Tolerability and Immunogenicity of a Single 40-µg Dose of Recombinant Botulinum Vaccine A/B (rBV A/B) for the Production of BabyBIG® in Volunteers With Existing Botulinum Immunity
Phase: PHASE2
Conditions: Botulism
Sponsor: California Department of Public Health



CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
 
 
 
CONFIDENTIAL 
Recombinant Botulinum Vaccine  
A/B (rBV A/B) 
CLINICAL PROTOCOL 
Protocol 
rBV A/B-CL-002 
 
Protocol rBV A/B-CL-002 
 
 
 
 
 
 
 
TITLE OF STUDY: 
 
Tolerability and Immunogenicity of a Single 40-µg Dose of Recombinant Botulinum Vaccine 
A/B (rBV A/B) for the Production of BabyBIG® in Volunteers with Existing Botulinum 
Immunity.   
 
 
 
 
 
 
Date of issue: 05 September 2018 
 
 
Sponsor: 
California Department of Public Health 
Infant Botulism Treatment and Prevention Program  
 
850 Marina Bay Parkway, Rm. E-361 
 
Richmond, CA 94804-6403 
 
Phone: 510-231-7600 
 
Fax: 510-231-7609 
 
 
 
 
 
Signatures of approval for protocol (Version 1.1) 
 
Affiliation 
Name 
Signature 
Date 
Sponsor-Investigator: 
Stephen S. Arnon, M.D., 
M.P.H. 
 
 
Medical monitor: 
John Edward Swartzberg, 
M.D., F.A.C.P 
 
 
 

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
 
 
Page 2 
This study is to be performed in accordance with Good Clinical Practice, the ethical principles that have 
their origin in the Declaration of Helsinki, Title 21 of the Code of Federal Regulations, Part 50 
(Protection of Human Subjects), Part 56 (Institutional Review Boards), Part 312 (Investigational New 
Drug Application) and the International Conference on Harmonisation E6 (Guideline for Good Clinical 
Practice). 
Sponsor-Investigator: 
Stephen S. Arnon, M.D., M.P.H., Chief 
 
Infant Botulism Treatment and Prevention Program  
Infectious Diseases Laboratory Branch 
Division of Communicable Disease Control 
Center for Infectious Diseases 
California Department of Public Health 
850 Marina Bay Parkway, Rm. E-361 
Richmond, CA 94804-6403 
 
Phone: 510-231-7600 
 
Fax: 510-231-7609 
 
E-mail: Stephen.Arnon@cdph.ca.gov 
 
 
 
 
Institutional review board: 
Committee for the Protection of Human Subjects (CPHS) 
 
2020 West El Camino Avenue, Suite 1000 
 
Sacramento, CA 95833 
 
Phone: 916-326-3660 
 
Fax: 916-322-2512 
 
E-mail: cphs-mail@oshpd.ca.gov 
 
 
 
Copernicus Group IRB (CGIRB) 
 
5000 Centregreen Way Suite 200 
 
Cary, NC 27513 
 
Phone : 919 465-4310 
 
Fax : 919-465-4311 
 
E-mail : irb@cgirb.com 
 
 
Medical monitor: 
John Edward Swartzberg, M.D., F.A.C.P. 
 
Clinical Professor, Emeritus 
 
UCB-UCSF Joint Medical Program 
 
Chair, Editorial Board, UC Berkeley Wellness Letter 
 
University of California, Berkeley 
 
570 University Hall 
 
Phone: 510-643-0499 
 
Fax: 510-643-8771 
 
E-mail: jes@berkeley.edu 
 
 

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
 
 
Page 3 
STUDY SYNOPSIS 
Name of sponsor company: California Department of Public Health (CDPH) 
Name of investigational product: Recombinant Botulinum Vaccine A/B (rBV A/B) 
Names of active ingredients: Recombinant Botulinum Antigen A and Antigen B adsorbed to 
0.2%  (wt/vol) Alhydrogel™ 
Title of study: Tolerability and Immunogenicity of a Single 40-µg Dose of Recombinant Botulinum 
Vaccine A/B (rBV A/B) for the Production of BabyBIG® in Volunteers with Existing Botulinum 
Immunity 
Sponsor Investigator: Dr. Stephen S. Arnon 
Number of sites: 2 
Study period: 18 months 
Phase of development: Phase 2 
Objectives:  
 
Immunogenicity: The immunogenicity objective of this study is to evaluate the effects of a single 40-
µg dose of the recombinant botulinum vaccine A/B (rBV A/B) on botulinum toxin type A and type B 
neutralizing antibody concentration (NAC) over a 12-week period following vaccination in participants 
who have previously been immunized with pentavalent botulinum toxoid (or pentavalent botulinum 
toxoid and rBV A/B) for occupational protection. 
 
Safety: The safety objective of this study is to obtain safety information during the 12-week study 
period and at 6 months post-vaccination on the use of rBV A/B in a population of participants 
previously immunized with pentavalent botulinum toxoid (or pentavalent botulinum toxoid and rBV 
A/B) for occupational protection.  
 
Exploratory: 
The exploratory objective of this study is to collect source plasma from participants that contains 
neutralizing antibodies against botulinum toxin type A and type B for the production of BabyBIG. 
Methodology: This Phase 2, open-label, uncontrolled study designed to evaluate safety, tolerability, 
and immunogenicity of a single dose of rBV A/B in healthy participants previously immunized with 
pentavalent botulinum toxoid (or pentavalent botulinum toxoid and rBV A/B) for occupational 
protection will be conducted to collect source plasma for potential use in the production of BabyBIG 
and to evaluate safety and immunogenicity of the vaccine in these participants over a 12-week period, 
with a follow-up safety assessment at 6 months.   
 
The study period is defined as the 12-week period that includes the clinic visits and plasmapheresis 
visits. The study period will end at Week 4 for participants who opt not to participate in plasmapheresis 
or who have been determined to be ineligible for plasma donation for the entire study.  
Number of participants (planned): Up to 50 participants are anticipated to be enrolled. 

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
STUDY SYNOPSIS (continued) 
 
 
Page 4 
Name of sponsor company: California Department of Public Health (CDPH) 
Name of investigational product: Recombinant Botulinum Vaccine A/B (rBV A/B) 
Names of active ingredients: Recombinant Botulinum Antigen A and Antigen B adsorbed to 
0.2%  (wt/vol) Alhydrogel™ 
Inclusion criteria: 
• 
Have received pentavalent botulinum toxoid (or pentavalent botulinum toxoid and rBV A/B) for 
occupational protection under BB-IND-0161 (or BB-IND-0161 and IND 015155) 
• 
Be 18 to 69 years old at the time of consent  
• 
Be healthy and have an acceptable medical history (defined as individuals who are free from 
significant cardiac, pulmonary, gastrointestinal, hepatic, renal, hematological, neurological, 
infective, muscular, infectious, rheumatic, immunological, or psychiatric diseases, as determined 
by medical history over the past 5 years, physical examination, and laboratory tests) that will not 
interfere with the objectives of the study 
• 
Meet the participant suitability requirements and recommendations for source plasma donors  
• 
If female and of childbearing potential, have a negative pregnancy test at screening and within 
24 hours prior to vaccination and must not plan to become pregnant for until after the last plasma 
donation or until the Week 12 visit (whichever occurs last). Every female participant is considered 
of childbearing potential unless she has had sterilization surgery or is postmenopausal and has not 
had a menstrual period for at least 12 months.  If the participant is capable of childbearing, she 
must use a reliable form of contraception approved by the investigator for 30 days before Day 0 
through the end of the study. Acceptable forms of contraception include intrauterine device, birth 
control pills, injectable birth control, implantable birth control device, or removable birth control 
device or any other United States Food and Drug Administration (U.S. FDA) -approved 
contraceptive method, or a monogamous relationship with vasectomized partner who has been 
vasectomized for 6 months or more prior to the participant’s study entry, or sexual abstinence.) 
• 
Have the ability to understand the requirements of the study, have provided written informed 
consent as evidenced by signature on an informed consent form approved by the Committee for 
the Protection of Human Subjects, and have agreed to abide by the study restrictions and return for 
the required assessments 
• 
Agree to complete the participant home diary on a daily basis for 7 days post-vaccination, as well 
as report any adverse events and  concomitant medications during the study period 
• 
Have provided written authorization for use and disclosure of protected health information 
• 
Agree not to donate blood or blood products (outside of study procedures) until after the last plasma 
donation or until the Week 12 visit (whichever occurs last) 
• 
Have personal health insurance 
 
Exclusion criteria:  
• 
Be pregnant or nursing 
• 
Have a history of laboratory evidence of syphilis, acquired immunodeficiency syndrome, 
Creutzfeldt-Jakob disease, or infection with human immunodeficiency viruses 1 or 2, human T-cell 
lymphotropic virus 1, hepatitis B virus, or hepatitis C virus 
• 
Have had a prior severe (Grade 3 or higher) local or severe (Grade 3 or higher) systemic reaction 
to last immunization with pentavalent botulinum toxoid or a prior severe immediate 
hypersensitivity reaction or severe systemic reaction to last vaccination on Day 0 with rBV A/B 
• 
Have a known allergy to aluminum compounds, yeast, or other components of the vaccine 
• 
Have donated one or more units of blood or undergone plasmapheresis within 49 days prior to the 
Vaccination Visit (Day 0) 

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
STUDY SYNOPSIS (continued) 
 
 
Page 5 
Name of sponsor company: California Department of Public Health (CDPH) 
Name of investigational product: Recombinant Botulinum Vaccine A/B (rBV A/B) 
Names of active ingredients: Recombinant Botulinum Antigen A and Antigen B adsorbed to 
0.2%  (wt/vol) Alhydrogel™ 
• 
Have received a blood product or immunoglobulin within 6 months of study entry or plans to 
receive such products during the study period (exclusive of returned red blood cells as part of the 
plasmapheresis procedure). For participants who choose to donate plasma, this will apply until 
their last plasma donation or at the Week 12 visit (whichever occurs last) 
• 
Have received licensed nonliving vaccine within 14 days prior to study entry, or licensed live 
vaccine within 60 days prior to study entry 
• 
Have received investigational products (drugs, biologics, vaccines, or implantable devices) within 
60 days prior to study entry or plans to receive experimental products at any time during the study 
period. For participants who choose to donate plasma, this will apply until their last plasma 
donation or at the Week 12 visit (whichever occurs last) 
• 
Have received prescription immunosuppressive or immunomodulatory agents, including 
parenteral, inhaled, or oral corticosteroids within 3 months of study entry or plans on receiving 
such therapy at any time during the study period. For participants who choose to donate plasma, 
this will apply until their last plasma donation or at the Week 12 visit (whichever occurs last) with 
the exceptions mentioned below: 
o Participants who have used prescription topical steroids may be enrolled 2 weeks after the 
therapy is completed 
o Intra-articular, bursal, or tendon injectable steroids are permitted 
o Any over-the-counter topical steroid use is permitted 
o Ophthalmic and intranasal steroids are permitted 
• 
Have received cytotoxic therapy at any time in the previous 5 years before study entry 
• 
Have an active systemic or recurrent disease that would place the participant at unacceptable risk 
of injury, require hospitalization, or require surgical intervention (This includes active mental 
illness or history of mental illness not responsive to treatment.) 
• 
Have a history of alcohol or drug abuse or dependence within 12 months of study entry 
• 
Have past, present, or suspected illicit injection drug use 
• 
Have inflammatory, vasculitic, or rheumatic disease, including systemic lupus erythematosus, 
polymyalgia rheumatica, rheumatoid arthritis, or scleroderma (Stable osteoarthritis treated with 
physical therapy and nonsteroidal anti-inflammatory drugs is not an exclusion criterion.) 
• 
Have any acute or chronic neuromuscular or neurologic disorder 
• 
Have clinically confirmed hepatic or renal insufficiency 
• 
Have uncontrolled hypertension, as defined as systolic blood pressure greater than 160 mmHg and 
diastolic blood pressure greater than 90 mm Hg 
• 
Have moderate to severe asthma, chronic obstructive pulmonary disease, or other significant 
pulmonary disease 
• 
Have a seizure disorder 
• 
Have moderate or severe illness or oral temperature of 100.4°F or greater within 3 days prior to 
Vaccination Visit (Day 0) 
• 
Be unsuitable for participation in this study for any reason, as assessed by the investigator 
 
 

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
STUDY SYNOPSIS (continued) 
 
 
Page 6 
Name of sponsor company: California Department of Public Health (CDPH) 
Name of investigational product: Recombinant Botulinum Vaccine A/B (rBV A/B) 
Names of active ingredients: Recombinant Botulinum Antigen A and Antigen B adsorbed to 
0.2%  (wt/vol) Alhydrogel™ 
Test product, dose, and mode of administration:  
rBV A/B injections will consist of 40-µg of total antigen (20 µg of Antigen A and 20 µg of Antigen B) 
adsorbed to 0.2% (wt/vol) Alhydrogel™, in a total dose volume of 0.5 mL.  The vaccine will be 
administered by intramuscular injection in the deltoid muscle, preferably in the nondominant arm. 
Reference therapy, dose, and mode of administration:  
No reference therapy will be employed. 
Duration of treatment: Vaccine administration for all enrolled participants will occur at Day 0, and 
participants may elect to undergo plasmapheresis up to two times a week for up to 12 weeks, with the 
final on-site visit at Week 12 (± 4 days) and follow-up phone call for safety assessment at Week 26 
after vaccination.  Participants can elect to continue plasmapheresis up to 14 weeks post-vaccination 
as long as long as they continue to meet source plasma donor eligibility requirements.. 
Criteria for Evaluation 
Populations: 
The immunogenicity population will include all participants who have received the study vaccine at 
the assigned dosage and for whom at least one post-baseline NAC was collected within 4 weeks of 
vaccination.  For each post-vaccination assessment time point, the per protocol population will include 
all participants who received the vaccine dose, have a baseline NAC, and have all immunogenicity 
assessments completed within the protocol-specified timelines (including visit windows) for the time 
periods summarized and do not have major protocol violations expected to affect immunogenicity.  A 
determination of major protocol violations expected to affect immunogenicity will be done by the 
sponsor-investigator before reviewing the immunogenicity data for the applicable participant. 
 
Immunogenicity: 
 
The primary endpoint is as follows: 
• 
The proportion of participants achieving a four times or greater increase in NAC by Week 4 
compared with Week 0. A positive response will be defined as achieving this level of increase in 
at least 50% of the participants for botulinum toxin A and toxin B. 
The secondary endpoints are as follows:   
• 
The proportion of participants achieving a two times increase in the area under the plasma 
concentration-time curve between Week 0 and Week 12 in NAC in comparison to a straight-line 
extension of the Week 0 NAC to Week 12. A positive response will be defined as achieving this 
level of increase in at least 50% of the participants for botulinum toxin A and toxin B. 
• 
The proportion of participants achieving a three times or greater increase in NAC by Week 4 
compared with Week 0. A positive response will be defined in at least 50% of the participants for 
botulinum toxin A and toxin B. 
 
