A Phase 2, Randomized, Controlled, Observer-blinded Study To Describe The Immunogenicity, Safety, And Tolerability Of Neisseria Meningitidis Serogroup B Bivalent Recombinant Lipoprotein 2086 Vaccine (Bivalent Rlp2086) In Healthy Subjects Aged >/= 24 Months To <10 Years
Phase: PHASE2
Conditions: MENINGOCOCCAL INFECTION
Sponsor: Pfizer

PF-05212366 (Neisseria meningitidis Serogroup B Bivalent Recombinant Lipoprotein 2086 Vaccine [Bivalent 
rLP2086; subfamily A and B; E coli])
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Page 1
A PHASE 2, RANDOMIZED, CONTROLLED, OBSERVER-BLINDED STUDY TO 
DESCRIBE THE IMMUNOGENICITY, SAFETY, AND TOLERABILITY OF 
NEISSERIA MENINGITIDIS SEROGROUP B BIVALENT RECOMBINANT 
LIPOPROTEIN 2086 VACCINE (BIVALENT rLP2086) IN HEALTHY SUBJECTS
AGED 24 MONTHS TO <10 YEARS
Compound:
PF-05212366
Compound Name:
Neisseria meningitidis Serogroup B Bivalent 
Recombinant Lipoprotein 2086 Vaccine
(Bivalent rLP2086)
United States (US) Investigational New 
Drug (IND) Number:
13812
European Clinical Trials Database 
(EudraCT) Number:
Universal Trial Number:
2014-000933-21
Not Applicable
Protocol Number:
B1971017
Phase:
2
 
 

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Document History
Document
Version Date
Summary of Changes
Protocol Amendment 1
03 Feb 2015

Updated description of control hepatitis 
A vaccine.

Updated the Introduction with current 
information.

Clarified text in Section 5.4.2 that
investigational product will be 
administered to subjects who are 
blinded.
Original protocol
12 May 2014
Not applicable
This amendment incorporates all revisions to date, including amendments made at the request of country health 
authorities, institutional review boards/ethics committees (IRBs/ECs), etc.

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ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
bivalent rLP2086
bivalent recombinant lipoprotein 2086 vaccine
CDC
Centers for Disease Control and Prevention (United States)
CI
confidence interval
CRF
case report form
CTA
clinical trial application
DAI
dosage and administration instructions
DTaP
diphtheria, tetanus, and acellular pertussis
DU
dispensable unit
EC
ethics committee
e-diary
electronic diary
EDMC
external data monitoring committee
EDP
exposure during pregnancy
ELISA
enzyme-linked immunosorbent assay
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act of 2007
GCP
Good Clinical Practice
GMT
geometric mean titer
HAV
hepatitis A virus
HPV
human papillomavirus
hSBA
serum bactericidal assay using human complement
IB
investigator’s brochure
ICD
informed consent document
ICH
International Conference on Harmonisation
IgG
immunoglobulin G
IMD
invasive meningococcal disease
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
ISC
independent statistical center
IUD
intrauterine device
LFT
liver function test
LLOQ
lower limit of quantitation

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LOD
limit of detection
LP2086
lipoprotein 2086
LSLV
last subject last visit
MCAR
missing completely at random
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MMRM
mixed-effects model with repeated measurement
MnB
Neisseria meningitidis serogroup B
NIP
national immunization program
OMV
outer membrane vesicle
PCD
primary completion date
PRP-OMP
polyribosylribitol phosphate oligosaccharide of Haemophilus 
influenzae type b conjugated to outer membrane protein
PT
prothrombin time
rLP2086
recombinant lipoprotein 2086
RRI
research-related injury
SAE
serious adverse event
SAP
statistical analysis plan
SRSD
single reference safety document
SRM
study reference manual
ULN
upper limit of normal
USPI
United States package insert

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PROTOCOL SUMMARY
Background and Rationale
Neisseria meningitidis is a leading cause of bacterial meningitis in infants, adolescents, and 
young adults. In particular, N meningitidis serogroup B (MnB) is responsible for 
approximately two-thirds of the cases of observed meningococcal infections in Europe, with 
an overall case-fatality rate of 6% to 8% from 1999 to 2006.  MnB disease accounts for 
approximately one-quarter of meningococcal cases seen in North America in the areas 
participating in the Active Bacterial Core surveillance program.  There is substantial 
morbidity among survivors, including neurological disability, limb loss, and hearing loss.
A recombinant, multicomponent MnB vaccine (Bexsero) is licensed in Europe, Canada, 
Australia, Chile, and the United States. Trumenba® (bivalent recombinant lipoprotein 2086 
vaccine [bivalent rLP2086]), developed by Pfizer, is approved in the United States for use in 
individuals 10 through 25 years of age for active immunization to prevent invasive 
meningococcal disease (IMD) caused by MnB. Recommendations for MnB vaccination are 
under consideration in various countries. However, to date, no broadly effective vaccine 
against MnB disease is available worldwide. General availability of a safe and immunogenic 
MnB vaccine remains an unmet medical need, and a successful vaccine will provide 
substantial improvement in prevention of meningococcal infection and a reduction in the 
burden of disease.
Bivalent rLP2086 is targeted to a conserved, surface-exposed lipoprotein, lipoprotein 2086
(LP2086), a meningococcal virulence factor that binds human factor H. N meningitidis
serogroup B recombinant lipoprotein 2086 (rLP2086) has been expressed in Escherichia coli
and formulated in a bivalent vaccine composed of 1 subfamily A strain and 1 subfamily B 
strain of rLP2086.
This study will assess the immunogenicity, safety, and tolerability of bivalent rLP2086 (final 
formulation) administered as a Month 0, 2, and 6 schedule in healthy subjects aged
24 months to <10 years. Randomization will be stratified to ensure that equal numbers of 
subjects are included in the 24-month to <4-year age group and the 4-year to <10-year age 
groups.
Objectives:
Primary Immunogenicity Objectives

To describe the immune response as measured by serum bactericidal assay using human 
complement (hSBA) performed with 4 primary MnB test strains, 2 expressing an LP2086 
subfamily A protein and 2 expressing an LP2086 subfamily B protein, measured 1 month 
after the third vaccination with bivalent rLP2086, in healthy subjects aged 24 months to 
<4 years at study entry.

To describe the immune response as measured by hSBA performed with 4 primary MnB 
test strains, 2 expressing an LP2086 subfamily A protein and 2 expressing an LP2086 

PF-05212366 (Bivalent rLP2086)
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subfamily B protein, measured 1 month after the third vaccination with bivalent rLP2086, 
in healthy subjects aged 4 years to <10 years at study entry.
Primary Safety Objective

To evaluate the safety profile of bivalent rLP2086 compared to a control (hepatitis A 
virus [HAV] vaccine), as measured by local reactions, systemic events, adverse events 
(AEs), serious adverse events (SAEs), newly diagnosed chronic medical conditions, 
medically attended AEs, and immediate AEs in healthy subjects aged 24 months to 
<4 years at study entry, in healthy subjects aged 4 years to <10 years at study entry, and 
in both age strata combined.
Secondary Objectives

To describe the immune response as measured by hSBA performed with 4 primary MnB 
test strains, 2 expressing an LP2086 subfamily A protein and 2 expressing an LP2086 
subfamily B protein, measured 1 month after the third vaccination with bivalent rLP2086, 
in healthy subjects aged 24 months to <10 years at study entry (ie, in both age strata 
combined).

To describe the immune response as measured by hSBA performed with 4 primary MnB 
test strains, 2 expressing an LP2086 subfamily A protein and 2 expressing an LP2086 
subfamily B protein, measured 1 month after the second vaccination and 6 months after 
the third vaccination with bivalent rLP2086, in healthy subjects aged 24 months to 
<4 years at study entry, 4 years to <10 years at study entry, and in both age strata 
combined.

 
 
 
 
Endpoints:
Because of the possibility of limited volumes of sera, for all primary and secondary
immunogenicity endpoints, approximately 50% of subjects randomly selected from each age 
stratum/group will be tested for hSBA on strain 
 (variant A22) and 
(B24), 
and the remaining 50% of subjects from each age stratum/group will be tested for hSBA on 
 (A56) and 
 (B44). 
 
.
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The lower limit of quantitation (LLOQ) for 
 (A22) is 1:16. The LLOQ for the other 
3 primary test strains is 1:8.
Primary Immunogenicity Endpoints

Proportion of subjects aged 24 months to <4 years (at study entry) with hSBA titer 
LLOQ for each of the 4 primary MnB test strains 1 month after the third vaccination 
with bivalent rLP2086.

Proportion of subjects aged 4 years to <10 years (at study entry) with hSBA titer 
LLOQ for each of the 4 primary MnB test strains 1 month after the third vaccination 
with bivalent rLP2086.
Primary Safety Endpoints
In healthy subjects aged 24 months to <4 years and in healthy subjects aged 4 years to 
<10 years at study entry and in both age strata combined:

Percentage of subjects reporting local reactions (pain, redness, and swelling) and by 
severity after each vaccination visit.

Percentage of subjects reporting systemic events (fever, vomiting, diarrhea, headache, 
fatigue, muscle pain other than muscle pain at any injection site, and joint pain) and by 
severity after each vaccination visit.

Percentage of subjects reporting the use of antipyretic medication after each vaccination 
visit.

Percentage of subjects with at least 1 SAE during the following time periods:

30 Days after each vaccination.

30 Days after any vaccination.

During the vaccination phase (from the first study vaccination [Visit 1] through 
1 month after the last study vaccination [Visit 6]).

During the follow-up phase (from 1 month after the last study vaccination [Visit 6]
through 6 months after the third study vaccination [Visit 7]).

Throughout the study period (from the first study vaccination [Visit 1] through 
6 months after the third study vaccination [Visit 7]).
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
Percentage of subjects with at least 1 medically attended AE occurring during the 
following time periods:

30 Days after each vaccination.

30 Days after any vaccination.

During the vaccination phase (from the first study vaccination [Visit 1] through
1 month after the last study vaccination [Visit 6]).

During the follow-up phase (from 1 month after the last study vaccination [Visit 6]
through 6 months after the third study vaccination [Visit 7]).

Throughout the study period (from the first study vaccination [Visit 1] through 
6 months after the third study vaccination [Visit 7]).

Percentage of subjects with at least 1 newly diagnosed chronic medical condition 
occurring during the following time periods:

30 Days after each vaccination.

30 Days after any vaccination.

During the vaccination phase (from the first study vaccination [Visit 1] through 
1 month after the last study vaccination [Visit 6]).

During the follow-up phase (from 1 month after the last study vaccination [Visit 6]
through 6 months after the third study vaccination [Visit 7]).

Throughout the study period (from the first study vaccination [Visit 1] through 
6 months after the third study vaccination [Visit 7]).

Percentage of subjects with at least 1 AE occurring during the following time periods:

30 Days after each vaccination.

30 Days after any vaccination.

During the vaccination phase (from the first study vaccination [Visit 1] through 
1 month after the last study vaccination [Visit 6]).

Percentage of subjects reporting at least 1 immediate AE after each vaccination.

For subjects at school, days of school missed because of AEs during the vaccination 
phase (Visit 1 though Visit 6).

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Secondary Immunogenicity Endpoints
In healthy subjects aged 24 months to <10 years at study entry:

Proportion of subjects with hSBA titer lower limit of quantitation (LLOQ) for each of 
the 4 primary MnB test strains 1 month after the third vaccination with bivalent rLP2086 
vaccine.
In healthy subjects aged 24 months to <4 years at study entry, 4 years to <10 years at 
study entry, and in both age strata combined:

Proportion of subjects with hSBA titer lower limit of quantitation (LLOQ) for each of 
the 4 primary MnB test strains 1 month after the second vaccination and 1 and 6 months 
after the third vaccination with bivalent rLP2086 vaccine.

Proportions of subjects achieving hSBA titers of 1:4, 1:8, 1:16, 1:32, 1:64, and 
1:128 for each of the 4 primary test strains at baseline, 1 month after the second 
vaccination, and 1 and 6 months after the third vaccination with bivalent rLP2086 
vaccine.

hSBA GMTs for each of the 4 primary test strains at baseline, 1 month after the second 
vaccination, and 1 and 6 months after the third vaccination with bivalent rLP2086 
vaccine.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
.
Study Design:
This is a Phase 2, randomized, controlled, observer-blinded, multicenter study in which 
approximately 400 healthy subjects will be randomized in a 3:1 ratio to receive either 
bivalent rLP2086 at Months 0, 2, and 6, or HAV vaccine at Months 0 and 6 and saline at 
Month 2. Subjects will be stratified equally into 2 age groups: 24 months to <4 years or 
4 years to <10 years.
The study is designed to assess the immunogenicity, safety, and tolerability of bivalent 
rLP2086 at the 120-g dose level.
Subjects will have vaccination visits at Months 0, 2, and 6. Follow-up visits will be 
conducted 1 month after each vaccination and 6 months after the third vaccination to collect 
safety data and/or a blood sample.
Vaccination 
(Vax) 1
Post–Vax 1 
Follow-up 
Vax 2
Post–Vax 2 
Blood Draw
Vax 3
Post–Vax 3 
Blood Draw
Month 12
Follow-up and 
Blood Draw
Visit 
number
1
2
3
4
5
6
7
Approx 
month
0
1
2
3
6
7
12
Group 1 
(300)
Bivalent 
rLP2086
Bivalent 
rLP2086
Bivalent 
rLP2086
Group 2
(100)
HAV 
vaccine
Saline
HAV 
vaccine
Blood 
draw
5-10 mL
5-10 mL
5-10 mL
5-10 mL
Abbreviations: HAV = hepatitis A virus; Vax = vaccination.
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Subject enrollment will be stratified according to age. The study will enroll approximately 
200 subjects aged 24 months to <4 years and approximately 200 subjects aged 4 to 
<10 years. Age stratification will ensure equal representation of both age groups.
Investigational Products:
The following are defined as investigational products and will be supplied by the sponsor:

Bivalent rLP2086
 
in a 
0.5-mL dose for injection.

Sterile saline solution for injection (0.85% sodium chloride) in a 0.5-mL dose.

