). If a positive result on any of these screening tests occurs, 
the subject will be referred for appropriate follow-up and results reported as required by state 
law. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
73 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Safety labs will only be required at screening in the rectal biopsy cohort. Safety labs may be 
repeated during the study at the investigator’s discretion as part of the assessment of abnormal 
clinical findings. 
 
8.6 
Halting Rules 
8.6.1 
Study Halting Criteria 
The study will be halted for SMC review/recommendations if any of the following are reported:   
• Any subject experiences an SAE after administration of study product that is considered 
related to study product. 
• Any subject experiences an SAE after a study procedure that is considered related to the 
study procedure. 
• An overall pattern of symptomatic, clinical, or laboratory events that the DMID Medical 
Monitor (MM) or SMC consider associated with the study product and that may appear 
minor in terms of individual events, but that may collectively represent a serious potential 
concern for safety. 
If any of the halting rules are met, the study will not continue without a review of the safety data 
by and recommendation from the SMC before proceeding. 
SMC retains the authority to suspend additional enrollment and administration of the study 
product during the entire study, as applicable. 
 
8.6.2 
Individual Halting Criteria 
A subject will be discontinued from second vaccination if:  
• Subject develops a new medical condition or medication change for which continued 
participation, in the opinion of the investigator, would pose a risk to the subject 
• Subject is no longer willing and/or able to adhere to study restrictions outlined in the 
Inclusion and Exclusion Criteria 
• Subject has a fever (defined as an oral temperature ≥38.0 °C) or an acute illness at the 
time of boost vaccination administration. The next study vaccination can be deferred until 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
74 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
the fever or illness resolves or only minor residual symptoms remain, that in the opinion 
of the investigator, will not interfere with the ability to assess safety parameters as 
required by the protocol, provided that the boost is given within the protocol-defined 
study window.  
• Subject has received COVID-19 vaccine <14 days prior to scheduled dose #2. The next 
study vaccination can be deferred until at least 14 days elapse from the time of any 
COVID-19 vaccination, if in the opinion of the investigator, will not interfere with study 
assessments as required by the protocol, provided that the boost is given within the 
protocol-defined study window. 
• Permission to administer vaccination outside the protocol-defined study window must be 
obtained from DMID Medical Officer. 
Note: In case the boost vaccination is postponed, the timing of the safety/immunogenicity visits 
post-boost will be planned relative to actual vaccination day. 
8.7 
Safety Oversight  
8.7.1 
Independent Safety Monitor (ISM) 
For this clinical trial an ISM is not required.  However, upon DMID Medical Monitor 
request, the PI will identify a physician with relevant expertise, to act as a Secondary Medical 
Assessor (SMA). The SMA will examine a subject and/or medical records and provide a medical 
assessment (or second medical opinion) to the DMID of the safety event in question. The PI will 
send to the DMID MM, a summary of the event and include the PI and SMA assessments.   
Note: In the case that DMID has requested this type of evaluation multiple times, DMID may 
request the site(s) identify an ISM to assist DMID with safety oversight. 
 
8.7.2 
Safety Monitoring Committee (SMC) 
This clinical study will utilize an SMC, which is an independent group of experts that advises the 
DMID. The primary responsibility of the SMC is to monitor subject safety. The SMC is external 
to the DMID and comprises at least 3 voting members. A simple majority will be considered a 
quorum for voting purposes. The SMC will consist of members with appropriate expertise to 
contribute to the interpretation of the data from this trial. Its activities will be delineated in a 
SMC charter that will describe the membership, responsibilities, and the scope and frequency of 
data reviews. The SMC will operate on a conflict-free basis independently of the study team. The 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
75 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
DMID or the SMC may convene ad hoc meetings of the SMC according to protocol criteria or if 
there are concerns that arise during the study. 
As defined in the charter, the SMC will review data at specified times during the course of the 
study for subject and overall study progress, and will conduct ad hoc reviews as appropriate 
when a halting rule is met or for immediate concerns regarding observations during this study. 
The SMC will convene for the following meetings: Organizational meeting, scheduled data 
review meetings, ad hoc meetings for a specific safety concern or issue, final meeting. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
76 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
9 
HUMAN SUBJECTS PROTECTION 
9.1 
Institutional Review Board/Independent Ethics Committee 
Each site PI 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 OHRP 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 and the IRB/IEC.  The investigator will notify the IRB/IEC of deviations 
from the protocol and reportable SAEs, as applicable to the IRB/IEC policy. 
The institution engaged in this research will hold a current FWA issued by the Office of OHRP 
for federally funded research. 
9.2 
Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation.  Before any study procedures 
are performed, informed consent will be obtained and documented.  Subjects will receive a 
concise and focused presentation of key information about the clinical trial, verbally and with a 
written consent form. The explanation will be organized, and presented in lay terminology and 
language that facilitates understanding why one might or might not want to participate. 
An investigator or designee will describe the protocol to potential subjects face-to-face. The key 
information about the purpose of the study, the procedures and experimental aspects of the study, 
risks and discomforts, any expected benefits to the subject, and alternative treatment will be 
presented first to the subject.   

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
77 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Subjects will also receive an explanation that the trial involves research, and a detailed summary 
of the proposed study procedures and study interventions/products.  This will include aspects of 
the trial that are experimental, the probability for random assignment to treatment groups, any 
expected benefits, all possible risks (including a statement that the particular treatment or 
procedure may involve risks to the subject or to the embryo or fetus, if the subject is or may 
become pregnant, that are currently unforeseeable), and the expected duration of the subject’s 
participation in the trial.  
Subjects will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in the trial. Subjects 
will receive an explanation as to whether any compensation and any medical treatments are 
available if injury occurs, and, if so, what they consist of, or where further information may be 
obtained. Subjects will be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact (e.g., the investigator) for 
answers to any questions relating to the research project.  
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the subject is otherwise entitled.   
The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed 
that the monitor(s), auditors(s), IRB, NIAID, and regulatory authority(ies) will be granted direct 
access to the subject’s original medical records for verification of clinical trial procedures and/or 
data without violating the confidentiality of the subject, to the extent permitted by the applicable 
laws and regulations, and that, by signing a written informed consent form, the subject is 
authorizing such access.  
Subjects will be informed that records identifying the subject will be kept confidential, and, to 
the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available and, if the results of the trial are published, the subject’s identity will remain 
confidential. Subjects will be informed whether private information collected from this research 
and/or specimens will be used for additional research, even if identifiers are removed.   
Subjects will be allowed sufficient time to consider participation in this research trial, and have 
the opportunity to discuss this trial with their family, friends or legally authorized representative, 
or think about it prior to agreeing to participate. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
78 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
ICFs will be IRB-approved and subjects will be asked to read and review the consent form. 
Subjects must sign the ICF prior to starting any study procedures being done specifically for this 
trial. 
Once signed, a copy of the ICF will be given to the subject(s) for their records.  The subject(s) 
may withdraw consent at any time throughout the course of the trial.  The rights and welfare of 
the subject(s) will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
Study personnel may employ recruitment efforts prior to obtaining study consent if a patient-
specific screening consent is on record or if the IRB has agreed that chart review is allowed 
without a fully executed screening consent.  In cases where there is not a patient-specific 
screening consent on record, site Clinical staff may pre-screen via chart review and refer 
potential subjects to the Research staff.  Research staff would obtain written consent per the 
standard informed consent process before conducting protocol-specific screening activities. 
New information will be communicated by the site PI 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.  Subjects will be given a 
copy of all ICFs that they sign. 
Human Genetic Testing 
No human genetic testing will be performed in this study. 
9.3 
Consent for Future Use of Stored Specimens and Data 
Residual samples/specimens and data are those that are left over after protocol-specified testing 
and this study has been completed. Subjects will be asked for permission to keep any data and 
any remaining (residual) specimens (serum and PBMCs) derived from venous blood samples, 
swabs and other mucosal samples for possible use in future research studies, such as examining 
additional immunological assessments or testing for antibodies against other viruses or bacteria. 
These residual specimens will be stored coded indefinitely at a DMID-contracted storage facility.  
Data or specimens may be shared with investigators at the participating site and with other 
investigators at U.S. or international institutions. The recipients of data or specimens will be 
informed that these specimens have a NIH certificate of confidentiality. The information 
provided to a recipient will not contain direct identifiable information. Use of the specimens will 
require a new protocol and review and approval of that protocol and the specimens for use by an 
IRB.   

