A Phase 1 Randomized, Observer Blind, Placebo Controlled, Dosage-Escalation Single Center Study to Evaluate the Safety and Immunogenicity of an RSV Fusion Glycoprotein (F) Subunit Vaccine in Healthy Adults
Phase: PHASE1
Conditions: Respiratory Syncytial Virus (RSV)
Sponsor: GlaxoSmithKline

Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 1 of 115 
Confidential 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL V122_01 Version 1.0 
 
A Phase 1 Randomized, Observer Blind, Placebo Controlled, Dosage-Escalation Single 
Center Study to Evaluate the Safety and Immunogenicity of an RSV Fusion Glycoprotein 
(F) Subunit Vaccine in Healthy Adults 
 
 
 
 
EUDRACT No. 2014-000145-69 
BB-IND No. TBD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Property of Novartis Vaccines and Diagnostics 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of Novartis Vaccines and Diagnostics. 
 
 
 
 
 
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Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 2 of 115 
Confidential 
 
 
PROTOCOL SYNOPSIS V122_01 V1.0 
 
Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
Title of Study: A Phase 1 Randomized, Observer Blind, Placebo Controlled, Dosage- 
Escalation Single Center Study to Evaluate the Safety and Immunogenicity of an RSV 
Fusion Glycoprotein (F) Subunit Vaccine in Healthy Adults 
Study Period: Approximately 13 
months for each subject. 
Clinical Phase: Phase 1 
Rationale: 
Respiratory syncytial virus (RSV) is the most important cause of acute lower respiratory 
tract infections (ALRIs) that result in hospital visits during infancy and early childhood. 
In the United States, more than 60% of infants are infected by RSV during their first 
RSV season, and nearly all have been infected by two to three years of age (Breese, 
2010; Glezen et al., 1986). Approximately 2.1 million US children less than five years of 
age are treated for RSV disease each year: 3% as inpatients, 25% in emergency 
departments, and 73% in pediatric practices (Hall et al., 2009). Disease burden is similar 
in Europe, with more than 1% of all children less than three years of age hospitalized 
annually and more than 7% receiving outpatient medical care (Forster et al., 2004). 
Globally, among children less than five years of age, RSV causes an estimated 33.8 
million ALRIs each year (more than 22% of all ALRIs), resulting in 66,000-199,000 
deaths, 99% of which occur in developing countries (Nair et al., 2010). In addition, RSV 
is a common cause of respiratory disease among the elderly, resulting in as many 
hospitalizations as influenza in a heavily influenza-immunized population (Falsey et al., 
2005). 
RSV spreads by respiratory droplets and close contact with infected persons or 
contaminated objects. In temperate climates there is an annual winter epidemic (Brandt 
et al., 1973), while in tropical areas seasonality is less distinct, but infection is most 
common during the rainy season (Weber et al., 1998). Infants are at highest risk for 
severe RSV disease in their first six months (Iwane et al., 2004; Hall et al., 2009), and 
hospitalization peaks at two to three months of age (Parrott et al., 1973). Preterm birth 
and cardiopulmonary disease are risk factors for severe disease, with 33.8% of infants 
with bronchopulmonary dysplasia hospitalized for RSV in their first year of life (Boyce 
et al., 2000). Bronchiolitis is the classic presentation, but RSV also causes pneumonia, 
rhinitis, and otitis media. Severe RSV infection in infancy is associated with higher rates 
 
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Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 3 of 115 
Confidential 
 
 
Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
of asthma later in childhood (Stein et al., 1999; Wu & Hartert, 2011). Recommended 
treatment of RSV bronchiolitis consists primarily of respiratory support and hydration 
(Subcommittee on diagnosis and management of bronchiolitis, 2006). No specific anti- 
viral therapy is recommended. The neutralizing monoclonal antibody (mAb), 
Palivizumab®, is used for prophylaxis of infants at highest risk for severe RSV disease, 
and although the monoclonal antibody can protect these infants, it is too expensive and 
impractical for universal use (Prescott et al., 2010). Induction of neutralizing antibody 
(NAb) should be the primary goal of vaccination because the severity of RSV disease is 
largely determined by the extent of viral replication (Graham, 2011). Although 
developing a safe and effective RSV vaccine is a global public health priority and will 
have a significant impact on RSV prevention, there is no licensed RSV vaccine. 
Novartis Vaccines and Diagnostics (NVD) has developed an investigational RSV 
subunit vaccine from an engineered recombinant RSV fusion (F) glycoprotein. The 
clinical program will evaluate the feasibility of passively protecting infants by 
immunizing pregnant women with the RSV F subunit vaccine. If maternal immunization 
during 24 to 32 weeks of gestation increases antibody titers eight-fold, the median peak 
of RSV disease in infants would be delayed from its current peak at two to three months 
of age to a new peak at approximately five to six months of age. This delay could 
significantly decrease the burden of RSV disease in infants in the first months of life and 
open an RSV disease-free interval during which active immunization of infants could 
further extend protection beyond six months of age. In the current study, we will test one 
dosage of the investigational RSV F subunit vaccine that is presumed to be below the 
dosage-response plateau (to establish that a maximal neutralizing antibody response 
cannot be achieved with a low dosage) and two higher dosages (to either establish the 
dosage-response plateau or indicate that higher dosages are needed in a subsequent 
study to reach the plateau). 
The purpose of this study is to evaluate the safety and immunogenicity of two doses of 
the investigational RSV F subunit vaccine administered intramuscularly (IM). In this 
current Phase 1, first-in-human study, the three different antigen amounts that have been 
selected will be evaluated in a stepwise manner in three different cohorts (cohort 1: low 
dosage of RSV F subunit vaccine [45 µg], cohort 2: middle dosage of RSV F subunit 
vaccine [90 µg], and cohort 3: high dosage of RSV F subunit vaccine [135 µg]). In 
addition, the effect of an adjuvant, either aluminum hydroxide [Al(OH)3] or MF59, and 
antibody kinetics post-vaccination at different time points will be evaluated as compared 
 
 
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Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 4 of 115 
Confidential 
 
 
Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
to unadjuvanted RSV F subunit vaccine at the same dosage levels. 
Objectives: 
Primary Safety Objective: 
1. To assess the safety of the RSV F subunit vaccine compared to placebo. 
Primary Immunogenicity Objective: 
1. To evaluate the serum neutralizing antibody (NAb) response to the RSV F subunit 
vaccine or placebo at Day 57 (28 days after the second dose). 
Secondary Immunogenicity Objectives: 
1. To evaluate the serum neutralizing antibody (NAb) response to the RSV F subunit 
vaccine or placebo at Day 1 (baseline), Day 29 (28 days after the first dose), and 
Day 181 (six months after the first dose). 
2. To evaluate the total serum antibody responses to the RSV F subunit vaccine or 
placebo at Day 1 (baseline), Day 29 (28 days after the first dose), Day 57 (28 days 
after the second dose), and Day 181 (six months after the first dose). 
3. To compare the ratio of RSV F subunit serum neutralizing antibody (NAb) titer to 
RSV F subunit serum total binding antibody titers to the RSV protein F in vaccine or 
placebo recipients at Day 1 (baseline), Day 29 (28 days after the first dose), Day 57 
(28 days after the second dose), and Day 181 (six months after the first dose). 
4. To compare the ratio of RSV F subunit serum neutralizing antibody (NAb) titer to 
RSV F subunit serum total binding antibody titers to each of the RSV proteins G and 
N in vaccine or placebo recipients at Day 1 (baseline), Day 29 (28 days after the first 
dose), Day 57 (28 days after the second dose), and Day 181 (six months after the 
first dose). 
 
 
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Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
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Confidential 
 
 
Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
Exploratory Objectives: 
1. To characterize the serum neutralizing antibody (NAb) and binding antibody 
responses against additional RSV strains and native or engineered RSV antigens at 
baseline and following vaccination in a subset of subjects. 
2. To determine the frequency of B cells specific for RSV proteins in a subset of 
subjects, and subsequently, explore the baseline immunity to RSV and the immune 
response to the RSV F subunit vaccine by analyzing the RSV-specific B-cell 
repertoire in a selected group of the subset of subjects. 
Methodology: 
Study Design: In total, approximately 288 healthy non-pregnant female and male adults 
(18 to 45 years of age) will be enrolled in the study in the ratio of 3:1. There is a higher 
ratio of female to male subjects because the RSV F subunit vaccine is ultimately 
intended for use in pregnant women. Approximately 216 subjects will be assigned to 
receive three different formulations of the investigational vaccine and 72 will be 
assigned to receive placebo. 
The approximately 216 healthy subjects assigned to receive the investigational vaccine 
will be further randomized (1:1:1) in a stepwise dosage-escalation manner and assigned 
to one of three cohorts (cohort 1: low dosage of RSV F subunit vaccine [45 µg], cohort 
2: middle dosage of RSV F subunit vaccine [90 µg], and cohort 3: high dosage of RSV 
F subunit vaccine [135 µg]). Within each cohort subjects will be randomly allocated 
(1:1:1) to receive vaccine with no adjuvant, with aluminum hydroxide, or with MF59, as 
outlined in Table 1. All subjects will receive two doses of a 0.5 mL intramuscular 
injection of the vaccine, with adjuvant (aluminum hydroxide [1 mg] or MF59 [0.25 mL; 
9.75 mg squalene and surfactants]) or without adjuvant. There will be approximately 24 
subjects in each treatment group. All the remaining 72 subjects (approximately 24 
subjects per cohort) will be assigned to receive placebo (saline) (Table 1). The 
minimum interval between the first and the second doses will be 28 days. 
Vaccination Plan: Eighteen (18) treatment groups (9 active treatment groups and 3 
placebo [saline] groups in each cohort) will be evaluated as shown in Table 1: 
 
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08 JAN 14 Final Version 1.0 
Protocol V122_01 
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Confidential 
 
 
Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
Table 1. Number of Subjects Randomized per Vaccine Treatment Group in Each 
Cohort 
Abbreviations: IM, intramuscular; mL, milliliter; Al(OH)3, aluminum hydroxide. 
†Administered at least 28 days apart. 
‡ Concentration of Al(OH)3 will be 1 mg per dose and that of MF59 will be 0.25 mL (1X, which contains 
9.75 mg squalene and surfactants). 
Safety Measurements: 
Solicited local and systemic adverse events (AEs) and unsolicited AEs will be collected 
using diary cards for 7 days following any dose of vaccine or placebo. Solicited local 
AEs include injection site pain, injection site induration, injection site swelling, and 
injection site erythema. Solicited systemic AEs include body temperature (oral or 
axillary), chills, nausea, generalized myalgia, generalized arthralgia, headache, fatigue, 
diarrhea, loss of appetite, cough, rhinorrhea, and wheezing. Safety telephone calls at 14 
and 21 days after each dose of vaccine or placebo will be used to collect unsolicited 
AEs occurring since the last study contact, as well as any solicited AEs continuing 
beyond the 7 day period after vaccination. See section 3.2.5 for further details. 
In addition, all SAEs, new onset of chronic disease (NOCDs), and adverse events of 
special interest (AESIs) will be collected from the date of signed informed consent until 
the end of the study (approximately 393 days after the first dose of vaccine or placebo 
[saline]). Monitoring for AESIs (see section 6.6.1.1 and Appendix A) will be extended 
through 12 months after the second vaccination and will be accomplished by clinic 
visits or telephone follow-up calls as detailed in Table 2. All AESIs will be reported in 
the same manner as SAEs. A tabulation of all AESIs, categorized by MedDRA 
preferred terms and assessed relationship to study vaccine will be performed. 
 