A licensed pediatric HAV vaccine in a 0.5-mL dose for injection.
Statistical Methods:
This is not a hypothesis-testing study; thus, an estimation approach will be used to assess the
primary, secondary, and exploratory objectives.
All of the binary endpoints (including primary endpoints) will be summarized with 2-sided 
95% confidence intervals (CIs) using the exact method. Geometric mean titers (GMTs) on 
hSBA results will also be summarized with 95% CIs.
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures. Refer to the Study Procedures and 
Assessments sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the subject.
Visit Identifier
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Approximate month
0
1
2
3
6
7
12
Visit description
Vaccination 1
Post–
Vaccination 1 
Follow-up
Vaccination 2
Post–
Vaccination 2 
Blood Draw
Vaccination 3
Post–
Vaccination 3 
Blood Draw
Month 12
Follow-up and 
Blood Draw
Visit window
Day 1
25 to 35 Days 
After Visit 1
42 to 70 Days 
After Visit 1
28 to 42 Days 
After Visit 3
105 to 126
Days After 
Visit 3
28 to 42 Days 
After Visit 5
168 to 196
Days After 
Visit 5
Informed consent
X
Review eligibility criteria
X
Confirm continued eligibility
X
X
X
X
X
X
Demography
X
Medical history and physical 
examination
X
Record previous PRP-OMP
vaccinations
X
Record previous vaccines with any 
meningococcal, DTaP, or HPV vaccine 
antigens
X
Temperature (measured as appropriate 
for age)
X
X
X

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Visit Identifier
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Approximate month
0
1
2
3
6
7
12
Visit description
Vaccination 1
Post–
Vaccination 1 
Follow-up
Vaccination 2
Post–
Vaccination 2 
Blood Draw
Vaccination 3
Post–
Vaccination 3 
Blood Draw
Month 12
Follow-up and 
Blood Draw
Visit window
Day 1
25 to 35 Days 
After Visit 1
42 to 70 Days 
After Visit 1
28 to 42 Days 
After Visit 3
105 to 126
Days After 
Visit 3
28 to 42 Days 
After Visit 5
168 to 196
Days After 
Visit 5
Urine pregnancy test (only for female
subjects biologically capable of having 
children)
X
X
X
Collect blood samplea
X
X
X
X
Randomization
X
Vaccination and observation
X
X
X
Record nonstudy vaccinations
X
X
X
X
X
Provide e-diary, thermometer, 
measuring tape/ruler, and caliper if 
required
X
X
X
Review e-diary
X
X
X
Collect e-diary
X
X
Assess reactogenicityb
Days 1-7
Days 1-7
Days 1-7
Record the use and type of antipyretic 
medication
Days 1-7
Days 1-7
Days 1-7
(S)AE collection appropriate to the visit
X
X
X
X
X
X
X
Provide the parent(s)/legal guardian
with a memory aid
X

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Visit Identifier
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Approximate month
0
1
2
3
6
7
12
Visit description
Vaccination 1
Post–
Vaccination 1 
Follow-up
Vaccination 2
Post–
Vaccination 2 
Blood Draw
Vaccination 3
Post–
Vaccination 3 
Blood Draw
Month 12
Follow-up and 
Blood Draw
Visit window
Day 1
25 to 35 Days 
After Visit 1
42 to 70 Days 
After Visit 1
28 to 42 Days 
After Visit 3
105 to 126
Days After 
Visit 3
28 to 42 Days 
After Visit 5
168 to 196
Days After 
Visit 5
Complete the Study Visit AE Checklistc
X
X
X
X
X
X
Record concomitant medications used 
to treat AEs
X
X
X
X
X
X
X
a.
Target volume: 5 mL for subjects aged ≥24 months to <4 years at the time of blood draw and approximately 10 mL for those aged ≥4 years at the time of 
blood draw.  Collect the blood sample only if the subject is eligible for vaccination on the same day.
b.
Between visits, review the e-diary data online at frequent intervals to ensure the parent(s)/legal guardian is completing the e-diary appropriately. Contact the 
parent(s)/legal guardian in order to obtain stop dates for any local reactions, systemic events, or use of antipyretic medication (including the type of 
medication) that was ongoing on the last day that the e-diary was completed.
c.
Checklist includes questions regarding newly diagnosed chronic medical conditions, neuroinflammatory and autoimmune conditions, medically attended 
AEs, and missed days of school.
Abbreviations: AE = adverse event; DTaP = diphtheria, tetanus, and acellular pertussis; e-diary = electronic diary; HPV = human papillomavirus;
PRP-OMP = polyribosylribitol phosphate oligosaccharide of Haemophilus influenzae type b conjugated to outer membrane protein; SAE = serious adverse event.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................19
1. INTRODUCTION ...............................................................................................................20
1.1. Mechanism of Action/Indication.............................................................................20
1.2. Background and Rationale ......................................................................................20
1.2.1. Neisseria meningitidis Disease Background ..............................................20
1.2.2. Bivalent Recombinant Lipoprotein 2086 Vaccine .....................................21
1.2.3. Functional Antibody Assay as a Surrogate of Efficacy..............................21
1.2.4. Clinical Experience.....................................................................................22
1.2.5. Study Rationale...........................................................................................23
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................24
2.1. Objectives................................................................................................................24
2.1.1. Primary Immunogenicity Objectives..........................................................24
2.1.2. Primary Safety Objective............................................................................24
2.1.3. Secondary Objectives .................................................................................24
2.1.4. Exploratory Objective.................................................................................25
2.2. Endpoints.................................................................................................................25
2.2.1. Primary Immunogenicity Endpoints...........................................................25
2.2.2. Primary Safety Endpoints...........................................................................25
2.2.3. Secondary Immunogenicity Endpoints.......................................................27
2.2.4. Exploratory Endpoints................................................................................27
3. STUDY DESIGN.................................................................................................................28
3.1. Description ..............................................................................................................28
3.2. Approximate Duration of Subject Participation......................................................29
3.3. Approximate Duration of the Study........................................................................29
3.4. Approximate Number of Subjects...........................................................................30
4. SUBJECT SELECTION......................................................................................................30
4.1. Inclusion Criteria.....................................................................................................30
4.2. Exclusion Criteria....................................................................................................31
4.3. Criteria for Temporarily Delaying Vaccine Administration...................................32
4.4. Criteria for Temporarily Delaying Blood Collection..............................................32

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4.5. Lifestyle Guidelines ................................................................................................33
4.6. Sponsor’s Qualified Medical Personnel..................................................................33
5. INVESTIGATIONAL PRODUCTS ...................................................................................34
5.1. Allocation to Investigational Product......................................................................34
5.2. Breaking the Blind ..................................................................................................35
5.3. Subject Compliance.................................................................................................35
5.4. Investigational Product Supplies.............................................................................35
5.4.1. Dosage Form(s) and Packaging..................................................................35
5.4.2. Preparation and Dispensing........................................................................36
5.5. Administration.........................................................................................................36
5.6. Investigational Product Storage ..............................................................................37
5.7. Vaccine Accountability...........................................................................................38
5.8. Concomitant Treatment...........................................................................................38
5.9. Prohibited During the Study....................................................................................38
5.10. Permitted During the Study...................................................................................39
5.11. Prior Treatment .....................................................................................................39
5.11.1. Prohibited Prior Treatments......................................................................40
6. STUDY PROCEDURES .....................................................................................................40
6.1. Informed Consent Process.......................................................................................40
6.2. Visit 1 (Day 1): Vaccination 1 ................................................................................40
6.3. Visit 2 (25 to 35 Days After Visit 1): Post–Vaccination 1 Follow-up....................43
6.4. Visit 3 (42 to 70 Days After Visit 1): Vaccination 2 ..............................................44
6.5. Visit 4 (28 to 42 Days After Visit 3): Post–Vaccination 2 Blood Draw.................46
6.6. Visit 5 (105 to 126 Days After Visit 3): Vaccination 3 ..........................................47
6.7. Visit 6 (28 to 42 Days After Visit 5): Post–Vaccination 3 Blood Draw.................49
6.8. Visit 7 (168 to 196 Days After Visit 5) Month 12 Follow-up and Blood Draw .....51
6.9. Unscheduled Visits..................................................................................................51
6.10. Subject Withdrawal...............................................................................................52
6.10.1. Final Telephone Contact for Withdrawn Subjects (168 to 196 Days 
After Last Study Vaccination) .........................................................................53
7. ASSESSMENTS..................................................................................................................54
7.1. Immunogenicity ......................................................................................................54

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7.1.1. Serum Sample Storage................................................................................54
7.1.2. Bivalent rLP2086 Serum Bactericidal Assay–Primary Test Strains ..........55
7.1.3. Additional Assays.......................................................................................55
7.2. Safety.......................................................................................................................56
7.2.1. Physical Examination .................................................................................56
7.2.2. Reactogenicity: E-Diary Events .................................................................56
7.3. Pregnancy Testing...................................................................................................57
7.4. Biological Samples..................................................................................................57
7.5. Electronic Diary ......................................................................................................57
7.6. Local Reactions.......................................................................................................58
7.6.1. Injection Site Redness and Swelling...........................................................58
7.6.2. Injection Site Pain.......................................................................................59
7.7. Systemic Events ......................................................................................................59
7.7.1. Temperature................................................................................................59
7.7.2. Use of Antipyretic Medication ...................................................................60
7.7.3. Other Systemic Events................................................................................60
7.8. Other Safety Monitoring .........................................................................................60
7.8.1. Adverse Events...........................................................................................60
7.8.2. Immediate Adverse Events.........................................................................60
7.8.3. Medically Attended Adverse Events and Newly Diagnosed Chronic 
Medical Conditions..........................................................................................61
7.8.4. Hospitalizations, Concomitant Medication Use, and Medical Facility 
Visits Associated With Adverse Events ..........................................................61
7.8.5. Memory Aid................................................................................................61
8. ADVERSE EVENT REPORTING......................................................................................62
8.1. Adverse Events........................................................................................................62
8.2. Research-Related Injury..........................................................................................62
8.3. Reporting Period .....................................................................................................63
8.4. Definition of an Adverse Event...............................................................................63
8.5. Medication Errors....................................................................................................64
8.6. Abnormal Test Findings..........................................................................................65
8.7. Serious Adverse Events...........................................................................................65
8.7.1. Protocol-Specified Serious Adverse Events...............................................66

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8.7.2. Potential Cases of Drug-Induced Liver Injury............................................67
8.8. Hospitalization ........................................................................................................68
8.9. Severity Assessment................................................................................................69
8.10. Causality Assessment............................................................................................69
8.11. Exposure During Pregnancy..................................................................................70
8.12. Occupational Exposure .........................................................................................71
8.13. Withdrawal Due to Adverse Events (See Also Section 6.10 Subject 
Withdrawal)...............................................................................................................71
8.14. Eliciting Adverse Event Information ....................................................................71
8.15. Reporting Requirements........................................................................................71
8.15.1. Serious Adverse Event Reporting Requirements .....................................72
8.15.2. Nonserious Adverse Event Reporting Requirements ...............................72
8.15.3. Medical Device Complaint Reporting Requirements...............................73
8.15.4. Sponsor Reporting Requirements to Regulatory Authorities ...................73
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................73
9.1. Sample Size Determination.....................................................................................74
9.2. Immunogenicity Analysis .......................................................................................74
9.2.1. Analysis of Primary Endpoints...................................................................74
9.2.2. Analysis of Secondary Endpoints and Exploratory Endpoints...................74
9.3. Immunogenicity Analysis Populations....................................................................75
9.4. Demographic and Baseline Characteristics.............................................................75
9.5. Safety Analysis........................................................................................................75
9.6. Analysis Timing ......................................................................................................76
9.7. Data Monitoring Committee ...................................................................................76
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................76
11. DATA HANDLING AND RECORD KEEPING .............................................................77
11.1. Case Report Forms/Electronic Data Record .........................................................77
11.2. Record Retention...................................................................................................77
12. ETHICS..............................................................................................................................78
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)...................................78
12.2. Ethical Conduct of the Study ................................................................................78
12.3. Subject Information and Consent..........................................................................78

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12.4. Subject Recruitment ..............................................................................................79
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................79
13. DEFINITION OF END OF TRIAL...................................................................................79
14. SPONSOR DISCONTINUATION CRITERIA ................................................................80
15. PUBLICATION OF STUDY RESULTS..........................................................................80
15.1. Communication of Results by Pfizer ....................................................................80
15.2. Publications by Investigators ................................................................................81
16. REFERENCES ..................................................................................................................82
LIST OF TABLES
Table 1.
Study Design.........................................................................................................29
Table 2.
Bivalent rLP2086 Investigational Product Formulation.......................................36
Table 3.
Grading of Redness and Swelling.........................................................................58
Table 4.
Grading of Pain.....................................................................................................59
Table 5.
Scale for Fever......................................................................................................59
Table 6.
Grading of Other Systemic Events .......................................................................60

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1. INTRODUCTION
1.1. Mechanism of Action/Indication
The development program for the Pfizer investigational Neisseria meningitidis serogroup B 
bivalent recombinant lipoprotein 2086 vaccine (bivalent rLP2086; subfamily A and B; 
Escherichia coli) aims for international licensure with an indication for active immunization 
to prevent invasive meningococcal disease (IMD) caused by Neisseria meningitidis
serogroup B (MnB) in adolescents and young adults, aged 10 through 25 years.
1.2. Background and Rationale
1.2.1. Neisseria meningitidis Disease Background
N meningitidis is a leading cause of bacterial meningitis in infants, adolescents, and young 
adults. In particular, MnB is responsible for approximately two-thirds of the cases of 
observed meningococcal infections in Europe, with an overall case-fatality rate of 6% to 8% 
from 1999 to 2006.1 MnB disease accounts for approximately one-quarter of meningococcal 
cases seen in North America in the areas participating in the Active Bacterial Core 
surveillance program.2 There is substantial morbidity among survivors, including 
neurological disability, limb loss, and hearing loss,1 even when appropriate antibiotic therapy 
is initiated promptly.
While incidence rates of invasive meningococcal disease (IMD) vary with age, they are often 
highest during infancy from age 1 month to 1 year, with a second peak in incidence during 
adolescence. In the United States, during 1998 to 2007, the overall rate of meningococcal 
disease in infants aged less than 2 years was 3.9 per 100,000. In children aged 2 to 10 years,
the incidence was 0.68 per 100,000, with 41% of cases in this age group occurring in 
children aged 2 to 3 years.3 The incidence rate in the youngest age groups is likely due to 
lack of serum bactericidal antibodies,4 and that in adolescents is due to behavioral risk 
factors.5
A number of countries worldwide have included vaccination against meningococcal disease 
in their routine immunization schedules, in accordance with recommendations of the World 
Health Organization – target groups for vaccination vary by country and may include infants, 
children, and/or young adults.6,7,8 In addition, the composition of the vaccine(s) 
recommended may also vary according to the epidemiology of the particular country.  Until 
recently, meningococcal vaccines have been directed against the organism’s capsular 
polysaccharide and are available to prevent invasive disease caused by serogroups A, C, W, 
and Y.  However, vaccine candidates aimed at producing antibodies to the capsular 
polysaccharide of serogroup B N meningitidis are unlikely to be useful, because they are 
poorly immunogenic. The serogroup B capsular polysaccharide is composed of polysialic 
acid repeating units that are chemically similar to molecules found on human neuronal cells; 
the poor immunogenicity is probably a result of cross-reactive epitopes between the 
serogroup B capsular polysaccharide and similar epitopes found on neuronal cells.9 Vaccines 
produced from outer membrane vesicles (OMVs) prepared from MnB strains have been 
shown to have clinical efficacy against homologous strains in children older than 4 years, but 
not against heterologous strains. A recombinant, multicomponent MnB vaccine (Bexsero) is