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
79 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
There are no benefits to subjects in the collection, storage and subsequent future use of their 
data/samples/specimens. These data/samples/specimens will not be sold or used directly for 
production of any commercial product. The data/sample/specimen will be encoded (labeled) only 
with a barcode and a unique tracking number that connects to a code key at the study site. 
Restricted access to the code key is maintained by the principal investigator to protect subject 
confidentiality. Reports from future research studies performed using subjects’ 
data/samples/specimens will NOT be kept in their health records. 
Subjects may be given the option to decide if they want their residual specimens with their data 
to be used for future research or have these specimens destroyed at the end of this trial. The 
subject’s decision can be changed at any time by notifying the study doctors or nurses in writing. 
However, if the subject originally consents to the future use of residual specimens with their 
data and subsequently changes his/her decision, any data already collected from a previously 
collected specimen may still be used for future research. 
9.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
This trial will include all healthy adults who meet the inclusion/exclusion criteria, regardless of 
religion, sex, or ethnic background. Only subjects, aged 18 to 49 years inclusive, will be 
included. This age range was selected to represent the population with the highest incidence of 
gonorrhea therefore children are excluded from this study. Special populations, e.g., non-English 
speakers, illiterate or non-writing individuals, and vulnerable populations, for which no benefit 
of trial participation has been identified, will not be enrolled in this trial. 
9.5 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study. No information concerning the study or the data generated from the study 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.  The study monitor or other authorized representatives of the sponsor or 
governmental regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the subjects in this study. The clinical study site will permit 
access to such records. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
80 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password protected systems. All non-clinical specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
9.6 
Certificate of Confidentiality 
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. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States 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 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 release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, or for the purposes of other research that is in compliance with applicable Federal 
regulations governing the protection of human subjects in research.  
 
9.7 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study product while taking part 
in this trial.  Procedures and treatment for clinical care may be billed to the subject, subject’s 
insurance or third party.  Subjects may be compensated for their participation in this trial.  