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Cohort 
Dosage 
Route of 
Administration 
Regimen: Two Doses † 
No Adjuvant 
Al(OH)3 ‡ 
MF59 ‡ 
1 
45 µg 
IM (0.5 mL) 
24 
24 
24 
Placebo (saline) 
IM (0.5 mL) 
8 
8 
8 
2 
90 µg 
IM (0.5 mL) 
24 
24 
24 
Placebo (saline) 
IM (0.5 mL) 
8 
8 
8 
3 
135 µg 
IM (0.5 mL) 
24 
24 
24 
Placebo (saline) 
IM (0.5 mL) 
8 
8 
8 

Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
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Confidential 
 
 
Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
Schedule of safety data collection: 
▫ Solicited local and systemic AEs, body temperature, and other indicators of 
reactogenicity will be collected for 7 days following receipt of first and second dose 
of vaccine (using diary cards). 
▫ All unsolicited AEs and solicited local and systemic AEs that continue beyond 7 
days after vaccination will be collected for 28 days following receipt of first and 
second dose of vaccine. 
▫ All SAEs, non-scheduled physician visits, unsolicited medically attended AEs, 
unsolicited AEs leading to study withdrawal, NOCDs, and AESIs will be collected 
from first vaccination to study completion. 
▫ All concomitant medications administered in relation to the reported AEs will be 
collected from first vaccination to study completion. 
Primary and Secondary Immunogenicity Measurements: 
Four blood samples per subject will be collected for serum preparation and 
determination of immune responses to the RSV F subunit vaccine at Visit 1, Visit 5, 
Visit 9, and Visit 12 as outlined in Table 2. Serum anti-RSV neutralizing antibody 
(NAb) titers will be evaluated for all subjects by a plaque reduction neutralization assay 
(PRNA); binding antibody to the RSV proteins F, G (subgroups Ga and Gb), and N will 
be evaluated by a microsphere-based fluorescence linked immunosorbent assay, 
multiplexed using Luminex® technology. See section 6.3 for further details. 
Safety Laboratory Parameters: 
To assess laboratory AEs, blood and urine samples will be collected for each subject at 
Screening, Visit 1, Visit 2, Visit 5, Visit 6, and Visit 9 as outlined in Table 2 to perform 
blood chemistry, hematology, and urine analyses for all subjects. 
Exploratory Measurements: 
The serum neutralizing antibody (NAb) and binding antibody responses against 
additional RSV strains and native or engineered RSV antigens at baseline and following 
vaccination will be performed in a subset of subjects, following evaluation of the 
primary and secondary immunogenicity evaluations and depending on volume of serum 
remaining for additional testing. 
 
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Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 8 of 115 
Confidential 
 
 
Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
In approximately the first 10 subjects enrolled in each of the four treatment groups of 
cohort 3 (three vaccine groups and placebo) who agree to a separate Informed Consent, 
additional blood will be collected at Visit 1, Visit 2, Visit 5, and Visit 12 for cell 
mediated immunity assays. The purpose of these assays is to determine the frequency of 
B cells specific for RSV proteins by enzyme-linked immunosorbent spot (ELISPOT). 
Subsequently, the analysis of the RSV-specific B-cell repertoire will be performed in a 
subset of these subjects. See section 6.8 for further details. 
Number of Subjects planned: 
Sample size is not driven by statistical assumptions for formal hypothesis testing as 
previous clinical trial data are not available and clinically meaningful group differences 
are not established. In addition, values for a correlate of protection are not known at 
present stage. Nevertheless, some information from the neutralization assay for human 
serum was available. 
Hence, the number of proposed subjects will be sufficient to provide a descriptive 
summary of the safety and immunogenicity of the RSV F subunit vaccine. Anticipating 
that about 10% of the subjects will be non-evaluable (due to being lost to follow-up, 
having insufficient samples, incomplete laboratory results, or protocol violations, etc.), 
approximately 288 subjects will be randomized to 12 different treatment groups 
(approximately 24 subjects in each vaccine treatment group and approximately 24 
subjects in each of the placebo cohorts), in order to obtain approximately 260 evaluable 
healthy adult subjects. 
Subject Population: 
Healthy adult volunteers between 18-45 years of age, inclusive. 
Subject Characteristics and Main Criteria for Inclusion and Exclusion: 
Key Inclusion (abridged for the synopsis): 
In order to participate in this study, all subjects must meet ALL of the inclusion criteria 
described. 
 
 
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Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 9 of 115 
Confidential 
 
 
Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
1. Healthy males and non-pregnant females 18 to 45 years of age at time of enrollment. 
Key Exclusion (abridged for the synopsis): 
In order to participate in this study, all subjects must meet NONE of the exclusion 
criteria described. 
1. Individuals with any severe chronic or acute disease. 
2. Individuals with a history of illness or with an ongoing illness that may pose 
additional risk to the subject if he/she participates in the study, including the 
following: 
- 
History of any chronic respiratory illness, including current diagnosis of asthma 
within 2 years, exercise induced wheezing, reactive airway disease, emphysema, 
chronic bronchitis, cystic fibrosis or chronic obstructive pulmonary disease 
(COPD). 
- 
Any respiratory illness (e.g. cough, sore throat, dyspnea, wheezing or nocturnal 
awakenings to respiratory symptoms) within 7 days prior to receiving the first 
study vaccination. 
- 
Any active pulmonary infection or other inflammatory conditions, even in the 
absence of febrile episodes, within 14 days prior to the first study vaccination. 
- 
Hepatitis B or hepatitis C infection. 
3. Individuals participating in any clinical trial with another investigational product 28 
days prior to receiving the first study vaccination or intent to participate in another 
clinical study at any time during the conduct of this study. 
4. Individuals who have received any vaccine 28 days prior to enrollment in this study, 
or who plan to receive any non-study vaccines within 28 days of the second dose of 
study vaccine. 
5. If female, ‘of childbearing potential’, sexually active and has not used any of the 
‘acceptable contraceptive methods’ for at least two months prior to study entry. 
Childbearing potential is defined as status post onset of menarche and not meeting 
any of the following conditions: menopausal for at least two years; sterile status 
 
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Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 10 of 115 
Confidential 
 
 
Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
after bilateral tubal ligation for at least one year, immediately after bilateral 
oophorectomy or after hysterectomy. 
Acceptable methods of birth control are defined as one or more of the following: 
- 
Hormonal contraceptives (such as oral, injection, transdermal patch, implant, 
cervical ring). 
- 
Barrier (condom with spermicide or diaphragm with spermicide) each and every 
time during intercourse. 
- 
Intrauterine device (IUD). 
- 
Monogamous relationship with vasectomized partner. Partner must have been 
vasectomized for at least six months prior to subject’s study entry. 
6. If female subject of childbearing potential and have a positive urine pregnancy test 
prior to study injections, or are currently lactating. 
7. If female of childbearing potential and sexually active, refusal to use an ‘acceptable 
contraceptive method’ through to three weeks after last study vaccination. 
The full list of inclusion and exclusion criteria is included in protocol section 4. 
Vaccines: 
The RSV F subunit vaccine is a lyophilized vaccine consisting of 135 µg of an 
engineered recombinant RSV fusion (F) glycoprotein. The vaccine for this study will be 
provided in a lyophilized pellet and reconstituted and mixed in saline and/or adjuvant by 
the unblinded designated site staff who is to follow a procedure as described in the 
Reconstitution Instructions in the Investigator Site File (i.e., the vaccine is prepared in 
the clinic prior administration). 
The lyophilized product is reconstituted with (a) sterile saline 0.9% NaCl to generate the 
non-adjuvanted RSV F subunit vaccine formulation, (b) in aluminum hydroxide 
[Al(OH)3] to generate the RSV F subunit vaccine formulated in Al(OH)3, or (c) sterile 
saline 0.9% NaCl and adjuvant MF59 to generate the RSV F subunit vaccine formulated 
with MF59. Preparation for each formulation of the RSV F subunit vaccine will require 
a separate kit and detailed instructions for reconstitution and dilution steps. See section 
 
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08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 11 of 115 
Confidential 
 
 
Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
5.3 for further details. 
In each cohort, subjects will be randomized to receive two injections of the vaccine or 
placebo (saline). The vaccine will be reconstituted in 0.5 mL of saline and/or adjuvant 
and injected intramuscularly (IM) in the deltoid muscle, with preference that the 
injection is administered in the non-dominant arm. 
Safety Endpoints: 
Safety will be assessed by measuring the frequency of local and systemic solicited 
adverse events (AEs), unsolicited AEs, serious adverse events (SAEs), new onset of 
chronic diseases (NOCD), adverse events of special interest (AESIs), and safety 
laboratory data for all subjects. Tolerability will be assessed by the joint evaluation of 
both reactogenicity and unsolicited AEs. 
▫ Reactogenicity will be assessed by the percentage and frequency of subjects with 
solicited local and solicited systemic adverse events up to 7 days after each 
vaccination. 
▫ Unsolicited AEs will be assessed by the percentage and frequency of subjects with 
any unsolicited AEs for 28 days after each vaccination. 
▫ Percentage and frequency of subjects with SAEs, non-scheduled physician visits, 
unsolicited medically attended AEs, unsolicited AEs leading to study withdrawal, 
NOCDs, and AESIs will be collected from study start until study completion. 
Primary Immunogenicity Endpoints: 
1. Geometric mean titer (GMT) of the serum anti-RSV neutralizing antibody (NAb) 
titer at Day 57 (28 days after the second dose). 
2. Proportion of subjects with a ≥4-fold increase in serum anti-RSV NAb titer from 
Day 1 (baseline) to Day 57 (28 days after the second dose). 
Secondary Immunogenicity Endpoints: 
1. GMT of the serum anti-RSV NAb titer at Day 1 (baseline), Day 29 (28 days after 
the first dose), and Day 181 (six months after the first dose). 
2. Proportion of subjects with a ≥4-fold increase in serum anti-RSV NAb titer from 
 
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Novartis Vaccines and Diagnostics 
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Page 12 of 115 
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Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
Day 1 (baseline) to all other time points (Day 29 [28 days after the first dose] and 
Day 181 [six months after the first dose]). 
3. Proportion of subjects at Day 29 (28 days after the first dose), Day 57 (28 days after 
the second dose), and Day 181 (six months after the first dose) who achieve serum 
anti-RSV NAb titers greater than the 3rd quartile of the serum anti-RSV NAb titers 
overall distribution at Day 1 (baseline). 
4. Reverse cumulative distribution of serum anti-RSV NAb titers at Day 1 (baseline), 
Day 29 (28 days after the first dose), Day 57 (28 days after the second dose), and Day 
181 (six months after the first dose). 
5. GMT of the serum total binding antibody to each of the RSV proteins F, G, and N at 
Day 1 (baseline), Day 29 (28 days after the first dose), Day 57 (28 days after the 
second dose), and Day 181 (six months after the first dose). 
6. Proportion of subjects with a ≥4-fold increase in serum total binding antibody titers 
to each of the RSV proteins F, G, and N from Day 1 (baseline) to all time points 
(Day 29 [28 days after the first dose], Day 57 [28 days after the second dose], and 
Day 181 [six months after the first dose]). 
7. Proportion of subjects at Days 29 (28 days after the first dose), Day 57 (28 days after 
the second dose), and Day 181 (six months after the first dose) who achieve serum 
total binding antibody titers to each of the RSV proteins F, G, and N greater than the 
3rd quartile of serum total binding antibody titers to RSV protein F at Day 1 
(baseline). 
8. Reverse cumulative distribution of serum total binding antibody to each of the RSV 
proteins F, G, and N at Day 1 (baseline), Day 29 (28 days after the first dose), Day 
57 (28 days after the second dose), and Day 181 (six months after the first dose). 
9. Ratio of RSV F subunit serum neutralizing antibody (NAb) titer to each of the RSV 
F subunit serum total binding antibody titers to RSV proteins F, G, and N at Day 1 
(baseline), Day 29 (28 days after the first dose), Day 57 (28 days after the second 
dose), and Day 181 (six months after the first dose). 
Exploratory Endpoints: 
1. Predominant isotype of the RSV-specific serum antibody at multiple time points. 
2. RSV-specific immune response against different RSV group A and group B strains 
 