Safety: 
 
Safety analyses will be performed on the safety population, defined as all participants who receive the 
investigational vaccine.  The following analyses will be performed: 

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
STUDY SYNOPSIS (continued) 
 
 
Page 7 
Name of sponsor company: California Department of Public Health (CDPH) 
Name of investigational product: Recombinant Botulinum Vaccine A/B (rBV A/B) 
Names of active ingredients: Recombinant Botulinum Antigen A and Antigen B adsorbed to 
0.2%  (wt/vol) Alhydrogel™ 
• 
Frequency of injection site reactions and systemic reactions in the study population that are 
characterized as severe or result in a serious adverse event (SAE) during the 0-7 day diary 
collection period.  
• 
Frequency of injection site reactions and systemic reactions that are characterized as serious 
adverse events (SAEs).  
• 
Participant incidence of treatment-related SAEs. 
• 
Participant incidence of serious new onset chronic illnesses (NOCIs).  
• 
Clinically significant changes from baseline health that result in an SAE.  
• 
Clinically significant changes in hematology between screening and Week 4 that result in a severe 
or serious AE.  
 
Exploratory: 
The exploratory endpoint will be the volume of source plasma containing neutralizing antibodies 
against botulinum toxin type A and type B collected by plasmapheresis for use in BabyBIG 
manufacture. 

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
STUDY SYNOPSIS (continued) 
 
 
Page 8 
Name of sponsor company: California Department of Public Health (CDPH) 
Name of investigational product: Recombinant Botulinum Vaccine A/B (rBV A/B) 
Names of active ingredients: Recombinant Botulinum Antigen A and Antigen B adsorbed to 
0.2%  (wt/vol) Alhydrogel™ 
Study design: This will be an open-label, uncontrolled study to evaluate the safety and 
immunogenicity of a single 40-µg intramuscular injection of rBV A/B in participants who were 
previously immunized with pentavalent botulinum toxoid (or pentavalent botulinum toxoid and rBV 
A/B) for occupational protection. Participants will receive the rBV A/B injection, and undergo 
plasmapheresis up to two times per week for up to 14 weeks.  Participants will be evaluated for safety 
and immunogenicity at each study visit with follow-up safety data collected at 6 months.  If participants 
opt not to participate in plasma collections or have been determined to be ineligible to donate plasma 
for the entire study, they will have a final on-site visit at Week 4 to provide a serum sample for NAC 
determination and an additional hematology specimen. Participants undergoing plasmapheresis will 
also have an additional hematology specimen collected at Week 4. Study participants participating in 
plasma donations will have a final on-site study visit at Week 12. All participants will have a final 
phone call for safety follow-up at Week 26.  
 
Experimental procedures: Participants who meet inclusion criteria and do not meet any exclusion 
criteria will receive a single rBV A/B injection at Week 0 and will complete a 7-day diary for the 
Week 1 telephone call. Clinical safety laboratory assessments (serum chemistry, hematology, and 
urinalysis) will be obtained for all participants at the screening visit. Hematology only will be assessed 
during the Week 4 visit.  Study participants who consent to plasma donation may report to the plasma 
collection center after the Week 1 visit where they will be assessed by the center for donor eligibility.  
Once donor eligibility has been confirmed, the participant may choose to donate plasma twice a week 
for up to 14 weeks. 
 
Safety considerations: Participants will be monitored for serious adverse events after vaccination 
throughout the 12-week study period and at the Week 26 phone call follow-up.  Administration site 
reactions and systemic reactions will be monitored with a diary provided to collect information, 
including diameter of any swelling and redness around the injection site and any generalized symptoms 
between Week 0 and Week 1 in order to determine if any severe reactions or serious adverse events 
occurred during this 1-week period post-vaccination.  All severe local and systemic reactions will be 
recorded in the electronic case report form (eCRF).  Hematology, serum chemistry, and urinalysis 
specimens will be collected at screening, and repeat hematology at Week 4 for monitoring of any 
clinically significant changes that result in a severe or serious AE.  Clinically significant changes in 
hematology that result in a severe or serious AE will be recorded on the eCRF. Female participants of 
childbearing potential will have a urine pregnancy test at screening and again at Week 0 prior to receipt 
of the vaccine. Source plasma collection will occur for eligible donors at licensed collection locations.  
If the participant fails to meet donor criteria at any time during the plasmapheresis period, the 
participant will continue to be followed for serious adverse events according to the study schedule.  
Participants will be contacted by phone at Weeks 1, 4, and 10. At Week 26, participants will be queried 
for occurrence of serious adverse events and serious  new onset chronic illnesses (NOCIs), which will 
be recorded by the investigator (or designee) on serious adverse events recording sheets and entered in 
the eCRF.  Vital signs will be monitored at screening, Week 0 (vaccine visit),  and at each plasma 
collection visit. 

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
STUDY SYNOPSIS (continued) 
 
 
Page 9 
Name of sponsor company: California Department of Public Health (CDPH) 
Name of investigational product: Recombinant Botulinum Vaccine A/B (rBV A/B) 
Names of active ingredients: Recombinant Botulinum Antigen A and Antigen B adsorbed to 
0.2%  (wt/vol) Alhydrogel™ 
Statistical methods: The data will be summarized in tables listing the mean, standard deviation or 
standard error, median, minimum, maximum, and number of participants for continuous data, or in 
tables listing count and percentage for categorical data, where appropriate. 
 
The immunogenicity parameters are NACs for botulinum toxin type A and type B.  These NAC 
parameters will be analyzed utilizing a validated mouse neutralization assay. 
 
Summaries of local and systemic severe AEs and SAEs related to vaccination (collected in the 7-day 
diaries) will be produced in tables, by category and severity. 
 
Summaries of clinically significant changes in hematology between screening and Week 4 resulting in 
a severe or serious AE will be listed.  
 
SAE data will be listed individually and summarized by system organ class and preferred terms and by 
severity and relatedness. 
 
SAE data of NOCIs will be listed individually and summarized by system organ class and preferred 
terms and by severity and relatedness. 
 
No formal sample size calculations will be done. 

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
 
 
Page 10 
TABLE OF CONTENTS 
 
Page 
 
TITLE OF STUDY: .................................................................................................................................... 1 
1.0 
INTRODUCTION ....................................................................................................................... 16 
1.1 
BACKGROUND........................................................................................................................... 16 
1.2 
STUDY RATIONALE .................................................................................................................. 17 
1.3 
DOSE RATIONALE .................................................................................................................... 17 
2.0 
OBJECTIVES ............................................................................................................................. 19 
2.1 
IMMUNOGENICITY ................................................................................................................... 19 
2.2 
SAFETY........................................................................................................................................ 19 
2.3 
EXPLORATORY ......................................................................................................................... 19 
3.0 
STUDY DESIGN ......................................................................................................................... 20 
3.1 
BASIC DESIGN CHARACTERISTICS ...................................................................................... 20 
3.2 
STUDY POPULATION ............................................................................................................... 20 
3.2.1 
Inclusion Criteria .......................................................................................................... 20 
3.2.2 
Exclusion Criteria ......................................................................................................... 22 
3.3 
ENDPOINTS ................................................................................................................................ 24 
3.3.1 
Immunogenicity ............................................................................................................ 24 
3.3.2 
Safety ............................................................................................................................ 25 
3.3.3 
Exploratory ................................................................................................................... 25 
3.4 
RANDOMIZATION AND BLINDING ....................................................................................... 26 
3.5 
REPLACEMENT OF DROPOUTS .............................................................................................. 26 
4.0 
DRUGS AND DOSAGES ........................................................................................................... 27 
4.1 
IDENTIFICATION AND DESCRIPTION OF INVESTIGATIONAL PRODUCT .................... 27 
4.1.1 
Investigational Product ................................................................................................. 27 
4.1.2 
Labeling ........................................................................................................................ 28 
4.2 
DOSING INSTRUCTIONS AND SCHEDULE ........................................................................... 28 
4.3 
STORAGE AND HANDLING OF INVESTIGATIONAL PRODUCT ...................................... 29 
4.4 
DOSE STOPPING RULES ........................................................................................................... 29 
4.4.1 
Individual Participant Stopping Rules .......................................................................... 29 
4.4.2 
Study Stopping Rules ................................................................................................... 29 
4.5 
CONCOMITANT MEDICATIONS ............................................................................................. 30 
5.0 
EXPERIMENTAL PROCEDURES .......................................................................................... 31 
5.1 
OVERVIEW: SCHEDULE OF TIME AND EVENTS ................................................................ 31 
5.2 
MEASUREMENTS AND EVALUATIONS................................................................................ 34 
5.2.1 
Screening Period (between Days –7 and –1) ................................................................ 34 
5.2.2 
Treatment Period (12 weeks, plasma donors; 4 weeks non-plasma donors) ................ 35 
5.2.3 
Final Study Follow-up (Day 182, Week 26) ................................................................. 40 
6.0 
PROCEDURES FOR HANDLING SERIOUS ADVERSE EVENTS .................................... 41 
6.1 
DEFINITION OF A SERIOUS ADVERSE EVENT ................................................................... 41 
6.2 
RECORDING SERIOUS ADVERSE EVENTS .......................................................................... 42 

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TABLE OF CONTENTS (continued) 
 
Page 
 
 
 
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6.3 
ASSESSMENT OF SEVERITY ................................................................................................... 43 
6.4 
ASSESSMENT OF CAUSALITY ................................................................................................ 44 
6.5 
EXPECTEDNESS OF ADVERSE EVENTS ............................................................................... 46 
6.6 
REPORTING OF SERIOUS ADVERSE EVENTS ..................................................................... 46 
6.7 
FOLLOW-UP OF SERIOUS ADVERSE EVENTS .................................................................... 48 
6.8 
LOCALIZED AND SYSTEMIC INJECTION SITE REACTIONS ............................................ 48 
6.9 
DATA AND SAFETY MONITORING BOARD ........................................................................ 49 
6.10 
PREGNANCY .............................................................................................................................. 49 
7.0 
STUDY OR SITE TERMINATION AND PARTICIPANTDISCONTINUATION ............. 51 
7.1 
PARTICIPANT DISCONTINUATION ....................................................................................... 51 
7.1.1 
Adverse Event .............................................................................................................. 51 
7.1.2 
Intercurrent Illness ........................................................................................................ 51 
7.1.3 
Noncompliance ............................................................................................................. 51 
7.1.4 
Refusal of Investigational Product Administration ....................................................... 52 
7.1.5 
Withdrawal of Consent ................................................................................................. 52 
7.2 
PREMATURE STUDY OR SITE TERMINATION .................................................................... 52 
8.0 
DATA COLLECTION AND PROCESSING AND STATISTICAL ANALYSIS ................. 54 
8.1 
DATA COLLECTION AND PROCESSING ............................................................................... 54 
8.2 
STATISTICAL ANALYSIS ......................................................................................................... 54 
8.2.1 
General Overview ......................................................................................................... 54 
8.2.2 
Populations of Interest .................................................................................................. 54 
8.2.3 
Baseline Comparability ................................................................................................ 55 
8.2.4 
Immunogenicity Analysis ............................................................................................. 55 
8.2.5 
Safety Analysis ............................................................................................................. 56 
8.2.6 
Sample Size .................................................................................................................. 57 
9.0 
CLINICAL STUDY ADMINISTRATION ............................................................................... 58 
9.1 
INFORMED CONSENT WITH AUTHORIZATION FOR USE AND DISCLOSURE OF 
PROTECTED HEALTH INFORMATION .................................................................................. 58 
9.2 
STUDY DOCUMENTATION ..................................................................................................... 58 
9.2.1 
Investigator Information ............................................................................................... 58 
9.2.2 
Investigators Study Files .............................................................................................. 58 
9.2.3 
Case Report Forms and Source Documentation ........................................................... 59 
9.2.4 
Retention of Study Documents ..................................................................................... 59 
9.3 
CONFIDENTIALITY ................................................................................................................... 60 
9.3.1 
Data .............................................................................................................................. 60 
9.3.2 
Participant Anonymity .................................................................................................. 60 
9.4 
PROTOCOL COMPLIANCE AND AMENDMENT PROCEDURES ........................................ 60 
9.5 
STUDY/DATA MONITOR FUNCTIONS AND RESPONSIBILITY ........................................ 61 
10.0 
REFERENCES ............................................................................................................................ 62 
 

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Page 12 
LIST OF TABLES 
 
Page 
 
Table 1. 
Schedule of Time and Events .......................................................................................................... 32 
Table 2. 
Classification of AEs by Severity ................................................................................................... 43 
Table 3. 
Assessment of Causality of Adverse Events ................................................................................... 45 
Table 4. 
Timeline for Reporting Serious Adverse Events ............................................................................. 47 
Table 5. 
Protocol Definitions for Severity of Localized Injection Site Reactions ........................................ 49 
 
 

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Page 13 
LIST OF FIGURES 
 
Page 
 
Figure 1. 
Sample vial label. ............................................................................................................................ 28 
 
 

CONFIDENTIAL 
 
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Page 14 
LIST OF APPENDICES 
 
 
Appendix A   Code of Federal Regulations Part 640:  Additional Standards for Human Blood  and Blood 
Products 
Appendix B   Toxicity Tables from Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Participants Enrolled in Preventive  Vaccine Clinical Trials 
Appendix C   Participant Diary 
Appendix D   Donor History Questionnaire 
Appendix E   Adverse Event Recording Sheet for Possible Serious Adverse Events (SAEs) 
 
 

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Page 15 
LIST OF ABBREVIATIONS 
 
 
AE 
adverse event 
BabyBIG 
CDPH proprietary name for Botulism Immune Globulin Intravenous (Human) (BIG-IV) 
BoNT 
botulinum neurotoxin 
CDC 
Centers for Disease Control and Prevention 
CDPH 
California Department of Public Health 
DSMB 
data and safety monitoring board 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ER 
emergency room 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
institutional review board 
ISF 
investigator site file 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAC 
neutralizing antibody concentration 
NOCI 
new onset chronic illness 
PBT 
pentavalent botulinum toxoid 
rBV A/B 
recombinant botulinum vaccine A/B 
SAE 
serious adverse event 
TEAE 
treatment-emergent adverse events 
U.S. FDA 
United States Food and Drug Administration 
 
 
 
 