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
81 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Compensation will be in accordance with the local IRB’s policies and procedures, and subject to 
IRB approval. 
If it is determined by the site PI 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 the participating site.  No 
financial compensation will be provided to the subject by the NIAID, NIH to the subject by the 
participating site for any injury suffered due to participation in this trial. 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
82 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
10 
STATISTICAL CONSIDERATIONS 
10.1 
Study Hypotheses 
The primary goal of this study is to assess the systemic and mucosal immunogenicity of two 
doses of 4CMenB compared to a placebo comparator.  A secondary goal is to assess the safety 
and reactogenicity of 4CMenB.  Though the study is not designed to formally test any 
hypotheses, p-values may be reported that compare the immunogenicity and/or safety data 
between treatment groups. The null hypotheses for these tests will be that there is no difference 
between treatment groups and the alternative hypotheses will be two-sided. 
10.2 
Sample Size Considerations 
A total of approximately 50 (maximum of 60), subjects will be enrolled and randomized to one 
of two study arms based on a 4:1 allocation ratio to the 4CMenB arm and placebo arm, 
respectively.. The 4:1 allocation ratio was not selected based on any formal statistical criteria but 
instead was selected to maximize the number of subjects administered 4CMenB, and thus 
maximize the amount of immunogenicity data collected on subjects administered 4CMenB. Of 
the approximate 50 subjects, approximately 20 subjects will be enrolled into the Rectal Mucosal 
Biopsy Cohort.  As with the overall sample size, this number was not selected based on any 
statistical criteria but was selected weighing the feasibility of enrolling subjects who would 
consent to the biopsy procedure against ensuring ample data was collected via rectal mucosal 
biopsy as there are no data on the impact of 4CMenB on immunologic responses at the human 
mucosal surfaces where GC is typically encountered. 
The study is not designed to formally test any hypotheses associated with the immunogenicity 
data.  Using the ELISA GMT estimates reported in Table 2 of Semchenko et al.,13 estimated 
GMT 95% confidence intervals were calculated for the 4CMenB group using the post-
vaccination estimates and for the placebo group using the pre-vaccination estimates. Table 2 
provides the estimated GMTs and GMT ratios between groups. To account for a small 
percentage of the approximate 50 randomized subjects not being eligible for the primary analysis 
(e.g., due to not having immunogenicity data available), a range of sample sizes from 36 to 50 
was explored. 
 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
83 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Table 2: 
95% Confidence Intervals for GMTs and GMT Ratios across a range of 
Sample Sizes and Antigens 
N 
(Vaccine / 
Placebo) 
Antigena 
Treatment 
Group 
GMT 
Estimate 
GMT 95% CI 
GMT 
Ratio 
GMT Ratio 
95% CI 
30 / 6 
Ng OMV 
Vaccine 
42224 
35234, 50601 
1.23 
0.77, 1.97 
Placebo 
34297 
16638, 70697 
Ng whole 
cell 
Vaccine 
78793 
61639, 100721 
1.62 
0.86, 3.05 
Placebo 
48503 
19329, 121713 
Nm whole 
cell 
Vaccine 
388023 
262806, 572900 
4.00 
1.53, 10.47 
Placebo 
97006 
29287, 321311 
Ng rNHBA 
Vaccine 
1176267 
876783, 1578046 
34.3 
16.98, 69.26 
Placebo 
34297 
16638, 70697 
35 / 8 
Ng OMV 
Vaccine 
42224 
35748, 49873 
1.23 
0.81, 1.87 
Placebo 
34297 
19275, 61026 
Ng whole 
cell 
Vaccine 
78793 
62863, 98760 
1.62 
0.93, 2.83 
Placebo 
48503 
23305, 100944 
Nm whole 
cell 
Vaccine 
388023 
271134, 555305 
4.00 
1.73, 9.26 
Placebo 
97006 
37363, 251856 
Ng rNHBA 
Vaccine 
1176267 
897654, 1541356 
34.3 
18.63, 63.14 
Placebo 
34297 
19275, 61026 
40 / 10  
Ng OMV 
Vaccine 
42224 
36161, 49303 
1.23 
0.85, 1.79 
Placebo 
34297 
20947, 56156 
Ng whole 
cell 
Vaccine 
78793 
63850, 97233 
1.62 
0.98, 2.68 
Placebo 
48503 
25906, 90811 
Nm whole 
cell 
Vaccine 
388023 
277922, 541742 
4.00 
1.88, 8.51 
Placebo 
97006 
42880, 219456 
Ng rNHBA 
Vaccine 
1176267 
914549, 1512881 
34.3 
19.85, 59.27 
Placebo 
34297 
20947, 56156 
a: From Semchenko (2018), Table 2.  Vaccine group estimates are derived from the post-vaccination estimates 
and placebo group estimates are derived from the pre-vaccination estimates. 
 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
84 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
10.3 
Treatment Assignment Procedures 
10.3.1 
Randomization Procedures 
Within each biopsy cohort (Rectal Mucosal Biopsy Cohort and No Rectal Mucosal Biopsy 
Cohort), subjects will be randomized 4:1 to 4CMenB or placebo. Randomization will be 
stratified by sex. Approximately twenty (20) subjects, approximately 10 males and 10 females, 
will be enrolled into the Rectal Mucosal Biopsy Cohort and approximately 30 subjects, 
approximately 15 males and 15 females, will be enrolled into the No Rectal Mucosal Biopsy 
Cohort.   
The list of randomized treatment assignments will be included in the enrollment module of 
Emmes’ Internet Data Entry System (IDES).  Advantage eClinical® will assign each enrolled 
participant to a treatment arm after demographic and eligibility data have been entered into the 
system.  A designated individual at each participating site will be provided with a coded list for 
emergency unblinding purposes, which will be kept in a secure place. 
Instructions for use of the enrollment module are included in the Advantage eClinical User’s 
Guide.  Manual back-up procedures and instructions are provided for use in the event that a 
participating site temporarily loses access to the Internet or the online enrollment system is 
unavailable. 
10.3.2 
Masking Procedures 
This is a double-blinded clinical trial.  Participants, site investigators, and study personnel who 
perform study assessments following study product administration, data entry personnel at the 
sites, and laboratory personnel performing study assays will be blinded to treatment assignment. 
Syringes will be labeled with an overlay/blinding tape containing the subject ID, and the 
treatment number from the treatment key, and expiration time for the syringe, and provided to 
the unblinded vaccine administrator. The unblinded vaccine administrator will be credentialed to 
administer vaccines but will not be involved in study-related assessments, subject contact, or 
data collection following vaccination (data entry related to the vaccination is acceptable). 
The randomization scheme will be generated by the Statistical and Data Coordinating Center 
(SDCC) and provided to unblinded study personnel (i.e., research pharmacists performing study 
product preparations and unblinded study product administrators) at the participating sites. The 
unblinded study product administrator is a study personnel member credentialed to administer 
study product and may also participate in dose preparation but will not be involved in study-
related assessments or have participant contact for data collection following study product 
administration to the participant. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
85 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
The SMC may receive data in aggregate and presented by study arm. The SMC may be 
unblinded to individual study treatment assignments, as needed, to adequately assess safety 
issues. The SMC will review grouped and unblinded data in the closed session only. 
10.4 
Planned Interim Analyses 
10.4.1 
Interim Safety Review  
As defined in the charter, the SMC will review data at specified times during the course of the 
study for subject and overall study progress, and will conduct ad hoc reviews as appropriate 
when a halting rule is met or for immediate concerns regarding observations during this study. 
10.4.2 
Interim Immunogenicity Review 
There will be an interim immunogenicity analysis, which may be used to optimize and prioritize 
research laboratory assays for exploratory outcomes. Results of the interim analyses will not be 
used to make any decisions concerning the conduct of this trial. 
 The interim immunogenicity analysis will include all available antibody data for the first 20 
subjects who complete Visit 6, which includes data addressing the primary and secondary 
objectives, as well as several exploratory objectives. The interim report will be prepared by the 
unblinded statistician at the SDCC after all relevant immunogenicity data through Visit 6 are 
received. Results will be shared only with relevant study personnel (i.e. PI, laboratory 
investigator(s), and DMID) and only in aggregate by treatment arm. Study personnel will remain 
blinded to individual subject treatment assignments. 
The interim immunogenicity analyses will include summaries of descriptive and aggregate 
antibody data against antigens from Neisseria gonorrhoeae and Neisseria meningitidis stratified 
by antigen, specimen type (serum and mucosal sites), pre- versus post-treatment timepoints, and 
treatment arm (4CMenB or placebo). No hypothesis tests or modeling will be included in the 
interim immunogenicity analysis. This interim analysis of the data is not intended to impact the 
conduct of this trial. No statistical adjustments are planned. 
10.5 
Final Analysis Plan 
A separate Statistical Analysis Plan (SAP) will be written that will contain the details of all 
planned analyses.  This section outlines the major components of the analyses. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
86 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
10.5.1 
Analysis Populations 
10.5.1.1 
Immunogenicity Population 
For the primary outcome analysis, the Immunogenicity Population at a specified follow-up visit 
will include all eligible subjects who have received all doses of study product prior to that visit 
and have immunogenicity data available for that visit.  Subjects will be classified according to 
the study product received.  To account for subjects having data available only for a subset of 
assays, assay-specific populations will be defined.   
Per-protocol populations may also be defined that further restrict the immunogenicity analysis 
populations to exclude subjects with major protocol deviations or events that may impact study 
product effectiveness or the ascertainment or interpretation of assay results.  These will be 
described in the SAP. For supplementary and exploratory analyses, additional analysis 
populations may be defined; details will be provided in the SAP.  
10.5.1.2 
Safety Population 
The Safety Population will include all subjects who received at least one dose of study product.  
Subjects will be classified according to the treatment received. 
10.5.2 
Baseline Characteristics 
Baseline and demographic characteristics will be summarized overall and by study arm. For both 
continuous and categorical variables, appropriate summary statistics will be applied. For 
continuous variables, descriptive statistics will include the number of non-missing values, mean, 
standard deviation, median, minimum, and maximum. For categorical variables, descriptive 
statistics will include counts and percentages per category. 
10.5.3 
Immunogenicity Analysis Plan 
For the analyses of the primary and secondary immunogenicity outcomes, the GMT and 
geometric mean fold rise (GMFR) for ELISA titers will be calculated for Days 1, 29, 43, 57, and 
181 in each study arm.  Point estimates and their 95% confidence intervals will be reported for 
each time point.  The distribution of titers will also be graphically summarized using reverse 
cumulative frequency distributions.  Anatomical sites will be summarized separately.   
Summaries of the ratio of serum to mucosal IgG concentration will be generated at each time 
point.  Geometric means and confidence intervals will be reported and scatter plots of serum vs. 
mucosal IgG concentrations will be generated.  Summaries of pairwise concentration ratios, 
comparing anatomical sites, will also be generated at each time point.  Summaries will include 
geometric means and confidence intervals as well as graphical summaries.   