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Name of Sponsor 
Novartis Vaccines 
and Diagnostics 
Protocol number: 
V122_01 
Health authority trial registration 
number(s): 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
or engineered RSV antigens at multiple time points. 
3. Frequency of B cells secreting RSV-specific antibodies at Day 1 (baseline), Day 8 
(seven days after the first dose), Day 29 (28 days after the first dose), and Day 181 
(six months after the first dose). 
4. Diversity of the B-cell repertoire at Day 1 (baseline), Day 8 (seven days after the 
first dose), Day 29 (28 days after the first dose), and Day 181 (six months after the 
first dose). 
Statistical Analysis of Primary Objective(s): 
Values below the detection limit (1:100) will be set at 1:50. 
GMTs: Antibody concentrations will be logarithmically transformed (base 10). For each 
treatment group within each cohort, GMTs of the serum anti-RSV NAb along with their 
associated 95% confidence intervals (CIs) will be computed by exponentiation of the 
corresponding log-transformed means and 95% CIs. 
Fold-rise: Proportions of subjects with a ≥4-fold increase in serum anti-RSV NAb titer 
from baseline will be presented, for each treatment group within each cohort, together 
with their two-sided 95% Clopper-Pearson CIs. 
The statistical analyses for GMTs will be conducted using an ANCOVA model with 
dosage and adjuvant as factors and baseline antibody level as covariate. Interactions 
between factors will be investigated and further described in the statistical analysis plan 
to be finalized and approved before the start of the trial. 
The primary immunogenicity analyses will be based on a per-protocol (PP) population. 
If the full analysis set (FAS) and PP differ by more than 10%, primary immunogenicity 
analyses will also be conducted on the FAS. 
Interim Analysis: 
An Interim Analysis will be performed on the immunogenicity and safety data collected 
from all subjects at Visit 1, Visit 5, and Visit 9. Further details regarding the interim 
 
 
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Name of Sponsor 
Protocol number: 
Health authority trial registration 
Novartis Vaccines 
V122_01 
number(s): 
and Diagnostics 
EudraCT No. 2014-000145-69 
BB-IND No. TBD 
analysis are contained in section 7.5 of the protocol. 
Data Monitoring Committee: 
A Data Monitoring Committee (DMC) will be implemented to review safety data during 
scheduled periodic reviews. The DMC will review safety data, as described in the DMC 
charter and in the statistical analysis plan, after enrollment of the first 12 subjects in 
each cohort, and shortly after Visit 2 (seven days after the first dose), before proceeding 
with enrollment of the remaining subjects in each cohort. In addition, the DMC will 
review safety data after enrollment of each cohort has been completed before 
proceeding with enrollment of the subsequent cohort. Please see section 6.9 of the 
protocol for more details. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2. 
Times and Events Table 
 
Study Period 
Screen 
Vaccine Dose #1 
& Safety Follow-up 
Vaccine Dose #2 
& Safety Follow-up 
Post-vaccination Follow-up 
Type of Visit 
Clinic 
Visit 
Clinic 
Visit 
Reminder 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Reminder 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Study Day 
-21 to -3 
1 
3, 5 
8 
15, 22 
29 
31, 33 
36 
43, 50 
57 
85 
113 
181 
209 
271, 
366, 
394 
Days post 1st dose 
0 
2, 4 
7 
14, 21 
28 
30, 32 
35 
42, 49 
56 
Days post 2nd dose 
0 
2, 4 
7 
14, 21 
28 
56 
Study Visit Window 
(min-max) in Days (d) 
n/a 
n/a 
n/a 
-1/ 
+4 d 
n/a 
+14 d 
n/a 
-3/ 
+3 d 
n/a 
-7/ 
+7 d 
-7/ 
+7 d 
-7/ 
+7 d 
-7/ 
+7 d 
-14/ 
+14 d 
-7/ 
+7 d 
Visit Number 
Screening 
1 
2 
3, 4 
5 
6 
7, 8 
9 
10 
11 
12 
13 
14, 
15, 16 
Informed Consent 
X 
Medical History 
X 
Physical Exam a 
X 
X b 
X 
X b 
X 
X 
X 
X 
X 
X 
Safety Laboratory 
Blood draw [max: 10 
mL whole blood] c 
X 
X b 
X 
X b 
X 
X 
Urinalysis d 
X 
X b 
X 
X b 
X 
X 
Pregnancy Test 
X 
X b 
X b 
Exclusion/Inclusion 
Criteria 
X 
Randomization 
X b 
Serology Blood draw 
[max: 15 mL whole 
blood] e 
X b 
X b 
X 
X 
 
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Study Period 
Screen 
Vaccine Dose #1 
& Safety Follow-up 
Vaccine Dose #2 
& Safety Follow-up 
Post-vaccination Follow-up 
Type of Visit 
Clinic 
Visit 
Clinic 
Visit 
Reminder 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Reminder 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Study Day 
-21 to -3 
1 
3, 5 
8 
15, 22 
29 
31, 33 
36 
43, 50 
57 
85 
113 
181 
209 
271, 
366, 
394 
Days post 1st dose 
0 
2, 4 
7 
14, 21 
28 
30, 32 
35 
42, 49 
56 
Days post 2nd dose 
0 
2, 4 
7 
14, 21 
28 
56 
Study Visit Window 
(min-max) in Days (d) 
n/a 
n/a 
n/a 
-1/ 
+4 d 
n/a 
+14 d 
n/a 
-3/ 
+3 d 
n/a 
-7/ 
+7 d 
-7/ 
+7 d 
-7/ 
+7 d 
-7/ 
+7 d 
-14/ 
+14 d 
-7/ 
+7 d 
Visit Number 
Screening 
1 
2 
3, 4 
5 
6 
7, 8 
9 
10 
11 
12 
13 
14, 
15, 16 
2° Exploratory Obj. 
Blood Draw [max: 50 
mL whole blood] f 
X b 
X 
X b 
X 
Study Vaccine 
Administered g 
V 
V 
30 Minutes Post 
Injection Assessment 
(Local/ Systemic AEs, 
Body Temperature) h 
X 
X 
Local/Systemic AEs, 
Body Temperature, 
Other Indicators of 
Reactogenicity i 
X 
X 
Diary Card Training j 
X 
X 
Diary Card Dispensed k 
X 
X 
Diary Card Reminder 
Call l 
X 
X 
 
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Study Period 
Screen 
Vaccine Dose #1 
& Safety Follow-up 
Vaccine Dose #2 
& Safety Follow-up 
Post-vaccination Follow-up 
Type of Visit 
Clinic 
Visit 
Clinic 
Visit 
Reminder 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Reminder 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Study Day 
-21 to -3 
1 
3, 5 
8 
15, 22 
29 
31, 33 
36 
43, 50 
57 
85 
113 
181 
209 
271, 
366, 
394 
Days post 1st dose 
0 
2, 4 
7 
14, 21 
28 
30, 32 
35 
42, 49 
56 
Days post 2nd dose 
0 
2, 4 
7 
14, 21 
28 
56 
Study Visit Window 
(min-max) in Days (d) 
n/a 
n/a 
n/a 
-1/ 
+4 d 
n/a 
+14 d 
n/a 
-3/ 
+3 d 
n/a 
-7/ 
+7 d 
-7/ 
+7 d 
-7/ 
+7 d 
-7/ 
+7 d 
-14/ 
+14 d 
-7/ 
+7 d 
Visit Number 
Screening 
1 
2 
3, 4 
5 
6 
7, 8 
9 
10 
11 
12 
13 
14, 
15, 16 
Diary Card Reviewed 
and Collected m 
X 
X 
Telephone Contact for 
Review of Safety Data n 
X 
X 
Assess all AEs, 
including SAEs and 
NOCDs Leading or not 
to Study Withdrawal o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess for AESIs p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant 
Medications/vaccines q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Termination r 
X 
a. 
Physical examination must be performed by a qualified health professional in accordance with local regulations and licensing requirements designated within 
the Site Responsibility Delegation Log. See section 6.2 for components of physical examination by visit. 
b. Procedure to be performed prior to vaccination. 
c. 
Safety laboratory assays that will be included are listed in section 3.5.3. 
 