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1.0 
INTRODUCTION 
1.1 
BACKGROUND 
Botulism Immune Globulin Intravenous (Human) (BIG-IV; BabyBIG®) has been 
demonstrated to significantly shorten hospital stay and improve outcomes in infant 
botulism patients.  BabyBIG is currently produced from antibodies collected from 
persons with existing botulinum immunity including individuals previously 
immunized with investigational pentavalent botulinum toxoid (PBT) for 
occupational protection and/or also boosted with investigational recombinant 
botulinum vaccine A/B (rBV A/B).  
PBT was distributed through the Centers for Disease Control and Prevention (CDC) 
under BB-IND-0161 for occupational safety.  The toxoid was administered to naïve 
recipients and was also administered as a booster in persons who had been 
previously immunized.  PBT-immunized individuals who have circulating 
antibodies against botulinum toxin type A and type B are eligible to donate plasma 
for manufacture of BabyBIG.  Donated plasma is fractionated and treated to yield 
a purified immunoglobulin G product that provides passive immunity to patients 
with infant botulism. 
However, the CDC no longer provides investigational PBT for immunization of 
laboratory workers at risk for occupational exposure to botulinum serotypes A, B, 
C, D, and E.  Specifically, on the basis of evidence of declining immunogenicity,  
increasing reactogenicity, and the age of the product, the CDC ceased distribution 
of PBT after 30 November 2011.[1]  Thus, a new immunogen against botulinum 
toxins is needed.   A recombinant botulinum vaccine for the toxin serotypes A and 
B (rBV A/B) has been developed and is being proposed as a replacement vaccine 
for boosting participants who previously received PBT for occupational protection.  
This study is the second phase 2 study under IND 15155 being conducted by the 
California Department of Public Health (CDPH) to determine if rBV A/B will 
stimulate production of neutralizing antibodies against botulinum toxin types A and 
B in participants previously immunized with PBT (or PBT and rBV A/B).  
Participants with a range in neutralizing antibody titers against the toxin types 
would be candidates for plasma collection for BabyBIG production under IND 
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1.2 
STUDY RATIONALE 
This protocol has as its ultimate goal the production of additional lots of the 
approved orphan drug Botulism Immune Globulin Intravenous (Human), (BIG-IV; 
BabyBIG®) for the treatment of infant botulism.  To enable production of BabyBIG, 
a group of high-titer immunized persons are needed who are willing to donate their 
hyperimmune plasma as a starting agent (i.e., Source Plasma) for BabyBIG.  This 
protocol is designed to determine botulinum toxin type A and type B neutralizing 
antibody levels in healthy participants who were previously immunized with PBT 
(or PBT and rBV A/B) for occupational protection and who receive rBV A/B (or 
rBV A/B boost).  A Phase 2b study conducted by CDPH (rBV A/B-CL-001) 
demonstrated a single 40-µg dose of rBV A/B was well tolerated and resulted in a 
significant increase in neutralizing antibodies against botulinum toxins type A and 
B in participants previously immunized with PBT. The proposed study will 
continue to evaluate the immunogenicity and safety of a single dose of the rBV A/B 
vaccine in this previously immunized population.  This study design is similar to 
rBV A/B-CL-001.  However, in this study a single 40-µg dose of rBV A/B will be 
used to stimulate the production of neutralizing antibodies against botulinum toxin 
type A and type B in participants that are rBV A/B naïve or in participants that 
volunteered for the rBV A/B-CL-001 clinical trial and received one dose of rBV 
A/B. 
1.3 
DOSE RATIONALE 
An rBV A/B dose of 40-µg of total antigen (20-µg of Antigen A and 20-µg of 
Antigen B) with Alhydrogel™ has been shown in Phase 1 and Phase 2 studies in 
healthy participants to be effective in stimulating a strong antibody response and 
has an acceptable safety profile.  Most treatment-emergent adverse events (TEAEs) 
were mild and transient.  Furthermore, the safety and immunogenicity of the 
rBV A/B vaccine in a naïve population was investigated in 372 participants using 
the same dose level and a three-dose schedule (under BB-IND 11756).  A Phase 2b 
study conducted by CDPH (rBV A/B-CL-001) demonstrated a single 40-µg dose 
of rBV A/B was well tolerated, and no safety concerns were identified during the 
study.  In addition, the single 40-µg dose resulted in a significant increase in 
neutralizing antibodies against botulinum toxin types A and B in participants 
previously immunized with PBT.  Therefore, the proposed dose in this study is 
expected to have an acceptable safety profile and be effective in stimulating 

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antibody response in persons previously immunized with PBT for occupational 
protection.  

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2.0 
OBJECTIVES 
2.1 
IMMUNOGENICITY 
The immunogenicity objective of this study is to evaluate the effects of a single 
40-µg dose of rBV A/B on the botulinum toxin type A and type B neutralizing 
antibody concentration (NAC) over a 12-week period following vaccination in 
participants previously immunized with PBT (or PBT and rBV A/B) for 
occupational protection. 
2.2 
SAFETY 
The safety objective of this study is to obtain safety information during the 12-week 
study period and at 6 months post-vaccination on the use of rBV A/B in a 
population of participants previously immunized with PBT (or PBT and rBV A/B) 
for occupational protection. 
2.3 
EXPLORATORY 
The exploratory objective of this study is to collect source plasma from participants 
that contains neutralizing antibodies against botulinum toxin type A and type B for 
the production of BabyBIG. 
 

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3.0 
STUDY DESIGN 
3.1 
BASIC DESIGN CHARACTERISTICS 
This will be an open-label, uncontrolled study to evaluate the safety and 
immunogenicity of a single intramuscular injection of 40-µg of rBV A/B in 
participants who were previously immunized with PBT (or PBT and rBV A/B) for 
occupational protection.  Participants will receive the rBV A/B injection, and may 
elect to undergo plasmapheresis at a maximum of two times per week up to 
12 weeks.  Participants can continue plasmapheresis up to 14 weeks as long as they 
continue to meet source plasma donor acceptance criteria.  Participants will be 
evaluated for safety and immunogenicity at each study visit with longer-term 
follow-up safety data collected at 6 months. 
The study period is defined as the 12-week period that includes the clinic visits and 
plasmapheresis visits. The study period will end at Week 4 for participants who opt 
not to participate or who have been determined to be ineligible for donation for the 
entire study. Participants undergoing plasmapheresis will also have an additional 
hematology specimen collected at Week 4.  Study participants participating in 
plasma donations will have a final on-site study visit at Week 12. All participants 
will have a final phone call for safety follow-up at Week 26. 
3.2 
STUDY POPULATION 
For this study, up to 50 participants are anticipated to be enrolled.  Eligibility will 
be established by the investigator(s) on the basis of the inclusion and exclusion 
criteria. 
3.2.1 
Inclusion Criteria 
To be considered eligible to participate in this study, a participant must meet the 
inclusion criteria listed below: 
1. Have received pentavalent botulinum toxoid (or pentavalent botulinum toxoid 
and rBV A/B) for occupational protection under BB IND 0161 (or BB-IND-
0161 and IND 015155) 
2. Be 18 to 69 years old at the time of consent  

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3. Be healthy and have an acceptable medical history (defined as individuals who 
are free from significant cardiac, pulmonary, gastrointestinal, hepatic, renal, 
hematological, neurological, infective, muscular, infectious, rheumatic, 
immunological, or psychiatric diseases, as determined by medical history over 
the past 5 years, physical examination, and laboratory tests) that will not 
interfere with the objectives of the study 
4. Meet the participant suitability requirements and recommendations for source 
plasma donors outlined in Appendix A. 
5. If female, and of childbearing potential, have a negative pregnancy test at 
screening and within 24 hours prior to vaccination and must not plan to become 
pregnant until after the last plasma donation or until the Week 12 visit 
([whichever occurs last].  Every female participant is considered of 
childbearing potential unless she has had sterilization surgery or is 
postmenopausal and has not had a menstrual period for at least 12 months.)  If 
the participant is capable of childbearing, she must use a reliable form of 
contraception approved by investigator for 30 days before Day 0 through the 
end of the study.  Acceptable forms of contraception include intrauterine device, 
birth control pills, injectable birth control, implantable birth control device, or 
removable birth control device or any other United States Food and Drug 
Administration (U.S. FDA) -approved contraceptive method, or a monogamous 
relationship with vasectomized partner, who has been vasectomized for 
6 months or more prior to the participant’s study entry, or sexual abstinence.) 
6. Have the ability to understand the requirements of the study, have provided 
written informed consent as evidenced by signature on an informed consent 
form (ICF) approved by the Committee for the Protection of Human Subjects, 
and have agreed to abide by the study restrictions and to return for the required 
assessments 
7. Agree to complete the participant home diary on a daily basis for 7 days 
post-vaccination, as well as to report any adverse events and concomitant 
medications during the study period 
8. Have provided written authorization for use and disclosure of protected health 
information 

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9. Agree not to donate blood or blood products (outside of study procedures) until 
after the last plasma donation or until the Week 12 visit (whichever occurs last) 
10. Have personal health insurance 
 
3.2.2 
Exclusion Criteria 
To be eligible for entry into the study, the participant must not meet any of the 
exclusion criteria listed below: 
1. Be pregnant or nursing 
2. Have a history of laboratory evidence of syphilis, acquired immunodeficiency 
syndrome, 
Creutzfeldt-Jakob 
disease, 
or 
infection 
with 
human 
immunodeficiency viruses (HIV) 1 or 2, human T-cell lymphotropic virus 1, 
hepatitis B virus (HBV), or hepatitis C virus (HCV) 
3. Have had a prior severe (Grade 3 or higher) local or severe (Grade 3 or higher) 
systemic reaction to last immunization with pentavalent botulinum toxoid or a 
prior severe immediate hypersensitivity reaction or severe systemic reaction to 
last vaccination on Day 0 with rBV A/B  
4. Have known allergy to aluminum, yeast, or other components of the vaccine 
5. Have donated one or more units of blood or undergone plasmapheresis within 
49 days of the Vaccination Visit (Day 0) 
6. Have received blood product or immunoglobulin within 6 months prior to study 
entry or plans to receive such products during the study period (exclusive of 
returned red blood cells as part of the plasmapheresis procedure). For 
participants who choose to donate plasma, this will apply until their last plasma 
donation or at the Week 12 visit (whichever occurs last) 
7. Have received licensed nonliving vaccine within 14 days prior to study entry, 
or licensed live vaccine within 60 days prior to study entry 

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8. Have received investigational products (drugs, biologics, vaccines, or 
implantable devices) 60 days prior to study entry or plans to receive 
experimental products at any time during the study period.  For participants who 
choose to donate plasma, this will apply until their last plasma donation or at 
the Week 12 visit (whichever occurs last) 
9. Have received prescription immunosuppressive or immunomodulatory agents, 
including parenteral, inhaled, or oral corticosteroids within 3 months of study 
entry or plans on receiving such therapy at any time during the study period 
[For participants who choose to donate plasma, this will apply until their last 
plasma donation or at the Week 12 visit (whichever occurs last)], with the 
exceptions mentioned below 
• Participants who have used prescription topical steroids may be enrolled 
2 weeks after the therapy is completed 
• Intra-articular, bursal, or tendon injectable steroids are permitted 
• Any over-the-counter topical steroid use is permitted 
• Ophthalmic and intranasal steroids are permitted 
10. Have received cytotoxic therapy at any time in the previous 5 years before study 
entry 
11. Have an active systemic or recurrent disease that would place the participant at 
unacceptable risk of injury, require hospitalization, or require surgical 
intervention (This includes active mental illness or history of mental illness not 
responsive to treatment.) 
12. Have a history of alcohol or drug abuse or dependence within 12 months of 
study entry 
13. Have past, present, or suspected illicit injection drug use 
14. Have inflammatory, vasculitic, or rheumatic disease, including systemic lupus 
erythematosus, polymyalgia rheumatica, rheumatoid arthritis, or scleroderma 

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(Stable osteoarthritis treated with physical therapy and nonsteroidal 
anti-inflammatory drugs is not an exclusion criterion.) 
15. Have any acute or chronic neuromuscular or neurologic disorder 
16. Have clinically confirmed hepatic or renal insufficiency 
17. Have uncontrolled hypertension, as defined a systolic blood pressure greater 
than 160 mmHg and diastolic blood pressure greater than 90 mmHg 
18. Have moderate to severe asthma, chronic obstructive pulmonary disease, or 
other significant pulmonary disease 
19. Have a seizure disorder 
20. Have moderate or severe illness or oral temperature of 100.4°F or greater within 
3 days of Vaccination Visit (Day 0) 
21. Be unsuitable for participation in this study for any reason, as assessed by the 
investigator 
 
3.3 
ENDPOINTS 
3.3.1 
Immunogenicity 
The primary immunogenicity endpoint is the proportion of participants achieving a 
four times or greater increase in NAC by Week 4 compared with Week 0. A 
positive response will be defined as achieving this level of increase in at least 50% 
of the participants for botulinum toxin type A and type B. 
The secondary immunogenicity endpoints are as follows: 
• 
The proportion of participants achieving a two times increase in the area under 
the plasma concentration-time curve between Week 0 and Week 12 in NAC 
in comparison to a straight-line extension of the Week 0 NAC to Week 12. A 

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positive response will be defined as achieving this level of increase in at least 
50% of the participants for botulinum toxin type A and type B. 
• 
The proportion of participants achieving a three times or greater increase in 
NAC by Week 4 compared with Week 0. A positive response will be defined 
as achieving this level of increase in at least 50% of the participants for 
botulinum toxin type A and type B. 
3.3.2 
Safety 
Primary safety endpoints will be collected over a 12-week period and will be as 
follows: 
• 
Frequency of injection site reactions and systemic reactions that are 
characterized as severe during the 0-7 day  diary collection period.  
• 
Frequency of injection site reactions and systemic reactions that are 
characterized as serious adverse events (SAEs) [Definitions for local 
injection site reactions are in Section 6.9 and systemic reactions are located 
in Appendix B.  Definition of SAE is located in Section 6.1 ]  
• 
Participant incidence of treatment-related serious adverse events (Adverse 
event toxicity tables are located in Appendix B) 
• 
Participant incidence of serious NOCIs 
• 
Clinically significant changes from baseline health resulting in serious 
adverse events 
• 
Clinically significant changes in hematology between screening and Week 4 
resulting in severe or serious adverse events 
3.3.3 
Exploratory 
The exploratory endpoint will be the volume of source plasma containing 
neutralizing antibodies against botulinum toxin type A and type B collected by 
plasmapheresis for use in BabyBIG manufacture. 

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3.4 
RANDOMIZATION AND BLINDING 
There will be no randomization or blinding of participants for safety assessments 
in this study. 
3.5 
REPLACEMENT OF DROPOUTS 
Dropouts will not be replaced in this study. 