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licensed in Europe, Canada, Australia, Chile, and the United States. Trumenba®
(bivalent rLP2086), developed by Pfizer, is approved in the United States for use in 
individuals 10 through 25 years of age for active immunization to prevent IMD caused by 
MnB. Recommendations for MnB vaccination are under consideration in various countries.
However, to date, no broadly effective vaccine against MnB disease is available worldwide. 
General availability of a safe and immunogenic MnB vaccine remains an unmet medical 
need, and a successful vaccine will provide substantial improvement in prevention of 
meningococcal infection and a reduction in the burden of disease.10,11
1.2.2. Bivalent Recombinant Lipoprotein 2086 Vaccine
Bivalent rLP2086 is a subcapsular protein vaccine based on major, antigenically stable, 
surface components that are expressed in most meningococci that cause invasive disease.12
Bivalent rLP2086 is targeted to a conserved, surface-exposed lipoprotein, lipoprotein 2086 
(LP2086), a meningococcal virulence factor that binds human factor H.13 The LP2086 gene 
is present in 100% of N meningitidis serogroup B strains in Pfizer’s strain collection of more 
than 1800 strains isolated from patients with invasive disease in the United States and 
Europe. The LP2086 protein is divided into 2 subfamilies. Subfamily B proteins are 
expressed in approximately 70% of isolates, and subfamily A proteins are expressed in 
approximately 30% of isolates. rLP2086 has been expressed in Escherichia coli and 
formulated in a bivalent vaccine composed of 1 subfamily A strain and 1 subfamily B strain 
of rLP2086. The recombinant proteins have been characterized biochemically and, in several 
animal species, have elicited bactericidal antibodies effective against subfamily A and B 
strains.14
1.2.3. Functional Antibody Assay as a Surrogate of Efficacy
MnB clearance from the bloodstream is primarily by complement-mediated bacteriolysis, 
and an effective complement system is critical for resistance against infections caused by 
MnB. Individuals with complement deficiencies have an increased risk of developing MnB 
disease.15,16 The in vivo complement-mediated bacteriolysis of MnB is mimicked by the 
in vitro serum bactericidal assay using human complement (hSBA), a functional serological 
assay shown to be the correlate of protection against IMD and recognized as the surrogate 
marker of vaccine efficacy.17
Disease incidence of MnB is approximately 1 in 100,000, meaning that extremely large 
numbers of subjects (400,000 to over 6 million) would be required to support a statistically 
significant assessment.
The sponsor has built an extensive MnB strain collection (N=1263) composed of 
IMD-causing isolates from Years 2000 to 2006. The isolates were systematically collected 
from the United States (US) Centers for Disease Control and Prevention (CDC) and health 
and reference laboratories from European countries.18 The rLP2086 gene was sequenced 
from each isolate to determine the sequence heterogeneity of these clinically relevant 
isolates.  In vitro surface expression of LP2086 was determined by flow cytometry to assess 
the surface accessibility of the LP2086 protein and potential susceptibility to killing in hSBA 
by immune sera to LP2086. Immunity elicited by vaccinating with bivalent rLP2086 

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(containing subfamily A and subfamily B rLP2086) will be determined using hSBAs against 
4 MnB test strains.
Briefly, the 4 primary MnB test strains for hSBA representative for LP2086 subfamily A and 
B variants were selected from the clinically relevant strain pool of N=1263 MnB isolates, 
taking into account the population distribution of LP2086 surface expression.18 It was known 
from earlier studies that in vitro surface expression of LP2086 is an important predictor of
hSBA susceptibility. Thus, only MnB strains with LP2086 surface-expression levels above 
that threshold (majority of isolates) were candidates for random selection of primary MnB 
test strains to be used in hSBAs supporting late-phase clinical studies. This approach, 
coupled with identification of epidemiologically prevalent (circulating) strains in the United 
States and Europe, was used to select the 4 Phase 3 primary MnB test strains: 2 each from 
subfamilies A and B. Two (2) MnB test strains (ie, 1 from subfamily A [
 and 1
from subfamily B [
 were selected in an unbiased fashion, while the other 2 test 
strains (i.e., 1 from subfamily A [
 and 1 from subfamily B [
 were 
selected based on epidemiological prevalence. These 4 test strains will be used for 
determination of the primary immunogenicity endpoints. A similar approach was used to 
select the 10 Phase 3 secondary MnB test strains for evaluation.
1.2.4. Clinical Experience
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.2.5. Study Rationale
The target population for the initial vaccine indication is subjects aged 10 to 25 years. Two 
(2) studies (B1971017 and B1971035) will together explore the immunogenicity and safety 
of the vaccine in children from 12 months up to 10 years of age. This study will assess the 
immunogenicity, safety, and tolerability of bivalent rLP2086 at the 120-g dose level (final 
formulation) administered to healthy subjects aged 24 months to <10 years as part of a 
Month 0, 2, and 6 schedule. Approximately 400 subjects will be randomized to 1 of 2 groups 
in a 3:1 ratio. Group 1 will receive bivalent rLP2086 at Month 0 (Visit 1) followed by 
subsequent vaccinations at Months 2 and 6. Group 2 will receive HAV vaccine at Month 0 
(Visit 1) and Month 6 and an injection with saline at Month 2. Randomization will be 
stratified to ensure that equal numbers of subjects are included in the 24-month to <4-year 
and 4-year to <10-year age groups.
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Risk/Benefits
Refer to the most recent version of the bivalent rLP2086 IB for a summary of findings from 
nonclinical studies that potentially have clinical significance and from clinical studies that are 
relevant to this study.  Also refer to the most recent version of the bivalent rLP2086 IB for a 
summary of the known and potential risks and benefits, if any, to human subjects.
Refer to the most recent version of the licensed pediatric HAV vaccine USPI for a summary 
of the known and potential risks and benefits, if any, to human subjects.
There may be pain and/or bruising with blood collections or with vaccine injection.
Any newly identified risks to the subjects must be reported promptly by the sponsor to the 
investigators.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Immunogenicity Objectives

To describe the immune response as measured by hSBA performed with 4 primary MnB 
test strains, 2 expressing an LP2086 subfamily A protein and 2 expressing an LP2086 
subfamily B protein, measured 1 month after the third vaccination with bivalent rLP2086, 
in healthy subjects aged 24 months to <4 years at study entry.

To describe the immune response as measured by hSBA performed with 4 primary MnB 
test strains, 2 expressing an LP2086 subfamily A protein and 2 expressing an LP2086 
subfamily B protein, measured 1 month after the third vaccination with bivalent rLP2086, 
in healthy subjects aged 4 years to <10 years at study entry.
2.1.2. Primary Safety Objective

To evaluate the safety profile of bivalent rLP2086 compared to a control (HAV vaccine), 
as measured by local reactions, systemic events, AEs, SAEs, newly diagnosed chronic 
medical conditions, medically attended AEs, and immediate AEs in healthy subjects aged 
24 months to <4 years and in healthy subjects aged 4 years to <10 years at study entry, 
and in both age strata combined.
2.1.3. Secondary Objectives

To describe the immune response as measured by hSBA performed with 4 primary MnB 
test strains, 2 expressing an LP2086 subfamily A protein and 2 expressing an LP2086 
subfamily B protein, measured 1 month after the third vaccination with bivalent rLP2086, 
in healthy subjects aged 24 months to <10 years at study entry (ie, in both age strata 
combined).

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
To describe the immune response as measured by hSBA performed with 4 primary MnB 
test strains, 2 expressing an LP2086 subfamily A protein and 2 expressing an LP2086 
subfamily B protein, measured 1 month after the second vaccination and 6 months after 
the third vaccination with bivalent rLP2086, in healthy subjects aged 24 months to 
<4 years at study entry, in healthy subjects aged 4 years to <10 years at study entry, and 
in both age strata combined.
2.1.4.
 
 
 
2.2. Endpoints
Because of the possibility of limited volumes of sera, for all primary and secondary 
immunogenicity endpoints, approximately 50% of subjects randomly selected from each age 
stratum/group will be tested for hSBA on strain 
 (variant A22) and 
(B24), 
and the remaining 50% of subjects from each age stratum/group will be tested for hSBA on 
 (A56) and 
 (B44).
 
The lower limit of quantitation (LLOQ) for 
 (A22) is 1:16. The LLOQ for the other 
3 primary test strains is 1:8.
2.2.1. Primary Immunogenicity Endpoints

Proportion of subjects aged 24 months to <4 years (at study entry) with hSBA titer 
LLOQ for each of the 4 primary MnB test strains 1 month after the third vaccination 
with bivalent rLP2086.

Proportion of subjects aged 4 years to <10 years (at study entry) with hSBA titer 
LLOQ for each of the 4 primary MnB test strains 1 month after the third vaccination 
with bivalent rLP2086.
2.2.2. Primary Safety Endpoints
The following endpoints will be applicable in healthy subjects aged 24 months to <4 years 
and in healthy subjects aged 4 years to <10 years at study entry, and in both age strata 
combined:

Percentage of subjects reporting local reactions (pain, redness, and swelling) and by 
severity after each vaccination visit.
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
Percentage of subjects reporting systemic events (fever, vomiting, diarrhea, headache, 
fatigue, muscle pain other than muscle pain at any injection site, and joint pain) and by 
severity after each vaccination visit.

Percentage of subjects reporting the use of antipyretic medication after each vaccination 
visit.

Percentage of subjects with at least 1 SAE during the following time periods:

30 Days after each vaccination.

30 Days after any vaccination.

During the vaccination phase (from the first study vaccination [Visit 1] through 
1 month after the last study vaccination [Visit 6]).

During the follow-up phase (from 1 month after the last study vaccination [Visit 6]
through 6 months after the third study vaccination [Visit 7]).

Throughout the study period (from the first study vaccination [Visit 1] through 
6 months after the third study vaccination [Visit 7]).

Percentage of subjects with at least 1 medically attended AE occurring during the 
following time periods:

30 Days after each vaccination.

30 Days after any vaccination.

During the vaccination phase (from the first study vaccination [Visit 1] through 
1 month after the last study vaccination [Visit 6]).

During the follow-up phase (from 1 month after the last study vaccination [Visit 6]
through 6 months after the third study vaccination [Visit 7]).

Throughout the study period (from the first study vaccination [Visit 1] through 
6 months after the third study vaccination [Visit 7]).

Percentage of subjects with at least 1 newly diagnosed chronic medical condition 
occurring during the following time periods:

30 Days after each vaccination.

30 Days after any vaccination.

During the vaccination phase (from the first study vaccination [Visit 1] through 
1 month after the last study vaccination [Visit 6]).

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
During the follow-up phase (from 1 month after the last study vaccination [Visit 6]
through 6 months after the third study vaccination [Visit 7]).

Throughout the study period (from the first study vaccination [Visit 1] through 
6 months after the third study vaccination [Visit 7]).

Percentage of subjects with at least 1 AE occurring during the following time periods:

30 Days after each vaccination.

30 Days after any vaccination.

During the vaccination phase (from the first study vaccination [Visit 1] through 
1 month after the last study vaccination [Visit 6]).

Percentage of subjects reporting at least 1 immediate AE after each vaccination.

For subjects at school, days of school missed because of AEs during the vaccination 
phase (Visit 1 though Visit 6).
2.2.3. Secondary Immunogenicity Endpoints
In healthy subjects aged 24 months to <10 years at study entry:

Proportion of subjects with hSBA titer LLOQ for each of the 4 primary MnB test 
strains 1 month after the third vaccination with bivalent rLP2086.
In healthy subjects aged 24 months to <4 years at study entry, in healthy subjects aged 
4 years to <10 years at study entry and in both age strata combined:

Proportion of subjects with hSBA titer LLOQ for each of the 4 primary MnB test 
strains 1 month after the second vaccination and 1 and 6 months after the third 
vaccination with bivalent rLP2086.

Proportions of subjects achieving hSBA titers of 1:4, 1:8, 1:16, 1:32, 1:64, and 
1:128 for each of the 4 primary test strains at baseline, 1 month after the second
vaccination, and 1 and 6 months after the third vaccination with bivalent rLP2086.

hSBA GMTs for each of the 4 primary test strains at baseline, 1 month after the second
vaccination, and 1 and 6 months after the third vaccination with bivalent rLP2086.
2.2.4.
 
 
 
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3. STUDY DESIGN
3.1. Description
This is a Phase 2, randomized, controlled, observer-blinded, multicenter study in which
approximately 400 subjects will be randomly assigned to 1 of 2 groups in a 3:1 ratio.
Group 1 will receive bivalent rLP2086 at Month 0 (Visit 1) followed by subsequent 
vaccinations at Months 2 and 6. Group 2 will receive a licensed pediatric HAV vaccine at 
Month 0 (Visit 1) and Month 6 and an injection with saline at Month 2. Randomization will 
be stratified to ensure that equal numbers of subjects are included in the 24-month to 
<4-year age group and the 4-year to <10-year age group.
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This study is designed to assess the immunogenicity, safety, and tolerability of bivalent 
rLP2086 at the 120-g dose level administered to healthy subjects aged 24 months to 
<10 years as part of a Month 0, 2, and 6 schedule. Follow-up visits will be conducted 
1 month after each vaccination and 6 months after the third vaccination to collect safety data 
and/or a blood sample.
Table 1.
Study Design
Vax 1
Post–
Vax 1 
Follow-
up 
Vax 2
Post–Vax 2 
Blood 
Draw
Vax 3
Post–Vax 3 
Blood 
Draw
Month 12
Follow-up and 
Blood Draw
Visit 
number
1
2
3
4
5
6
7
Approx 
month
0
1
2
3
6
7
12
Group 1 
(300)
Bivalent 
rLP2086
Bivalent 
rLP2086
Bivalent 
rLP2086
Group 2
(100)
HAV 
vaccine
Saline
HAV 
vaccine
Blood draw
5-10 mL
5-10 mL
5-10 mL
5-10 mL
Abbreviations: HAV = hepatitis A virus; Vax = vaccination.
Subject enrollment will be stratified according to age. The study will enroll approximately 
200 subjects aged 24 months to <4 years and approximately 200 subjects aged 4 to 
<10 years. Age stratification will ensure equal representation of both age groups.
HAV vaccine administered at Months 0 and 6 has been chosen as the control in this study in 
order that those randomized to the control group receive a personal benefit from participating 
in the study. In comparison to other recommended vaccines for this age group, HAV vaccine
has a well-established tolerability profile. In addition, HAV vaccine will provide protection
to subjects who may become at increased risk for hepatitis A viral infection either during 
future travel or other exposures. The generally recommended regimen for HAV vaccine is 
2 doses at Months 0 and 6. In this study, saline is given at Month 2 to maintain the study 
blind.
3.2. Approximate Duration of Subject Participation
Subjects will participate in the study for up to 13 months. The duration of subject 
participation is calculated using the last day of each of the visit windows.
3.3. Approximate Duration of the Study
This study will be completed in approximately 20 months.

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3.4. Approximate Number of Subjects
Approximately 400 subjects will participate in this study. Subjects withdrawn from the study 
will not be replaced, regardless of the reason for withdrawal.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled. The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document (ICD) indicating 
that the subject’s parent(s)/legal guardian has been informed of all pertinent aspects of 
the study.
2. Parent(s)/legal guardian and subject who are willing and able to comply with scheduled 
visits, vaccine regimen, laboratory tests, and other study procedures.
3. Male or female subjects aged 24 months and <10 years at time of randomization, 
stratified equally by age (24 months to <4 years or 4 years to <10 years).
4. Subject is available for the entire study period and subject’s parent(s)/legal guardian can 
be reached by telephone.
5. Healthy subject as determined by medical history, physical examination, and judgment of 
the investigator.
6. Subject must have received all vaccinations in the relevant national immunization 
program (NIP) for their age group.
7. Male and female subjects of childbearing potential and at risk for pregnancy must agree 
to use a highly effective method of contraception throughout the study. A subject is of 
childbearing potential if, in the opinion of the investigator, he/she is biologically capable 
of having children and is sexually active.  Refer to Section 4.5 for further information.
8. Negative urine pregnancy test for all female subjects who are biologically capable of 
having children.