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d. Urinalysis testing will include at a minimum protein, glucose, and presence of red blood cells. 
e. 
Maximal blood draw refers to volume drawn for each type of assay at each specified visit. See section 3.5.1 for greater detail regarding blood sampling 
volumes. 
f. 
The first 10 subjects enrolled in each treatment group of Cohort 3 who agree to the additional blood draws will need to sign an additional consent prior to the 
blood draw for the secondary exploratory objective. 
g. Subjects will receive two doses of vaccine or placebo according to the study randomization scheme. 
h. A 30 minute post-injection local and systemic adverse event and body temperature measurement will be performed by the subject under site staff supervision 
at the clinic during Visit 1 and Visit 5. 
i. 
Beginning 6 hours following study vaccine administration at Visit 1 and Visit 5, and daily thereafter through 7 days after each vaccination, solicited local 
and systemic adverse events including other reactions (i.e. body temperature measurements and use of analgesics/antipyretics) will be reported daily by the 
subject on a diary card. 
j. 
Subjects will receive training on the diary card at Visit 1 and Visit 5. 
k. The diary card will be dispensed at Visit 1 and Visit 5, and subjects will be reminded that diary cards must be returned at the next clinic visit (Visit 2 or Visit 
6). 
l. 
Site staff will contact subjects by phone 2 and 4 days after each vaccination to remind them to complete their diary cards each day, and to bring the diary 
cards to their next clinic visit. 
m. Review of safety data captured on diary cards will be completed at Visit 2 and Visit 6. Diary cards will be collected and stored with subject files. 
n. Safety data will be collected for 28 days following each vaccination. At 14 and 21 days after each dose, subjects will be interviewed by site staff using a 
scripted interview for collection of safety data. These safety data will be transcribed on source documents by the site staff performing the interviews. 
o. All medically attended AEs that lead to an unscheduled visit to a healthcare practitioner and/or a visit to the emergency department or its equivalent will be 
collected for 28 days following signing of the informed consent. SAEs, NOCDs and AEs leading to study or vaccine withdrawal will be collected through 1 
year after receipt of the second dose. Please see section 6.6 for greater detail regarding methods for SAE and AEs leading to study or vaccine withdrawal 
collection. 
p. Adverse events of special interest (AESIs) will also be documented in all study subjects for the duration of the study. Monitoring for AESIs will be extended 
through 1 year after receipt of the second dose and will be accomplished at clinic visits or by a telephone follow-up call. A tabulation of all AESIs, 
categorized by MedDRA preferred terms and assessed relationship to study vaccine will be submitted as an addendum to the Clinical Study Report (CSR) if 
not included in the CSR. 
q. Collect concomitant medications and vaccination history according to the study procedures outlined in protocol section 3.2.5 and 5.4. 
r. 
Any subject who terminates the study after receipt of vaccine (prior to Visit 9) is recommended to undergo study-related procedures required at Visit 9. For 
subjects who terminate after Visit 9, a telephone contact to assess for SAEs/AEs and associated concomitant medications is required. 
 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS V122_01 V1.0 ............................................................................ 2 
TABLE OF CONTENTS ................................................................................................... 19 
LIST OF ABBREVIATIONS ............................................................................................ 24 
1.0 
BACKGROUND AND RATIONALE .................................................................. 27 
2.0 
OBJECTIVES ........................................................................................................ 33 
2.1 
Primary Objective(s) .......................................................................................... 33 
2.2 
Secondary Objectives ......................................................................................... 33 
3.0 
STUDY DESIGN AND INVESTIGATIONAL PLAN ........................................ 35 
3.1 
Overview of Study Design ................................................................................. 35 
3.1.1 
Study Period ............................................................................................... 36 
3.2 
Study Visit Procedures ....................................................................................... 36 
3.2.1 
Informed Consent ....................................................................................... 36 
3.2.2 
Screening Procedures ................................................................................. 37 
3.2.3 
Enrollment .................................................................................................. 38 
3.2.4 
Randomization ........................................................................................... 38 
3.2.5 
Visit Procedures ......................................................................................... 39 
3.2.5.1 
Pre-vaccination Procedures .................................................................... 39 
3.2.5.2 
Vaccination Procedures ......................................................................... 40 
3.2.5.3 
Post-vaccination Procedures .................................................................. 40 
3.2.5.4 
Reminder Telephone Calls ..................................................................... 41 
3.2.5.5 
Clinic Visits after Vaccination ............................................................... 42 
3.2.5.6 
Safety Calls ............................................................................................ 44 
3.2.5.7 
“For cause” Visits .................................................................................. 45 
3.2.5.8 
Termination Visits ................................................................................. 45 
3.3 
Blinding Procedures ........................................................................................... 45 
3.4 
Data Collection .................................................................................................. 47 
3.4.1 
Data Collected From Subjects .................................................................... 47 
3.4.2 
Electronic Case Report Forms ................................................................... 47 
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3.5 
Laboratory Assessments .................................................................................... 48 
3.5.1 
Processing, Labeling and Storage of Serum Samples for Serology ........... 48 
3.5.2 
Pregnancy Testing ...................................................................................... 48 
3.5.3 
Safety Laboratory Assessments ................................................................. 48 
3.5.4 
Cell Mediated Immunity Assessments ....................................................... 50 
3.5.5 
Culture/PCR/Genotyping Assessments ..................................................... 51 
3.6 
Stopping/Pausing Guidelines ............................................................................. 51 
3.7 
Premature Withdrawal and Early Study Termination ........................................ 52 
3.8 
Early Termination Visit ..................................................................................... 54 
4.0 
SELECTION OF STUDY POPULATION ........................................................... 56 
4.1 
Inclusion Criteria ............................................................................................... 56 
4.2 
Exclusion Criteria .............................................................................................. 56 
4.3 
Criteria for Delay of Vaccination and/or Blood Sampling ................................ 58 
4.4 
Criteria for Repeat Vaccination in the Study ..................................................... 59 
5.0 
TREATMENT OF SUBJECTS ............................................................................. 60 
5.1 
Study Vaccine(s) ................................................................................................ 60 
5.2 
Non-Study Vaccines .......................................................................................... 61 
5.3 
Vaccines Preparation and Administration ......................................................... 61 
5.4 
Prior and Concomitant Medications and Vaccines ............................................ 62 
5.5 
Vaccine Supply, Labeling, Storage, and Tracking ............................................. 63 
6.0 
MEASUREMENTS ............................................................................................... 66 
6.1 
Appropriateness of Measurements ..................................................................... 66 
6.2 
Demographics, Medical History and Physical Examination ............................. 66 
6.3 
Immunogenicity Measurements ......................................................................... 67 
6.4 
Efficacy Measurements ...................................................................................... 67 
6.5 
Solicited Safety Measurements .......................................................................... 67 
6.6 
Unsolicited Safety Measurements ...................................................................... 70 
6.6.1 
Adverse Events .......................................................................................... 70 
6.6.1.1 
Adverse Events of Special Interest ........................................................ 72 
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6.6.1.2 
New Onset of Chronic Disease .............................................................. 73 
6.6.2 
Serious Adverse Events ............................................................................. 73 
6.6.3 
Methods for Assessing and Recording AEs and SAEs .............................. 75 
6.6.4 
Pregnancies ................................................................................................ 76 
6.7 
Safety Laboratory Measurements ...................................................................... 77 
6.8 
Other Measurements .......................................................................................... 77 
6.9 
Data Monitoring Committee .............................................................................. 79 
7.0 
ENDPOINTS AND STATISTICAL ANALYSES................................................ 81 
7.1 
Endpoints ........................................................................................................... 81 
7.1.1 
Primary Endpoint(s) ................................................................................... 81 
7.1.2 
Secondary Immunogenicity Endpoints ...................................................... 81 
7.1.3 
Secondary Efficacy Endpoints ................................................................... 82 
7.1.4 
Safety Endpoints ........................................................................................ 82 
7.1.5 
Other Endpoints ......................................................................................... 83 
7.1.6 
Exploratory Endpoints ............................................................................... 83 
7.2 
Success Criteria .................................................................................................. 83 
7.2.1 
Success Criteria for Primary Objectives .................................................... 83 
7.2.2 
Success Criteria for Secondary Immunogenicity Objectives ..................... 83 
7.2.3 
Success Criteria for Secondary Efficacy Objectives .................................. 83 
7.2.4 
Success Criteria for Safety Objectives ....................................................... 83 
7.3 
Analysis Sets ...................................................................................................... 84 
7.3.1 
All Enrolled Set .......................................................................................... 84 
7.3.2 
Exposed Set ............................................................................................... 84 
7.3.3 
Full Analysis Set (FAS) Immunogenicity Set ............................................ 84 
7.3.4 
Per Protocol (PP) Population, Immunogenicity Set ................................... 84 
7.3.5 
Safety Set ................................................................................................... 85 
7.3.6 
Other Analysis Sets .................................................................................... 85 
7.3.7 
Subgroups .................................................................................................. 85 
7.3.8 
Protocol Deviations .................................................................................... 85 
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7.4 
Analysis Plan ..................................................................................................... 87 
7.4.1 
Analysis of Demographic and Baseline Characteristics ............................. 87 
7.4.2 
Analysis of Primary Objectives ................................................................. 87 
7.4.2.1 
Statistical Hypotheses for Primary Objectives ...................................... 87 
7.4.2.2 
Analysis Populations for Primary Objectives ........................................ 87 
7.4.2.3 
Statistical Methods for Primary Objectives ........................................... 87 
7.4.2.4 
Sample Size and Power Considerations of Primary Objectives ............. 87 
7.4.2.5 
Analysis of Safety Objectives ................................................................ 88 
7.4.2.5.1 
Analysis of Extent of Exposure ....................................................... 88 
7.4.2.5.2 
Analysis of Solicited Local and Systemic Adverse Events and Other 
Reactions 88 
7.4.2.5.3 
Analysis of Spontaneously Reported Adverse Events .................... 89 
7.4.2.5.4 
Analysis of Safety Laboratory Values ............................................. 90 
7.4.3 
Analysis of Key Secondary Immunogenicity Objectives .......................... 90 
7.4.4 
Analysis of Key Secondary Efficacy Objectives ....................................... 90 
7.4.5 
Analysis of Key Secondary Other Objectives ............................................ 91 
7.4.6 
Analysis of Non-Key Objectives ............................................................... 91 
7.5 
Planned Interim Analysis ................................................................................... 91 
8.0 
SOURCE DOCUMENTATION, STUDY MONITORING, AND AUDITING .. 92 
8.1  Source Documentation ....................................................................................... 92 
8.2 
Study Monitoring and Source Data Verification ............................................... 93 
9.0 
DATA MANAGEMENT ....................................................................................... 94 
9.1 
Data Entry and Management .............................................................................. 94 
9.2 
Data Clarification ............................................................................................... 95 
9.3 
Data Coding Procedures .................................................................................... 95 
9.4 
Data Protection ................................................................................................... 95 
10.0 
RECORD RETENTION ........................................................................................ 96 
11.0 
USE OF INFORMATION AND PUBLICATION ................................................ 97 
12.0 
ETHICS .................................................................................................................. 98 
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12.1 
Regulatory and Ethical Compliance ................................................................... 98 
12.2 
Informed Consent Procedures ............................................................................ 98 
12.3 
Responsibilities of the Investigator and IRB/EC ............................................... 99 
12.4 
Protocol Adherence .......................................................................................... 100 
12.5 
Protocol Amendments ...................................................................................... 100 
13.0 
REFERENCE LIST ............................................................................................. 101 
APPENDIX A: ADVERSE EVENTS OF SPECIAL INTEREST (AESI) ..................... 108 
APPENDIX B: TOXICITY GRADING SCALES FOR SOLICITED LOCAL ADVERSE 
EVENTS .......................................................................................................................... 109 
APPENDIX C: TOXICITY SCALES FOR SOLICITED SYSTEMIC ADVERSE 
EVENTS .......................................................................................................................... 110 
APPENDIX D: TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(SERUM) ......................................................................................................................... 111 
APPENDIX E: TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(HEMATOLOGY) ........................................................................................................... 113 
APPENDIX F: TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(URINE) ........................................................................................................................... 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
ACIP 
Advisory Committee on Immunization Practices 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALRI 
Acute Lower Respiratory Infection 
ALT 
Alanine Aminotransferase 
Al(OH)3 
Aluminum hydroxide 
ANCOVA 
Analysis of Covariance 
AP 
(Statistical) Analysis Plan 
AST 
Aspartate Aminotransferase 
BCDM 
Biostatistics and Clinical Data Management 
B&SR 
Biostatistics and Statistical Reporting 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CBER 
Center for Biologics Evaluation, Research and Review 
CDC 
Centers for Disease Control and Prevention 
cDNA 
Complementary Deoxyribonucleic acid 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Human Medicinal Products for Human Use 
CI 
Confidence Interval 
CMI 
Cell Mediated Immunity 
COPD 
Chronic Obstructive Pulmonary Disease 
CPK 
Creatinine Phosphokinase 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive Protein 
CSR 
Clinical Study Report 
DCF 
Data Clarification Form 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eDiary 
Electronic Diary 
EDT 
Electronic Data Transfer 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELISPOT 
Enzyme-linked Immunosorbent Spot 
EMA 
European Medicines Agency 
F 
Fusion (glycoprotein) 
FAS 
Full Analysis Set 
 
 
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FDA 
Food and Drug Administration 
FI 
Formalin-inactivated 
FSFV 
First Subject First Visit 
γGT 
Gamma-glutamyl Transpeptidase 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices 
GMC 
Geometric Mean Concentration 
GMR 
Geometric Mean Ratio 
GMT 
Geometric Mean Titer 
HEENT 
Head, Ears, Eyes, Nose, and Throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
ID 
Identification (Subject ID), Intradermal 
Ig 
Immunoglobulin 
IUD 
Intrauterine Device 
IM 
Intramuscular 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LDH 
Lactate Dehydrogenase 
LSLV 
Last Subject Last Visit 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MITT 
Modified Intention-To-Treat 
mL 
Milliliters 
MPV 
Mean Platelet Volume 
NAb 
Neutralizing antibody 
NCR 
Non Carbon-Copy Paper 
NOCD 
New onset of chronic disease 
NVD 
Novartis Vaccines and Diagnostics 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PIV 
Paramyxovirus 
 
 
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PP 
Per Protocol 
PPT 
Partial Thromboplastin Time 
PRNA 
Plaque Reduction Neutralization Assay 
PRO 
Patient Reported Outcome 
PT 
Prothrombin Time 
RBC 
Red Blood Cell 
RSV 
Respiratory Syncytial Virus 
SAE 
Serious Adverse Event 
SDA 
Source Data Agreement 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
VSAE 
Vaccine Serious Adverse Event 
WBC 
White Blood Cell 
WHO 
World Health Organization 
µg 
Microgram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.0 
BACKGROUND AND RATIONALE 
 
A comprehensive review of the RSV F subunit vaccine is contained in the Investigator’s 
Brochure (IB) supplied by NVD; this document should be reviewed prior to initiating the 
study. 
 
Respiratory syncytial virus (RSV) is the most important cause of acute lower respiratory 
tract infections (ALRIs) that result in hospital visits during infancy and early childhood. In 
the United States, more than 60% of infants are infected by RSV during their first RSV 
season, and nearly all have been infected by two to three years of age (Breese, 2010; 
Glezen et al., 1986). Approximately 2.1 million US children less than five years of age  
are treated for RSV disease each year: 3% as inpatients, 25% in emergency departments, 
and 73% in pediatric practices (Hall et al., 2009). Disease burden is similar in Europe, 
with more than 1% of all children less than three years of age hospitalized annually and 
more than 7% receiving outpatient medical care (Forster et al., 2004). Globally, among 
children less than five years of age, RSV causes an estimated 33.8 million ALRIs each 
year (more than 22% of all ALRIs), resulting in 66,000-199,000 deaths, 99% of which 
occur in developing countries (Nair et al., 2010). In addition, RSV is a common cause of 
respiratory disease among the elderly, resulting in as many hospitalizations as influenza in 
a heavily influenza-immunized population (Falsey et al., 2005). 
 