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4.0 
DRUGS AND DOSAGES 
4.1 
IDENTIFICATION AND DESCRIPTION OF INVESTIGATIONAL 
PRODUCT 
4.1.1 
Investigational Product 
rBV A/B is manufactured by DynPort Vaccine Company LLC, a GDIT Company 
(Frederick, Maryland).  The procedure used to manufacture the active ingredient of 
rBV A/B is described below. 
The recombinant botulinum neurotoxin antigens are expressed from synthetic 
genes encoding the carboxy-terminal region of the botulinum neurotoxins (BoNT) 
heavy-chains [rBoNT(HC)] of BoNT/A and BoNT/B, designated Antigen A and 
Antigen B.  These fragments are from the binding domain of the heavy-chain and 
do not have neurotoxic activity.  Antigen A and Antigen B are expressed in the 
methylotrophic yeast Pichia pastoris as 50 kDa and 52 kDa proteins, respectively.  
Antigen A is derived from the BoNT/A1 expressed by Clostridium botulinum strain 
NCTC 2916 (Group I, proteolytic), and Antigen B is derived from BoNT/B1 
expressed by C.  botulinum strain Danish (Group I, proteolytic).  These proteins 
have been expressed individually by using a methanol induction system from 
synthetic genes introduced into P. pastoris.  The bulk antigens were manufactured 
at high purity (each antigen purified drug substance is >95% pure), formulated and 
combined in a 1:1 ratio based on mass (in micrograms) to produce the final drug 
product. 
The formulation used for this study will have 40 micrograms (μg) total antigen 
(20 μg Antigen A and 20 μg Antigen B) with 100 mM sodium chloride, 15 mM 
sodium phosphate, and 50 mM sodium acetate with Alhydrogel™ (0.2% weight 
per volume) balanced to a pH of 5.5 for a total dose volume of 0.5 mL. 
 
 

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4.1.2 
Labeling 
Each vial in Lot D1200138 will be labeled as shown in Figure 1. 
Figure 1. 
Sample vial label.  
 
4.2 
DOSING INSTRUCTIONS AND SCHEDULE 
Participants will receive a 0.5 mL intramuscular injection of rBV A/B in the deltoid 
muscle, preferably in the nondominant arm.  The injection will be administered by 
the investigator or delegated site personnel.  Site personnel will document the time 
of the injection in the electronic case report form (eCRF).  Each vial should be 
visually inspected for particulate matter, discoloration, signs of adulteration, or 
contamination before administration.  If the product appears discolored or has 
visible particulate matter, it should not be used and both the study monitor and 
principal investigator should be notified.  If the investigational product in the vial 
is suspect, it should not be dispensed or administered.  Instead, a new dose should 
be obtained, inspected, and the dose withdrawn then administered.  The occurrence 
of such an event should be recorded in the ISF (investigator site file). 
Each vial will be prepared by swirling gently immediately before use.  
Approximately 0.5 to 0.6 mL of investigational product will be drawn into a sterile, 
1 mL latex-free tuberculin syringe (Becton Dickinson & Co.) or equivalent with a 
sterile, 21-gauge, 1-inch BD PrecisionGlide™ Needle (Becton Dickinson & Co.) 
or equivalent.  To ensure a full dose is able to be drawn from each vial, the vial may 
need to be inverted with the bevel of the needle inserted just above the rubber 
stopper.  The date, time, and administrator’s initials will be recorded in the 
participant’s source record and on the Investigational Product Accountability Log 
upon administering the investigational product to the participant.  In addition, the 

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site of vaccination (e.g., deltoid muscle of left arm) will be recorded in the 
participant’s source medical record. 
4.3 
STORAGE AND HANDLING OF INVESTIGATIONAL PRODUCT 
All vials will be stored at 2°C to 8°C (35.6°F to 46.4°F) in a secure storage location.  
The refrigerator temperature will be recorded continuously and monitored daily.  
The investigational product must not be frozen.  A copy of the temperature logs for 
the storage refrigerator must be filed in the site study files to document appropriate 
storage conditions. 
The principal investigator must ensure that accurate records of receipt of all 
vaccine, including date of receipt, are maintained throughout the study.  In addition, 
accurate records must be kept regarding when and how much vaccine was used. 
Study personnel must not destroy or throw away any vial of vaccine, including 
empty, damaged, or partially used ones.  At the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all vaccine will be 
reconciled and the study monitor will verify that the remaining vials have been 
either returned to designee as determined by the sponsor-investigator or destroyed 
following the sponsor-investigator’s instructions. 
4.4 
DOSE STOPPING RULES 
4.4.1 
Individual Participant Stopping Rules 
Because only one dose of vaccine is administered per participant, there will be no 
individual participant stopping rules to preclude further vaccination. 
Participants who develop a Grade 3 (or higher) immediate hypersensitivity reaction 
to the vaccine will be counselled by the investigator that future exposure to rBV 
A/B would not be advisable.    
4.4.2 
Study Stopping Rules 
For this study, the following are the dose stopping rules; and, if they occur, all 
dosing will stop, the DSMB (Section 6.10) will convene, review the data collected, 
and make a recommendation for continued dosing. 

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• 
If any participant has an SAE (see Section 6.1 for a definition) considered 
possibly, probably, or definitely related to the vaccine 
• 
Two or more participants with a Grade 3 (severe) or higher similar 
hematologic abnormality, considered possibly, probably or definitely related 
to the vaccine 
• 
Two or more participants with neuromuscular AEs considered possibly, 
probably or definitely related to the vaccine 
If the DSMB determines that an SAE was a vaccine-related SAE, then the 
sponsor-investigator will provide the DSMB’s recommendation along with the 
SAE report to the FDA and seek the Agency’s guidance on resuming the study. 
4.5 
CONCOMITANT MEDICATIONS 
There are no restrictions on concomitant medications for the treatment of adverse 
events.  All prior and current medications taken within 60 days prior to Screening 
will be collected and recorded in the eCRF.  Concomitant medications will be 
queried for at each study visit. Any concomitant medication used to treat a severe 
injection site or systemic reaction from Week 0-1 as well as any SAEs or serious 
NOCIs throughout the study (through Week 26) will be recorded in the eCRF. 
Enrolled participants should not receive licensed preparations of botulinum toxin A 
or B used to treat spastic disorders because they are already immune to the 
therapeutic benefits. 
Enrolled participants should not receive any additional vaccines during the study 
period. For participants who choose to donate plasma, this will apply until their last 
plasma donation or at the Week 12 visit (whichever occurs last).  
Participants should not receive prescription immunosuppressive agents, including 
corticosteroids (systemic and inhalational), during the study period.  For 
participants who choose to donate plasma, this will apply until their last plasma 
donation or at the Week 12 visit (whichever occurs last).  Intra-articular, bursal or 
tendon injectable steroids are permitted.  Ophthalmic and intranasal steroids are 
permitted.  Over-the counter topical steroids are permitted. 

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5.0 
EXPERIMENTAL PROCEDURES 
5.1 
OVERVIEW: SCHEDULE OF TIME AND EVENTS 
For this clinical trial there is a 7-day screening period (Days –7 to –1) in which 
participant eligibility will be determined.  Participants will enter either a 4-week 
(non-plasma donors) or a 12-week (plasma donors) treatment period in which a 
single rBV A/B injection will be administered on Day 0 to stimulate the production 
of antibodies against botulinum toxin type A and type B.  Participants will be able 
to donate plasma starting 1 week after injection with rBV A/B at a frequency of up 
to two times a week, for up to 12 weeks with the possibility of extending the 
donation times up to 14 weeks post-vaccination in accord with FDA plasma 
donation regulations and guidelines.[2]  NAC sample collections are required for all 
participants at Week 0 and Week 4.  NAC sample collection is required for plasma 
donors with each donated unit.  Safety assessments for non-plasma donors are 
scheduled on Week 0, Week 1 (by phone), and Week 4 (final on-site visit).  Safety 
assessments for plasma donors are at Week 0 with follow-up phone calls at Weeks 
1, 4 and 10, and a final on-site study visit at Week 12 to assess general health status 
and query for the interim occurrence of any SAEs or NOCIs. All participants will 
have a final phone call for safety follow-up at Week 26.  Concomitant medications 
will be queried for at each study visit. Any concomitant medication used to treat a 
severe injection site or systemic reaction from Week 0-1 as well as any SAEs or 
serious NOCIs throughout the study will be recorded in the eCRF.  
The schedule of events is presented in Table 1. 
 

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Table 1. 
Schedule of Time and Events  
 
 
 
 
Study Period 
 
 
 
 
Measurements/Evaluations 
Screening 
Vaccination 
Visit 
Telephone 
Call 
Telephone Call 
Telephone 
Call 
Plasmapheresis  
Final Study Visit 
Follow-up Call 
Day -7 to 
-1 
Week 0, 
Day 0 
Week 1a 
Week 4a, b 
Week 10a 
Week 2- 14c 
Week 12d 
Week 26e 
Informed consent 
X 
 
 
 
 
Xf 
 
 
Physical examination 
X 
 
 
 
 
Xg 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
Urine pregnancy test 
X 
Xh 
 
 
 
 
X 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Vital signs 
X 
Xi 
 
 
 
X 
 
 
Informed consent for plasma 
collection 
X 
 
 
 
 
 
 
 
HIV, HBV, and HCV testsj 
 
 
 
 
 
X 
 
 
Hematology 
Xk 
 
 
Xl 
 
 
 
 
Serum chemistry 
Xk 
 
 
 
 
 
  
 
Urinalysis 
Xk 
 
 
 
 
 
  
 
NAC sample collection 
 
Xm 
 
Xn 
 
X 
X 
 
Plasmapheresiso 
 
 
 
 
 
X 
 
 
rBV A/B injection 
 
X 
 
 
 
 
 
 
Injection site evaluation 
 
Xp 
 
X 
 
 
X 
 
Diary distributionq 
 
X 
 
 
 
 
 
 
Diary review 
 
 
X 
 
 
 
 
 
Serious adverse event 
collectionr 
 
X 
X 
X 
X 
 
X 
X 
Concomitant medication 
information 
Xt 
 
Xs 
Xs 
Xs 
 
Xs 
Xs 
Phone call 
 
 
X 
X 
X 
 
 
X 
HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; NAC = neutralizing antibody concentration; rBV A/B = recombinant botulinum vaccine A/B. 
a. Week 1, Week 4, and Week 10 Follow-up Calls must occur with ±3 days of the scheduled time. 
b. Final Study Visit will be an on-site visit at Week 4 for participants who opt not to participate or who have been determined to be ineligible for donation for the entire study.  All 
final assessments occurring at Week 12 will occur at Week 4 for these participants.  
c. Extension of plasmapheresis for up to 14 weeks is optional 

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d. Final on-site Study Visit must occur within ± 7 days of the scheduled time. 
e. Final follow-up call for safety must occur within ±1 week of the scheduled time. 
f. Plasmapheresis-specific informed consent formed will be signed at the source plasma center. 
g. Physical examination will be performed as part of source plasma donor screening at the plasma collection center 
h. Female participants of childbearing potential must have a negative pregnancy test within 24 hours prior to vaccination. 
i. Participants will have vital signs taken twice at Visit 1: prior to injection, and 30 minutes (± 5 minutes) after receiving the injection. 
j. HIV, HBV, and HCV tests will be performed on each donated source plasma unit 
k. Results from screening tests must be available before Vaccination Visit  
l. Study participants will go to central lab or plasma center for this draw (not an on-site visit).   
m. Baseline NAC sample must be collected before rBV A/B injection and before plasmapheresis 
n.  Participants not donating plasma must go to site for NAC collection within ±3 days of the scheduled time. 
o. May occur up to twice a week for up to 14 weeks (if hemoglobin and total protein remain within acceptable range) following vaccination with rBV A/B. 
p. At this visit, participants will be monitored for at least 30 minutes after injection for a possible reaction. 
q. In the diaries, participants record adverse events in order to determine SAE, oral temperature and injection site information. 
r. Only serious adverse events and new onset chronic illnesses are to be queried for and collected 
s.. All concomitant medication used to treat a severe injection site or systemic reaction from Week 0-1 as well as any SAEs or serious NOCIs throughout the study (through Week 
26) will be queried for and collected. 
t. All prior and current medications taken within 60 days prior Screening will be queried for and collected. 
 
 
 

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5.2 
MEASUREMENTS AND EVALUATIONS 
This section details the visits that occur during the study and the assessments that 
are conducted at each visit.  Details of the assessments performed during the study 
are provided at the visit at which they are first performed. 
NAC determinations will be performed at Battelle Biomedical Research Center 
(Columbus, Ohio) using a fully validated mouse neutralization assay for all NAC 
determinations in the BabyBIG program.   
5.2.1 
Screening Period (between Days –7 and –1) 
 
Before the initiation of screening assessments, the participant will be given a 
complete explanation of the purpose and evaluations of the study.  Subsequently, 
the participant must sign and receive a copy of the institutional review board (IRB) 
approved ICF (Section 9.1) that includes authorization for use and disclosure of 
protected health information (Section 9.1).  Once the ICF has been obtained, the 
baseline screening assessments will be performed and the eligibility of the 
participant will be determined.  The participant will be assigned a participant 
number once the ICF is signed.  A separate plasmapheresis ICF must be obtained 
for participants donating plasma. 
Screening must occur between 1 and 7 days before Visit 1 (i.e. Vaccination Visit 
[Day 0]).  The following evaluations will be performed to assess the participant’s 
eligibility for the study:   
• Medical history 
• Physical examination, including weight and height; head, eyes, ears, nose, and 
throat; respiratory; cardiovascular; gastrointestinal; extremities; skin; 
neurologic and mental status evaluation 
• Vital signs (temperature, blood pressure, heart rate, and respiratory rate) 
• Urine pregnancy test (If positive, perform confirmatory blood test.) 
• Listing of prior and current medications for past 60 days 
• Hematology panel: 

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– Hemoglobin 
– White blood cell count (with absolute count lymphocytes, neutrophils, 
eosinophils) 
– Platelets 
• Serum chemistry panel: 
– Glucose 
– Blood urea nitrogen 
– Creatinine 
– Alanine aminotransferase 
– Calcium 
– Potassium 
– Aspartate aminotransferase 
– Alkaline phosphatase 
– Bilirubin 
• Urinalysis (dipstick testing of clean-catch sample) 
– Protein 
– Glucose 
– Blood  
– Ketones 
– Leukocyte esterase 
The investigator may use clinical judgment when determining the clinical relevance 
of laboratory parameter findings throughout the study.  Depending on study criteria, 
the medical monitor maybe consulted before enrollment about a potential 
participant with abnormal laboratory values.  Guidance on abnormal laboratory 
values is given in Appendix B. 
Total blood volume collected at this visit will be 10 mL (5 mL each for the 
hematology and serum chemistry).  Total urine volume collected will be 
approximately 30 mL for the urinalysis and urine pregnancy test. 
5.2.2 
Treatment Period (12 weeks, plasma donors; 4 weeks non-plasma donors) 
During this period, participants will have visits and phone calls as outlined below.  
If the participant discontinues, effort should be made to conduct the assessments of 
the Week 12 visit or end-of-study visit for the participant at Week 4. 