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
87 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
All geometric mean calculations will use log10 transformed data, and the anti-log of the resulting 
point estimates will be reported for means and confidence intervals.  Missing immunogenicity 
data will not be imputed and no search for outliers will be performed.  The logarithmic 
transformation is used to improve the distributional properties of the immunogenicity data to 
reduce the impact of potential outliers. 
Additional supplementary and/or sensitivity analyses of the primary and secondary outcomes as 
well as analysis of the exploratory immunogenicity outcomes will be described in the separate 
SAP. 
10.5.4 
Safety Analysis Plan 
Safety evaluations will be based on the frequency and severity of reactogenicity events, AEs, and 
SAEs occurring from the time of first study product administration through the final study visit.  
AEs and SAEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA®) for 
preferred term and system organ class. The rate and exact 95% CIs of AEs and SAEs in 
aggregate, as well as by MedDRA categories, will be computed. The number of SAEs will be 
reported by a detailed listing showing the type, MedDRA coding, relevant dates (treatment 
dosing date(s) and SAE onset and resolution dates), severity, relatedness, and outcome for each 
event. 
Solicited local injection site and systemic reactogenicity will be summarized by severity for each 
day post injection (for each injection) and as the maximum severity over the entire assessment 
period (across injections). Additionally, solicited AEs will be analyzed by taking the most severe 
response over the follow-up period, dichotomizing into a binary variable (none vs. any severity) 
and using exact confidence intervals to summaries the proportion/percentage of subjects 
reporting each symptom any infection site symptom, and any systemic symptom.  Solicited AEs 
will be summarized separately for each infection, and over both injections by study arm. 
Vital sign and physical exam findings will also be summarized and/or providing in subject-level 
listings. 
Missing safety data will not be imputed and no search for outliers will be performed. 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
88 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
11 
ELECTRONIC CASE REPORT FORMS AND ACCESS 
TO SOURCE DATA  
The participating VTEU site will maintain appropriate medical and research records in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for the 
protection of confidentiality of subjects. The site will permit authorized representatives of 
DMID, its designees, and appropriate regulatory agencies to examine (and when required by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, 
and evaluation of the study safety and progress. These representatives will be permitted access to 
all source data and source documents (paper and electronic), which include, but are not limited 
to, hospital records, clinical and office charts, laboratory notes, memoranda, 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 the 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. 
The study uses direct data entry for the participating clinic site. All eCRFs serve as the source 
documents.  
Subject memory aids will not be source documents. Subjects will be trained to use a database to 
complete a web based “e-Memory aid” and are expected to enter information in the e-Memory 
aid each day. Subjects using the e-Memory aid will also be provided a paper memory aid for 
their use in the event they are unable to access the web-based system. The subjects will be asked 
to enter the information from the paper memory aid into the e-Memory aid once they are able to 
access the web-based system. Subjects will record temperature, local and systemic symptoms 
and any new medications used following vaccination or changes to previously reported 
medications daily for 8 days after study vaccination. 
Subjects will be instructed to contact the clinic staff immediately if they experience severe 
symptoms at any time during the study, for prompt follow-up in real time. The study clinic will 
be alerted in real time of any potential solicited events of Grade 3 severity entered in the e- 
Memory Aid. An email alert will be sent to the clinic site and the Emmes study team. Within one 
business day of site awareness, the site must attempt to follow up with the subject on the severe 
solicited event and send an email to Emmes confirming attempted follow up with the subject. 
Instructions for completing the e-Memory aid are provided in the MOP and in a separate e-
Memory aid instructions document that will be provided to the subjects at each vaccination. The 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
89 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
site staff must review the e-Memory aid information and interview the subject at the next 
scheduled visit. The subject-entered data will be available for review by the clinician during the 
clinical interview. 
The site staff will be the data originators for the clinically reviewed data in Advantage 
eClinical® that will be used for the study endpoints. A list of all authorized site staff data 
originators will be included on the Study Personnel/Signature Responsibility List.  