RSV spreads by respiratory droplets and close contact with infected persons or 
contaminated objects. In temperate climates there is an annual winter epidemic (Brandt et 
al., 1973). In tropical areas seasonality is less distinct, but infection is most common 
during the rainy season (Weber et al., 1998). Infants are at highest risk for severe RSV 
disease in their first six months (Iwane et al., 2004; Hall et al., 2009), and hospitalization 
peaks at two to three months of age (Parrott et al., 1973). Preterm birth and 
cardiopulmonary disease are risk factors for severe disease, with 33.8% of infants with 
bronchopulmonary dysplasia hospitalized for RSV in their first year of life (Boyce et al., 
2000). Bronchiolitis is the classic presentation of RSV. RSV also causes pneumonia, 
rhinitis, and otitis media. Severe RSV infection in infancy is associated with higher rates 
of asthma later in childhood (Stein et al., 1999; Wu & Hartert, 2006). Recommended 
treatment of RSV bronchiolitis consists primarily of respiratory support and hydration 
(Subcommittee on diagnosis and management of bronchiolitis, 2006). No specific anti- 
viral therapy is recommended. The neutralizing monoclonal antibody (mAb), 
Palivizumab®, directed to a single epitope of the RSV fusion glycoprotein (F), is used for 
prophylaxis of infants at highest risk for severe RSV disease, and although the 
monoclonal antibody can protect these infants, it is too expensive and impractical for 
universal use (Prescott et al., 2010). Induction of neutralizing antibody (NAb) should be 
the primary goal of vaccination because the severity of RSV disease is largely determined 
by the extent of viral replication (Graham, 2011). Although developing a safe and 
 
 
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effective RSV vaccine is a global public health priority and will have a significant impact 
on RSV prevention, there is no licensed RSV vaccine. 
 
A history of RSV vaccine-mediated disease enhancement raises safety concerns for 
vaccine studies in RSV-naive infants.  In a key RSV vaccine clinical trial in the late 
1960s, infants and young children were immunized with a formalin-inactivated whole 
virion RSV preparation (FI-RSV) or an equivalent paramyxovirus control preparation (FI- 
PIV). Five percent of the subjects who were immunized with FI-PIV and then naturally 
infected by RSV during the next RSV season were hospitalized; 80% of those who were 
immunized with FI-RSV and then infected by RSV were hospitalized, and two of them 
died (Kim et al., 1969). FI-RSV-mediated RSV disease enhancement has been attributed 
to FI-RSV’s failure to elicit neutralizing antibodies combined with its priming for an 
exaggerated, Th2-predominant immune response to subsequent RSV infection 
(Bouhvalova et al., 2006; Graham et al., 1993; Kalina et al., 2004; Connors et al., 1994; 
De Swart et al., 2002; Polack et al., 2002; The Impact-RSV Study Group, 1998; Shaw et 
al., 2013). 
 
Given the early age of peak RSV disease (Iwane et al., 2004; Hall et al., 2009; Parrott et 
al., 1973), an RSV vaccine would ideally be administered to neonates and young infants, 
elicit neutralizing antibodies, and prime for an immune response to RSV infection that 
prevents rather than enhances RSV disease. However, it is difficult to actively immunize 
infants to protect them by two to three months of age because time must elapse after 
immunization for a neutralizing antibody response, and more than one dose of vaccine 
may be needed. Direct infant immunization is also challenged by the inhibitory effects of 
maternal antibody (Crowe, 2001; Wood & Siegrist, 2011; Philbin & Levy, 2009; Shaw et 
al., 2013) and the immaturity of the neonatal immune system, which has impaired 
antigen-presenting cell responses, Th2-biased cellular responses, and impaired antibody 
affinity maturation. 
 
Novartis Vaccines and Diagnostics (NVD) has developed an investigational RSV subunit 
vaccine from an engineered recombinant RSV fusion (F) glycoprotein. The engineered 
recombinant F antigen is modified from the wild type F glycoprotein of RSV strain A2, a 
laboratory group A prototype strain isolated in 1961 from an infant with bronchiolitis. 
The wild type RSV F glycoprotein is a homotrimer that is anchored in the viral envelope 
by a C-terminal transmembrane region. The RSV F protein mediates virus-cell fusion, is 
highly conserved among RSV isolates, and is a major target of neutralizing antibodies 
(Shaw et al., 2013). The clinical program will evaluate the feasibility of passively 
protecting infants by immunizing pregnant women with the RSV F subunit vaccine. The 
inverse correlation between maternal, cord blood, or infant serum RSV neutralizing titers 
and early RSV disease in infants demonstrates that maternal antibody can protect infants 
(Glezen et al., 1981; Piedra et al., 2003). Although a precise correlate of protection has 
not yet been agreed, studies of passive protection by maternal antibody or administered 
 
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immunoglobulin and studies of RSV infection of cotton rats suggest that infant serum 
neutralizing titers of approximately 1:200 to 1:400 prevent severe RSV disease (Piedra et 
al., 2003; Groothuis et al., 1993; Prince et al., 1985; Siber et al., 1994; Shaw et al., 2013). 
The half-life of maternal antibody in infants predicts that each doubling of titer should 
extend passive infant protection by approximately one month (Ochola et al., 2009; 
Brandenburg et al., 1997). If maternal immunization during 24 to 32 weeks of gestation 
increases antibody titers eight-fold, the median peak of RSV disease in infants would be 
delayed by approximately three months from its current peak at two to three months of 
age to a new peak at approximately five to six months of age. This delay could 
significantly decrease the burden of RSV disease in infants in the first months of life and 
open an RSV disease-free interval during which active immunization of infants could 
further extend protection beyond six months of age. 
 
Because the duration of protection of an infant receiving transplacental antibody from an 
immunized pregnant woman is expected to be directly dependent on the woman’s 
neutralizing titer to RSV, there is no maximum desirable neutralization titer. This is an 
important distinction between immunization of a subject to actively protect that subject 
and immunization of a pregnant woman to passively protect her infant from a disease 
with an extended period of vulnerability after birth. With immunization for active 
immunity, achievement of a threshold immune response indicates that the subject’s 
immune system is sufficiently primed to protect against future disease, often remote 
future disease, and the goal is to achieve that threshold response. On the other hand, with 
immunization for passive protection, the infant receives a finite placental transfer of 
antibody before birth, and that protective antibody decays to zero over time, leaving no 
priming of the immune system of the infant to protect against future and distant 
infections. As a consequence, the goal for passive immunization is to elicit the highest 
level of neutralizing antibodies in the pregnant subject that can be achieved safely, 
tolerably, and practically, so that a maximal neutralizing antibody titer is transferred to 
the infant before birth, providing the longest possible period of passive protection after 
birth. Given the extended vulnerability of infants to severe RSV infections, at least 
through two years of age, and the approximately one month half-life of passively 
transferred antibody (Breese, 2010; Glezen et al., 1986; Hall et al., 2009; Ochola et al., 
2009; Brandenburg et al., 1997), any achievable maternal neutralization titer is unlikely to 
protect throughout the complete period of vulnerability. 
 
Preclinical animal experiments with the investigational RSV F subunit vaccine have 
shown different effects of dosage levels, number of doses, and need for adjuvant, 
depending on the RSV infection history of the animal. The difference between the 
responses of RSV-naïve and recently RSV-infected animals complicates extrapolation of 
the results to immunization of adult humans, who are likely to have been more remotely 
infected. In RSV-naïve cotton rats or mice, aluminum hydroxide [Al(OH)3] or MF59 was 
required for high titer neutralizing responses. There was a clear dosage level-response for 
 
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both adjuvanted and unadjuvanted RSV F subunit vaccine (two intramuscular [IM] 
injections at a three week interval) in mice, with a plateau achieved with approximately 
3.3 µg of aluminum hydroxide-adjuvanted and 10 µg of unadjuvanted RSV F subunit 
vaccine, respectively. Maximum neutralizing titers of approximately 1:1,000 in mice and 
1:7,000 in cotton rats were less than two-fold higher with aluminum hydroxide than with 
MF59 in both species. However, cotton rats and mice infected intranasally with RSV that 
were subsequently immunized once IM with 5 µg, 0.5 µg, or 0.05 µg of RSV F subunit 
vaccine seven weeks later (cotton rats) or eleven weeks later (mice), showed a four-fold 
increase (cotton rats) and 10 to 50-fold increase (mice) in neutralizing titers after 
immunization – but the neutralizing titers were minimally impacted by the RSV F subunit 
vaccine dosage level, by the inclusion of adjuvant (none, aluminum hydroxide, or MF59), 
or by a second vaccine injection given three weeks after the first. 
 
The discrepancy between the effect of dosage level in previously RSV-infected and RSV- 
naïve rodents, the unknown (and possibly long) expected interval between natural RSV 
infection and immunization of adult humans, the lack of predictable scaling of dosage- 
response with body size, and species-specific adjuvant effects make the animal data a 
poor guide to dosage level and regimen determination for testing the RSV F subunit 
vaccine in humans. Therefore, previous clinical trial experience with other F-containing, 
non-replicating RSV vaccines, rather than the animal data, serve as the primary guide for 
the initial selection of dosage levels for testing of Novartis’s RSV F subunit vaccine 
candidate in humans. Available clinical trial results suggest that adult humans respond in 
a manner that is intermediate between the RSV-naïve and previously RSV-infected mice 
and cotton rats, and require higher dosage levels than those used to immunize rodents 
(Glenn et al., 2013; Muñoz et al, 2003; Falsey & Walsh, 1996; Falsey & Walsh, 1997; 
Falsey et al., 2008; Langley et al., 2009). 
 
Because the adult human population is seropositive for RSV, RSV vaccination in adults 
will act as a booster. Boosting immunity in RSV-seropositive individuals may be 
challenging and may require use of adjuvant. Aluminum hydroxide [Al(OH)3] and 
aluminum phosphate salts are the most commonly used adjuvant in licensed vaccines 
worldwide and they have a well-established safety profile, including in pregnant women 
(Baylor et al., 2002; Silveira et al., 1995; Blencowe et al., 2010; Murphy et al., 2008; 
ACIP, 2011; Mast et al., 2005; Levy & Koren, 1991; Tsai et al., 2010; Vecchi et al., 
2012). MF59 is a nanoemulsion of squalene, polysorbate 80, sorbitan trioleate, and 
citrate. MF59 is used in subunit influenza vaccines that are licensed in European and 
other countries (not including the United States), such as Fluad® (seasonal), Aflunov® 
(H5N1 pre-pandemic), Foclivia® (H5N1 pandemic), Focetria® (H1N1 pandemic), and 
Celtura® (cell culture-produced H1N1 pandemic). More than 100 million doses of MF59- 
adjuvanted influenza vaccines have been distributed in licensed products. Although 
MF59-adjuvanted vaccines are somewhat more reactogenic than equivalent non- 
adjuvanted vaccines, clinical trials and post-marketing surveillance demonstrate MF59’s 
 
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good safety and tolerability profile (O’Hagan 2007; 2013; Pellegrini et al., 2009; Tsai et 
al., 2010; Schultze et al., 2008; Black et al., 2010). An estimate of >90,000 pregnant 
women were vaccinated with Focetria during the 2009 pandemic. Preliminary data from 
observational studies, spontaneously reported events, and ongoing post-marketing studies 
(a pregnancy registry and a prospective interventional study) have provided no evidence 
of direct or indirect harmful effects to mother or fetus from the use of MF59-adjuvanted 
vaccines during pregnancy (Banzhoff et al., 2011; Parretta et al., 2011; Zuccotti et al., 
2010; Huang et al., 2011). The mechanism of action of adjuvants is not completely 
understood, but both aluminum hydroxide and MF59 are thought to increase local 
cytokines and chemokines and increase cell recruitment (including eosinophils for 
aluminum hydroxide, neutrophils for MF59, and monocytes and macrophages for both) 
(Awate et al., 2013). Aluminum hydroxide is also proposed to increase antigen 
presentation, while MF59 increases antigen uptake, increases antigen-loaded neutrophils 
and monocytes, and activates muscle cells (Awate et al., 2013). In total, approximately 
150 million doses of MF59-adjuvanted vaccines have been distributed (O’Hagan et al., 
2013). No safety concerns have been observed related to MF59 (O’Hagan et al., 2013). 
Similarly, hundreds of millions of doses of aluminum-containing adjuvants have been 
administered without any major safety findings (Lamprecht et al., 2009). 
 