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5.2.2.1 
Vaccination Visit (Week 0, Day 0) 
During this visit, the following activities will occur: 
• Review of baseline health assessment and inclusion and exclusion criteria 
• Urine pregnancy test for female participants of childbearing potential, 
performed within 24 hours preceding receipt of the study vaccine.   
• Collection of 20 mL of blood to determine NAC  
• Vital signs (temperature, blood pressure, heart rate, and respiratory rate) 
assessed before the injection and 30 minutes (± 5 minutes) after the injection 
• Injection of rBV A/B  
• Participant monitored for at least 30 minutes after injection for localized and 
systemic reactions, including vital signs taken at the end of the 30-minute period 
• Reaction Recording Sheet – Participant Home Diary distributed to the 
participant to record injection site information and systemic reactions, if any, 
as well as concomitant medications taken for potential reactions (copy of diary 
is in Appendix C) 
• Adverse Event Recording Sheet for Identification of Possible Serious Adverse 
Events distributed to the participant to record adverse events, for 7 days (copy 
of recording sheet is in Appendix E) 
Total blood volume collected at this visit will be 20 mL for NAC. 
5.2.2.2 
Plasma Donation Period (up to 14 weeks) 
After receiving the rBV A/B vaccination, the participant may participate as a source 
plasma donor if they choose. A screening physical exam will be performed at the 
plasma collection center. Donor eligibility will be determined at the sponsor-
approved, licensed source plasma collection center.  Once donor eligibility has been 
confirmed, the participant may begin donating plasma 1 week after vaccination up 
to twice a week for the next 12 weeks, with the possibility of continuing for up to 
14 weeks, consistent with FDA plasma donation regulations and guidelines.[2]  

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During the first visit to the plasma collection center, the following activities will 
occur: 
• Brief physical examination by a licensed physician or otherwise authorized 
designee at the plasma collection center (the medical exam for plasmapheresis 
is repeated on an annual basis) 
• Measurement of vital signs (temperature, blood pressure, heart rate, and 
respiratory rate) 
• Obtaining informed consent for plasma donation and procedures 
• Completion of donor history questionnaire (Appendix D) 
• Finger prick for hemoglobin measurement and total serum protein measurement 
• Approximately 10 mL of whole blood collected for atypical antibody 
measurements, serologic test for syphilis, and serum protein electrophoresis at 
4-month intervals 
• Obtaining 20 mL whole blood by side sample collections for NAC 
determination 
• Plasma donation (takes approximately 1 to 1.5 hours) per the donation site’s 
procedures 
• Each donated unit will be tested for infectious markers using nucleic acid 
testing 
During each subsequent visit to the plasma collection center, the following 
activities will occur: 
• Completion of the donor history questionnaire 
• Measurement of vital signs (temperature, blood pressure, heart rate, and 
respiratory rate) 
• Finger prick for hemoglobin measurement and total serum protein measurement 
• Obtaining 20 mL whole blood by side sample collections for NAC 
determination 

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• Plasma donation (takes approximately 1 to 1.5 hours) per the donation site’s 
procedures 
• Each donated unit will be tested for infectious markers using nucleic acid 
testing 
Samples for NAC determination will be obtained before plasma collection.  The 
source plasma from plasmapheresis will be retained and is eligible for use in the 
production of BabyBIG.   
Participants will be able to complete plasma donations at a maximum of twice a 
week up to 12 weeks after the rBV A/B injection, with the possibility of further 
donation time up to 14 weeks consistent with FDA plasma donation regulations and 
guidelines for hemoglobin and total protein. At 4-month intervals, the participant 
will have an additional tube of whole blood drawn at the plasmapheresis center for 
atypical antibody measurements and serum protein electrophoresis.  These 
additional blood draw results will not be included among the study data.  
5.2.2.3 
Telephone Call (Week 1) 
Study personnel will call participants at Week 1 (± 3 days) to review the Reaction 
Recording Sheet – Participant Home Diary injection site and systemic reactions, as 
well as any potential SAEs occurring over the past week and any NOCIs and 
concomitant medications.  Study personnel should inquire about participants 
overall well-being and any concomitant medications. Participants should use the 
provided Adverse Event Recording Sheet for Identification of Possible Serious 
Adverse Events form (Appendix E) between phone calls to assist during the inquiry.  
The information recorded by the delegated site personnel during the phone call will 
serve as the source documentation.  
5.2.2.4 
Week 4 Visit and Laboratory Draws 
Participants not participating in plasma donation must return to the site at Week 4 
(± 3 days) for their final study visit.  During this visit, the following activities will 
occur: 
• Injection site inspection 

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• Review of serious adverse events 
• Review of any new onset chronic illnesses 
• Collection of concomitant medication information, if any 
• Collection of 20 mL of blood to determine NAC  
• Urine pregnancy test for female participants of childbearing potential 
• Repeat of hematology conducted at screening (Section 5.2.1) 
• Completion of final on-site study record 
Total blood volume collected at this visit will be 25 mL (20 mL for NAC and 5 mL 
for hematology).  Total urine volume collected will be approximately 10 mL for 
the urine pregnancy test.   
All participants continuing in the study will go to a central lab or plasma center (not 
on site) for hematology. 
5.2.2.5 
Telephone Calls (Weeks 4 and 10) 
Study personnel will call plasma donating participants at Weeks 4 (± 3 days) and10 
(± 3 days) to inquire about participants overall well-being, SAEs, if any, that 
occurred since the last visit or phone call, any concomitant medication used, any 
NOCIs, any AEs that increased in severity and injection site or systemic reactions.  
SAEs, including serious NOCIs, serious injection site or systemic reactions and 
concomitant medication used as treatment will be recorded in the eCRF. 
5.2.2.6 
Week 12 Visit 
For all participants participating in plasma donation, the final on-site study visit 
must occur within 1 week of Week 12. During this visit, the following activities 
will occur: 
• Injection site inspection 
• Review of serious adverse events or serious NOCIs 

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• Collection of concomitant medication information used for treatment of any 
SAEs or serious NOCIs, if any 
• Collection of 20 mL of blood to determine NAC  
• Urine pregnancy test for female participants of childbearing potential 
• Completion of final on-site study record 
Total blood volume collected at this visit will be 20 mL for NAC determinations.  
Total urine volume collected will be approximately 10 mL for the urine pregnancy 
test. 
5.2.3 
Final Study Follow-up (Day 182, Week 26) 
Within 1 week of Week 26, site personnel will contact the participant by phone to 
assess the participant’s general health status.  Interim occurrence of any SAEs or 
serious NOCIs will be queried for and recorded. Any concomitant medications used 
to treat SAEs or serious NOCIs will be recorded and entered in the eCRF. 

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6.0 
PROCEDURES FOR HANDLING SERIOUS ADVERSE EVENTS 
6.1 
DEFINITION OF A SERIOUS ADVERSE EVENT 
In this clinical trial, a serious adverse event is defined as an AE that meets any of 
the following criteria: 
• Results in death 
• Is life-threatening 
The term life-threatening in the definition of an SAE refers to an event in which 
the participant was at risk of death at the time of the event.  Life-threatening 
does not refer to an event that hypothetically might have caused death if it were 
more severe. 
• Requires hospitalization or a prolongation of an existing hospitalization 
In general, hospitalization signifies that the participant has been detained at the 
hospital or emergency department for observation or treatment that would not 
have been appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalization are AEs, but not necessarily 
SAEs.  An occurrence or complication that prolongs hospitalization is an SAE.  
When there is doubt as to whether hospitalization occurred or was necessary, 
the AE should be considered an SAE.  Hospitalization for elective treatments 
of a preexisting condition that did not worsen from its original baseline level is 
not considered an SAE. 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
This definition is not intended to include AEs of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, or accidental trauma (e.g., sprained ankle) that may interfere or 
prevent everyday life functions but do not constitute a substantial disruption. 
• A congenital anomaly or birth defect 
 
 

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• Other important medical events 
Medical or scientific judgment should be exercised in deciding whether 
reporting is appropriate for other important medical events that may not result 
in death, be life threatening, or require hospitalization but still may jeopardize 
the participant or may require medical intervention to prevent one of the 
outcomes listed in this definition.  These events should also be considered 
serious. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse.  
An SAE requires additional detailed reports and follow-up.  The content of these 
detailed reports must address the investigator’s estimate of causality.  The medical 
monitor will review the SAE to determine if it is an expected SAE (i.e., whether or 
not the SAE is identified in nature, severity, or frequency in the Investigator’s 
Brochure).  
The investigator is responsible for performing periodic and specific assessments for 
SAEs at study visits.  The investigator and clinical staff will note all SAEs 
mentioned by the participant during and after administration of the investigational 
product until the end of the study.  All clinical complaints volunteered by, or 
elicited from, the participant during the study will be recorded on the appropriate 
page of the source documentation for the indicated study period.  Information 
related to serious adverse events will be recorded on the eCRF.  The participant will 
receive appropriate treatment guidance for any SAE that occurs. 
All SAEs judged to be clinically significant, including clinically significant 
laboratory abnormalities, will be followed until resolution or considered stable by 
the investigator.  All SAEs will be summarized in the annual report or more 
frequently, if requested by the regulatory agency.  Serious adverse events require 
special reporting in addition to documentation in the eCRF as described in Section 
6.2.   
6.2 
RECORDING SERIOUS ADVERSE EVENTS 
When an SAE occurs, the investigator is responsible for reviewing all 
documentation (e.g., hospital progress notes, laboratory and diagnostic reports) 
relevant to the event(s).  The investigator will record all relevant information about 

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the SAEs on the SAE page of the eCRF.  It is not acceptable for the investigator to 
send photocopies of the participant’s medical records in lieu of the properly 
completed SAE pages of the eCRF.  These types of documents should not be sent 
unless they are specifically requested by pharmacovigilance.  If this request occurs, 
all participant identifiers and protected health information will be blinded on the 
copies of the medical records before submission to the appropriate authorities. 
The investigator will also attempt to report a diagnosis versus signs, symptoms, or 
other clinical information for the SAE.  The diagnosis, not the individual signs and 
symptoms, should be documented on the appropriate page of the eCRF as the SAE.  
In addition, SAEs need to be reported on the SAE report form. 
6.3 
ASSESSMENT OF SEVERITY 
The investigator will assess the severity for each SAE reported during the study.  
The assessment will be based on the investigator’s clinical judgment.   
The classifications in Table 2 should be used in assigning severity of each AE 
recorded in the eCRF.  Additional guidance is provided in Appendix B for specific 
AEs, laboratory abnormalities, and changes in vital signs. 
Table 2. 
Classification of AEs by Severity 
Severity 
Definition 
Grade 1 
Mild AE 
Transient or mild discomfort (<48 hours); no medical intervention or 
therapy required 
Grade 2 
Moderate AE 
Mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention or therapy required 
Grade 3 
Severe AE 
Marked limitation in activity, some assistance usually required; 
medical intervention or therapy required, hospitalization possible 
Grade 4 
Life-threatening AE or 
Death 
Extreme limitation in activity, significant assistance required; 
significant medical intervention or therapy required, hospitalization or 
hospice care probable 
AE = adverse event. 
 
 
Any SAE that changes in  severity during its course will be recorded in the eCRF 
at the highest level experienced by the participant. 
Severity of an AE is graded as follows: Mild, moderate, severe or life-threatening 
myocardial infarction.  An AE that is assessed as severe should not be confused 
with an SAE.  An event  may be of relatively minor medical significance, such as 
a severe headache, but not be considered an SAE.  Both AEs and SAEs can be 

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assessed as severe.  An AE is defined as serious when it meets one of the predefined 
outcomes as described in Section 6.1. 
6.4 
ASSESSMENT OF CAUSALITY 
The investigator must estimate the relationship between the investigational product 
and the occurrence of each SAE by using his or her best clinical judgment.  
Elements to consider include the history of the underlying disease, concomitant 
therapy, other risk factors and the temporal relationship of the event to the 
investigational product.  The investigator will also consult the Investigator’s 
Brochure or product-labeling information for marketed products in estimating the 
relationship. 
Because of reporting timelines, the investigator might have minimal information to 
include in the initial SAE report.  However, the investigator must always make an 
assessment of causality for every event prior to the transmission of the SAE report.  
The investigator may change his or her opinion of the causality in light of follow-
up information, with subsequent amendment of the SAE report.  Causality 
assessment is one of the criteria used to determine regulatory reporting 
requirements and should not be left blank.  Table 3 provides the definitions to use 
in the assessment. 
 
 

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Table 3. 
Assessment of Causality of Adverse Events  
Term 
Definition 
Definitely 
The AE follows a reasonable temporal sequence from treatment and 
is consistent with the Investigator’s Brochure.  
Probably 
• 
The AE follows a reasonable temporal sequence from the 
administration of the investigational drug. 
• 
The AE cannot be easily explained from the participant’s 
clinical condition, environmental or toxic factors, or other 
therapy administration. 
• 
The AE disappears or diminishes on cessation or reduction in 
dose, except in case of irreversible damage (positive de-
challenge). 
• 
The AE follows a known pattern or response of the 
investigational drug. 
• 
The AE reappears upon re-administration of the investigational 
drug (positive re-challenge). 
Possibly  
• 
The AE follows a reasonable temporal sequence from the 
administration of the investigational drug. 
• 
The AE cannot easily be explained from the participant’s 
clinical condition, environmental or toxic factors, or other 
therapy administration. 
• 
The AE follows a known pattern or response of the 
investigational drug. 
• 
The AE disappears or diminishes on cessation or reduction in 
dose, except in case of irreversible damage (positive de-
challenge). 
Unlikely 
• 
The AE follows a reasonable temporal sequence from 
administration of the investigational drug. 
• 
The AE can be easily explained from the participant’s clinical 
condition, environmental or toxic factors, or other therapy 
administration. 
• 
The AE does not follow a known response pattern of the 
investigational drug. 
Not Related 
• 
The AE does not follow a reasonable temporal sequence from 
administration of the investigational drug and occurrence of the 
AE. 
• 
The AE could readily have been produced by the participant’s 
clinical state, environmental or toxic factors, or other therapy 
administration. 
• 
The AE does not follow a known response pattern to the 
investigational drug. 
• 
The AE does not reappear or worsen when the investigational 
drug is re-administered (negative re-challenge). 
AE = adverse event. 
 