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
90 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
12 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the participating site is 
responsible for conducting routine QA and quality control (QC) activities to internally monitor 
study progress and protocol compliance.  The site principal investigator will provide direct 
access to source data/eCRFs and reports for the purpose of monitoring and auditing by the 
sponsor, and inspection by local and regulatory authorities.  The site PI will ensure all study 
personnel are appropriately trained and applicable documentations are maintained on site. 
The SDCC 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 participating site for clarification and resolution. 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
91 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
13 
DATA HANDLING AND RECORD KEEPING 
13.1 
Data Management Responsibilities 
The site PI is responsible to ensure the accuracy, completeness, legibility, and timeliness of the 
data reported. 
Data will be entered electronically over the Internet by site study staff into Advantage eClinical, 
developed and maintained by the SDCC. The eCRFs serve as the source documents for data 
collected.  Paper case report forms derived from the eCRF are provided by the SDCC and are to 
be used only when Advantage eClinical is unavailable. Details on data handling procedures, 
procedures for data monitoring, and instructions for use of the system and completion of the 
eCRFs are provided in the study MOP, eCRF Instructions, and Advantage eClinical User’s 
Guide. 
The sponsor and/or its designee will provide guidance to the site principal investigators and other 
study personnel on making corrections to the eCRF. 
13.2 
Data Coordinating Center/Biostatistician Responsibilities 
All eCRFs and laboratory reports must be reviewed by the clinical team and data entry 
personnel, who will ensure that they are accurate and complete. AEs must be recorded on the 
appropriate eCRF, assessed for severity and relationship, and reviewed by the site PI or 
appropriate sub-investigator. 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site PI. During the study, the site PI must maintain complete and 
accurate documentation for the study. 
The SDCC for this study will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
13.3 
Data Capture Methods 
Clinical (including, but not limited to, AE/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values), reactogenicity and immunogenicity data 
will be entered into eCRFs via a 21 CFR Part 11-compliant internet data entry system provided 
by the SDCC. The data system includes password protection and internal quality checks, such as 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
92 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly into eCRFs by the study personnel.   
Site staff who are delegated the responsibility by the study PI will be the data originators for 
clinical data entered directly into the eCRF. A list of all authorized data originators, including 
site staff, will be included on the Study Personnel/Signature Responsibility List. 
13.4 
Types of Data 
Data for this trial will include clinical, safety, and outcome measures (e.g., clinical laboratory 
values, reactogenicity, and immunogenicity data). 
13.5 
Study Records Retention 
Study records and reports including, but not limited to, eCRFs, source documents, ICFs, 
laboratory test results, and study drug disposition records will be retained for 2 years after a 
marketing application is approved for the study product for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for the study 
product, until 2 years after the investigation is discontinued and the FDA has been notified. 
These documents will be retained for a longer period, however, if required by local regulations. 
ICFs for future use will be maintained as long as the sample/specimen exists. 
No records will be destroyed without the written consent of the sponsor. It is the responsibility of 
the sponsor to inform the site PI when these documents no longer need to be retained. The 
participating VTEU sites must contact DMID for authorization prior to the destruction of any 
study records. 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
93 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
14 
CLINICAL MONITORING 
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 (SOP).  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, ICFs, medical and laboratory reports, and 
protocol and GCP compliance.  Site monitors will have access through study personnel, and all 
study documentation according to the DMID-approved site monitoring plan.  Study monitors 
will meet with the site PI to discuss any problems and actions to be taken, and will document site 
visit findings and discussions. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
94 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
15 
PUBLICATION POLICY 
Following completion of the study, the lead PI is expected to publish the results of this research 
in a scientific journal.  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 SAP 
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 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
95 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
16 
LITERATURE REFERENCES 
1. 
Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, Stevens G, 
Gottlieb S, Kiarie J, Temmerman M. Global Estimates of the Prevalence and Incidence of Four 
Curable Sexually Transmitted Infections in 2012 Based on Systematic Review and Global 
Reporting. PLoS One. 2015;10(12):e0143304. doi: 10.1371/journal.pone.0143304. PubMed 
PMID: 26646541; PMCID: PMC4672879. 
2. 
Gonorrhea: Division of STD Prevention; 2018 [cited 2019 March 22]. Available from: 
https://www.cdc.gov/std/stats17/gonorrhea.htm. 
3. 
Katz AR, Komeya AY, Kirkcaldy RD, Whelen AC, Soge OO, Papp JR, Kersh EN, 
Wasserman GM, O'Connor NP, O'Brien PS, Sato DT, Maningas EV, Kunimoto GY, Tomas JE. 
Cluster of Neisseria gonorrhoeae Isolates With High-level Azithromycin Resistance and 
Decreased Ceftriaxone Susceptibility, Hawaii, 2016. Clin Infect Dis. 2017;65(6):918-23. doi: 
10.1093/cid/cix485. PubMed PMID: 28549097. 
4. 
Petousis-Harris H, Paynter J, Morgan J, Saxton P, McArdle B, Goodyear-Smith F, Black 
S. Effectiveness of a group B outer membrane vesicle meningococcal vaccine against 
gonorrhoea in New Zealand: a retrospective case-control study. Lancet. 2017;390(10102):1603-
10. doi: 10.1016/S0140-6736(17)31449-6. PubMed PMID: 28705462. 
5. 
Paynter J, Goodyear-Smith F, Morgan J, Saxton P, Black S, Petousis-Harris H. 
Effectiveness of a Group B Outer Membrane Vesicle Meningococcal Vaccine in Preventing 
Hospitalization from Gonorrhea in New Zealand: A Retrospective Cohort Study. Vaccines 
(Basel). 2019;7(1). doi: 10.3390/vaccines7010005. PubMed PMID: 30621260. 
6. 
Whelan J, Klovstad H, Haugen IL, Holle MR, Storsaeter J. Ecologic Study of 
Meningococcal B Vaccine and Neisseria gonorrhoeae Infection, Norway. Emerg Infect Dis. 
2016;22(6):1137-9. doi: 10.3201/eid2206.151093. PubMed PMID: 27191543; PMCID: 
PMC4880101. 
7. 
Pérez O, Campo Jd, Cuello M, González E, Nuñez N, Cabrera O, Llanes R, Acevedo R, 
Zayas C, Balboa J, Romeu B, Baró M, Campa C, Lantero MI, Sierra G, Galindo MA, Harandi 
AM, Lastre M. Mucosal approaches in Neisseria vaccinology. VacciMonitor. 2009;18(2):53-5. 
8. 
Holst J, Oster P, Arnold R, Tatley MV, Naess LM, Aaberge IS, Galloway Y, McNicholas 
A, O'Hallahan J, Rosenqvist E, Black S. Vaccines against meningococcal serogroup B disease 
containing outer membrane vesicles (OMV): lessons from past programs and implications for the 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
96 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
future. Hum Vaccin Immunother. 2013;9(6):1241-53. doi: 10.4161/hv.24129. PubMed PMID: 
23857274; PMCID: PMC3901813. 
9. 
Martin DR, Ruijne N, McCallum L, O'Hallahan J, Oster P. The VR2 epitope on the PorA 
P1.7-2,4 protein is the major target for the immune response elicited by the strain-specific group 
B meningococcal vaccine MeNZB. Clin Vaccine Immunol. 2006;13(4):486-91. doi: 
10.1128/CVI.13.4.486-491.2006. PubMed PMID: 16603616; PMCID: PMC1459632. 
10. 
MacNeil JR, Rubin L, Folaranmi T, Ortega-Sanchez IR, Patel M, Martin SW. Use of 
Serogroup B Meningococcal Vaccines in Adolescents and Young Adults: Recommendations of 
the Advisory Committee on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep. 
2015;64(41):1171-6. doi: 10.15585/mmwr.mm6441a3. PubMed PMID: 26492381. 
11. 
GSK Vaccines. Bexsero Prescribing Information. 2015. 
12. 
Longtin J, Dion R, Simard M, Betala Belinga J-F, Longtin Y, Lefebvre B, Labbe A-C, 
Deceuninck G, De Wals P. Possible Impact of Wide-scale Vaccination Against Serogroup B 
Neisseria Meningitidis on Gonorrhea Incidence Rates in One Region of Quebec, Canada.  
IDWeek 2017; San Diego, CA. 2017. 
13. 
Semchenko EA, Tan A, Borrow R, Seib KL. The serogroup B meningococcal vaccine 
Bexsero elicits antibodies to Neisseria gonorrhoeae. Clin Infect Dis. 2018. doi: 
10.1093/cid/ciy1061. PubMed PMID: 30551148. 
14. 
Beernink PT, Ispasanie E, Lewis LA, Ram S, Moe GR, Granoff DM. A Meningococcal 
Native Outer Membrane Vesicle Vaccine With Attenuated Endotoxin and Overexpressed Factor 
H Binding Protein Elicits Gonococcal Bactericidal Antibodies. J Infect Dis. 2019;219(7):1130-7. 
doi: 10.1093/infdis/jiy609. PubMed PMID: 30346576. 
15. 
Folaranmi T, Rubin L, Martin SW, Patel M, MacNeil JR, Centers for Disease C. Use of 
Serogroup B Meningococcal Vaccines in Persons Aged >/=10 Years at Increased Risk for 
Serogroup B Meningococcal Disease: Recommendations of the Advisory Committee on 
Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(22):608-12. Epub 
2015/06/13. PubMed PMID: 26068564; PMCID: PMC4584923. 
16. 
Duffy J, Johnsen P, Ferris M, Miller M, Leighton K, McGilvray M, McNamara L, 
Breakwell L, Yu Y, Bhavsar T, Briere E, Patel M. Safety of a meningococcal group B vaccine 
used in response to two university outbreaks. J Am Coll Health. 2017;65(6):380-8. Epub 
2017/04/01. doi: 10.1080/07448481.2017.1312418. PubMed PMID: 28362241; PMCID: 
PMC6574050. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
97 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
17. 
Toneatto D, Ismaili S, Ypma E, Vienken K, Oster P, Dull P. The first use of an 
investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in humans. Hum 
Vaccin. 2011;7(6):646-53. Epub 2011/09/10. doi: 10.4161/hv.7.6.15482. PubMed PMID: 
21904120. 
18. 
Kimura A, Toneatto D, Kleinschmidt A, Wang H, Dull P. Immunogenicity and safety of 
a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal 
CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at 
increased risk for occupational exposure to meningococcal isolates. Clin Vaccine Immunol. 
2011;18(3):483-6. Epub 2010/12/24. doi: 10.1128/CVI.00304-10. PubMed PMID: 21177912; 
PMCID: PMC3067382. 
19. 
Findlow J, Bai X, Findlow H, Newton E, Kaczmarski E, Miller E, Borrow R. Safety and 
immunogenicity of a four-component meningococcal group B vaccine (4CMenB) and a 
quadrivalent meningococcal group ACWY conjugate vaccine administered concomitantly in 
healthy laboratory workers. Vaccine. 2015;33(29):3322-30. Epub 2015/05/31. doi: 
10.1016/j.vaccine.2015.05.027. PubMed PMID: 26025807. 
20. 
Hong E, Terrade A, Taha MK. Immunogenicity and safety among laboratory workers 
vaccinated with Bexsero(R) vaccine. Hum Vaccin Immunother. 2017;13(3):645-8. Epub 
2016/11/04. doi: 10.1080/21645515.2016.1241358. PubMed PMID: 27808594; PMCID: 
PMC5360120. 
21. 
American Society for Gastrointestinal E, Ikenberry SO, Anderson MA, Banerjee S, 
Baron TH, Dominitz JA, Gan SI, Harrison ME, Jagannath S, Levy M, Lichtenstein D, Shen B, 
Fanelli RD, Stewart L, Khan K. Endoscopy by nonphysicians. Gastrointest Endosc. 
2009;69(4):767-70. doi: 10.1016/j.gie.2008.11.006. PubMed PMID: 19327469. 
22. 
Society of Gastroenterology Nurses and Associates Inc. Guideline for Performance of 
Flexible Sigmoidoscopy by Registered Nurses for the Purpose of Colorectal Cancer Screening 
2009. 
23. 
Gatto NM, Frucht H, Sundararajan V, Jacobson JS, Grann VR, Neugut AI. Risk of 
perforation after colonoscopy and sigmoidoscopy: a population-based study. J Natl Cancer Inst. 
2003;95(3):230-6. doi: 10.1093/jnci/95.3.230. PubMed PMID: 12569145. 
24. 
Levin TR, Conell C, Shapiro JA, Chazan SG, Nadel MR, Selby JV. Complications of 
screening flexible sigmoidoscopy. Gastroenterology. 2002;123(6):1786-92. doi: 
10.1053/gast.2002.37064. PubMed PMID: 12454834. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
98 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
25. 
Koobatian GJ, Choi PM. Safety of surveillance colonoscopy in long-standing ulcerative 
colitis. Am J Gastroenterol. 1994;89(9):1472-5. PubMed PMID: 8079922. 
26. 
Rutter MD, Saunders BP, Wilkinson KH, Rumbles S, Schofield G, Kamm MA, Williams 
CB, Price AB, Talbot IC, Forbes A. Thirty-year analysis of a colonoscopic surveillance program 
for neoplasia in ulcerative colitis. Gastroenterology. 2006;130(4):1030-8. doi: 
10.1053/j.gastro.2005.12.035. PubMed PMID: 16618396. 
27. 
Yao MD, von Rosenvinge EC, Groden C, Mannon PJ. Multiple endoscopic biopsies in 
research subjects: safety results from a National Institutes of Health series. Gastrointest Endosc. 
2009;69(4):906-10. doi: 10.1016/j.gie.2008.05.015. PubMed PMID: 19136110; PMCID: 
PMC5050003. 
28. 
Chiu WK, Brand RM, Camp D, Edick S, Mitchell C, Karas S, Zehmisch A, Ho K, Brand 
RE, Harrison J, Abo S, Cranston RD, McGowan I. The Safety of Multiple Flexible 
Sigmoidoscopies with Mucosal Biopsies in Healthy Clinical Trial Participants. AIDS Res Hum 
Retroviruses. 2017;33(8):820-6. doi: 10.1089/aid.2016.0293. PubMed PMID: 28296471; 
PMCID: PMC5564058. 
 