Recently, Novavax (Rockville, MD) performed a Phase 1 randomized, observer-blinded, 
placebo-controlled clinical trial with a similar recombinant RSV F subunit vaccine to 
evaluate its safety and immunogenicity in healthy adults (Glenn et al., 2013). The results 
of the Phase 1 clinical trial showed that 30 µg and 60 µg (with or without aluminum 
phosphate) induced a two-fold increase in neutralizing titers after two IM injections; the 
two-fold increase in neutralizing titers was negatively correlated with baseline 
neutralizing titers. The small magnitude of the increase of neutralizing titers and large 
range of baseline neutralizing titers led to variable increases in neutralizing titers with 
dosage level or use of adjuvant. Dosage level-responses for RSV F binding antibodies 
(including those that compete with Palivizumab®) covered a broader range (Glenn et al., 
2013). There was no plateau in binding antibody titers between the two highest dosage 
levels tested, 30 and 60 µg, but there were increases in binding titers with aluminum 
phosphate adjuvant and a modest increase with a second injection (a maximum 1.6-fold 
increase at 5 µg or 15 µg with aluminum phosphate and a smaller increase at higher 
dosage levels) (Glenn et al., 2013). A subsequent clinical trial is currently being 
performed in women of child bearing age with 60 and 90 µg of their RSV F subunit 
vaccine candidate.  Although other trials in the literature do not provide as clearly 
relevant information (Muñoz et al, 2003; Falsey & Walsh, 1996; Falsey & Walsh, 1997; 
Falsey et al., 2008; Langley et al., 2009; Tristram et al., 1993; Belshe et al., 1993; 
Paradiso et al., 1994; Piedra et al., 2003), their results are broadly consistent with those of 
the Novavax Phase 1 clinical trial (Glenn et al., 2013), which closely followed the 
intended immunization regimen for the NVD investigational RSV F subunit vaccine 
 
 
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candidate. In previous clinical trials of former (or still current) non-replicating RSV F 
subunit vaccine candidates, including trials conducted in RSV seropositive infants, typical 
dosage levels of RSV antigens tested IM have been in the range of 5 to 100 µg per dose 
(Glenn et al., 2013; Muñoz et al, 2003; Falsey & Walsh, 1996; Falsey & Walsh, 1997; 
Falsey et al., 2008; Langley et al., 2009; Tristram et al., 1993; Belshe et al., 1993; 
Paradiso et al., 1994; Piedra et al., 2003). 
 
To provide the longest period of protection from RSV disease in infants, the goal is to 
maximize neutralizing antibody titers in pregnant women through immunization. In the 
current study, we will test one dosage of the investigational RSV F subunit vaccine that is 
presumed to be below the dosage-response plateau (to establish that a maximal 
neutralizing antibody response cannot be achieved with a low dosage) and two higher 
dosages (to either establish the dosage-response plateau or indicate that higher dosages 
are needed in a subsequent study to reach the plateau). Therefore, for the current study, 
two doses (administered IM at least 28 days apart) of three dosage levels of the 
investigational RSV F subunit vaccine will be tested in healthy adults: 45 µg, 90 µg, and 
135 µg. The two-dose regimen was selected because clinical data with a similar vaccine 
candidate (Glenn et al., 2013) have shown an increase in titers following the second dose. 
Based on the previous clinical experience with similar vaccine candidates, the lowest 
dosage level (45 µg) is not anticipated to be on the dosage-response plateau. In a non- 
GLP preclinical toxicology study in rabbits, two simultaneous injections of 135 µg of the 
RSV F subunit vaccine candidate were well-tolerated, and the preclinical safety and 
tolerability of a 135 µg dosage will be confirmed in the GLP preclinical toxicology study 
before this Phase 1 study starts. Based on these constraints, the two upper dosages, 90 µg 
and 135 µg, have been selected to maximize the chances that a dosage-response plateau 
will be established in this study. 
 
The purpose of this study is to evaluate the safety and immunogenicity of two doses of the 
investigational RSV F subunit vaccine administered IM. In this current Phase 1, first- in-
human study, the three different antigen amounts that have been selected will be evaluated 
in a stepwise manner in three different cohorts (cohort 1: low dosage of RSV F subunit 
vaccine [45 µg], cohort 2: middle dosage of RSV F subunit vaccine [90 µg], and cohort 3: 
high dosage of RSV F subunit vaccine [135 µg]). In addition, the effect of an adjuvant, 
either aluminum hydroxide [Al(OH)3] or MF59, and antibody kinetics post- vaccination at 
different time points will be evaluated as compared to unadjuvanted RSV F subunit 
vaccine at the same dosage levels. The trial will be conducted in compliance with the 
protocol, GCP and applicable regulatory requirement(s). 
 
 
 
 
 
 
 
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2.0 
OBJECTIVES 
 
2.1 
Primary Objective(s) 
Primary Immunogenicity Objective 
 
1. To evaluate the serum neutralizing antibody (NAb) response to the RSV F subunit 
vaccine or placebo at Day 57 (28 days after the second dose). 
 
Primary Safety Objective 
 
1. To assess the safety of the RSV F subunit vaccine compared to placebo. 
 
2.2 
Secondary Objectives 
Secondary Immunogenicity Objectives 
1. To evaluate the serum neutralizing antibody (NAb) response to the RSV F subunit 
vaccine or placebo at Day 1 (baseline), Day 29 (28 days after the first dose), and Day 
181 (six months after the first dose). 
2. To evaluate the total serum antibody responses to the RSV F subunit vaccine or 
placebo at Day 1 (baseline), Day 29 (28 days after the first dose), Day 57 (28 days 
after the second dose), and Day 181 (six months after the first dose). 
3. To compare the ratio of RSV F subunit serum neutralizing antibody (NAb) titer to 
RSV F subunit serum total binding antibody titers to the RSV protein F in vaccine or 
placebo recipients at Day 1 (baseline), Day 29 (28 days after the first dose), Day 57 
(28 days after the second dose), and Day 181 (six months after the first dose). 
4. To compare the ratio of RSV F subunit serum neutralizing antibody (NAb) titer to 
RSV F subunit serum total binding antibody titers to each of the RSV proteins G and 
N in vaccine or placebo recipients at Day 1 (baseline), Day 29 (28 days after the first 
dose), Day 57 (28 days after the second dose), and Day 181 (six months after the first 
dose). 
 
 
Secondary Exploratory Objectives 
 
1. To characterize the serum neutralizing antibody (NAb) and binding antibody 
responses against additional RSV strains and native or engineered RSV antigens at 
baseline and following vaccination in a subset of subjects. 
 
 
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2. To determine the frequency of B cells specific for RSV proteins in a subset of 
subjects, and subsequently, explore the baseline immunity to RSV and the immune 
response to the RSV F subunit vaccine by analyzing the RSV-specific B-cell 
repertoire in a selected group of the subset of subjects. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.0 
STUDY DESIGN AND INVESTIGATIONAL PLAN 
 
3.1 
Overview of Study Design 
This is a Phase 1, randomized, observer blind, placebo-controlled, dosage-escalation, 
single center study, enrolling healthy adults. In total, approximately 288 healthy non- 
pregnant female and male adults (18 to 45 years of age) will be enrolled in the study in 
the ratio of 3:1. There is a higher ratio of female to male subjects because the RSV F 
subunit vaccine is ultimately intended for use in pregnant women. Men are still being 
included in this study because the vaccine may also be tested in the future in elderly 
subjects. 
 
Approximately 216 healthy subjects will be randomized to receive the investigational 
vaccine. Subjects will be enrolled (1:1:1) in a stepwise dosage-escalation manner in to 
one of three cohorts (cohort 1: low dosage of RSV F subunit vaccine [45 µg], cohort 2: 
middle dosage of RSV F subunit vaccine [90 µg], and cohort 3: high dosage of RSV F 
subunit vaccine [135 µg]). Cohort 1 will be enrolled first, followed by cohort 2, and 
finally cohort 3.Within each cohort subjects will be randomly allocated (1:1:1) to receive 
vaccine with no adjuvant, with aluminum hydroxide, or with MF59, as outlined in Table 
1. All subjects will receive two doses of a 0.5 mL intramuscular injection of the vaccine, 
with adjuvant (aluminum hydroxide [1 mg] or MF59 [0.25 mL; 9.75 mg squalene and 
surfactants]) or without adjuvant. There will be approximately 24 subjects in each 
treatment group. All the remaining 72 subjects will be assigned to receive placebo (saline) 
(approximately 24 subjects per cohort) (Table 1). 
 
The minimum interval between doses will be 28 days. The study duration for a given 
subject will be approximately 13 months. An Interim Analysis will be performed on the 
immunogenicity and safety data collected from all subjects at Visit 1 (baseline), Visit 5 
(28 days after the first dose), and Visit 9 (28 days after the second dose). Further details 
regarding the interim analysis are contained in section 7.5. 
 
Vaccination Plan: Eighteen (18) treatment groups (9 active treatment groups and 3 placebo 
[saline] groups in each cohort) will be evaluated as shown in Table 1: 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3.1-1: 
Number of Subjects Randomized per Vaccine Treatment Group in 
Each Cohort 
 
Cohort 
Dosage 
Route of 
Administration 
Regimen: Two Doses † 
No Adjuvant 
Al(OH)3 ‡ 
MF59 ‡ 
1 
45 µg 
IM (0.5 mL) 
24 
24 
24 
Placebo (saline) 
IM (0.5 mL) 
8 
8 
8 
2 
90 µg 
IM (0.5 mL) 
24 
24 
24 
Placebo (saline) 
IM (0.5 mL) 
8 
8 
8 
3 
135 µg 
IM (0.5 mL) 
24 
24 
24 
Placebo (saline) 
IM (0.5 mL) 
8 
8 
8 
Abbreviations: IM, intramuscular; mL, milliliter; Al(OH)3, aluminum hydroxide. 
†Administered at least 28 days apart. 
‡ Concentration of Al(OH)3 will be 1 mg per dose and that of MF59 will be 0.25 mL (1X, which contains 
9.75 mg squalene and surfactants). 
 
 
3.1.1 Study Period 
 
The expected duration of the study for an individual subject is approximately 13 months. 
 
3.2 
Study Visit Procedures 
 
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical trial. 
 
3.2.1 Informed Consent 
"Informed consent" is the voluntary agreement of an individual or his/her legal guardian 
to participate in research. Consent must be given with free will of choice, and without 
undue inducement. The individual must have sufficient knowledge and understanding of 
the nature of the proposed research, the anticipated risks and potential benefits, and the 
requirements of the research to be able to make an informed decision. 
 
Informed consent following local IRB/EC guidance must be obtained before conducting 
any study-specific procedure (i.e., all of the procedures described in the protocol). The 
process of obtaining informed consent should be documented in the subject source 
documents in addition to maintaining a copy of the signed and dated informed consent. 
 
If a subject is unable to read, an impartial witness should be present during the entire 
informed consent discussion. An impartial witness is defined as a person who is 
independent from trial conduct, who cannot be unfairly influenced by those involved with 
 
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the trial, who attends the informed consent process if the subject or the subject's legally 
acceptable representative cannot read, and who reads the informed consent form and any 
other written information supplied to the subject. After the written informed consent 
form and any other written information to be provided to subjects, is read and explained 
to the subject and after the subject has verbally consented to the subject’s participation in 
the trial and, if capable of doing so, has signed and personally dated the informed consent 
form, the witness should sign and personally date the consent form. By signing the 
consent form, the witness attests that the information in the consent form and any other 
written information was accurately explained to, and apparently understood by, the 
subject and that informed consent was freely given by the subject. 
 