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4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
1. Previous vaccination with any meningococcal serogroup B vaccine.
2. Subjects who have received prior HAV vaccination.
3. Contraindication to vaccination with any HAV vaccine or known latex allergy.
4. Subjects receiving any allergen immunotherapy with a nonlicensed product or subjects 
receiving allergen immunotherapy with a licensed product and who are not on stable 
maintenance doses.
5. A previous anaphylactic reaction to any vaccine or vaccine-related component.
6. Bleeding diathesis or condition associated with prolonged bleeding time that would 
contraindicate intramuscular injection.
7. A known or suspected defect of the immune system that would prevent an immune 
response to the vaccine, such as subjects with congenital or acquired defects in B-cell 
function, those receiving chronic systemic (oral, intravenous, or intramuscular) 
corticosteroid therapy, or those receiving immunosuppressive therapy. Subjects with 
terminal complement deficiency may be included.  Additional details will be provided in 
the study reference manual (SRM).
8. History of microbiologically proven disease caused by N meningitidis or Neisseria 
gonorrhoeae.
9. Significant neurological disorder or history of seizure (excluding simple febrile seizure).
10. Receipt of any blood products, including immunoglobulin, within 6 months before the 
first study vaccination.
11. Current chronic use of systemic antibiotics.
12. Participation in other studies involving investigational product(s)/device(s) (Phases 1-4) 
within 28 days before administration of the first study vaccination. Participation in 
purely observational studies is acceptable.
13. Any neuroinflammatory or autoimmune condition, including but not limited to transverse 
myelitis, uveitis, optic neuritis, and multiple sclerosis.
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.

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15. Pregnant female subjects, breastfeeding female subjects, male subjects with partners who 
are currently pregnant, or male and female subjects of childbearing potential who are 
unwilling or unable to use a highly effective method of contraception as outlined in this 
protocol for the duration of the study.
16. Subjects who are children of investigational site staff members directly involved in the 
conduct of the study and their family members, subjects who are children of site staff 
members otherwise supervised by the investigator, or subjects who are children of Pfizer 
employees directly involved in the conduct of the study.
4.3. Criteria for Temporarily Delaying Vaccine Administration
The following conditions are temporary or self-limiting and a subject may be vaccinated 
once the conditions have resolved and the subject is eligible for vaccination:
1. Current febrile illness (temperature 38.0C [100.4F]) or other acute illness within 
48 hours before investigational product administration.
2. Subject has received prophylactic antipyretic medication or other pain medication to 
prevent symptoms associated with investigational product on the planned day of 
vaccination.
3. Subject has received a nonlive vaccine (or intramuscular/sublingual allergen 
immunotherapy) within 14 days, or live vaccine within 28 days, before investigational 
product administration.
4. Subject has received any nonstudy meningococcal vaccines or any vaccine containing all 
or individual antigens included in diphtheria, tetanus, and acellular pertussis (DTaP) or 
human papillomavirus (HPV) vaccines within the previous 28 days. See Section 5.9.
5. Subject is less than 5 days into a course of systemic antibiotic therapy.
6. Subject has received systemic (oral, intravenous, or intramuscular) corticosteroid therapy 
within the previous 28 days.
If a subject meets any delay criteria for vaccination, all study procedures, including blood 
sample collection relating to that visit, should be delayed until the day of vaccination.  Blood 
samples must always be collected prior to vaccination.
4.4. Criteria for Temporarily Delaying Blood Collection
The following condition is temporary or self-limiting and blood may be drawn once the 
condition has resolved and the subject is eligible for blood collection:
1. Subject has received systemic antibiotic therapy within the last 5 days.

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4.5. Lifestyle Guidelines
All male and female subjects who, in the opinion of the investigator, are biologically capable 
of having children and are sexually active must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the study. The investigator, or 
his/her designee, in consultation with the subject and parent(s)/legal guardian, will select the 
most appropriate method of contraception for the individual subject from the permitted list of 
contraception methods, and instruct the subject in its consistent and correct use. Subjects 
need to affirm that they meet at least one of the selected methods of contraception.  The 
investigator or his/her designee will discuss with the subject the need to use highly effective 
contraception consistently and correctly according to the schedule of activities and document 
such conversation in the subject’s chart.  In addition, the investigator, or his/her designee,
will instruct the subject to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, inserted, injected, or implanted hormonal methods of 
contraception are allowed provided the subject plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used with a spermicide (ie, foam, gel, film, cream, 
suppository).
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
4.6. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the SRM.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subject and parent(s)/legal guardian are provided with a contact card.  
The contact card contains, at a minimum, protocol and investigational compound identifiers, 
subject study number, contact information for the investigational site, and contact details for 
a help desk in the event that the investigational site staff cannot be reached to provide advice 
on a medical question or problem originating from another healthcare professional not 
involved in the subject’s participation in the study.  The help desk number can also be used 
by investigational staff if they are seeking advice on medical questions or problems;
however, it should only be used in the event that the established communication pathways 

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between the investigational site and the study team are not available.  It is therefore intended 
to augment, but not replace, the established communication pathways between the 
investigational site and study team for advice on medical questions or problems that may 
arise during the study.  The help desk number is not intended for use by the subject’s 
parent(s)/legal guardian directly and if a subject’s parent(s)/legal guardian calls that number,
he/she will be directed back to the investigational site.
5. INVESTIGATIONAL PRODUCTS
Subjects will receive 1 dose of 120 g of bivalent rLP2086 or HAV vaccine/saline/HAV 
vaccine at Months 0, 2, and 6 according to the Schedule of Activities.
Standard vaccination practices must be observed and vaccine must not be injected into blood 
vessels.  Appropriate medication and other supportive measures for management of an acute 
hypersensitivity reaction should be available in accordance with local guidelines for standard 
immunization practices.
Only an unblinded, medically qualified member of the study staff will administer the 
investigational products. Investigational product administration details (ie, date of
administration, kit number, volume, route, and site of administration) will be recorded on the 
case report form (CRF). Investigational product accountability will be documented as per
Section 5.7.
For the purpose of vaccine administration, a medically qualified member of the study staff is 
a study physician or a study nurse, as applicable to the investigator’s local practice.
In the event of a product quality complaint, which is defined as a report regarding a physical, 
chemical, microbiologic, or other alleged defect of a Pfizer Vaccine Research investigational 
product, the investigator or designee will telephone the appropriate person as detailed in the 
SRM and follow the instructions therein.
5.1. Allocation to Investigational Product
Allocation of subjects to vaccine groups will proceed through the use of an interactive 
response technology (IRT) system that is accessible 24 hours a day, 365 days a year. Having 
logged in, the site personnel (study coordinator or specified designee) will be required to 
enter or select certain information including but not limited to the user’s identification (ID)
and password, protocol number, the subject number, and the date of birth of the subject. The 
site personnel will then be provided with a subject randomization number and dispensable 
unit (DU) or container number. The randomization number and the date on which the 
randomization number was assigned will be recorded on the CRF. Once subject numbers, 
DU numbers, and randomization numbers have been assigned, they cannot be reassigned.
The IRT system will provide a confirmation report containing the subject randomization 
number and DU or container number assigned.  The confirmation report must be stored in the 
site’s files.

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There is a 24-hour-a-day, 365-days-a-year IRT help desk available for any questions or 
issues.  The study-specific IRT reference manual will provide contact information and further 
details on the use of the IRT.
5.2. Breaking the Blind
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind.  The method will be either a manual or an electronic process.  Blinding codes should 
only be broken in emergency situations for reasons of subject safety.  In this 
observer-blinded study, the study staff dispensing and administering the vaccine will be 
unblinded, but all other study personnel, including the principal investigator and the sponsor, 
will be blinded. In particular, the individuals who evaluate subject safety as well as the 
subject will be blinded.  Because the study vaccines are different in physical appearance, the 
study vaccine syringes will be labeled in a manner that prevents the study subjects from 
identifying the vaccine type based on its appearance.
The responsibility of unblinded dispenser and administrator must be assigned to an individual 
or individuals who will not participate in the evaluation of any study subjects. Contact 
between the unblinded dispenser and study subjects and unblinded administrator and study 
subjects should be kept to a minimum. The remaining site personnel must not know 
investigational product assignments.
In case of an emergency, when knowledge of the investigational product assignment is 
required for the medical management of an individual subject, it may be unblinded. The 
investigator must notify a member of the study team immediately after determining that it is 
necessary to unblind the assignment. The investigator must also indicate in source 
documents that the blind was broken and provide the date and reason for breaking the blind.
Any AE or SAE associated with breaking the blind must be recorded and reported as 
specified in this protocol.
5.3. Subject Compliance
All doses of investigational product will be administered by the appropriately designated 
study staff at the investigational site.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Bivalent rLP2086 (containing 60 g each of a purified subfamily A and subfamily B 
rLP2086 protein, adsorbed to aluminum in a sterile buffered isotonic suspension) is provided 
in a 0.5-mL dose for injection.

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The bivalent rLP2086 final formulation is described in Table 2.
Table 2.
Bivalent rLP2086 Investigational Product Formulation
Component Grade
Function
Batch Formula
 
 
 
 
 
a
 
 
The investigational products (bivalent rLP2086, HAV vaccine, and saline) will be provided 
by the sponsor to each study site. Study vaccines will be packed and labeled as 
investigational product in accordance with current guidelines and applicable local and legal 
regulatory requirements. Each investigational product will be labeled with a unique 
dispensable unit (DU) or container number.
A licensed pediatric HAV vaccine will be provided in a 0.5-mL dose for injection. 
Information on which licensed pediatric HAV vaccine is to be used is contained in the 
investigational product manual.
The placebo consists of sterile saline solution for injection (0.85% sodium chloride) supplied 
as a 0.5-mL dose.
5.4.2. Preparation and Dispensing
See the dosage and administration instructions (DAI) or package insert for instructions on 
how to prepare the investigational product for administration.  Investigational product should 
be prepared and dispensed by unblinded appropriately qualified and experienced member of 
the study staff (eg, physician, nurse, physician’s assistant, practitioner, or pharmacist) as 
allowed by local, state, and institutional guidance.  The investigational product will be 
administered to subjects who are blinded.
5.5. Administration
Standard vaccination practices must be observed and vaccine must not be injected into blood 
vessels. Appropriate medication and other supportive measures for management of an acute 
hypersensitivity reaction should be available in accordance with local guidelines for standard 
immunization practices.
CCI
C
C
I

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Administration of investigational products should be performed by an appropriately 
qualified, Good Clinical Practice (GCP)-trained, and vaccine-experienced member of the 
study staff (eg, physician, nurse, physician’s assistant, practitioner, pharmacist, or medical 
assistant) as allowed by local, state, and institutional guidance. In this observer-blinded 
study, the study staff dispensing and administering the vaccine will be unblinded, but all 
other study personnel, including the principal investigator and the sponsor, will be blinded.
Investigational product administration details (ie, date of administration, container number, 
volume, route, and site of administration, administration errors) will be recorded on the CRF.
During the study, subjects in Group 1 will be administered bivalent rLP2086 by 
intramuscular injection at Months 0, 2, and 6 into the upper deltoid muscle of the arm.
Subjects in Group 2 will be administered HAV vaccine/saline/HAV vaccine at Months 0, 2, 
and 6 into the upper deltoid muscle of the arm.
5.6. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparative agents and/or marketed products, are 
stored in a secured area with controlled access under recommended storage conditions and in 
accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
vaccine label. For storage, the preferred orientation of the vaccine is horizontal.  See the 
DAI or package insert for storage conditions of the product.
Storage conditions stated in the SRSD will be superseded by the storage conditions stated in 
the labeling.
All vaccines will be shipped at +2C to +8C to each study site upon request. Upon receipt 
at the study site, the vaccines should be immediately transferred to a +2C to +8C 
temperature-monitored refrigerator for storage.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations 
(as applicable, including frozen, refrigerated, and/or room-temperature products).  This 
should be captured from the time of investigational product receipt throughout the study.  
Even for continuous monitoring systems, a log or site procedure that ensures active daily 
evaluation for excursions should be available.  The operation of the temperature monitoring 
device and storage unit (for example, refrigerator), as applicable, should be regularly 
inspected to ensure it is maintained in working order.
Any excursions from the product label storage conditions should be reported upon discovery. 
The site should actively pursue options for returning the product to labeled storage 
conditions, as soon as possible.  Deviations from the storage requirements, including any 
actions taken, must be documented and reported to the sponsor.

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Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.
Specific details regarding temperature monitoring, procedures for the review of temperature 
deviations, and information the site should report for each excursion will be provided to the 
site in the investigational product manual.
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of labeled temperature range are not considered excursions.
5.7. Vaccine Accountability
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the vaccine supplies.
Unused investigational product may be destroyed according to procedures and local 
environmental regulations after all investigational product accountability documentation has 
been completed, unless there are regulatory requirements for this to be returned.  Empty 
investigational product containers may be destroyed after the sponsor has performed 
accountability.  Only outer containers are used to perform accountability while syringes are 
discarded at the point of use. Investigational product return must be documented on the 
accountability log.
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).
5.8. Concomitant Treatment
The name and date of administration of any nonstudy vaccine (or allergen immunotherapy) 
given from the signing of the ICD up to Visit 6 will be recorded on the CRF.
The name, start and stop date, and route of administration for concomitant medications 
(prescription and nonprescription) used to treat an AE (excluding events recorded only in 
electronic diary [e-diary]) from the signing of the ICD to Visit 7 will be recorded in the CRF.
5.9. Prohibited During the Study

Prophylactic antipyretics and other pain medications to prevent symptoms associated 
with investigational product are not permitted. If the subject has received such 
medications prior to a planned administration of investigational product, vaccination 
should be temporarily delayed as specified in Section 4.3.

Receipt of any blood products, including immunoglobulin.

Nonstudy meningococcal vaccines or vaccines containing all or individual antigens 
included in DTaP or HPV vaccines are not permitted before Visit 3 and within 28 days of 
any study vaccination.

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
Receipt of any other serogroup B meningococcal vaccine is prohibited throughout the 
course of the study.

Other nonlive or live nonstudy vaccines are not permitted within 14 and 28 days, 
respectively, of any study vaccination.

Intramuscular/sublingual allergen immunotherapy is not permitted within 14 days of any 
study vaccination.

Systemic (oral, intravenous, or intramuscular) corticosteroid therapy within 28 days of 
any study vaccination.
5.10. Permitted During the Study

Nonstudy vaccines used in the event of a disease outbreak or pandemic are allowed. 
However, while prioritizing standard clinical care, efforts should be made not to 
administer nonstudy vaccines within 14 days (for nonlive vaccines) or 28 days (for live 
vaccine) as specified below.

Nonstudy vaccines (other than any meningococcal vaccines and vaccines containing all 
or individual antigens included in DTaP and HPV vaccines) that are part of 
recommended immunization schedules are allowed anytime during the study but should 
not be administered within 14 days (for nonlive vaccines) and 28 days (for live vaccines) 
of study vaccine administration. Please refer to Section 5.9 regarding restrictions on 
administration other serogroup B meningococcal vaccines and vaccines containing all or 
individual antigens included in the DTaP and HPV vaccines.

Antipyretics and other pain medications to treat symptoms associated with investigational 
product are permitted.

A local anesthetic may be used at the site of the blood draw.

Topical antibiotics are permitted.

Topical and inhaled corticosteroids are permitted.
5.11. Prior Treatment
If the subject is known to have ever received a polyribosylribitol phosphate oligosaccharide 
of Haemophilus influenzae type b conjugated to outer membrane protein (PRP-OMP)
vaccine, the name of the vaccine and date of administration will be recorded on the CRF.
Please refer to the SRM for a list of PRP-OMP–containing vaccines that are or have been 
commercially available.