 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
99 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
17 
APPENDICES 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
100 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 Appendix A. SCHEDULE OF EVENTS 
Procedures 
Screening (Visit 00A) 
Day -56 to -1 (-56 to -28 
for biopsy cohort) 
Screening (Visit 00B) 
Day -7 to -1 (-34 to -28 
for biopsy cohort) 
Baseline Rectal Mucosal 
Biopsy, Visit 00C, Day -
28 to -14 
Study Visit 00P (Phone 
visit), Day -27 to -12 
Enrollment/Baseline 
Visit 1, Day 1 
Study Visit 2  
Day 8 ± 1 day 
Study Visit 3 
Day 15 ± 1 days 
Study Visit 4e 
Day 29 ± 1 days 
Study Visit 5 
Day 36 ± 1 days 
Study Visit 6f 
Day 43 ± 3 days 
Study Visit 6P (Phone 
visit) 
Day 44 + 1 days 
Study Visit 7 
Day 57 ± 1 days 
Final Study Visit 8 
Day 181 ± 7 days 
Early Termination Visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Eligibility Criteria 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X----------------------------------------X 
 
X-----------------------------------------------------------------X 
 
X---------------------X 
X 
Sexual history 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication review 
X----------------------------------------X 
 
X-----------------------------------------------------------------X 
 
X---------------------X 
X 
Review COVID-19 vaccine 
history 
 
 
X 
 
 
X 
 
 
 
 
 
Vital signs 
X 
(X) 
X 
 
X 
(X) 
(X) 
X 
(X) 
X 
 
(X) 
(X) 
(X) 
Physical exam 
X 
(X) 
(X) 
 
(X)--------------------------------------------------------------------------------------------------------(X) 
(X) 
Administer study intervention 
 
 
 
 
X 
 
 
Xe 
 
 
 