3.2.2 Screening Procedures 
 
After an individual has consented to participate in the study and informed consent/assent 
is signed, that individual will be given a unique screening number which is documented in 
the Screening & Enrollment Log. Screening procedures will include the following: 
 
▫ Medical history, including but not limited to: 
- 
Prior vaccinations 
- 
Concomitant medications 
- 
Previous and ongoing illnesses or injuries 
▫ Physical examination, including but not limited to: 
- 
Vital signs 
- 
Assessment of general appearance 
- 
Examination of head, ears, eyes, nose, and throat (HEENT) 
- 
Examination of skin 
- 
Auscultation of heart and lungs 
- 
Palpation of abdomen 
- 
Examination of extremities 
▫ Safety laboratory blood draw 
▫ Urinalysis 
▫ Pregnancy test (for female subjects) 
See section 3.5.3, section 6.2, and Table 2 for more information. 
 
 
 
 
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In the event that the individual is determined ineligible for study participation, he/she is 
considered a “screen failure”. The reason for screen failure must be documented in the 
Screening & Enrollment Log. If the individual is determined to be eligible for the study, 
he/she should be enrolled into the study as described in section 3.2.3. 
 
3.2.3 Enrollment 
 
After an individual is determined to be eligible for study participation, the subject will be 
enrolled using a computerized randomization system that automatically assigns a unique 
Subject ID. The Subject ID consists of a 7 digit number resulting from the combination of 
the site number and the subject’s order of randomization at the site. Access to the system 
can be obtained by the site staff either via web or telephone (as back up). 
 
Enrollment of all three cohorts will not occur simultaneously. Instead, subjects will be 
enrolled in to each cohort in a step-wise manner based on the dosage-escalation design. 
The first 12 subjects will be enrolled in cohort 1, a safety review of cohort 1 data through 
Visit 2 will be performed by the DMC, and then the remaining subjects in cohort 1 will be 
enrolled. After a safety review of cohort 1 data through Visit 9 is performed by the DMC, 
the first 12 subjects will be enrolled in cohort 2. After the safety review of cohort 2 data 
through Visit 2 is completed the remainder of cohort 2 subjects will be enrolled. Once 
safety review of cohort 2 data through Visit 9 has been completed by the DMC, the first 
12 subjects of cohort 3 will be enrolled. Finally, cohort 3 enrollment will be completed 
after DMC review of cohort 3 safety data through Visit 2. 
 
3.2.4 Randomization 
Subjects will be randomly assigned to study groups in a pre-specified ratio as described in 
section 3.1. The computerized randomization system will allocate the subject to one of the 
study groups and assign a Pack Number corresponding to the pack containing the 
treatment to be administered to the subject according to the randomization list. The list of 
randomization assignments will be produced by the service provider and approved by 
NVD Biostatistics and Clinical Data Management department (BCDM) according to 
applicable NVD SOP. 
 
If for any reason, after signing the informed consent form (ICF), the subject (who has 
passed screening) fails to be randomized, the reason for not being randomized should be 
recorded on source documents as specified in the source data agreement. The information 
on these subjects, who are randomization failures, should be kept distinct in the source 
documentation from screen failures, which are described in section 3.2.2. 
 
 
 
 
 
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3.2.5 Visit Procedures 
The following sections provide an overview of procedures to be performed during the 
study. Where applicable, references to other sections of the protocol are provided for 
further details. Timing of procedures can also be found in Table 2, Times and Events 
Table. Unless otherwise stated, all tests and procedures described in the protocol are 
required. 
 
3.2.5.1 
Pre-vaccination Procedures 
 
The following procedures will be performed at a Screening visit prior to the day of first 
vaccination: 
 
1. Informed consent (refer to sections 3.2.1 and 12.2 for further detail) 
2. Demography: refer to section 6.2 for details 
a. prior vaccination and concomitant medication (refer to section 5.4 for further 
detail) 
b. medical history: refer to section 6.2 for details 
3. Review of systems: a structured interview that queries the subject as to any 
complaints the subject has experienced across each organ system 
4. “General” physical examination: refer to section 6.2 for details 
5. Height and weight: height will be measured in centimeters while standing; weight 
will be measured in kilograms 
6. Safety laboratory blood draw: blood will be drawn to perform safety laboratory 
assessments (refer to section 3.5.3 for further detail) 
7. Urinalysis: a urine sample will be collected (refer to section 3.5.3 for further detail) 
8. Pregnancy testing: all women of child-bearing potential will be tested; refer to section 
3.5.2 for guidance regarding the procedure 
9. Review of eligibility criteria: refer to sections 4.1 and 4.2 for the list 
 
The following procedures will be performed at Visit 1 and Visit 5 prior to vaccination: 
 
1. Randomization (Visit 1 only): refer to section 3.2.4 
2. Limited physical examination: refer to section 6.2 for details 
3. Blood sampling: Prior to study vaccination, blood will be drawn from the subjects for 
serology and safety laboratory assessments. For subjects in cohort 3 who sign an 
 
 
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additional Informed Consent for exploratory immunology assays, additional blood 
will be collected (see section 3.5.4). Details regarding the volume of blood and testing 
to be performed are in sections 3.5.1, 3.5.3, and 3.5.4. 
4. Urinalysis: a urine sample will be collected (refer to section 3.5.3 for further detail) 
5. Pregnancy testing: all women of child-bearing potential will be tested; refer to section 
3.5.2 for guidance regarding the procedure 
 
 
3.2.5.2 
Vaccination Procedures 
Subjects will receive two (2) doses of vaccine according to their assigned treatment in a 
blinded fashion. Vaccination will be performed at Visit 1 and Visit 5. The minimum 
interval between vaccinations will be 28 days. 
 
After confirming eligibility and enrolling subject into the study at Visit 1, perform 
vaccination of the subject according to the assigned study vaccine and according to the 
procedures described in section 5.3 and observing the blinding procedures described in 
section 3.3. At Visit 5, confirm that the subject does not meet any criteria for delaying or 
cancelling additional study vaccinations, as described in section 4.3 and section 4.4 of the 
protocol. 
 
3.2.5.3 
Post-vaccination Procedures 
 
The following post-vaccination procedures will be performed at Visit 1 and Visit 5. 
 
1. Subjects will be provided with a diary card at Visit 1 and Visit 5. 
2. Careful training of the subject on how to measure local reactions and body 
temperature, how to complete and how often to complete the diary card is crucial. 
Training should be directed at the individual(s) who will perform the measurements of 
reactions and those who will enter the information into the diary card. This individual 
can be someone other than the subject, but if a person other than the subject enters 
information into the diary card, this person’s identity must be documented in the study 
file and this person must receive training on the diary card. Training of the subject on 
how to measure an injection site reaction should be performed while the subject is 
under observation after vaccination. 
3. The subject must understand that timely completion of the diary card on a daily basis 
is a critical component to study participation. The subject should also be instructed to 
write clearly and to complete the diary card in pen. Any corrections to the diary card 
that are performed by the person completing the diary card should include a single 
 
 
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strikethrough line with a brief explanation for any change. No changes can be made to 
the diary card when it is returned to the clinic. 
4. Starting on the day of vaccination, the subject will check in the evening for specific 
types of reactions at the injection site (solicited local adverse events), any specific 
generalized symptoms (solicited systemic adverse events), body temperature (taken 
preferably orally), any other symptoms or change in the subject’s health status, and 
any medications taken (excluding vitamins and minerals). These solicited adverse 
events and body temperature will be recorded in the “six hour” location on the diary 
card. 
5. Body temperature measurement is to be performed using the thermometer provided by 
the site. If the subject feels unusually hot or cold during the day, the subject should 
check body temperature. If the subject has a fever, the highest body temperature 
observed that day should be recorded on the diary card. The measurement of solicited 
local adverse events is to be performed using the ruler provided by the site. The 
collection of body temperature, solicited local adverse events, and solicited systemic 
adverse events will continue for a total of 7 days on the diary card. The collection of 
unsolicited adverse events and medications will continue for 7 days on the diary card, 
(or until the subject returns for the next clinic visit). 
6. After vaccination, the subject will be observed for at least 30 minutes including 
observation for unsolicited adverse events, solicited adverse events, and body 
temperature measurement. The site staff should take the opportunity to remind the 
subject how to measure solicited reactions and body temperature as part of this 
observation period. Record all safety data collected in the subject’s source 
documents. 
7. The site should schedule the next study activity (reminder call) with the subject. 
8. The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to complete the diary card daily and to contact the site if 
there are any questions and to contact the site immediately (or as soon as the subject is 
medically stable) if the subject has a medical condition that leads to a hospitalization 
or an emergency room visit. 
 
 
3.2.5.4 
Reminder Telephone Calls 
 
1. Reminder calls will be performed 2 and 4 days after each vaccination. 
2. The purpose of this call is to remind the subject about completion of the diary card. It 
is a conversation that follows the reminder telephone call script provided to the site, 
and it is not intended to be a call for collection of safety data. If the subject wishes to 
describe safety information, this information should only be collected by a trained 
 
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healthcare professional at the site, and the safety data described must be written down 
on source documents. The subject should be reminded to write the information down 
in the diary card and to contact the site via the telephone number provided in the 
informed consent to discuss medical questions. 
 
 
3.2.5.5 
Clinic Visits after Vaccination 
Clinic visits that do NOT include vaccine administration include Visits 2, 6, 9, 10, 11, 12, 
and 13. The following procedures will be performed at the indicated clinic visits: 
 
1. Visit 2 and Visit 6: 
a. The diary card will be reviewed and collected. Please see section 3.4.1 for 
additional guidance on diary card review. The subject will be interviewed to 
determine if any unsolicited adverse events occurred and if any concomitant 
medications or vaccines were taken/received in the time since the last clinic visit. 
The healthcare professional reviewing these data will discuss the symptoms (if 
any) reported by the subject and will determine if any additional diagnoses and/or 
adverse events are present. All AEs, SAEs, NOCDs (see section 6.6.1.2), or 
AESIs (see section 6.6.1.1) will be recorded on source documents. All 
medications taken or vaccines received will also be recorded on the source 
documents. 
b. A symptom-directed physical exam will be performed (see section 6.2). 
c. Blood will be collected for safety laboratory assessments (see section 3.5.3). 
d. A urine sample will be collected for urinalysis (see section 3.5.3). 
e. For subjects in cohort 3 who sign an additional Informed Consent for exploratory 
immunology assays, additional blood will be collected (Visit 2 only; see section 
3.5.4). 
f. The site should schedule the next study activity (safety call) with the subject. 
g. The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency 
room visit. 
2. Visit 9: 
a. The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken/received in 
 
 
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the time since the last clinic visit. The healthcare professional reviewing these 
data will discuss the symptoms (if any) reported by the subject and will determine 
if any additional diagnoses and/or adverse events are present. All AEs, SAEs, 
NOCDs, or AESIs will be recorded on source documents. All medications taken 
or vaccines received will also be recorded on the source documents. 
b. A symptom-directed physical exam will be performed (see section 6.2). 
c. Blood will be collected for safety laboratory assessments (see section 3.5.3). 
d. A urine sample will be collected for urinalysis (see section 3.5.3). 
e. Blood for serology will be drawn (see section 3.5.1). 
f. The site should schedule the next study activity (clinic visit) with the subject. 
g. The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency 
room visit. 
3. Visits 10, 11, and 13: 
a. The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken/received in 
the time since the last clinic visit. The healthcare professional reviewing these data 
will discuss the symptoms (if any) reported by the subject and will determine if 
any additional diagnoses and/or adverse events are present. All AEs, SAEs, 
NOCDs, or AESIs will be recorded on source documents. All medications taken 
or vaccines received will also be recorded on the source documents. 
b. A symptom-directed physical exam will be performed (see section 6.2). 
c. The site should schedule the next study activity (clinic visit or safety call) with the 
subject. 
d. The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency 
room visit. 
4. Visit 12: 
a. The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken/received in 
the time since the last clinic visit. The healthcare professional reviewing these 
data will discuss the symptoms (if any) reported by the subject and will determine 
 
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if any additional diagnoses and/or adverse events are present. All AEs, SAEs, 
NOCDs, or AESIs will be recorded on source documents. All medications taken 
or vaccines received will also be recorded on the source documents. 
b. A symptom-directed physical exam will be performed (see section 6.2). 
c. Blood for serology will be drawn (see section 3.5.1). 
d. For subjects in cohort 3 who sign an additional Informed Consent for exploratory 
immunology assays (approximately 40 subjects in total, 10 from each treatment 
group), additional blood will be collected (see section 3.5.4). 
e. The site should schedule the next study activity (clinic visit) with the subject. 
f. The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency 
room visit. 
 