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If the subject has received any meningococcal vaccines and any vaccines containing all or 
individual antigens included in DTaP or HPV vaccines prior to the study, the trade name 
(if known) and date of administration (mm/yyyy) of the most recent vaccination for each of 
these will be recorded on the CRF. Verbal vaccination history is acceptable and should be 
supplemented with written confirmation if possible.
5.11.1. Prohibited Prior Treatments
The following are prohibited:

Receipt of any blood products, including immunoglobulin, within 6 months before the 
first study vaccination.
6. STUDY PROCEDURES
6.1. Informed Consent Process
The investigator or authorized designee is responsible for obtaining written informed consent 
from the parent(s)/legal guardian for each subject enrolled prior to any study procedures.
Each signature on the ICD must be personally dated by the signatory. A copy of the signed 
and dated ICD will be given to the parent(s)/legal guardian. The subject’s source documents 
must reflect that informed consent was obtained before participation in the study.
A study-specific assent form will be provided to the subject (age dependent on local 
requirements).  It is to be understood as the child’s will to participate in a study after having 
received age-appropriate information, and is sometimes also referred to as “knowing 
agreement.”  It is understood that wherever informed consent is used in this document, this 
also applies to assent for minor subjects.
6.2. Visit 1 (Day 1): Vaccination 1

In the case of temporary delay of vaccination, procedures and assessments below will be 
reperformed or reconfirmed, as applicable, on the day of vaccination.

Obtain written informed consent before performing study-specific procedures. The date 
of informed consent will be recorded on the CRF.

Record the subject’s demographic information (including date of birth, sex, race, and 
ethnicity).

Record the presence of chronic conditions and/or medical history of significance,
including relevant surgical procedures and cardiac medical history.

Record previous PRP-OMP vaccinations as described in the Prior Treatment section 
(Section 5.11).

Record trade name (if known) and date (mm/yyyy) of previous receipt of any
meningococcal vaccine and any vaccine containing all or individual antigens included in 
DTaP and HPV vaccines as described in the Prior Treatment section.

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
Perform a physical examination including height, weight, and vital signs, evaluating any 
clinically significant abnormalities within the following body systems: general 
appearance, skin, head, eyes, ears, nose, throat, heart, lungs, abdomen, extremities, 
neurological, musculoskeletal, and lymph nodes, including worsening of medical history 
conditions. Results must be recorded on source documents and the CRF. Findings from 
a physical examination conducted as part of standard routine care and before informed 
consent may be used for purposes of the study only if the examination was performed no 
more than 2 days before vaccination. A brief examination must be performed on the day 
of vaccination to document that no change in health has occurred in the interim.

On the day of vaccination, perform a urine pregnancy test on all female subjects who are 
biologically capable of having children. A negative pregnancy test result is required 
before the subject may receive the investigational product.

On the day of and before vaccination, measure and record the subject’s temperature
(measured as appropriate for age, according to routine practice) and route by which 
temperature was taken.

Ensure that all of the inclusion criteria, none of the exclusion criteria, and none of the 
temporary delay criteria are met.

If a subject is eligible for the study, enroll and randomize the subject to 1 of the 2 groups 
using the IRT system.

Before vaccination, collect a blood sample (approximately 5 mL for subjects aged 
24 months to <4 years at the time of blood draw and approximately 10 mL for those 
aged 4 years at the time of blood draw) from the subject. Collect the blood sample only 
if the subject is eligible for vaccination on the same day.

Investigational product will be administered by intramuscular injection, by an unblinded 
dispenser, into the upper deltoid muscle of the arm. The time of administration will be 
recorded on the CRF.

Observe the subject for at least 30 minutes after the investigational product 
administration for any acute reactions. Record any AEs observed during the 30-minute 
observation period; these AEs are defined as immediate AEs (Section 7.2).

Record AEs as described in the AE Reporting Requirements section and the 
Schedule of Activities. The time of onset will be recorded for any AEs that occur on the 
same day as investigational product administration.

Record concomitant medications used to treat AEs as described in the Concomitant 
Treatment section (Section 5.8).

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
Issue a subject e-diary and provide instructions on the collection and recording of local 
reactions, systemic events (reactogenicity), and use and type of antipyretic medication. 
Ask the subject’s parent(s)/legal guardian to complete the e-diary from Day 1 to Day 7 
after vaccination, with Day 1 being the day of vaccination. Instructions on daily transfer 
of data and charging the battery should also be provided.

Ask the parent(s)/legal guardian to complete the e-diary from Day 1 to Day 7 after 
vaccination.

Issue a caliper, measuring tape/ruler, and a digital thermometer and provide verbal and 
written instructions on their use.

Agree with the parent(s)/legal guardian, and record in the CRF, which route will be 
used to measure the subject’s temperature using the thermometer provided during the 
7 days after study vaccination.

Ask the parent(s)/legal guardian to use the caliper to measure the maximum diameter 
of redness and swelling at the injection site each day for the 7 days after study 
vaccination and record in the e-diary as described in Section 7.6.1.

Ask the parent(s)/legal guardian to contact the investigator immediately if the subject 
experiences a severe redness or swelling (>14 caliper units) at the injection site, a 
fever 39.0C (102.1F), or a severe headache within 7 days after vaccination, as an 
unscheduled visit should be arranged (Section 6.9).

If the reaction exceeds the maximum size the caliper is able to measure 
(>14 caliper units [Section 7.6.1]), the parent(s)/legal guardian should also use the 
measuring tape/ruler to measure the maximum diameter of redness and/or 
swelling at the injection site, and report this immediately to the investigator.  
These measurements will be recorded in the CRF.

Ask the parent(s)/legal guardian to report the maximum diameter of the redness 
and/or swelling at the injection site to the investigator daily until the reaction 
becomes 14 caliper units.

Ask the parent(s)/legal guardian to contact the investigator immediately if any significant 
illness or hospitalization occurs.

Remind the subject’s parent(s)/legal guardian that nonstudy vaccinations should not be 
administered within a 28-day window (live vaccines) or 14-day window (nonlive 
vaccines) either before or after a study vaccine administration.

Schedule an appointment for the next study visit within the time window per protocol.

Remind the parent(s)/legal guardian to bring the e-diary to the next study visit.

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
Complete the source documents.

Complete the CRFs and update the investigational product accountability records.
Between visits, review the e-diary data online at frequent intervals. Contact the 
parent(s)/legal guardian in order to obtain stop dates for any local reactions, systemic events, 
or use of antipyretic medication that was ongoing on the last day that the e-diary was 
completed. The stop dates should be documented in the source documents and the 
information entered into the CRF at the next study visit of the subject.
6.3. Visit 2 (25 to 35 Days After Visit 1): Post–Vaccination 1 Follow-up

Ensure that the subject continues to be eligible for the study and meets none of the 
withdrawal criteria (Section 6.10).

Review the subject’s e-diary data and follow up on any ongoing reactogenicity or use of 
antipyretic medication.

Complete the Study Visit AE Checklist to:

Inquire whether the subject had any newly diagnosed chronic medical conditions 
since the last visit. Inquire whether the subject had any of the following related to an 
AE since the last visit: hospitalizations, visits to other medical facilities, medication 
use, or missed days of school (if appropriate). Please refer to the SRM for additional 
details.

Inquire about neuroinflammatory and autoimmune conditions, such as transverse 
myelitis, uveitis, optic neuritis, and multiple sclerosis. Please refer to the SRM for 
additional details.

Record AEs as described in the AE Reporting Requirements section and the 
Schedule of Activities.

Review AEs that were ongoing from the previous visit and record their end dates or 
confirm that they are still continuing.

Record concomitant medications used to treat AEs as described in the Concomitant 
Treatment section (Section 5.8).

Record nonstudy vaccinations as described in the Concomitant Treatment section 
(Section 5.8).

Ask the parent(s)/legal guardian to contact the investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the next study visit and confirm that it is scheduled within 
the time window per protocol.

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
Complete the source documents.

Complete the CRFs.
6.4. Visit 3 (42 to 70 Days After Visit 1): Vaccination 2

Ensure that the subject continues to be eligible for the study, meets none of the 
withdrawal criteria (Section 6.10), and meets none of the temporary delay of vaccination 
criteria (Section 4.3).

In the case of temporary delay of vaccination, procedures and assessments below will be 
reperformed or reconfirmed, as applicable, on the day of vaccination.

Complete the Study Visit AE Checklist to:

Inquire whether the subject had any newly diagnosed chronic medical conditions 
since the last visit. Inquire whether the subject had any of the following related to an 
AE since the last visit: hospitalizations, visits to other medical facilities, medication 
use, or missed days of school (if appropriate). Please refer to the SRM for additional 
details.

Inquire about neuroinflammatory and autoimmune conditions, such as transverse 
myelitis, uveitis, optic neuritis, and multiple sclerosis. Please refer to the SRM for 
additional details.

Record AEs as described in the AE Reporting Requirements section and the 
Schedule of Activities. The time of onset will be recorded for any AEs that occur on the 
same day as investigational product administration.

Review AEs that were ongoing from the previous visit and record their end dates or 
confirm that they are still continuing.

Record concomitant medications used to treat AEs as described in the Concomitant 
Treatment section (Section 5.8).

Record nonstudy vaccinations as described in the Concomitant Treatment section 
(Section 5.8).

On the day of vaccination, perform a urine pregnancy test on female subjects who are 
biologically capable of having children. A negative pregnancy test result is required 
before the subject may receive the investigational product.

On the day of and before vaccination, measure and record the subject’s temperature
(measured as appropriate for age, according to routine practice) and route by which 
temperature was taken.

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
Investigational product will be administered by intramuscular injection, by an unblinded 
dispenser, into the upper deltoid muscle of the arm. The time of administration will be 
recorded on the CRF.

Observe the subject for at least 30 minutes (or longer as per local practice) after the 
investigational product administration for any acute reactions. Record any AEs observed 
during the 30-minute observation period; these AEs are defined as immediate AEs 
(Section 7.2).

Ask the parent(s)/legal guardian to complete the e-diary from Day 1 to Day 7 after 
vaccination and provide instructions on the collection and recording of local reactions, 
systemic events (reactogenicity), and use and type of antipyretic medication. Ask the 
subject’s parent(s)/legal guardian to complete the e-diary from Day 1 to Day 7 after 
vaccination, with Day 1 being the day of vaccination. Instructions on daily transfer of 
data and charging the battery should also be provided.

If required, issue a new e-diary, caliper, measuring tape/ruler, or digital thermometer and 
provide instructions for use.

Agree with the parent(s)/legal guardian, and record, which route will be used to 
measure the subject’s temperature during the 7 days after study vaccination.

Ask the parent(s)/legal guardian to use the caliper to measure the maximum diameter 
of redness and swelling at the injection site each day for the 7 days after study 
vaccination and record in the e-diary as described in Section 7.6.1.

Ask the parent(s)/legal guardian to contact the investigator immediately if the subject 
experiences a severe redness or swelling (>14 caliper units) at the injection site, a 
fever 39.0C (102.1F), or a severe headache within 7 days after vaccination, as an 
unscheduled visit should be arranged (Section 6.9).

If the reaction exceeds the maximum size the caliper is able to measure 
(>14 caliper units [Section 7.6.1]), the parent(s)/legal guardian should also use the 
measuring tape/ruler to measure the maximum diameter of redness and/or 
swelling at the injection site, and report this immediately to the investigator.  
These measurements will be recorded in the CRF.

Ask the parent(s)/legal guardian to report the maximum diameter of the redness 
and/or swelling at the injection site to the investigator daily until the reaction 
becomes 14 caliper units.

Ask the parent(s)/legal guardian to contact the investigator immediately if any significant 
illness or hospitalization occurs.

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
Remind the subject’s parent(s)/legal guardian that nonstudy vaccinations should not be 
administered within a 28-day window (live vaccines) or 14-day window 
(nonlive vaccines) before or after a study vaccine administration.

Schedule an appointment for the next study visit within the time window per protocol.

Remind the parent(s)/legal guardian to bring the e-diary to the next visit.

Complete the source documents.

Complete the CRFs and update the investigational product accountability records.
Between visits, review the e-diary data online at frequent intervals. Contact the 
parent(s)/legal guardian to obtain stop dates for any local reactions, systemic events, or use of 
antipyretic medication that was ongoing on the last day that the e-diary was completed. The 
stop dates should be documented in the source documents and the information entered into 
the CRF at the next study visit of the subject.
6.5. Visit 4 (28 to 42 Days After Visit 3): Post–Vaccination 2 Blood Draw

Ensure that the subject continues to be eligible for the study, meets none of the 
withdrawal criteria (Section 6.10), and meets none of the temporary delay of blood draw 
criteria (Section 4.4).

Collect the subject’s e-diary.

Review the subject’s e-diary data since the previous visit and follow up on any ongoing 
reactogenicity or use of antipyretic medication.

Complete the Study Visit AE Checklist to:

Inquire whether the subject had any newly diagnosed chronic medical conditions 
since the last visit. Inquire whether the subject had any of the following related to an 
AE since the last visit: hospitalizations, visits to other medical facilities, medication 
use, or missed days of school (if appropriate). Please refer to the SRM for additional 
details.

Inquire about neuroinflammatory and autoimmune conditions, such as transverse 
myelitis, uveitis, optic neuritis, and multiple sclerosis. Please refer to the SRM for 
additional details.

Record AEs as described in the AE Reporting Requirements section and the 
Schedule of Activities.

Review AEs that were ongoing since the previous visit and record their end dates or 
confirm that they are still continuing.

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
Record concomitant medications used to treat AEs as described in the Concomitant 
Treatment section (Section 5.8).

Record nonstudy vaccinations as described in the Concomitant Treatment section 
(Section 5.8).

Collect a blood sample (approximately 5 mL for subjects aged 24 months to <4 years at 
the time of blood draw and approximately 10 mL for those aged 4 years at the time of 
blood draw) from the subject. Collect the blood sample only if the subject meets none of 
the temporary delay of blood sample collection criteria described in Section 4.4.

Ask the parent(s)/legal guardian to contact the investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the next visit within the time window per protocol.

Complete the source documents.

Complete the CRFs.
6.6. Visit 5 (105 to 126 Days After Visit 3): Vaccination 3

Ensure that the subject continues to be eligible for the study, meets none of the 
withdrawal criteria (Section 6.10), and meets none of the temporary delay of vaccination 
criteria (Section 4.3).

In the case of temporary delay of vaccination, procedures and assessments below will be 
reperformed or reconfirmed, as applicable, on the day of vaccination.

Complete the Study Visit AE Checklist to:

Inquire whether the subject had any newly diagnosed chronic medical conditions 
since the last visit. Inquire whether the subject had any of the following related to an 
AE since the last visit: hospitalizations, visits to other medical facilities, medication 
use, or missed days of school (if appropriate). Please refer to the SRM for additional 
details.

Inquire about neuroinflammatory and autoimmune conditions, such as transverse 
myelitis, uveitis, optic neuritis, and multiple sclerosis. Please refer to the SRM for 
additional details.

Record AEs as described in the AE Reporting Requirements section and the 
Schedule of Activities. The time of onset will be recorded for any AEs that occur on the 
same day as investigational product administration.

Review AEs that were ongoing from the previous visit and record their end dates or 
confirm that they are still continuing.

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
Record concomitant medications used to treat AEs as described in the Concomitant 
Treatment section (Section 5.8).

Record nonstudy vaccinations as described in the Concomitant Treatment section 
(Section 5.8).

On the day of vaccination, perform a urine pregnancy test on female subjects who are 
biologically capable of having children. A negative pregnancy test result is required 
before the subject may receive the investigational product.

On the day of and before vaccination, measure and record the subject’s temperature
(measured as appropriate for age, according to routine practice) and route by which 
temperature was taken.