 
 

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6.5 
EXPECTEDNESS OF ADVERSE EVENTS 
An expected AE is one that is consistent with the known risk information described 
in the current Investigator’s Brochure.  An AE is considered unexpected if it is not 
listed the in the Investigator’s Brochure or it is not listed at the specificity or 
severity that has been observed.  This will be assessed by the medical monitor or 
sponsor-investigator upon receipt of the initial AE report. 
6.6 
ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest that are particularly specific to this study will be 
collected, assessed and recorded in the eCRF as an AE. These events of special 
interest will be collected in addition to the SAEs described in Section 6.1 and 
include the following clinical situations (see Section 3.3.2): 
• Frequency of injection site reactions and  systemic reactions among the study 
participants that are assessed as severe between Day 0 and 7 will be captured as 
an AE. 
• Clinically significant changes in hematology between screening and Week 4 
that are assessed as  severe will be captured as an AE.  
 
6.7 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any SAE occurring after the participant has been vaccinated with rBV A/B must 
be reported to the medical monitor and sponsor-investigator by phone, fax, or e-
mail within 24 hours of the time the investigator becomes aware of the SAE  
(Table 4).  Urgent reporting of SAEs is required for the following reasons: 
1. To enable the sponsor-investigator to fulfill the reporting requirements to the 
appropriate regulatory authority 
2. To facilitate the sponsor-investigator’s rapid dissemination of information 
about SAEs to other investigators or sites in a multicenter study 
3. To facilitate reporting unanticipated and/or serious problems involving risk to 
participants to the IRB within 48 hours. 

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Table 4. 
Timeline for Reporting Serious Adverse Events to Medical 
Monitor and Sponsor-Investigator  
Initial SAE Report 
Follow-up SAE Report 
Time Frame 
Documents 
Time Frame 
Documents 
24 hours 
SAE report 
7 days 
Updated SAE 
report 
SAE = serious adverse event. 
 
 
The SAE report form will be completed as thoroughly as possible, including the 
following information: 
• Participant identification information 
• All available details about the event 
• Causality of each SAE  
• Signature of the investigator 
The SAE report will be forwarded to the DSMB within the designated time frames.  
If the investigator does not have all information about an SAE, the investigator will 
NOT wait to receive additional information before notifying the DSMB of the SAE 
and completing the form.  The form will be updated when additional information 
is received.  
IND Safety Reports:  The investigator will report a suspected adverse reaction that 
is both “serious” and “unexpected” to FDA in accordance with the timeframe 
outlined in 21 CFR 312.32.  FDA and all participating investigators will be notified 
of potentially serious risks identified from any source within 15 calendar days after 
the sponsor-investigator receives the safety information and determines that it is 
reportable [21 CFR312.32 (c) (1)].  The sponsor-investigator must also notify FDA 
of any unexpected fatal or life-threatening suspected adverse reaction as soon as 
possible but in no case later than 7 calendar days after the sponsor-investigator’s 
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6.8 
FOLLOW-UP OF SERIOUS ADVERSE EVENTS 
All SAEs (as well as clinically significant changes in hematology that result in a 
severe or serious adverse event) will be followed until the occurrence of one of the 
following: 
• The event resolves. 
• The condition stabilizes. 
• The event is otherwise explained. 
• The participant is lost to follow-up. 
The appropriate SAE report form will be updated for SAEs only once the SAE 
resolves, stabilizes, is otherwise explained, or the participant is lost to follow-up.  
The investigator will also ensure that additional updates include any supplemental 
data that may explain causality of the event(s). 
New or updated information will be recorded on a copy of the initially completed 
SAE report, with all the changes signed and dated by the investigator or designee.  
The updated SAE report will then be signed by the investigator and resubmitted to 
the DSMB as outlined in Table 4. 
6.9 
INJECTION SITE AND SYSTEMIC REACTIONS 
Commonly seen injection site reactions for rBV A/B are consistent with reactions 
in participants vaccinated with other recombinant protein vaccines that include 
Alhydrogel™.  The majority of reactions at the injection site seen to date with 
rBV A/B have been mild or moderate in severity and included erythema, pain, 
pruritus, and swelling.  Participants will be actively monitored for localized and 
systemic reactions to the injections and an anaphylaxis (epinephrine) kit will be 
available at the time of injections. 
The definitions to be used to determine severity of injection site reactions are 
provided in Table 5. 

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Table 5. 
Protocol Definitions for Severity of Injection Site, ie., Local 
Reactions 
Local Reaction 
to Injectable 
Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-Threating 
(Grade 4) 
Injection site 
pain  
Does not 
interfere with 
activity 
Repeated use of 
nonnarcotic 
pain reliever 
>24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Injection site 
tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Injection site 
erythema 
(redness)a 
2.5-5.0 cm 
5.1-10.0 cm 
>10.0 cm 
Bullae, necrosis, 
or exfoliative 
dermatitis 
Injection site 
swelling 
(induration)b 
2.5-5.0 cm and 
does not 
interfere with 
activity 
5.1-10.0 cm or 
interferes with 
activity 
>10.0 cm or 
prevents daily 
activity 
Necrosis 
ER = emergency room. 
a 
In addition to grading the measured local reaction at the greatest single diameter, the 
measurement should be recorded as a continuous variable. 
b 
Induration (swelling) should be evaluated and graded using the functional scale as well as the 
actual measurement. 
 
 
Systemic reactions collected in the diary are severity of muscle weakness, malaise, 
rash, headache, nausea, chest discomfort, breathing difficulties, anxiety, feelings of 
depression, and neuromuscular TEAEs.  For systemic reactions, use the guidance 
provided in Appendix B. 
6.10 
DATA AND SAFETY MONITORING BOARD 
The DSMB will meet quarterly throughout the study and as needed as described in 
Section 4.4.  The specific information that will be reviewed to make its 
recommendation will be safety data and neutralizing antibody concentrations. 
In addition, the DSMB will convene at any time during the study if a stopping rule 
is met (see Section 4.4.2) 
6.11 
PREGNANCY 
If a participant becomes pregnant at any time after receipt of the study vaccine, she 
should report the pregnancy via telephone to the study investigators within 24 hours 

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of being made aware of it; study investigators will then promptly complete the 
pregnancy report form and forward the form to the medical monitor and sponsor-
investigator.  The female participant will be discontinued from further study 
procedures, including plasmapheresis.  The pregnancy will be followed until there 
is an outcome and the outcome is reported to the study investigators. 

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7.0 
STUDY OR SITE TERMINATION AND 
PARTICIPANTDISCONTINUATION 
7.1 
PARTICIPANT DISCONTINUATION 
Participants will be encouraged to complete the study; however, they may 
voluntarily withdraw at any time.  The investigator will provide a written 
explanation of the reason for discontinuation in a source document, which will be 
transcribed to the appropriate eCRF page.  If a participant withdraws before 
completion, every effort should be made to complete the assessments scheduled 
during the final on-site study visit.  In addition, the participant will be offered safety 
follow-up for the planned duration of the study (through the Week 26 telephone 
contact) regardless of the reason for discontinuation.  
A participant may be removed from the study for the reasons described in 
Section 7.1.1 through Section 7.1.5. 
7.1.1 
Adverse Event 
If a participant suffers an AE that, in the judgment of the investigator, the 
sponsor-investigator, or the medical monitor, presents an unacceptable 
consequence or risk to the participant, the participant may be discontinued from the 
study.   
7.1.2 
Intercurrent Illness 
A participant may be discontinued from the study if, in the judgment of the 
investigator, the participant develops an intercurrent illness or complication that is 
not consistent with the protocol requirements or that, in any way, justifies 
withdrawal from the study. 
7.1.3 
Noncompliance 
After consultation among the investigator, the medical monitor, and study/data 
monitor, a participant may be discontinued from the study for failure to comply 
with protocol requirements.  Upon being discontinued from the study, the 
participant will be notified by study personnel and the reason for discontinuation 
documented in the appropriate eCRF page and on study source documents. 

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7.1.4 
Refusal of Investigational Product Administration 
Any participant refusing vaccination with rBV A/B for any reason will be 
discontinued from the study, and the reason(s) will be documented on the 
appropriate eCRF page.  Efforts should be made to monitor the participant for AEs 
and to complete follow-up assessments after discontinuation.  These efforts should 
be documented on the appropriate eCRF page. 
7.1.5 
Withdrawal of Consent 
Any participant that withdraws consent for any reason at any time during the study 
will be discontinued from the study, and the reason(s) will be documented on the 
appropriate eCRF page.   
7.2 
PREMATURE STUDY OR SITE TERMINATION 
If the sponsor, investigator, medical monitor, study/data monitor, or appropriate 
regulatory officials discover conditions arising during the study that indicate that 
the study should be halted or that the site should be terminated, this action may be 
taken after appropriate consultation among the sponsor-investigator, medical 
monitor, and study/data monitor.  Conditions that may warrant termination of the 
study include, but are not limited to, the following: 
• The discovery of an unexpected, serious, or unacceptable risk to the participants 
enrolled in the study 
• A decision on the part of the sponsor-investigator or product manufacturer to 
suspend or discontinue testing, evaluation, or development of the product 
A study conducted at a single site in a multicenter study may also warrant 
termination under the following conditions: 
• Failure of the investigator to enroll participants into the study at an acceptable 
rate 
• Failure of the investigator to comply with pertinent regulations of appropriate 
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• Submission of knowingly false information from the site to the 
sponsor-investigator, study/data monitor, or appropriate regulatory authority 
• Insufficient adherence to protocol requirements 
Study termination and follow-up will comply with the conditions set forth in the 
ICH E6 Guideline for Good Clinical Practice, Sections 4.12, 4.13, 5.20, and 5.21. 

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8.0 
DATA COLLECTION 
AND 
PROCESSING 
AND 
STATISTICAL 
ANALYSIS 
8.1 
DATA COLLECTION AND PROCESSING 
eCRFs will be used to capture study assessments and data.  The study investigator 
or other delegated study personnel will enter data from source documents into the 
eCRFs.  All eCRFs and their data will be reviewed and source verified by the 
study/data monitor. The medical monitor may examine the eCRFs for preliminary 
medical review.  Once the eCRFs are completed and source-verified, the study 
investigator will sign and date all required pages, thereby verifying the accuracy of 
all data contained in the eCRFs. 
8.2 
STATISTICAL ANALYSIS 
8.2.1 
General Overview 
The data will be summarized in tables listing the mean, standard deviation or 
standard error, median, minimum, maximum and number of participants for 
continuous data or in tables listing count and percentage for categorical data, where 
appropriate.  Data will be listed by “participant ID.”  All statistical analyses will be 
performed and data appendices will be created by using SAS.   
8.2.2 
Populations of Interest 
8.2.2.1 
Immunogenicity Population 
The immunogenicity population defines participants who have received the vaccine 
dose, have a baseline NAC, and have at least one post-vaccination immunogenicity 
assessment up to and including 4 weeks after administration of rBV A/B. 
8.2.2.2 
Per Protocol Population 
The per protocol population defines participants who have received the vaccine 
dose, have a baseline NAC, and have the relevant immunogenicity assessments 
completed within the protocol-specified timelines (including visit windows) for the 
time point(s) summarized and who do not have major protocol violations expected 
to affect immunogenicity.  Determination of a major protocol violation expected to 

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affect immunogenicity will be done by the sponsor-investigator before reviewing 
the immunogenicity data for the applicable participant.  The precise reasons for 
excluding participants from the per protocol population will be fully defined and 
documented.  (Note:  It is possible for a participant to be included in the primary 
per protocol analysis for Week 4, even if the subsequent blood draws occur outside 
of the study windows.) 
8.2.2.3 
Safety Population 
The safety population comprises all participants enrolled into the study who 
received the vaccine dose and had at least one post-baseline safety assessment (this 
assessment can include a response from a participant that no adverse events 
occurred).  
8.2.2.4 
Plasma-Donating Population 
The plasma-donating population will include all participants who receive the 
vaccine and donate at least one plasma unit. 
8.2.3 
Baseline Comparability 
No formal baseline comparability testing is planned for this study. 
8.2.4 
Immunogenicity Analysis 
The immunogenicity population will be used for all immunogenicity endpoints. 
The per protocol population will be used in the case that any sensitivity analyses 
are deemed necessary.   
The immunogenicity parameters are concentrations of neutralizing antibodies 
against botulinum toxin type A and toxin type B.  These parameters will be 
analyzed by using NAC data from a validated mouse neutralization assay. 
For the primary endpoint, a positive response will be defined as achieving a greater 
than or equal to four times increase (point estimate) above baseline in NAC by 
Week 4 compared with Week 0 in at least 50% of the participants in the 
immunogenicity population for botulinum toxin type A and type B, respectively.  

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A point estimate and two-sided 95% confidence interval for the proportion of 
participants who achieve this endpoint will be provided. 
For the first secondary immunogenicity endpoint, a positive response will be 
defined as achieving a two times increase above baseline in the estimated area under 
the plasma NAC-time curve in the period from Week 0 to Week 12 in comparison 
to straight-line extension of the Week 0 antibody concentration from Week 0 to 
Week 12 in least 50% of the participants.   
For the second secondary immunogenicity endpoint, a positive response will be 
defined as is achieving a three times or greater increase in NAC above baseline by 
Week 4 in at least 50% of the participants for botulinum toxin type A and type B.  
A point estimate and two-sided 95% confidence interval for the proportion of 
participants who achieve this endpoint will be provided. 
Further details of the analysis, will be provided as needed in a separate statistical 
analysis plan. 
In the event that the primary endpoint is not met for neutralizing antibodies against 
botulinum toxin type A and type B, the sponsor-investigator will determine if the 
plasma collected during the study contains sufficient antibody titers for meeting 
specifications for BabyBIG production.  If the immune responses meet 
specifications to permit the production of BabyBIG, then the trial will still be 
considered successful.  Also, a second booster dose of rBV A/B vaccine may be 
considered; however, this will require operational modifications (e.g., a protocol 
amendment and updated consent form). 
8.2.5 
Safety Analysis 
The safety analysis will use the safety population. 
Localized and systemic severe AEs and SAEs collected from the Week 1 telephone 
call will be summarized by category and severity.  A point estimate of incidence, 
with 95% confidence limits will be computed and reported (not coded into the 
Medical Dictionary for Regulatory Activities [MedDRA] terminology or assessed 
for relatedness).  The time period summarized will include throughout the study as 
a whole and again within Days 0 through 7.  For tables summarizing severity, the 

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highest reported severity grade will be used.  In addition, the average duration, by 
category, will be summarized. 
All other SAE data will be listed individually and summarized by system organ 
class and preferred terms for each treatment group.  When calculating the incidence 
of SAEs, each SAE based on preferred terminology from MedDRA will be counted 
only once for a given participant.  If the same SAE occurs on multiple occasions in 
a participant, the occurrence with the highest severity and highest causality 
relationship to the vaccine will be reported.  If two or more SAEs are reported as a 
unit, the individual terms will be reported as separate experiences. 
Treatment-emergent abnormal values that occur prior to the end of the study will 
be summarized. Laboratory abnormalities will be assessed for relatedness.  
Treatment-emergent changes from normal to abnormal values in key laboratory 
parameters will be identified. 
Presentation of relatedness in tables will be based on the investigator’s assessment. 
8.2.6 
Sample Size 
No formal power calculations will be performed for this study.  The sample size 
will consist of up to 50 participants.  On the basis of prior sponsor-investigator 
experience, this sample size is considered adequate for fulfilling the study 
objectives. 
 