 
 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
101 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Procedures 
Screening (Visit 00A) 
Day -56 to -1 (-56 to -28 
for biopsy cohort) 
Screening (Visit 00B) 
Day -7 to -1 (-34 to -28 
for biopsy cohort) 
Baseline Rectal Mucosal 
Biopsy, Visit 00C, Day -
28 to -14 
Study Visit 00P (Phone 
visit), Day -27 to -12 
Enrollment/Baseline 
Visit 1, Day 1 
Study Visit 2  
Day 8 ± 1 day 
Study Visit 3 
Day 15 ± 1 days 
Study Visit 4e 
Day 29 ± 1 days 
Study Visit 5 
Day 36 ± 1 days 
Study Visit 6f 
Day 43 ± 3 days 
Study Visit 6P (Phone 
visit) 
Day 44 + 1 days 
Study Visit 7 
Day 57 ± 1 days 
Final Study Visit 8 
Day 181 ± 7 days 
Early Termination Visit 
Pre-vaccine Administration 
Reactogenicity Assessment 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Post-vaccination Observation 
(for ≥15 minutes) to Assess 
Acute Reactions 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Evaluation of Vaccination Site to 
Assess for Reactogenicity and 
AE/SAEs after ≥15 minutes 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Memory Aid 
 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
(X) 
Adverse event review and 
evaluation 
 
 
Xd 
Xd 
X-----------------------------------------------------------------X 
Xd 
X-------------------X 
X 
Sampling procedures 
Hematology (CBC, PT, aPTT)a 
X 
(X) 
(X) 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
X 
(X) 
 
 
X 
 
 
X 
 
 
 
 
 
(X) 
STI screeningb 
Xc 
 
 
 
(X)-------------------------(X) 
X 
(X)------------(X) 
 
(X) 
X 
 
Rectal mucosal biopsya 
 
 
X 
 
 
 
 
 
 
Xf 
 
 
 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
102 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Procedures 
Screening (Visit 00A) 
Day -56 to -1 (-56 to -28 
for biopsy cohort) 
Screening (Visit 00B) 
Day -7 to -1 (-34 to -28 
for biopsy cohort) 
Baseline Rectal Mucosal 
Biopsy, Visit 00C, Day -
28 to -14 
Study Visit 00P (Phone 
visit), Day -27 to -12 
Enrollment/Baseline 
Visit 1, Day 1 
Study Visit 2  
Day 8 ± 1 day 
Study Visit 3 
Day 15 ± 1 days 
Study Visit 4e 
Day 29 ± 1 days 
Study Visit 5 
Day 36 ± 1 days 
Study Visit 6f 
Day 43 ± 3 days 
Study Visit 6P (Phone 
visit) 
Day 44 + 1 days 
Study Visit 7 
Day 57 ± 1 days 
Final Study Visit 8 
Day 181 ± 7 days 
Early Termination Visit 
Vaginal secretion sampling 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
(X) 
Rectal secretion sampling 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
(X) 
Oropharyngeal secretion 
sampling 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
(X) 
Blood draw for serum antibody 
assays 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
(X) 
Blood draw for systemic 
immunity assays 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
(X) 
aOnly to be performed in the rectal mucosal biopsy cohort (approximate N=20) 
bSTI screening will include GC/CT NAAT of urine, pharynx, and rectum, and RPR. HIV antibody testing will occur at Visit 00A and 08 only 
cBaseline STI screening in non-pregnant females will also include NAAT for Trichomonas 
dAE review and evaluation at Visit 00C will include only AEs from the baseline biopsy procedure 
e The following will be reviewed for safety prior to administering the second dose: interim medical history, concomitant medications, COVID-19 vaccination status, vital signs, and negative 
pregnancy test result for females of childbearing potential.  
f The following will be reviewed for safety prior to the rectal mucosal biopsy procedure: interim medical history, concomitant medications, and vital signs.  

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
103 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Procedures 
Screening (Visit 00A) 
Day -56 to -1 (-56 to -28 
for biopsy cohort) 
Screening (Visit 00B) 
Day -7 to -1 (-34 to -28 
for biopsy cohort) 
Baseline Rectal Mucosal 
Biopsy, Visit 00C, Day -
28 to -14 
Study Visit 00P (Phone 
visit), Day -27 to -12 
Enrollment/Baseline 
Visit 1, Day 1 
Study Visit 2  
Day 8 ± 1 day 
Study Visit 3 
Day 15 ± 1 days 
Study Visit 4e 
Day 29 ± 1 days 
Study Visit 5 
Day 36 ± 1 days 
Study Visit 6f 
Day 43 ± 3 days 
Study Visit 6P (Phone 
visit) 
Day 44 + 1 days 
Study Visit 7 
Day 57 ± 1 days 
Final Study Visit 8 
Day 181 ± 7 days 
Early Termination Visit 
Abbreviations: X, study procedure for all participants; (X), study procedures to be determined by study staff; CBC, complete blood count; PT, prothrombin time; aPTT, activated partial 
thromboplastin time; STI, sexually transmitted infection 
 
 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
104 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 Appendix B. TABLE OF STUDY ASSAYS AND BLOOD VOLUME COLLECTION 
 
1st screen 
(V00A) 
2nd screen 
(V00B) 
V00Ca 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Study Day relative 
to Vaccination #1 
(D1) 
D-56 to -1 
(D-56 to -28 for 
rectal biopsy 
cohort) 
D-7 to -1 
(D-34 to -28 for 
rectal biopsy 
cohort) 
-28 to  -
14 
1 
8 
15 
29 
36 
43 
57 
181 
Sampling Procedures (blood volumes in mL) 
Clinical Laboratory 
Screening serology (RPR) 
8 
 
 
 
 
8 
8 
Hematology (CBC)a 
4 
4 
 
Coagulation testing (PT/aPTT)a 
4 
4 
 
GC/CT NAAT x3 mucosal sites 
X 
X 
Xb 
X 
Trichomonas NAAT 
Xc 
 
 
 
 
 
 
 
 
 
 
Mucosal Immunity 
Rectal mucosal IgG against Ng 
antigens 
X 
X 
X 
X 
X 
Vaginal mucosal IgG against Ng 
antigens 
X 
X 
X 
X 
X 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
105 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
1st screen 
(V00A) 
2nd screen 
(V00B) 
V00Ca 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Study Day relative 
to Vaccination #1 
(D1) 
D-56 to -1 
(D-56 to -28 for 
rectal biopsy 
cohort) 
D-7 to -1 
(D-34 to -28 for 
rectal biopsy 
cohort) 
-28 to  -
14 
1 
8 
15 
29 
36 
43 
57 
181 
Oropharyngeal mucosal IgG against 
Ng antigens 
X 
X 
X 
X 
X 
Rectal mucosal IgA against Ng 
antigens 
X 
X 
X 
X 
X 
Vaginal mucosal IgA against Ng 
antigens 
X 
X 
X 
X 
X 
Oropharyngeal mucosal IgA against 
Ng antigens 
X 
X 
X 
X 
X 
Rectal mucosal T cell phenotyping 
(ICS)a 
X 
X 
Systemic Immunity 
Serum IgG against Ng antigens 
(ELISA) 
8 
8 
8 
8 
8 
Serum IgA against Ng antigens 
(ELISA) 
 