Investigational product will be administered by intramuscular injection, by an unblinded 
dispenser, into the upper deltoid muscle of the arm. The time of administration will be 
recorded on the CRF.

Observe the subject for at least 30 minutes (or longer as per local practice) after the 
investigational product administration for any acute reactions. Record any AEs observed 
during the 30-minute observation period; these AEs are defined as immediate AEs 
(Section 7.2).

Ask the parent(s)/legal guardian to complete the e-diary from Day 1 to Day 7 after 
vaccination and provide instructions on the collection and recording of local reactions, 
systemic events (reactogenicity), and use and type of antipyretic medication. Ask the 
subject’s parent(s)/legal guardian to complete the e-diary from Day 1 to Day 7 after 
vaccination, with Day 1 being the day of vaccination. Instructions on daily transfer of 
data and charging the battery should also be provided.

If required, issue an e-diary, caliper, measuring tape/ruler, and digital thermometer and 
provide instructions for use.

Agree with the parent(s)/legal guardian, and record, which route will be used to 
measure the subject’s temperature during the 7 days after study vaccination.

Ask the parent(s)/legal guardian to use the caliper to measure the maximum diameter 
of redness and swelling at the injection site each day for the 7 days after study 
vaccination and record in the e-diary as described in Section 7.6.1.

Ask the parent(s)/legal guardian to contact the investigator immediately if the subject 
experiences a severe redness or swelling (>14 caliper units) at the injection site, a 
fever 39.0C (102.1F), or a severe headache within 7 days after vaccination, as an 
unscheduled visit should be arranged (Section 6.9).

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
If the reaction exceeds the maximum size the caliper is able to measure 
(>14 caliper units [Section 7.6.1]), the parent(s)/legal guardian should also use the 
measuring tape/ruler to measure the maximum diameter of redness and/or 
swelling at the injection site, and report this immediately to the investigator.  
These measurements will be recorded in the CRF.

Ask the parent(s)/legal guardian to report the maximum diameter of the redness 
and/or swelling at the injection site to the investigator daily until the reaction 
becomes 14 caliper units.

Ask the parent(s)/legal guardian to contact the investigator immediately if any significant 
illness or hospitalization occurs.

Remind the subject’s parent(s)/legal guardian that nonstudy vaccinations should not be 
administered within a 28-day window (live vaccines) or 14-day window (nonlive 
vaccines) before or after a study vaccine administration.

Schedule an appointment for the next study visit within the time window per protocol.

Remind the parent(s)/legal guardian to bring the e-diary to the next visit.

Complete the source documents.

Complete the CRFs and update the investigational product accountability records.
Between visits, review the e-diary data online at frequent intervals. Contact the 
parent(s)/legal guardian to obtain stop dates for any local reactions, systemic events, or use of 
antipyretic medication that was ongoing on the last day that the e-diary was completed. The 
stop dates should be documented in the source documents and the information entered into 
the CRF at the next study visit of the subject.
6.7. Visit 6 (28 to 42 Days After Visit 5): Post–Vaccination 3 Blood Draw

Ensure that the subject continues to be eligible for the study, meets none of the 
withdrawal criteria (Section 6.10), and meets none of the temporary delay of blood draw 
criteria (Section 4.4).

Collect the subject’s e-diary.

Review the subject’s e-diary data since the previous visit and follow up on any ongoing 
reactogenicity or use of antipyretic medication.

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
Complete the Study Visit AE Checklist to:

Inquire whether the subject had any newly diagnosed chronic medical conditions 
since the last visit. Inquire whether the subject had any of the following related to an 
AE since the last visit: hospitalizations, visits to other medical facilities, medication 
use, or missed days of school (if appropriate). Please refer to the SRM for additional 
details.

Inquire about neuroinflammatory and autoimmune conditions, such as transverse 
myelitis, uveitis, optic neuritis, and multiple sclerosis. Please refer to the SRM for 
additional details.

Record AEs as described in the AE Reporting Requirements section and the 
Schedule of Activities.

Review AEs that were ongoing since the previous visit and record their end dates or 
confirm that they are still continuing.

Record concomitant medications used to treat AEs as described in the Concomitant 
Treatment section (Section 5.8).

Record nonstudy vaccinations as described in the Concomitant Treatment section 
(Section 5.8).

Provide the subject’s parent(s)/legal guardian with a memory aid.  Instruct the 
parent(s)/legal guardian to use the memory aid between Visits 6 and 7 to remind them to 
review any significant illnesses, hospitalizations, newly diagnosed medical conditions, or 
AEs that resulted in evaluation at a medical facility with study site personnel.  Please 
refer to the SRM and Section 7.2 for additional details.

Collect a blood sample (approximately 5 mL for subjects aged 24 months to <4 years at 
the time of blood draw and approximately 10 mL for those aged 4 years at the time of 
blood draw) from the subject. Collect the blood sample only if the subject meets none of 
the temporary delay of blood sample collection criteria described in Section 4.4.

Ask the parent(s)/legal guardian to contact the investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the next visit within the time window per protocol.

Complete the source documents.

Complete the CRFs.

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6.8. Visit 7 (168 to 196 Days After Visit 5) Month 12 Follow-up and Blood Draw

Ensure that the subject meets none of the withdrawal criteria (Section 6.10) and meets 
none of the temporary delay of blood draw criteria (Section 4.4).

Complete the Study Visit AE Checklist to:

Inquire whether the subject had any newly diagnosed chronic medical conditions 
since the last visit. Inquire whether the subject had any of the following related to an 
AE since the last visit: hospitalizations, visits to other medical facilities, medication 
use, or missed days of school (if appropriate). Please refer to the SRM for additional 
details.

Inquire about neuroinflammatory and autoimmune conditions, such as transverse 
myelitis, uveitis, optic neuritis, and multiple sclerosis. Please refer to the SRM for 
additional details.

Record AEs as described in the AE Reporting Requirements section and the 
Schedule of Activities.

Report any SAEs to the sponsor as defined in Section 8.15.1.

Review AEs that were ongoing since the previous visit and record their end dates or 
confirm that they are still continuing.

Record concomitant medications used to treat AEs as described in the Concomitant 
Treatment section (Section 5.8).

Collect a blood sample (approximately 5 mL for subjects aged 24 months to <4 years at 
the time of blood draw and approximately 10 mL for those aged 4 years at the time of 
blood draw) from the subject. Collect the blood sample only if the subject meets none of 
the temporary delay of blood sample collection criteria described in Section 4.4.

Complete the source documents.

Complete the CRFs.
6.9. Unscheduled Visits
If the subject experiences a severe redness or swelling at the injection site (>14 caliper units), 
a temperature 39.0C (102.1F), or a severe headache in the 7 days after vaccination, the 
subject/parent(s)/legal guardian must be contacted and a study site visit must be scheduled as 
soon as possible to assess the extent of the event.  The subject contact will be documented in 
the CRF.

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If the reaction exceeds the maximum size the caliper is able to measure (>14 caliper units), 
ensure the subject has measured the maximum diameter of the redness and/or swelling at the 
injection site using the measuring tape/ruler provided.  Ask the subject to report the 
maximum diameter of the redness and/or swelling at the injection site daily until the reaction 
becomes 14 caliper units.  Record these measurements in the CRF.
At an unscheduled visit, the subject’s temperature should be measured (as appropriate for 
age, according to routine practice) and the symptom that prompted the visit should be 
assessed by a medically qualified member of the study staff. Findings will be recorded in the 
CRF.  If the subject experiences any AEs, these should be recorded on the AE CRF.
If the unscheduled visit does not take place following subject report of fever 39.0C 
(102.1F), severe redness/swelling or severe headache, the reason must be documented in the 
CRF (for example, reaction no longer present or e-diary entry error).
For the purpose of assessments performed during unscheduled visits, a medically qualified 
member of the study staff is a study physician or a study nurse, as applicable to the 
investigator’s local practice.
6.10. Subject Withdrawal
The investigator and/or sponsor may withdraw a subject from the study if deemed 
appropriate at any time. Eligibility criteria as listed under inclusion criteria (refer to
Section 4.1) and exclusion criteria (refer to Section 4.2) should be taken into consideration 
when determining if a subject must be withdrawn. The investigator is not required to repeat 
the physical examination completed at Visit 1, unless clinically indicated.
Reasons why a subject may discontinue or be withdrawn from the study include, but are not 
limited to, AE (including any neuroinflammatory and autoimmune conditions, such as 
transverse myelitis, uveitis, optic neuritis, and multiple sclerosis), parent(s)/legal guardian or 
subject request, investigator request, death, discontinuation of the study by the sponsor, 
protocol violation, and being lost to follow-up. Subjects who have received investigational 
product will not be replaced.
An effort must be made to determine why a subject fails to return for the necessary visits or 
is withdrawn from the study. Information detailing the circumstances leading to the 
withdrawal of a subject from the study, as well as the date of withdrawal, will be recorded on 
the study outcome CRF.

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The decision to withdraw a subject from the study should be discussed with the sponsor.
Every attempt must be made to collect all AEs or SAEs following each vaccination. Any 
AEs or SAEs that are continuing at the time of withdrawal from the study must be followed 
until the events have subsided, until values have returned to baseline, or, in case of 
permanent impairment, until the condition stabilizes. When a subject discontinues or is 
withdrawn from the study, the investigator will notify the sponsor and, when possible, will 
perform the procedures indicated for the next visit and complete the CRFs for Visit 7 
(Month 12 Follow-up and Blood Draw) if the subject has received at least 1 study 
vaccination.
Subjects may withdraw from the study at any time at their own request or parent(s)/legal 
guardian’s request, or they may be withdrawn at any time at the discretion of the investigator 
or sponsor for safety or behavioral reasons or the inability of the subject to comply with the 
protocol-required schedule of study visits or procedures at a given study site. If a subject 
does not return for a scheduled visit, every effort should be made to contact the subject. All 
attempts to contact the subject and information received during contact attempts must be 
documented in the subject’s medical record).  In any circumstance, every effort should be 
made to document subject outcome, if possible. The investigator should inquire about the 
reason for withdrawal, request the subject to return the e-diary, request the subject to return 
for a final visit, if applicable, and follow up with the subject regarding any unresolved AEs.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
6.10.1. Final Telephone Contact for Withdrawn Subjects (168 to 196 Days After Last 
Study Vaccination)

The final telephone contact should occur approximately 6 months after the last study 
vaccination for subjects who have withdrawn; this contact should be attempted for all 
subjects who have withdrawn from the study and who have received at least 1 study 
vaccination, unless they have withdrawn consent.

Contact the subject by telephone and complete the Study Visit/Telephone Contact 
Checklist to:

Inquire about SAEs, newly diagnosed chronic medical conditions, and AEs that 
resulted in evaluation at a medical facility since the last visit.  Please refer to the SRM 
for additional details.

Inquire about neuroinflammatory and autoimmune conditions, such as transverse 
myelitis, uveitis, optic neuritis, and multiple sclerosis.  Please refer to the SRM for 
additional details.

Review AEs that were ongoing since the previous visit and record their end dates or 
confirm that they are still continuing.

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
Report any SAEs to the sponsor as defined in Section 8.15.1.

Record AEs as described in the AE Reporting Requirements section and the 
Schedule of Activities.

Record concomitant medications used to treat AEs as described in the Concomitant 
Treatment section (Section 5.8).

Complete the source documents.

Complete the CRFs.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that
he/she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
7.1. Immunogenicity
To facilitate immunogenicity analysis, subjects will have approximately 5 to 10 mL 
(dependent upon age) of blood collected immediately before Vaccination 1, 1 month after 
Vaccination 2, and 1 and 6 months after study Vaccination 3. Sample collection, storage,
and shipping information can be found in the SRM.
Target volume for blood draw is 5 mL for subjects aged 24 months to <4 years at the time 
of blood draw and approximately 10 mL for those aged 4 years at the time of blood draw.
7.1.1. Serum Sample Storage
All serum samples should be stored in an upright position in a laboratory-grade manual 
defrost freezer that does not cycle and forms ice that must be removed (a non–frost-free 
freezer) and that maintains a temperature of –20C or lower within the limits specified by the 
manufacturer.
It is the responsibility of the investigator(s) (or designee) to record daily freezer temperature 
readings (working days only), to maintain a daily temperature log for the freezer, and to alert 
the sponsor of any deviations. Deviations from storage requirements, including any actions 
taken, must be documented and reported to the sponsor. Guidance on temperature 
monitoring and procedures for the review of temperature deviations will be provided in the 
SRM.

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7.1.2. Bivalent rLP2086 Serum Bactericidal Assay–Primary Test Strains
For assessment of the immune response to bivalent rLP2086, functional antibodies will be 
analyzed in hSBAs using human complement with meningococcal serogroup B strains. The 
hSBA measures antibodies in human sera that result in complement-dependent killing of the 
target meningococcal strain. Four (4) primary test strains, 
 (A22), 
 (A56), 
 (B24), and 
 (B44), will be used in the hSBAs for determination of the 
immunogenicity endpoints in this study. Sera obtained from all subjects prior to the first 
study vaccination, 1 month after the second study vaccination, and 1 and 6 months after the 
third study vaccination will be used in these assays.  The MnB hSBAs will be validated 
before any testing is performed.
Two (2) of the primary strains (
[A22] and 
[B24]) will be tested at each 
blood sampling time points for half of the subjects (in both groups), and the other 2 primary 
strains (
[A56] and 
[B44]) will be tested at each blood sampling time 
point for the remaining half of the subjects.
Once all subjects have completed enrollment (Visit 1), the independent statistical center 
(ISC; a statistical team not involved in the conduct of the study) will provide 2 subject 
listings (50% subjects randomly selected to be tested for A22/B24 and the remaining 50% 
subjects to be tested for A56/B44) to the sponsor’s sample management team. Both listings 
should follow the same randomization ratio (3:1) and age-strata distribution (50% in each 
stratum) as in the study design.
7.1.3. Additional Assays
Additional assays to assess the immune response to the study vaccine may also be conducted. 
 (A22) and 
 (B24) may be tested in serum samples from the 50% of 
subjects who received bivalent rLP2086 and were originally tested for 
 (A56) and 
 (B44). Conversely, 
 (A56) and 
 (B44) may be tested in serum 
samples from the 50% of subjects who received bivalent rLP2086 and were originally tested 
for 
 (A22) and 
 (B24).
The intention, volume of serum permitting, is to obtain data on all 4 primary test strains in as 
many subjects as possible.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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7.2. Safety
Any subject who receives at least 1 dose of investigational product will be included in the 
evaluation for safety. The following safety parameters will be assessed as described in the 
Study Procedures section (Section 6) and the Schedule of Activities:
7.2.1. Physical Examination
The subject’s medical history, physical examination, and vital signs should be obtained and 
documented at Visit 1 to capture baseline information and should include the following as a 
minimum:

Vaccination history, past and present medical and surgical history of significance, 
relevant medication use, and allergies.  When taking the medical history, particular care 
must be taken to note any neuroinflammatory and autoimmune conditions, such as 
transverse myelitis, uveitis, optic neuritis, and multiple sclerosis.

Weight, height (or length for nonwalking subjects), general appearance, skin, head, eyes, 
ears, nose, throat, heart, lungs, abdomen, extremities, neurological status, 
musculoskeletal, and lymph nodes.  Significant observations from the physical 
examination will be documented in the CRF.