 

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9.0 
CLINICAL STUDY ADMINISTRATION 
9.1 
INFORMED CONSENT WITH AUTHORIZATION FOR USE AND 
DISCLOSURE OF PROTECTED HEALTH INFORMATION  
Written informed consent with authorization of use and disclosure of protected 
health information must be obtained from each participant before performing any 
study-specific screening/baseline period evaluations.  The informed consent form 
that includes authorization for use and disclosure of protected health information 
must have been reviewed and approved by the sponsor-investigator, the study/data 
monitor, and the investigator’s IRB prior to the initiation of the study.  The ICF 
will conform to the 20 elements of informed consent described in ICH E6, 
Section 4.8 and will include the elements required by Title 45 of the Code of 
Federal Regulations, Section 164.508(b) and any local regulations for valid 
authorizations.  One copy of the signed ICF with authorization for use and 
disclosure of protected health information form will be given to the participant, and 
the investigator will retain the original in the Investigators’ Study Files. 
9.2 
STUDY DOCUMENTATION 
9.2.1 
Investigator Information 
Investigator information is included in the study procedure manual, which is 
updated as needed. 
9.2.2 
Investigators’ Study Files 
Documentation about the investigator and study staff, the IRB, and the institution 
is required before study site initiation.  Copies of these documents will be kept on-
site in study site–specific binders or files, along with the following supplemental 
information: a list of investigator’s obligations; the current Investigator’s Brochure; 
the clinical trial protocol and amendments; safety information; information about 
investigational product, biological samples, and the laboratory; the study procedure 
manual and study logs; and records of monitoring activities. 
The investigator is responsible for ensuring frequent backup of all electronic data 
systems used for primary documentation or source documentation.  Electronic 

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(eCRF) data will be backed up periodically as described in the EDC vendor’s 
standard operating procedures.   
9.2.3 
Case Report Forms and Source Documentation 
The investigator must make study data accessible to the study/data monitor, other 
authorized representatives of the sponsor-investigator, and the appropriate 
regulatory authority inspectors.  The eCRF for each participant will be checked 
against source documents at the study site by the study/data monitor, and a final 
copy of the eCRF will be signed by the investigator with an electronic signature.  A 
copy of the final eCRFs will be provided to the investigator in portable document 
format on computer disc after study closure to be kept in the investigator’s study 
files. 
9.2.4 
Retention of Study Documents 
According to ICH E6, Section 4.9, all eCRFs, as well as supporting paper and 
electronic source documentation and administrative records, must be retained by 
the investigator until at least 2 years after the last approval of a marketing 
application and until there are no pending or contemplated marketing applications 
or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product in the United States.  The 
sponsor-investigator is responsible for informing the investigator and institution as 
to when these documents no longer need to be retained.  No study documents will 
be destroyed or moved to a new location without prior written approval from the 
sponsor-investigator.  If the investigator relocates, retires, or withdraws from the 
clinical study for any reason, all records required to be maintained for the study 
should be transferred to a designee approved by the sponsor-investigator, such as 
another investigator at the institution where the study was conducted. 
Audit trails for electronic documents must be retained for a period at least as long 
as that required for the participant electronic records to which they pertain.  The 
investigator must retain either the original or a certified copy of audit trails. 

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9.3 
CONFIDENTIALITY 
9.3.1 
Data 
The investigator shall keep all information about the nature of the proposed 
investigation provided by the sponsor-investigator or study monitor to the 
investigator confidential (with the exception of information required by law or 
regulations to be disclosed to the IRB, the participant, or the appropriate regulatory 
authority).  Additionally, de-identified data (safety and immunological) will be 
disclosed to DynPort Vaccine Company LLC to be used for safety reporting 
required by regulatory authorities. 
9.3.2 
Participant Anonymity 
The anonymity of participating participants must be maintained.  Participants will 
be identified by an assigned participant number on eCRFs and other documents 
retrieved from the site or sent to the study/data monitor, sponsor-investigator, 
regulatory agencies, central laboratories, or blinded reviewers.  Documents that 
identify the participant (e.g., the signed informed consent form) must be maintained 
in strict confidence by the investigator and designated study staff, except to the 
extent necessary to allow auditing by the appropriate regulatory authority, the 
study/data monitor, or sponsor-investigator representatives. 
9.4 
PROTOCOL COMPLIANCE AND AMENDMENT PROCEDURES 
Substantive changes in the protocol include changes that affect the safety of 
participants or changes that meaningfully alter the scope of the investigation, the 
scientific quality of the study, the experimental design, dosages, assessment 
variable(s), the number of participants treated, or the participant selection criteria.  
Such changes must be prepared as a protocol amendment by the sponsor-
investigator and implemented only upon joint approval of the sponsor-investigator 
and the IRB.  In parallel with the IRB approval process, the protocol amendment 
will be submitted to the appropriate regulatory authority as an amendment to the 
regulatory submission under which the study is being conducted.  If a protocol 
amendment requires changes in the informed consent form, the revised informed 
consent form prepared by the investigator must also be approved by the sponsor-
investigator, study/data monitor, and the IRB before implementation. 

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Deviations from the protocol are allowed only in situations for which the deviation 
would eliminate an immediate risk to a participant and that are deemed crucial for 
the safety and well-being of that participant.  The investigator or the attending 
physician also will contact the medical monitor as soon as possible in the case of 
such a deviation.  These deviations do not require preapproval by the IRB; however, 
the IRB and medical monitor must be notified in writing or via e-mail as soon as 
possible after the deviation occurs.  In addition, the investigator will document in 
the participant’s eCRF the reasons for the protocol deviation and the ensuing 
events.  
9.5 
STUDY/DATA MONITOR FUNCTIONS AND RESPONSIBILITY 
The study/data monitor, in accordance with the sponsor-investigator’s 
requirements, will ensure that the clinical trial is conducted and documented 
properly by carrying out the activities outlined in ICH E6, Section 5.18.4. 
 

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10.0 
REFERENCES 
1. 
Centers for Disease Control and Prevention. Notice of CDC's 
discontinuation of investigational pentavalent (ABCDE) botulinum toxoid 
vaccine for workers at risk for occupational exposure to botulinum toxins. 
MMWR 2011;60(42):1454-1455. 
2. 
U.S. Department of Health and Human Services, Food and Drug 
Administration. Code of Federal Regulations Title 21, Part 640 additional 
standards for human blood and blood products.  Revised 01 April 2013; 
Available 
at: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?
CFRPart=640&showFR=1&subpartNode=21:7.0.1.1.7.7. 
 
 

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APPENDICES 

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APPENDIX A 
 
 
CODE OF FEDERAL REGULATIONS PART 640:  
ADDITIONAL STANDARDS FOR HUMAN BLOOD  
AND BLOOD PRODUCTS 

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CODE OF FEDERAL REGULATIONS PART 640—ADDITIONAL STANDARDS 
FOR HUMAN BLOOD AND BLOOD PRODUCTS 
Subpart G—Source Plasma  
§ 640.63 Suitability of donor.   
(a) 
Method of determining. The suitability of a donor for Source Plasma will be determined 
by a qualified licensed physician or by persons under his or her supervision and trained 
in determining donor suitability. Such determination will be made on the day of 
collection from the donor by means of a medical history, tests, and such physical 
examination as appears necessary to the qualified licensed physician. 
(b) 
Initial medical examinations.  
(1) 
Each donor will be examined by a qualified licensed physician on the day of the 
first donation or no more than 1 week before the first donation and at subsequent 
intervals of no longer than 1 year. 
(2) 
 
(i) 
A donor who is to be immunized for the production of high-titer plasma 
will be examined by a qualified licensed physician. The medical 
examination will be performed within no more than 1 week before the first 
immunization injection. The medical examination for plasmapheresis need 
not be repeated, if the first donation occurs within 3 weeks after the first 
injection. 
(ii) 
A donor who is an active participant in a plasmapheresis program, and has 
been examined in accordance with paragraph (b)(1) of this section, need 
not be reexamined before immunization for the production of high-titer 
plasma. 
(3) 
Each donor will be certified to be in good health by the examining physician. The 
certification of good health will be on a form supplied by the licensed 
establishment and will indicate that the certification applies to the suitability of 
the individual to be a plasmapheresis donor and, when applicable, an immunized 
donor. 

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(c) 
Qualification of donor. Donors will be in good health on the day of donation, as 
indicated in part by: 
(1) 
Normal temperature; 
(2) 
Demonstration that systolic and diastolic blood pressures are within normal 
limits, unless the examining physician is satisfied that an individual with blood 
pressures outside these limits is an otherwise qualified donor under the provisions 
of this section; 
(3) 
For female donors, a blood hemoglobin level of no less than 12.5 g of hemoglobin 
per 100 mL of blood or a hematocrit level of 38% (female donors may have a 
hemoglobin level of between 12.0 and 12.5 g hemoglobin per 100 mL of blood , 
or a hematocrit between 36 and 38% provided additional steps ensure the health 
of the donor will not be adversely affected due to donation); For male donors, a 
blood hemoglobin level of no less than 13.0 g of hemoglobin per 100 mL, or a 
hematocrit level no less than 39%; 
(4) 
A normal pulse rate; 
(5) 
A total serum or total plasma protein of no less than 6.0 g per 100 mL of blood; 
(6) 
Weight, which will be at least 110 pounds; 
(7) 
Freedom from acute respiratory diseases; 
(8) 
Freedom from any infectious skin disease at the site of phlebotomy and from any 
such disease generalized to such an extent as to create a risk of contamination of 
the plasma; 
(9) 
Freedom from any disease, other than malaria, transmissible by blood transfusion, 
insofar as can be determined by history and examinations indicated in this section; 
(10) Freedom of the arms and forearms from skin punctures or scars indicative of 
addiction to self-injected narcotics; 
(11) Freedom from a history of viral hepatitis after the 11th birthday; 
(12) Freedom from a history of close contact within 12 months of donation with an 
individual having viral hepatitis; 
(13) Freedom from a history of having received, within 12 months, human blood or 
any derivative of human blood that the Food and Drug Administration has advised 
the blood establishment is a possible source of viral hepatitis, except for specific 
immunization performed in accordance with 640.66. 

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(d) 
General. Any donor who, in the opinion of the interviewer, appears to be under the 
influence of any drug, alcohol, or for any reason does not appear to be providing reliable 
answers to medical history questions, will not be considered a suitable donor. 
(e) 
Failure to return red blood cells. Any donor who has not had the red blood cells returned 
from a unit of blood collected during a plasmapheresis procedure or who has been a 
donor of a unit of whole blood will not be subjected to plasmapheresis for a period of 8 
weeks, unless: 
(1) 
The donor has been examined by a qualified licensed physician and certified by 
the physician to be acceptable for further plasmapheresis before expiration of the 
8-week period; 
(2) 
The donor possesses an antibody that is  
(i) transitory,  
(ii) of a highly unusual or infrequent specificity, or  
(iii) of an unusually high titer; and 
(3) 
The special characteristics of the antibody and the need for plasmapheresing the 
donor are documented. 

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APPENDIX B 
 
 
TOXICITY TABLES FROM GUIDANCE FOR INDUSTRY: TOXICITY 
GRADING SCALE FOR HEALTHY ADULT AND ADOLESCENT 
PARTICIPANTS ENROLLED IN PREVENTIVE  
VACCINE CLINICAL TRIALS 

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Table 6. 
Clinical Abnormalities from Vital Signs 
Vital Signsa 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever 
(°C)b 
 
(°F)b 
38.0-38.4 
100.4-101.1 
38.5-38.9 
101.2-102.0 
39.0-40.0 
102.1-104.0 
>40.0 
>104.0 
Tachycardia  
(beats per minute) 
101-115 
116-130 
>130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardiac 
(beats per minute) 
50-54 
45-49 
<45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension: systolic 
(mm Hg) 
141-150 
151-155 
>155 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension: diastolic 
(mm Hg) 
91-95 
96-100 
>100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension: systolic 
(mm Hg) 
85-89 
80-84 
<80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory rate 
(breaths per minute) 
17-20 
21-25 
>25 
Intubation 
ER = emergency room. 
a Participant should be at rest for all vital sign measurements. 
b Oral temperature should be taken, and there should be no consumption of recent hot or cold beverages or 
smoking. 
c Use clinical judgment when characterizing bradycardia among some healthy participant populations, for 
example conditioned athletes. 
 
 
 
 

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Table 7. 
Systemic Clinical Abnormalities 
Systemic 
(General) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/vomiting 
No interference 
with activity, or 1 
to 2 episodes per 
24 hours 
Some interference 
with activity or 
>2 episodes per 
24 hours 
Prevents daily 
activity, requires 
outpatient 
intravenous 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2 to 3 loose stools 
or <400 g per 
24 hours 
4 to 5 stools or 
400 to 800 g per 
24 hours 
6 or more watery 
stools or >800 g 
per 24 hours or 
requires outpatient 
intravenous 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with activity 
Repeated use of 
nonnarcotic pain 
reliever >24 hours 
or some 
interference with 
activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue 
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Illness or clinical 
adverse event  
No interference 
with activity 
Some interference 
with activity, but 
not requiring 
medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization 
ER = emergency room. 
 