 
 
8 
 
 
8 
 
8 
8 
8 
Ng specific MBC (ELISPOT) 
24 
24 
24 
24 
Ng specific T cell (ELISPOT) 
16 
16 
16 
16 
16 
16 
16 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
106 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
1st screen 
(V00A) 
2nd screen 
(V00B) 
V00Ca 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Study Day relative 
to Vaccination #1 
(D1) 
D-56 to -1 
(D-56 to -28 for 
rectal biopsy 
cohort) 
D-7 to -1 
(D-34 to -28 for 
rectal biopsy 
cohort) 
-28 to  -
14 
1 
8 
15 
29 
36 
43 
57 
181 
OMV and peptide antigen specific T 
cell (ICS) 
32 
32 
32 
32 
32 
Serum bactericidal Ab 
8 
8 
8 
8 
8 
Serum IgG against Nm antigens 
(ELISA) 
8 
 
8 
 
8 
Nm specific MBC (ELISPOT) 
16 
16 
16 
 
 
Nm specific T cell (ELISPOT) 
16 
 
16 
 
 
16 
 
 
Blood volumes (mL) 
Per visit 
16 
8 
0 
136 
16 
64 
112 
16 
136 
72 
56 
Cumulative 
16 
24 
24 
160 
176 
240 
352 
368 
504 
576 
632 
aOnly for subjects in the rectal mucosal biopsy cohort 
bOnly if indicated based on interim sexual history 
cFemale subjects only 
Abbreviations: Ng, Neisseria gonorrhoeae; Nm, Neisseria meningitidis 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
107 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 Appendix C. TOXICITY TABLE 
Local (Injection Site) Reactogenicity Grading 
Local (Injection Site) 
Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain – experienced 
without touching the 
injection site 
(spontaneous discomfort) 
Subject is aware of pain, 
but it does not interfere 
with daily activity, and it 
does not require  pain 
medication or it requires 
use of a non-narcotic pain 
reliever ≤24hours 
Subject is aware of pain; 
there is interference with 
daily activity or it 
requires repeated use of a 
non-narcotic pain reliever 
for >24 hours 
Subject is aware of pain, 
and it prevents daily 
activity or requires any use 
of a narcotic pain reliever 
Tenderness – hurts only 
when injection site is 
touched or the arm is 
moved 
The area immediately 
surrounding the injection 
site hurts only when 
touched or with arm 
motion, and it does not 
interfere with daily 
activity 
The area immediately 
surrounding the injection 
site hurts when touched or 
with arm motion, and it 
interferes with daily 
activity 
The area immediately 
surrounding the injection 
site hurts when touched or 
with arm motion, and it 
prevents daily activity 
Pruritus (Itching) 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Ecchymosis (Bruising)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Erythema (Redness)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Induration 
(Hardness)/Swelling* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
* Size will also be measured in mm but will not be used as a halting criterion. 
 
Ecchymosis (bruising), erythema (redness), and induration (hardness)/swelling as analyzed by 
measurement will be graded as follows: 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
108 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
Local (Injection Site) Reactogenicity Measurements 
Local (Injection Site) Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Ecchymosis (Bruising)* 
25 mm – 50 mm 
51 mm – 100 mm 
>100 mm 
Erythema (Redness)* 
25 mm – 50 mm 
51 mm – 100 mm 
>100 mm 
Induration (Hardness)/Swelling* 
25 mm – 50 mm 
51 mm – 100 mm 
>100 mm 
* Will not be used as halting criteria. 
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 
Significant interference, 
prevents daily activity 
Fatigue (Tiredness) 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Malaise (General Unwell 
Feeling) 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Myalgia (Body 
Aches/Muscular Pain)* 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Arthralgia (Joint Pain)* 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Headache 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Nausea 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
* Not at injection site. 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
109 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
Oral temperature# will be graded as follows: 
Quantitative Systemic Reactogenicity Grading 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever* - oral† 
38.0°C – 38.4°C 
100.4°F – 101.1°F 
38.5°C – 38.9°C 
101.2°F – 102.0°F 
>38.9°C 
>102.0°F 
# Oral temperature assessed on Day 1 prior to the first study vaccination will be considered as 
baseline. 
* A fever can be considered not related to the vaccine 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. 
 
 
 
Additional Adverse Event Severity Grading 
Pulse and blood pressure# will be graded as follows: 
Physiologic Parameter 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Bradycardia - beats per minute 
50 – 54 
45 – 49 
<45 
Tachycardia - beats per minute 
101 – 115 
116 – 130 
>130 
Hypotension (systolic) mmHg 
85 – 89 
80 – 84 
<80 
Hypotension (diastolic) mmHg 
50 – 54 
45 – 49 
<45 
Hypertension (systolic) mmHg 
141 – 150 
151 – 155 
>155 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
110 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Hypertension (diastolic) mmHg 
91 – 95 
96 – 100 
>100 
# Pulse and blood pressure assessed on Day 1 prior to the first study vaccination will be considered 
as baseline. 
 
 

DMID Protocol 19-0015 
Version 7.0 
Mucosal immunity against GC after 4CMenB vaccination 
14 August 2023 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
CONFIDENTIAL 
 
 
 
 
111 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
Clinical safety laboratory results* will be graded as follows: 
Clinical Safety Laboratory Adverse Event* 
Hematology 
Normal Range 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
WBC 103/µL (Low) 
3.8 – 10.8 
2.5 – 3.7 
1.5 – 2.4 
<1.5 
WBC 103/µL (High) 
3.8 – 10.8 
10.9 – 15.0 
15.1 – 20.0 
>20.0 
Hgb g/dL (Low) (Female) 
11.7 – 15.5 
11.0 – 11.6 
9.5 – 10.9 
<9.5 
Hgb g/dL (Low) (Male) 
13.2 – 17.1 
12.0 – 13.1 
10.0 – 11.9 
<10.0 
Platelets 103/µL (Low) 
140 – 400 
125 – 139 
100 – 124 
<100 
Platelets 103/µL (High) 
140 – 400 
401 – 550 
551– 750 
>750 
PT (seconds) (increase by factor) 
(prothrombin time) 
9.0 – 11.5 
>1.0 – 1.1 x ULN 
>1.1 – 1.2 x ULN 
> 1.2 x ULN 
aPTT (seconds) (increase by factor) 
(activated partial thromboplastin 
time) 
22.0 – 34.0 
>1.0 – 1.2 x ULN 
>1.2 – 1.4 x ULN 
>1.4 x ULN 
 
*Clinical laboratory evaluations assessed at the screening visit will be considered as baseline