In addition, a urine pregnancy test will be performed on all female subjects who are 
biologically capable of having children.
7.2.2. Reactogenicity: E-Diary Events
The safety parameters include reactogenicity, ie, both local reactions and systemic events, 
including fever, that occur in the 7 days (Days 1 to 7) after investigational product 
administration.  These prospectively collected events are considered e-diary events and 
include:

Local reactions at the site of investigational product administration (redness, swelling, 
and pain).

Systemic events (fever, vomiting, diarrhea, headache, fatigue, muscle pain other than 
muscle pain at the injection site, and joint pain).

Local reactions, systemic events, and use and type of antipyretic medication will be 
collected using an e-diary.  Stop dates of local reactions, systemic events, or use of
antipyretic medication that was ongoing on the last day the diary was completed by the 
parent(s)/legal guardian will be collected on the Symptom Resolved Date CRF.

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7.3. Pregnancy Testing
For all female subjects of childbearing potential, a urine pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed immediately before administration of each vaccine dose. 
A negative pregnancy test result is required before the subject may receive the investigational 
product. In the case of a positive confirmed pregnancy test, the subject will be withdrawn 
from investigational product administration but may remain in the study.  Pregnancy tests 
may also be repeated as per request of institutional review boards (IRBs)/ethics committees 
(ECs) or if required by local regulations.
7.4. Biological Samples
Serum samples will be used only for scientific research.  Each sample will be labeled with a 
code so that the laboratory personnel testing the samples will not know the subject’s identity. 
Any remaining sera will be stored, and may be used for additional assays to assess immune 
response to vaccines given as part of this protocol or for assay development.  The sera will 
not be used for any unrelated research and no genetic testing will be performed.  The samples 
will be stored for up to 15 years after the end of the study and then destroyed.
The subject’s parent(s)/legal guardian may request that his or her child’s samples, if still 
identifiable, be destroyed at any time; however, any data already collected from that sample 
will still be used for this research.  The serum samples will remain the property of the 
sponsor and may be shared with other researchers as long as confidentiality is maintained.
7.5. Electronic Diary
The subject’s parent(s)/legal guardian will be issued an e-diary, based on a personal digital 
assistant or equivalent technology, and used to monitor and record the subject’s local 
reactions, systemic events, and use and type of antipyretic medication for 7 days after each 
vaccination. Grading scales for local reactions and systemic events are based on US Food 
and Drug Administration (FDA) Guidance for Industry, Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers in Preventive Vaccine Clinical Trials.19 The e-diary allows 
recording of these assessments only within a fixed time-window, thus providing the accurate 
representation of the subject’s experience at that time. Only the most severe rating for any of 
the local reactions or systemic events each day will be recorded in the e-diary; entry updates 
where the symptom worsens on any day are possible.  End dates of local reactions, systemic 
events, or use of antipyretic medication that was ongoing on the last day the diary was 
completed by the parent(s)/legal guardian will be collected on the CRF. The investigator or 
designee must contact the parent(s)/legal guardian in order to obtain stop dates for any 
e-diary events (such as local reactions and systemic events, including fever) or other e-diary 
events ongoing on the last day that the e-diary was completed.
Data reported on the e-diary will be transferred electronically to the e-diary vendor (a trusted 
third party), where they will be available for review by investigators at all times via an 
Internet-based portal. At intervals agreed upon between the vendor and Pfizer, these data 
will be transferred electronically into Pfizer's database for analysis and reporting. These data 
do not need to be reported by the investigator on the CRF.

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Investigators will be required to review the e-diary data online at frequent intervals to 
evaluate subject compliance and as part of the ongoing safety review.
7.6. Local Reactions
Local reactions (redness, swelling, and pain) at the site of the study vaccine injection will be 
recorded daily for 7 days (Day 1 to Day 7) after each vaccination.
7.6.1. Injection Site Redness and Swelling
Redness and swelling will be measured and recorded in caliper units (range: 1 to 14) for the 
first 7 days following vaccination (Days 1 to 7), and then categorized as mild, moderate, or 
severe based on the scale given below. Each caliper unit represents 0.5 cm. A caliper will be 
issued with instructions for measuring any redness or swelling at the injection site. The 
caliper will be used to measure and to report the largest diameter of a local reaction. In the 
event that a caliper measurement is between 2 values, the higher value should be reported.
The measurements will then be recorded in the e-diary.
In the event the reaction exceeds the maximum size the caliper is able to measure 
(>14 caliper units), the parent(s)/legal guardian will also measure the maximum diameter of 
the redness and/or swelling at the injection site using the measuring tape/ruler provided and 
report this immediately to the investigator.  The parent(s)/legal guardian will report the 
maximum diameter of the redness and/or swelling at the injection site to the investigator 
daily until the reaction becomes 14 caliper units.  These measurements will be recorded in 
the CRF.
Table 3.
Grading of Redness and Swelling
Mild
0.5 to 2.0 cm (1 to 4 caliper units)
Moderate
2.5 to 7.0 cm (5 to 14 caliper units)
Severe
>7.0 cm (>14 caliper units)

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7.6.2. Injection Site Pain
The parent(s)/legal guardian will be asked to assess whether pain is present at the injection 
site for the first 7 days following vaccination (Day 1 to Day 7).  If the subject experiences 
injection site pain, the pain will be graded using the following scale:
Table 4.
Grading of Pain
Mild
Does not interfere with activity
Moderate
Interferes with activity
Severe
Prevents daily activity
The assessment will then be recorded in the e-diary.
7.7. Systemic Events
7.7.1. Temperature
A digital thermometer will be given to the parent(s)/legal guardian with instructions on how 
to measure their child’s temperature at home. Temperature will be collected at bedtime daily 
for 7 days (Day 1 to Day 7) after each vaccination, and at any time during the 7 days when 
fever is suspected. The highest temperature for each day will be recorded in the e-diary.
Fever is defined as temperature of 38.0C (100.4F).  The subject’s temperature should be 
measured using the thermometer provided and using a method appropriate for the age of the 
child. The route of temperature measurement will be recorded in the CRF.
Temperature will be measured and recorded to 1 decimal place and then categorized 
according to the following scale:
Table 5.
Scale for Fever
Temperature 38.0C to 38.4C (100.4F to 101.1F)
Temperature 38.5C to 38.9C (101.2F to 102.0F)
Temperature 39.0C to 39.4C (102.1F to 103.0F)
Temperature >39.5C to 40.0C (103.1F to 104.0F)
Temperature >40.0C (>104.0F)

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7.7.2. Use of Antipyretic Medication
Prophylactic antipyretics and other pain medications to prevent symptoms associated with 
investigational product are not permitted. If the subject has received such medications prior 
to a planned administration of investigational product, vaccination should be temporarily 
delayed as specified in Section 4.3.
Antipyretics and other pain medications to treat symptoms associated with investigational 
product are permitted.
The use and type of antipyretic medication will be recorded in the e-diary daily during the 
active safety observation period (Day 1 to Day 7) for each vaccination.
7.7.3. Other Systemic Events
The e-diary will be used to record the presence of other systemic events, including vomiting, 
diarrhea, headache, fatigue, muscle pain other than muscle pain at the injection site, and joint 
pain daily for 7 days (Day 1 to Day 7) after each vaccination, using the following scales:
Table 6.
Grading of Other Systemic Events
Grade 1
(Mild)
Grade 2
(Moderate)
Grade 3
(Severe)
Vomiting
1 to 2 times in 24 hours
> 2 times in 24 hours
Requires IV hydration
Diarrhea
2 to 3 loose stools in 24 
hours
4 to 5 loose stools in 
24 hours
6 or more loose stools in 
24 hours
Headache
Does not interfere with 
activity
Some interference with 
activity
Prevents daily routine 
activity
Fatigue
Does not interfere with 
activity
Some interference with 
activity
Prevents daily routine 
activity
Muscle pain (other than 
muscle pain at the 
injection site)
Does not interfere with 
activity
Some interference with 
activity
Prevents daily routine 
activity
Joint pain
Does not interfere with 
activity
Some interference with 
activity
Prevents daily routine 
activity
Abbreviation: IV=intravenous
7.8. Other Safety Monitoring
7.8.1. Adverse Events
Reporting of AEs and SAEs outside of the e-diary is described in Section 8.
7.8.2. Immediate Adverse Events

Immediate AEs, defined as AEs occurring within the first 30 minutes after investigational 
product administration, will be assessed and documented in the AE CRF.  The time of 
onset will be recorded for any AEs that occur on the same day as investigational product 
administration.

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7.8.3. Medically Attended Adverse Events and Newly Diagnosed Chronic Medical 
Conditions
Medically attended AEs and newly diagnosed chronic medical conditions will be also 
assessed throughout the study and documented on the appropriate AE CRF.  A medically 
attended AE is defined as a nonserious AE that results in an evaluation at a medical facility.
A newly diagnosed chronic medical condition is defined as a disease or medical condition, 
not previously identified, that is expected to be persistent or otherwise long-lasting in its 
effects.  This includes conditions that are undiagnosed prior to study entry (diagnosed while 
on the study) and that are not considered temporary conditions based upon the expected 
natural history of the condition.
7.8.4. Hospitalizations, Concomitant Medication Use, and Medical Facility Visits 
Associated With Adverse Events
AEs (serious and nonserious), newly diagnosed chronic medical conditions, and visits to 
other medical facilities will be assessed at study visits as specified in the 
Schedule of Activities and reported as defined in Adverse Event Section 8.
AE-related hospitalizations, visits to other medical facilities, and medication use and days of 
school (if appropriate) missed will be collected and recorded in the AE CRF.
Hospitalizations and visits to medical facilities not associated with an AE, such as elective 
hospitalizations, healthcare visits for preventive care, or routine physical examinations, will 
not be collected.  Non–AE-related concomitant medications (other than vaccinations) and 
days of school missed (if appropriate) not associated with an AE will not be collected.  A 
study visit AE checklist will be used as a guide, completed at each scheduled study visit, and 
included in the source documentation.  The checklist includes questions regarding newly 
diagnosed chronic medical conditions, medically attended AEs, and missed days of school.
Please refer to the SRM for details.
7.8.5. Memory Aid
The parent(s)/legal guardian will be given a memory aid at Visit 6.  The memory aid will be 
used to remind them to review any significant illnesses, hospitalizations, newly diagnosed 
medical conditions, or AEs that resulted in evaluation at a medical facility with study site 
personnel.  The parent(s)/legal guardian may use the memory aid as needed during the 
Month 12 Follow-up and Blood Draw Visit (Visit 7) to prompt recall of events.  These may 
be used to assist in reporting and discussion of events with study staff, but these memory aids 
will not be considered source documents and will not be collected at study visits.  Only 
information collected by study staff as part of the study visits will be included in the source 
documents and entered into the CRF.
In addition, AEs and SAEs will be recorded and reported as described in Section 7.8.

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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative. For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE. The investigator is required to assess causality. Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Research-Related Injury
Applicable to Visit 7 only.
Should a subject, in the investigator’s opinion, suffer a medically important research-related 
injury (RRI) caused by his or her participation in the protocol, Pfizer or its representative 
must be informed immediately.
A medically important RRI is any untoward medical occurrence that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity;

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an injury is an 
important medical event.  An important medical event may not be immediately 
life-threatening and/or result in death or hospitalization.  However, if it is determined that the 
event may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above, the important medical event should be reported as an 
RRI.

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An investigator may be requested by Pfizer to obtain specific additional follow-up 
information in an expedited fashion.  In general, this will include a description of the injury 
in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality.  Information on other possible causes of the event, such 
as concomitant medications and illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative.
8.3. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 6 months after the last 
administration of the investigational product. SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
A subject’s AEs (serious and nonserious) will be reported and recorded from the signing of 
the ICD through Visit 6.
At Month 12 (Visit 7: Follow-up and Blood Draw), the site will inquire about SAEs, newly 
diagnosed chronic medical conditions, or AEs that resulted in evaluation at a medical facility 
since Visit 6.
At all visits, particular care must be taken to note any neuroinflammatory and autoimmune 
conditions, such as transverse myelitis, uveitis, optic neuritis, and multiple sclerosis.
At Visit 7, the site will inquire about any AEs, as well as RRIs (Section 8.2), for events 
occurring during the 48-hour period after blood draw.  These events must be recorded in the 
CRF for the visit at which the blood was drawn and the event must be followed.
At all visits, stop dates for any reported AEs that were ongoing at the previous visit will be 
recorded in the CRF. The investigator must instruct the parent(s)/legal guardian on the need
to report AEs and SAEs during this time period.
8.4. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
vaccine or usage. Examples of AEs include but are not limited to:

Abnormal test findings;

Clinically significant symptoms and signs;

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
Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breast feeding;

Medication error.

Occupational exposure.
8.5. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong vaccine, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product.

Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating subject.

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Other examples include but are not limited to:

The administration of expired investigational product.

The administration of an incorrect investigational product.

The administration of an incorrect dosage.

Administration of an investigational product that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the 
investigational product under question is acceptable for use.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error should be captured on the medication error version of the 
AE page and, if applicable, any associated AEs are captured on an AE CRF page.
8.6. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; and/or

Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.7. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

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
Results in congenital anomaly/birth defect.

Lack of efficacy in an approved indication should be reported as an SAE.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization. However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as 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.
Medical device complaints may meet the SAE reporting requirement criteria (see section on 
Medical Device Complaint Reporting Requirements).  An incident is any malfunction (ie, the 
failure of a device to meet its performance specifications or to perform as intended; 
performance specifications include all claims made in the labeling for the device) that, 
directly or indirectly, might lead to or might have led to the death of a subject, or user, or of 
other persons, or to a serious deterioration in their state of health.
A serious injury that can cause a serious deterioration in state of health can include:

a life-threatening illness, even if temporary in nature;

a permanent impairment of a body function or permanent damage to a body structure;

a condition necessitating medical or surgical intervention to prevent the above 2 bulleted 
items
Examples: clinically relevant increase in the duration of a surgical procedure, a condition that 
requires hospitalization or significant prolongation of existing hospitalization;

any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;

fetal distress, fetal death, or any congenital abnormality or birth defects.
8.7.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section 8.15.1).

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8.7.2. Potential Cases of Drug-Induced Liver Injury
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to run LFTs because of clinical 
sign/symptom presentation in a subject, such LFT results should be handled and followed up 
as described below.
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events.
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence of 
hemolysis and an alkaline phosphatase value 2 X ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal range:
AST or ALT values 2 times the baseline values and 3 X ULN, or 8 X ULN 
(whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: Total 
bilirubin level increased from baseline by an amount of at least 1 X ULN or if the value 
reaches 3 X ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 

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blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted. All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for LFT abnormalities identified at the time, should be 
considered potential Hy’s law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
law cases should be reported as SAEs.
8.8. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE. Examples include:

Admission for treatment of a preexisting condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (eg, for workup of 
persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

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
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE and the resulting 
appendectomy should be recorded as treatment of the AE.
8.9. Severity Assessment
If required on the AE case report forms (CRFs), the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the AE. For 
purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example, a headache may be severe (interferes significantly with 
subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.10. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable. An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided. If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see section on Reporting Requirements). If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records.

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In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.11. Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy occurs 
if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product. An example of environmental exposure 
would be a case involving direct contact with a Pfizer product in a pregnant woman 
(eg, a nurse reports that she is pregnant and has been exposed to chemotherapeutic 
products).