 
 
 

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Table 8. 
Modified Table for Laboratory Abnormalities 
Seruma 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)b 
Glucose: 
hypoglycemia (mg/dL) 
65–69 
55–64 
45–54 
<45 
Glucose: 
hyperglycemia fasting 
(mg/dL);  
random (mg/dL) 
 
 
100–110 
110–125 
 
 
111–125 
126–200 
 
 
>125 
>200 
Insulin 
requirements or 
hyperosmolar 
coma 
Blood urea nitrogen 
(mg/dL) 
23–26 
27–31 
>31 
Requires dialysis 
Creatinine (mg/dL) 
1.5–1.7 
1.8–2.0 
2.1–2.5 
>2.5 or requires 
dialysis 
Alkaline phosphate: 
increase by factor 
1.1–2.0 × ULN 
2.1–3.0 × ULN 
3.1–10 × ULN 
>10 × ULN 
Liver function tests: 
ALT, AST, increase 
by factor 
1.1–2.5 × ULN 
2.6–5.0 × ULN 
5.1–10 × ULN 
>10 × ULN 
Bilirubin: when 
accompanied by any 
increase in liver 
function test, increase 
by factor 
1.1–1.25 × ULN 
1.26–1.5 × ULN 
1.51–1.75 × ULN 
>1.75 × ULN 
Bilirubin: when liver 
function test is normal, 
increase by factor 
1.1–1.5 × ULN 
1.6–2.0 × ULN 
2.0–3.0 × ULN 
>3.0 × ULN 
Potassium - 
Hyperkalemia 
(mEq/L) 
5.1–5.2 
5.3–5.4 
5.5–5.6 
>5.6 
Potassium - 
Hypokalemia (mEq/L) 
3.5–3.6 
3.3–3.4 
3.1–3.2 
<3.1 
Calcium - 
Hypocalcemia 
(mg/dL) 
8.0–8.4 
7.5–7.9 
7.0–7.4 
<7.0 
Calcium - 
Hypercalcemia 
(mg/dL) 
10.5–11.0 
11.1–11.5 
11.6–12.0 
>12.0 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of the normal range. 
a 
The laboratory values provided in the table serve as guidelines and are dependent on institutional normal 
parameters.  Institutional normal reference ranges should be provided to demonstrate that the laboratory 
values are appropriate. 
b 
The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of 
the laboratory abnormalities as potentially life-threatening (Grade 4).  For example, a low potassium value 
that falls within a Grade 3 parameter should be recorded as a Grade 4 hypokalemia event if the participant 
had a new arrhythmia event associated with the low potassium value. 
 
 
 
 

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Table 9. 
Modified Hematology Clinical Abnormalities 
Hematologya 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin: female 
(g/dL) 
11.0-12.0 
9.5-10.9 
8.0-9.4 
<8.0 
Hemoglobin: male 
(g/dL) 
12.5-13.5 
10.5-12.4 
8.5-10.4 
<8.5 
WBC increase 
(cell/mm3) 
10.800-15,000 
15,001-20,000 
20,001-25,000 
>25,000 
WBC decrease 
(cell/mm3) 
2,500-3, 500 
1,500-2,499 
1,000-1,499 
<1,000 
Lymphocytes 
decrease 
(cell/mm3) 
750-1,000 
500-749 
250-499 
<250 
Neutrophils decrease 
(cell/mm3) 
1,500-2,000 
1,000-1,499 
500-999 
<500 
Eosinophils 
(cell/mm3) 
650-1,500 
1,501-5,000 
>5,000 
Hypereosinophilic 
Platelets decrease 
(cell/mm3) 
125,000-140,000 
100,000-124,999 
25,000-99,999 
<25,000 
WBC = white blood count. 
a 
The laboratory values provided in the table serve as guidelines and are dependent on institutional normal 
parameters.  Institutional normal reference ranges should be provided to demonstrate that the laboratory 
values are appropriate. 
 
 
Table 10. 
Clinical Abnormalities from Urinalysis Values 
Urinea 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or 
dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization for 
hyperglycemia 
Blood (microscopic): 
red blood cells per 
high-power field 
1-10 
11-50 
>50 and/or gross 
blood 
Hospitalization or 
packed red blood 
cells transfusion 
a 
The laboratory values provide in the table serve as guidelines and are dependent on institutional normal 
parameters.  Institutional normal reference ranges should be provided to demonstrate that the laboratory 
values are appropriate. 
 

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
 
 
Page 5 
Table 11. Neuromuscular Toxicities 
Neurological Event 
Mild 
Grade 1 
Moderate 
Grade 2 
Severe 
Grade 3 
Potentially 
Life 
Threatening 
Grade 4 
Muscle Weaknessa 
 
subjective 
weakness with no 
objective 
symptoms or signs 
mild objective 
signs or 
symptoms and 
no decrease in 
function 
objective 
weakness 
function limited 
paralysis 
Ophthalmoplegia / 
Diplopia (double vision)  
 
Intermittently 
symptomatic, 
intervention not 
indicated 
Symptomatic 
and interfering 
with function 
but not with 
interfering with 
ADL; mild 
objective signs 
or symptoms; 
intervention not 
indicated 
Symptomatic 
and interfering 
with function 
and  ADL; 
objective 
weakness; 
medical 
intervention 
indicated 
Disabling; 
Paralysis; 
medical 
intervention 
indicated 
Vision – blurred vision 
Vision - photophobia 
 
Intermittently 
symptomatic, 
intervention not 
indicated 
Symptomatic 
and interfering 
with function 
but not 
interfering with 
ADL; mild 
objective signs 
or symptoms 
Symptomatic 
and interfering 
with function 
and  ADL; 
objective 
weakness;  
Disabling 
Voice changes / dysarthria 
(e.g., hoarseness, loss or 
alteration of voice) 
 
Mild or 
Intermittent 
hoarseness or voice 
change, but fully 
understandable 
Moderate or 
persistent voice 
changes, may 
require 
occasional 
repetition but 
understandable 
on telephone 
 
Severe voice 
changes 
including 
predominantly 
whispered 
speech; may 
require frequent 
repetition or 
face-to-face 
contact for 
understandability 
Disabling; non-
understandable 
voice or 
aphonic;  
Dyspnea 
(shortness of breath) 
 
Dyspnea on 
exertion, but can 
walk one flight of 
stairs without 
stopping 
Dyspnea on 
exertion, but 
unable to walk 
one flight of 
stairs without 
stopping  
Dyspnea 
interfering with 
ADL 
Dyspnea at 
rest; intubation 
may be 
indicated 
Neuro-Cerebellar 
(lack of coordination, tremor) 
slight 
incoordination 
dysdiadochokinesis 
intention 
tremor, 
dysmetria, 
slurred speech; 
nystagmus 
locomotor ataxia 
incapacitated 
Cranial neuropathy 
Asymptomatic, 
detected on 
examination 
Symptomatic, 
not interfering 
with ADL 
Symptomatic, 
interfering with 
ADL 
Life-
threatening, 
disabling 
a   Check for generalized, cranial muscles (see sentence below), extremities (upper and lower), and specific areas 
(extra ocular, facial, ocular, and trunk).  Symptoms or signs of cranial muscle involvement are disruption of the 
appearance or functioning of the senses, facial muscles, pharynx, larynx, and neck.  

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
 
 
 
APPENDIX C 
 
 
PARTICIPANT DIARY 

CONFIDENTIAL 
 
California Department of Public Health 
 
 
IND #15155 
Tolerability and Immunogenicity of a Single 40-µg Dose of Recombinant 
Botulinum Vaccine A/B (rBV A/B) for the Production of BabyBIG® in 
Volunteers with Existing Botulinum Immunity 
Reaction Recording Sheet – Participant Home Diary 
Study Site/Location*: _________/_____________ 
Participant Study ID Number*: _____________ 
* To be filled in by study staff 
Ver. August 2018 
Page 1 of 1 
 
 
Participant Name: ___________________________________________  
 
Recombinant vaccine given:              Date: ________/_________/________   Time: ___________________ AM / PM 
 
 
 
1 day 
24 hrs 
2 days 
48 hrs 
3 days 
72 hrs 
4 days 
96 hrs 
5 days 
120 hrs 
6 days 
144 hrs 
7 days 
168 hrs 
Local reactions: 
 
Soreness? 
 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Itching? 
 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Erythema? (mm)a 
 
 
_____ 
 
_____ 
 
_____ 
 
_____ 
 
_____ 
 
_____ 
 
_____ 
Induration? (mm)a 
 
 
_____ 
 
_____ 
 
_____ 
 
_____ 
 
_____ 
 
_____ 
 
_____ 
Systemic reactions: 
 
General malaise? 
 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Fatigue? 
 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Lethargy? 
 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Chills, fever? 
 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Lumps, soreness? (not local) 
 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Stiff back, stiff neck? 
 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Nausea, vomiting, or diarrhea? 
 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Other GI symptoms? 
 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Itching, hives? 
 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
a Please use tool provided to measure. Please list any medications used to treat the potential reactions 
above:  
____________________________________________________________________ 
____________________________________________________________________ 
If you answered yes to any of the above potential reactions, please record additional comments i.e., 
date/time of reaction, symptoms 
________________________________________________________________________ 
________________________________________________________________________ 
 
If additional space required, please continue on back of this form. 

CONFIDENTIAL 
NOT AUTHORIZED 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
 
 
 
APPENDIX D 
 
 
DONOR HISTORY QUESTIONNAIRE 

  
PPTA Abbreviated Donor History Questionnaire 
For Frequent Plasma Donors  
 
This document is one component of the PPTA donor history 
questionnaire documents to be used by source plasma 
organizations. The PPTA abbreviated donor history questionnaire 
documents must be used collectively.  
 
July 2016 
 
    v2.0 

  
PPTA Abbreviated Donor History Questionnaire 
For Frequent Plasma Donors  
 
                      Current Health  
Yes 
 No 
 
1. Are you feeling healthy and well today? 
 
 
Please Read the Medication List 
 
2. Since you last donated plasma have you taken any medications on the 
medication list?  
 
                 
 
 
Changes in Health 
 
Since you last donated plasma: 
 
 
 
   
 
  Yes    No 
 
3. Female Donors: Have you been pregnant or are 
      you pregnant now? 
 
4.   Have you had any new medical problems or diagnoses? 
    
5. Have you had any new medical treatments,   
 vaccinations or medications?  
 
6. Have you had contact with someone who had a  
      smallpox vaccination? 
 
7. Have you donated whole blood, platelets or plasma at  
another center?  
 
 
 
 
 
 
 
Risk Activities 
 
Please review our Risk Poster 
 
 
 
 
   Yes    No 
 
8. Did you review the Risk Poster? 
 
9. Do you have any questions about anything mentioned  
on the Risk Poster? 
 
10. Since you last donated plasma, does anything on the  
 Risk Poster apply to you? 
 
Since you last donated plasma:  
 
 
  
   Yes    No 
 
   11. Have you gotten a tattoo or had one touched up? 
 
   12. Have you had an ear or body piercing? 
July 2016 
 
    v2.0 

  
PPTA Abbreviated Donor History Questionnaire 
For Frequent Plasma Donors  
 
  
 
 
 
 
 
 
 
 
   Yes    No 
 
Optional Question A. Have you had surgery or a diagnostic, medical or dental 
procedure? 
  
 
Optional Question B. Have you had acupuncture? 
 
 
Additional Questions: 
 
 
 
 
 
Acknowledgment: 
 
1. I have reviewed the educational materials regarding infections that can be 
transmitted by my donation, such as, Syphilis, HIV, Hepatitis B and C. 
2. I agree not to donate if my donation could result in a potential risk to people who 
receive plasma products.  
3. A sample of my blood will be tested for infections that can be transmitted by my 
donation, such as, Syphilis, HIV, Hepatitis B and C. 
4. I understand you will attempt to notify me if for any reason I cannot donate and 
records will be maintained indicating the reason for the deferral and the deferral 
time period.  
5. I have reviewed the information regarding the potential risks and hazards of 
donating Source Plasma. 
6. I have been given the opportunity to ask questions and understand that I may 
withdraw from the donation procedure at any time.  
 
Donor Signature: ____________________________________Date: ______________ 
 
 
 
 
 
July 2016 
 
    v2.0 

CONFIDENTIAL 
 
CDPH 
 
rBV A/B 
Clinical Protocol 
IND 015155 
 
 
 
 
APPENDIX E 
 
 
ADVERSE EVENT RECORDING SHEET FOR IDENTIFICATION OF 
POSSIBLE SERIOUS ADVERSE EVENTS (SAES) 

CONFIDENTIAL  
California Department of Public Health 
 
IND #15155 
 
Tolerability and Immunogenicity of a Single 40-µg Dose of Recombinant 
Botulinum Vaccine A/B (rBV A/B) for the Production of BabyBIG® in Volunteers 
with Existing Botulinum Immunity 
Adverse Events Recording Sheet for Identification of Possible Serious 
Adverse Events (SAEs) 
Study Site/Location*: __________/_______________ 
Participant Study ID Number*: _____________ 
* To be filled in by study staff 
Ver. August  2018   
 
Site Investigator’s Initials________ 
 
Participant Name:  _________________________________________ 
 
Recombinant vaccine given:         Date: ________/_________/________                Time: _______________ AM / PM 
 
 
• 
You may or may not experience any adverse events.  The purpose of this recording sheet is for you to 
document at home any adverse events during the course of the study, if such should occur. 
• 
If you make an error while recording, please draw a single line through the error, add your correction and 
initial.  Please no white out or multiple lines through errors.    
• 
The information you document on this form will be queried for by study staff during on-site study visits and 
phone call follow-up for safety at Weeks 1, 4, 10 and 26.  
• 
Please indicate the date and time (if relevant) of each event’s occurrence, as well as the date/time of the 
event’s resolution.   
• 
Please categorize the event’s severity as indicated below.   
 
Note: If you experience severe, life-threatening or any of the following neuromuscular symptoms (blurred or double 
vision, drooping of eyelids, drooping of the mouth, dry mouth, difficulty swallowing, difficulty speaking, weakness of 
an arm or leg, lack of coordination, shallow breathing, sensitivity to sunlight, or inability to perspire), please seek 
medical attention immediately and notify Dr. Khouri (24/7/365 phone # 925-408-5935) or Dr. Bloomfield 
(24/7/365 phone #: 614-595-5505) as soon as possible.    
 
*Please categorize the severity of the reaction as:  
 
mild   
 
= you are able to perform all routine daily activities 
 
moderate 
= you are able to perform some routine activities, but are limited in others 
 
severe  
= you are unable to perform all routine activities, often seeking medical care 
 
# 
Reaction or Event 
Description/Location 
New 
Event? 
(Y/N) 
Date / 
Time 
Started 
Date / 
Time 
Ended 
Severity 
Treatment 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional Comments, if any (please continue on reverse side).  

CONFIDENTIAL  
California Department of Public Health 
 
IND #15155 
 
Tolerability and Immunogenicity of a Single 40-µg Dose of Recombinant 
Botulinum Vaccine A/B (rBV A/B) for the Production of BabyBIG® in Volunteers 
with Existing Botulinum Immunity 
Adverse Events Recording Sheet for Identification of Possible Serious 
Adverse Events (SAEs) 
Study Site/Location*: __________/_______________ 
Participant Study ID Number*: _____________ 
* To be filled in by study staff 
Ver. August  2018   
 
Site Investigator’s Initials________ 
 
Additional Comments, if any:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reviewed by: ____________________________ Date:  ___/___/___ Time: ____AM/PM  
                   Site Principal Investigator or Designee 
              
Title: ___________________________