A male subject has been exposed (eg, because of vaccination or environmental exposure)
to the investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on a Serious Adverse Event (SAE) Report Form 
and Exposure During Pregnancy (EDP) supplemental form, regardless of whether an SAE 
has occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a subject reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EDP 
supplemental form. This must be done irrespective of whether an AE has occurred and 
within 24 hours of awareness of the exposure. The information submitted should include the 
anticipated date of delivery (see below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion or until pregnancy termination (ie, induced abortion) and notify Pfizer of the 
outcome as a follow-up to the initial EDP supplemental form. In the case of a live birth, the 
structural integrity of the neonate can be assessed at the time of birth. In the event of a 
termination, the reason(s) for termination should be specified and, if clinically possible, the 
structural integrity of the terminated fetus should be assessed by gross visual inspection 
(unless preprocedure test findings are conclusive for a congenital anomaly and the findings 
are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.

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Additional information about pregnancy outcomes that are reported as SAEs follows:

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs 
when the investigator assesses the neonatal death as related or possibly related to 
exposure to investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator. Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays). In the case of paternal 
exposure, the investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner. The investigator must document in the source 
documents that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner.
8.12. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to safety within 24 hours of the investigator’s 
awareness, using the SAE Report Form, regardless of whether there is an associated 
AE/SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not reported on a CRF; however, a copy of the completed SAE Report Form is 
maintained in the study master file.
8.13. Withdrawal Due to Adverse Events (See Also Section 6.10 Subject Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.14. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject or subject’s parent(s)/legal guardian. In addition, each study subject or 
subject’s parent(s)/legal guardian will be questioned about AEs.
8.15. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs. If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.

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8.15.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information. This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy and exposure via 
breastfeeding cases and occupational exposure cases.
If the investigator is aware of an SAE with an onset on the day of investigational product 
administration or during the calendar day following investigational product administration, 
the investigator must contact the Pfizer study physician directly immediately after sending 
the SAE Report Form to Pfizer. These procedures do not replace any of the standard SAE 
reporting requirements as described above. Additional information can be found in the SRM.
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above. In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion. This information collected for SAEs is more detailed than that captured 
on the AE case report form. In general, this will include a description of the AE in sufficient 
detail to allow for a complete medical assessment of the case and independent determination 
of possible causality. Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided. In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative.
SAEs are to be reported throughout the study from signing of the ICD up to the study end 
(Visit 7: Month 12 Follow-up and Blood Draw).
At Month 12 (Visit 7: Month 12 Follow-up and Blood Draw), the site will inquire about 
SAEs, newly diagnosed chronic medical conditions, or medically attended events (AEs that 
resulted in evaluation at a medical facility) since Visit 6.
8.15.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page of the CRF. It should be noted that the form for 
collection of SAE information is not the same as the AE CRF. Where the same data are 
collected, the forms must be completed in a consistent manner. For example, the same AE 
term should be used on both forms. AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.

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Nonserious AEs will be reported from the signing of the ICD to up to Visit 6 
(Post-Vaccination 3 Blood Draw).
Nonserious AEs starting between Visits 6 and 7 will only be reported in the CRF if they are 
either a newly diagnosed chronic medical condition or a medically attended event that 
resulted in evaluation at a medical facility since Visit 6.
At all visits, particular care must be taken to note any neuroinflammatory and autoimmune 
conditions, such as transverse myelitis, uveitis, optic neuritis, and multiple sclerosis.
At all visits, stop dates for any reported AEs that were ongoing at the previous visit will be 
recorded in the CRF. The investigator must instruct on the need to report AEs during this 
time period.
The investigator must contact the Pfizer study physician directly as soon as possible after 
becoming aware of an AE that required medical attention that began on the day of 
investigational product administration or during the calendar day following investigational 
product administration. These procedures do not replace any of the standard 
AE Reporting Requirements as described above. Additional information can be found in the 
SRM.
8.15.3. Medical Device Complaint Reporting Requirements
All medical device complaints regardless of whether the medical device complaint is 
associated with an AE will be collected on the applicable pages within the CRF.  This 
includes potential incidents or malfunctions associated with the use of a medical device 
product.  An incident or malfunction is an event that might have led to death or serious 
deterioration in health, or if it occurred again might have led to death or serious deterioration 
in health.
Pfizer is to be notified of all medical device complaints within 24 hours of the investigator’s 
awareness of the event.  See the SRM for reporting instructions.
8.15.4. Sponsor Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be finalized before the 
start of any analyses and will be maintained by the sponsor. This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition and/or its analysis will be reflected both in the amended protocol and in the SAP.
The SAP amendment will follow the protocol amendment.

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9.1. Sample Size Determination
The study sample size is not based on hypothesis-testing criteria. This study will enroll 
approximately 400 subjects with a randomization ratio of 3:1 (bivalent rLP2086 group:
control).
9.2. Immunogenicity Analysis
This is not a hypothesis-testing study; thus, an estimation approach will be used to assess the 
primary, secondary, and exploratory objectives.
As assay data are expected to be missing completely at random (MCAR)
(Scott & Hsu, 201120), the primary analysis for the primary objectives will be based upon the 
observed, determinate observations. If all subjects have hSBA tested for all of the 4 primary 
MnB test strains, descriptive summaries will be provided to describe the hSBA data missing 
reason and the relationship between the missing data indicator and other design variables or 
covariates (age, race, gender, center, etc) and the observed hSBA data. Additionally, a 
sensitivity analysis using mixed effects model with repeated measurement (MMRM) will be 
applied to the primary endpoints. The MMRM uses the maximum likelihood estimation, and 
it is under the assumption that the missing is at random (MAR). If 50% of the subjects or 
less have 2 strains tested and the remaining have the other 2 strains tested, no sensitivity 
analyses will be planned because the missing assumption is MCAR.21
For the calculation of GMTs, hSBA results below LLOQ will be set as ½ of LLOQ as 
primary analysis.
9.2.1. Analysis of Primary Endpoints
The proportion of subjects in each group achieving hSBA titer LLOQ 1 month after the 
third vaccination will be computed for each test strain along with 2-sided 95% exact22
confidence intervals (CIs), for each of the age strata.
All of the binary endpoints (including primary endpoints) will be summarized with 2-sided 
95% CIs using the exact method. GMTs on hSBA results will also be summarized with 
95% CIs.
9.2.2. Analysis of Secondary Endpoints and Exploratory Endpoints
The hSBA GMTs will be summarized at each blood sampling time point by randomization 
group for each test strain, along with 2-sided 95% CIs. The CIs will be constructed by back 
transformation of the confidence limits computed for the mean of the logarithmically 
transformed assay data based on Student t distribution.
The proportions of subjects with hSBA titer 1:4, 1:8, 1:16, 1:32, 1:64, and 1:128 will 
be descriptively summarized with 95% exact CIs for each primary test strain at each blood 
sampling time point.
The proportion of subjects achieving hSBA titers with at least a 4-fold rise from baseline and 
the composite response will be summarized similarly.

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All of the analyses will be summarized for each age stratum as well as for the combined age 
group. The analyses may also be summarized by other demographic variables.
9.3. Immunogenicity Analysis Populations
An evaluable immunogenicity population and a modified intent-to-treat (mITT) population 
will also be defined for the immunogenicity analyses.  The evaluable immunogenicity 
population will be the primary population for the immunogenicity analyses.  For the 
immunogenicity analysis, subjects will be analyzed according to the investigational product 
to which they were randomized.
In general, the evaluable population will include all subjects who were randomized to the 
study group of interest, were eligible, received all investigational products as randomized, 
had blood drawn for assay testing within the required time frames, had valid and determinate 
assay results for the proposed analysis, and had no important protocol deviations.  An 
important protocol deviation is a protocol deviation that, in the opinion of the sponsor’s 
global medical monitor, would materially affect assessment of immunogenicity, eg, subject 
receipt of a prohibited vaccine or medication that might affect immune response or a 
medication error with suspected decrease in potency of the vaccine.
The mITT population will include all randomized subjects who have at least 1 valid and 
determinate assay result.
9.4. Demographic and Baseline Characteristics
The following demographic characteristics will be descriptively summarized: sex, race, 
ethnicity, and age at first vaccination.  Medical history and baseline physical examination 
data will also be descriptively summarized.
9.5. Safety Analysis
The safety population will be used for all safety analyses.  The safety population will include 
all subjects who have received at least 1 dose of an investigational product and for whom 
safety information is available.  For the safety analysis, subjects will be analyzed according 
to the investigational product received. Missing safety data will not be replaced or imputed.
The proportion of subjects reporting local reactions at the investigational product 
administration sites and systemic events within the 7-day period after each vaccination will 
be descriptively summarized by group.  Severities of local reactions and systemic events 
reported after each vaccination will also be descriptively summarized by group.  
Two (2)-sided 95% CIs based on the Clopper-Pearson method will be presented with the 
proportions.
All of the AEs and SAEs will be categorized according to the Medical Dictionary for 
Regulatory Activities (MedDRA) and will be summarized. A medically attended AE is 
defined as a nonserious AE that results in an evaluation at a medical facility.  A newly 
diagnosed chronic medical condition is defined as a disease or medical condition not 
previously identified that is expected to be persistent or otherwise long-lasting in its effects. 

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All summaries will show the number and percentage of subjects experiencing at least 1 event 
and the number of events.  Two (2)-sided 95% CIs based on the Clopper-Pearson method 
will also be presented for the SAE and AE percentages.
Comparisons will be made on the safety endpoints between Group 1 and Group 2. The 
reactogenicity data and immediate AEs between the vaccine and control will be compared 
with unconditional exact test. Fisher exact test will be used to compare the endpoints related 
to AEs, SAE, medically attended AEs, and newly diagnosed medical conditions.
For each subject, the number of days of school missed because of AEs will be aggregated 
across the vaccination phase. Then summary statistics using mean (standard deviation), 
median, and range will be descriptively tabulated for the total days by each group.
The CIs and statistical tests presented for the incidence of safety events will not be used to 
test hypotheses but will be used to determine which events may need further clinical 
investigation. No adjustment for multiplicity is needed.
All of the analyses will be performed for each age stratum as well as for the combined age 
group. Safety analyses may also be summarized by other demographic variables.
9.6. Analysis Timing
No interim analysis is planned for this study.  The study database will be unblinded after all 
of the data are cleaned. The analyses will then be performed to include all of the data 
summaries.
9.7. Data Monitoring Committee
This study will use an external data monitoring committee (EDMC). The ISC will provide 
the safety reports to the EDMC. Unblinded safety data will be reviewed by the EDMC 
throughout the study and no type I error will be adjusted for the multiple looks at the data.
The EDMC will be responsible for ongoing monitoring of the safety of subjects in the study
according to the charter. The recommendations made by the EDMC to alter the conduct of 
the study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
that are not endpoints, to regulatory authorities, as appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and GCPs are being followed. The monitors will review source documents 
to confirm that the data recorded on CRFs are accurate. The investigator and institution will 
allow Pfizer monitors or its agents and appropriate regulatory authorities direct access to 
source documents to perform this verification.

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The study site may be subject to review by the IRB/EC, and/or to quality assurance audits 
performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to inspection 
by appropriate regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject. The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs and source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital's or the physician's subject chart. In 
these cases data collected on the CRFs must match the data in those charts.
In some cases, the CRF, or part of the CRF, may also serve as source documents. In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed ICDs/assents, 
copies of all CRFs, safety reporting forms, source documents, and detailed records of 
treatment disposition, and adequate documentation of relevant correspondence (eg, letters, 
meeting minutes, telephone call reports). The records should be retained by the investigator 
according to International Conference on Harmonisation (ICH), according to local 
regulations, or as specified in the clinical study agreement, whichever is longer.

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If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer.
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, ICDs/assents, and other relevant documents, eg, recruitment 
advertisements, if applicable, from the IRB/EC. All correspondence with the IRB/EC should 
be retained in the Investigator File. Copies of IRB/EC approvals should be forwarded to 
Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 and 2008).
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data on any sponsor forms, reports, publications, or in any other 
disclosures, except where required by laws.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify the study subject. The 
study site will maintain a confidential list of subjects who participated in the study linking 
their numerical code to the subject’s actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subject personal data consistent 
with applicable privacy laws.

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The ICD/assent must be in compliance with ICH GCP, local regulatory requirements, and 
legal requirements, including applicable privacy laws.
The ICD(s)/assents used during the informed consent process must be reviewed by the 
sponsor, approved by the IRB/EC before use, and available for inspection.
In addition, a study-specific assent form will be provided to the subject as required by local 
regulations.  It is to be understood as the child’s will to participate in a study after having 
received age-appropriate information and is sometimes also referred to as "knowing 
agreement."
The investigator must ensure that each study subject, or his/her parent(s)/legal guardian, is
fully informed about the nature and objectives of the study and possible risks associated with 
participation.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject’s parent(s)/legal guardian before any study-specific 
activity is performed. The investigator will retain the original of each subject's signed 
consent/assent document.
12.4. Subject Recruitment
Advertisements approved by ECs and investigator databases may be used during recruitment 
procedures.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed the study as stated in the 
regulatory application (ie, clinical trial application [CTA]) and ethics application in the 
Member State. Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.

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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer. In 
addition, Pfizer retains the right to discontinue development of bivalent rLP2086 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator. After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) immediately. As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov) and/or the European Clinical 
Trials Database (EudraCT), and other public registries in accordance with applicable local 
laws/regulations.
www.clinicaltrials.gov
Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product.

The timing of the posting depends on whether the Pfizer product is approved for 
marketing in any country at the time the study is completed:

For studies involving products applicable under the US Food and Drug Administration 
Amendments Act of 2007 (FDAAA), ie, FDA-approved products, Pfizer posts results 
within 1 year of the primary completion date (PCD). For studies involving products 
approved in any country, but not FDA approved, Pfizer posts results 1 year from last 
subject last visit (LSLV);

For studies involving products that are not yet approved in any country, Pfizer posts the 
results of already-completed studies within 30 days of US regulatory approval, or 1 year 
after the first ex-US regulatory approval of the product (if only submitted for approval 
ex-US);

For studies involving products whose drug development is discontinued before approval, 
Pfizer posts the results within 1 year of discontinuation of the program (if there are no 
plans for outlicensing, or within 2 years if outlicensing plans have not completed).
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.

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www.pfizer.com
Pfizer posts clinical trial results on www.pfizer.com for all Pfizer-sponsored interventional 
studies in patients that assess the safety and/or efficacy of an `FDA-approved Pfizer product 
with a LSLV on or after 27 Sep 2007 for which Basic Results were posted on 
www.clinicaltrials.gov.
EudraCT
Pfizer posts clinical trial results on EudraCT in accordance with Commission Guideline 
2012/C 302/03 Guidance on posting and publication of result-related information on clinical 
trials in relation to the implementation of Article 57(2) of Regulation (EC) No 726/2004 and 
Article 41(2) of Regulation (EC) No 1901/2006 for studies with centers in the European 
Economic Area and with LSLV on or after 01 May 2004, regardless of the marketing status 
of the compound.
15.2. Publications by Investigators
Pfizer has no objection to publication by investigator of any information collected or 
generated by investigator, whether or not the results are favorable to the investigational 
product. However, to ensure against inadvertent disclosure of confidential information or 
unprotected inventions, the investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc) to Pfizer at 
least 30 days before they are submitted for publication or otherwise disclosed.  If any patent 
action is required to protect intellectual property rights, the investigator agrees to delay the 
disclosure for a period not to exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information (other than the study results themselves) before disclosure.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.

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Publication of study results is also provided for in the clinical study agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the clinical study agreement.
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Borrow R, Balmer P, Miller E. Meningococcal surrogates of protection – serum 
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