 
3.2.5.6 
Safety Calls 
Safety telephone calls will be performed for Visits 3, 4, 7, and 8 (14 and 21 days after 
each dose). Additional safety telephone calls will be performed for Visits 14 and 15 (9 
and 12 months after the first dose). 
 
1. Safety telephone calls are calls made to the subject by a trained healthcare provider. 
These calls will follow a script which will facilitate the collection of relevant safety 
information. The subject will be interviewed according to the script, and information 
relating to unsolicited adverse events, including serious adverse events (SAEs), 
adverse events of special interest (AESIs), new onset of chronic disease, and AEs 
leading to study or vaccine withdrawal, and concomitant medications or vaccinations 
associated with those events. All safety information described by the subject must be 
written down in a designated location within the source documents and not written on 
the script used for the telephone call. 
2. The site should schedule the next study activity (clinic visit, reminder call, or safety 
call) with the subject. 
3. The subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency room 
visit. 
 
 
 
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3.2.5.7 
“For cause” Visits 
 
Not applicable for this study. 
 
3.2.5.8 
Termination Visits 
 
1. The termination visit will occur at Visit 16 (12 months after the second dose). For 
visit procedures to be performed for a subject whose planned study participation ends 
prematurely, please see section 3.8. 
2. During the phone call, the following procedures will be performed: 
a. The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken/received in 
the time since the last clinic visit. 
b. The healthcare professional reviewing these data will discuss the symptoms (if 
any) reported by the subject and will determine if any additional diagnoses and/or 
adverse events are present. 
c. All AEs, SAEs, NOCDs, or AESIs will be recorded on source documents. 
d. All medications taken or vaccines received will be recorded on the source 
documents. 
3. After thanking the subject for study participation, the site will review the plan of when 
information relating to the subject’s participation in the study may be available (e.g., 
study results, treatment assignments). It will also be discussed how information 
relating to the subject’s participation in the study will be shared with the subject’s 
healthcare provider, if the subject chooses to share this information. 
 
 
The site will complete the termination CRF page and this will mark the completion of the 
subject’s participation in the study. 
 
3.3 
Blinding Procedures 
This is an observer-blind study. The investigator, subjects, monitors, site personnel, and 
laboratory staff will be blinded to the vaccine administered, with the following 
exceptions: 
 
▫ An unblinded designee (i.e., unblinded pharmacist or equivalent) will be assigned to 
administer the vaccine to all subjects. If deemed necessary, a second unblinded 
designee may be allowed to assist with vaccine preparation. The designee(s) will have 
no other study functions than vaccine management, documentation, accountability, 
 
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and administration. They will not be involved in subject evaluations. They will not 
reveal the vaccine treatment assignment to either the subject or the site personnel 
involved in the conduct of the study, unless this information is necessary in the case 
of an emergency. 
The vaccine treatment assignment will be concealed to the extent possible by having the 
unblinded designee(s) (i.e., unblinded pharmacist) prepare the vaccine out of view of the 
subject or other site personnel. Each vaccine treatment group will receive a single 0.5 mL 
dose at each vaccination visit. In case the color or appearance of different dosages of the 
vaccine (or the placebo) differ, the subject will be shielded from view of the syringe and 
injected arm. 
 
A Data Monitoring Committee (DMC) will perform a review of safety data after Visit 2 
(seven days after the first dose) has been completed by the first 12 subjects in each cohort, 
and after Visit 9 (28 days after the second dose) has been completed for all subjects in 
each cohort. Details of the DMC review of safety data and stopping guidelines can be 
found in the DMC Charter. 
 
An interim analysis of immunogenicity and safety data will be performed after results of 
serology assays for all samples through Visit 9 (28 days after the second dose) from all 3 
cohorts are available. The analysis will include serology results from all subjects at Visits 
1, 5, and 9. This interim analysis will be used to evaluate the optimal dosage and/or 
adjuvant for use in future clinical trials. An unblinded statistician from NVD will perform 
the interim analysis; results of the interim analysis will be confirmed by the DMC. 
Interim safety assessments will be performed by the DMC according to the DMC charter. 
The DMC will determine whether any safety issues exit. An unblinded statistician from 
NVD may assist with the evaluations. In the event a safety issue arises, the cluster 
physician and NVD pharmacovigilance department will be informed. 
 
Note: Emergency unblinding should only be undertaken when it is essential to protect an 
individual subject’s safety. There are limited circumstances in a vaccine study where 
unblinding would change the course of medical treatment or care of a subject. 
 
For an emergency unblinding, the investigator will retrieve the subject’s assigned vaccine 
from the computerized randomization system either via web or phone (as backup). Details 
of the unblinding procedures will be described in the system’s Site User manual. 
 
 
 
 
 
 
 
 
 
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3.4 
Data Collection 
 
3.4.1 
Data Collected From Subjects 
All data collected from subjects and provided to the sponsor for analysis must be stripped 
of any identifiers that reveal the identity of that individual (beyond the use of subject ID, 
as described in section 3.2.3). 
 
The use of any written or verbal information identifying the subject such as name, initials, 
photos or testimonials, requires separate and appropriate documented consent from each 
subject. 
 
Diary cards will be the only source document allowed for solicited systemic and local 
adverse events (including body temperature measurements). The following additional 
rules apply to documentation of safety information collected by diary card: 
 
1. No corrections or additions to the diary card will be allowed after it is delivered to the 
site. 
2. Any blank or illegible fields on the diary card must be described as missing in the 
CRF. 
3. The site must enter all readable entries in the diary card into the CRF, including those 
values that may be biologically implausible (e.g. body temperature: 400°C). 
4. Any illegible or implausible data should be reviewed with the subject to determine if 
an underlying solicited or unsolicited adverse event is described. For example, if the 
subject with a body temperature of 400°C describes that the body temperature was 
actually 40°C on the day in which body temperature: 400°C was written into the diary 
card, this fever of 40°C should be described in the study file and reported as an 
unsolicited adverse event in the adverse event CRF. 
5. Any newly described safety information (including a solicited reaction) must NOT be 
written into the diary card and must be described in the study file as a verbally 
reported event. Any adverse reaction reported in this fashion must be described as an 
unsolicited reaction and therefore entered on the adverse event CRF. 
 
 
3.4.2 
Electronic Case Report Forms 
Electronic CRFs will be used in this study. Data will be entered into the database from the 
paper source documents, diaries, or the VSAE form. Paper CRFs will be used in this 
study for pregnancy and pregnancy follow-up CRFs. All data will be recorded by the 
investigator and/or the investigator’s dedicated site staff. See section 9.1 for more details. 
 
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3.5 
Laboratory Assessments 
 
3.5.1 
Processing, Labeling and Storage of Serum Samples for Serology 
A minimum of approximately 10 mL sample of blood will be drawn from all subjects at 
Visit 1 before vaccination, and at Visits 5, 9, and 12 for serology assays. The blood 
volume drawn for serology will not exceed 15 mL at each time point in order to provide 
the necessary serum volume (approximately half of the blood draw volume) for the 
serology assays. Additional blood samples may be drawn at these time points for safety 
labs and additional immunology assays. 
 
Please refer to the Laboratory Manual in the Investigator Site File for instructions on 
drawing and processing blood samples, including the minimum volume of blood required 
and what to do in the case of failed attempts at drawing blood. Please see section 6.3 for 
details on the serology assays and analysis of serology data. 
 
Samples will be retained in accordance with regulatory guidance for retention of essential 
study documents as described in section 10. 
 
3.5.2 
Pregnancy Testing 
 
A urine pregnancy test will be performed at Screening, Visit 1, and Visit 5, at the study 
site prior to vaccination for all female subjects of childbearing potential (see section 4.2). 
Subjects must agree in the informed consent to use an appropriate method of birth control 
through 3 weeks after the last study vaccination at Visit 5 (i.e., until the Visit 8 safety 
call). Please refer to the instructions included with the test kits when performing urine 
pregnancy tests. Any subject with a positive urine pregnancy test at screening or Visit 1 
will be excluded from the study. Any subject with a positive urine pregnancy test prior to 
receipt of the second vaccination at Visit 5 will not be vaccinated, and must be followed 
for safety and pregnancy outcomes. Results of pregnancy testing must be recorded in the 
source documents. 
 
3.5.3 
Safety Laboratory Assessments 
 
A minimum of approximately 8 mL sample of blood will be drawn from all subjects at 
Screening, Visit 1 before vaccination, Visit 2, Visit 5 before vaccination, Visit 6, and  
Visit 9 for safety labs. The blood volume drawn for safety labs will not exceed 10 mL at 
each time point. Additional blood samples may be drawn at these time points for serology 
and immunology assays. Please refer to the Laboratory Manual in the Investigator Site 
File for instructions on drawing blood and shipping samples to the safety laboratory, 
including the minimum volume of blood required and what to do in the case of failed 
attempts at drawing blood. 
 
 
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Safety laboratory assessments from serum will include: 
 
▫ Sodium 
▫ Potassium 
▫ Chloride 
▫ Bicarbonate (or CO2) 
▫ Glucose 
▫ Blood urea nitrogen (BUN) 
▫ Calcium 
▫ Magnesium 
▫ Phosphorous 
▫ Creatinine 
▫ Creatine phosphokinase (CPK) 
▫ Albumin 
▫ Total protein 
▫ Alkaline phosphatase 
▫ Liver function tests (ALT, AST, γGT) 
▫ Total bilirubin 
▫ Direct bilirubin 
▫ Indirect bilirubin 
▫ Cholesterol 
▫ LDH 
▫ Pancreatic enzymes (amylase, lipase) 
 
 
Hematology tests will include: 
 
▫ CBC test (WBC, WBC differential, RBC, RBC indices, hemoglobin, hematocrit, 
platelets, and mean platelet volume [MPV]) 
▫ Fibrinogen 
▫ Prothrombin time (PT) 
 
 
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▫ Partial thromboplastin time (PPT) 
▫ International Normalized Ratio (INR) 
▫ C-reactive protein (CRP) 
▫ D-dimer 
 
 
A urine sample will be collected from all subjects at Screening, Visit 1 before 
vaccination, Visit 2, Visit 5 before vaccination, Visit 6, and Visit 9. Please refer to the 
Laboratory Manual in the Investigator Site File for instructions on collecting urine 
samples and shipping samples to the safety laboratory, including the minimum volume 
required. 
 
Safety laboratory assessments from urine will include (but may not be limited to): 
 
▫ Protein 
▫ Glucose 
▫ Presence of red blood cells 
The investigator MUST assess all safety laboratory results. If a laboratory result is outside 
the normal range based on the institution’s normal values or CBER guidance (see 
Appendix D, E, and F), it must be classified as clinically significant or not. If the 
laboratory result is determined to be clinically significant it must be reported in the 
subject’s medical history (in the case of screening and baseline samples tested prior to 
vaccination) or as an adverse event. 
 
3.5.4 
Cell Mediated Immunity Assessments 
 
Cell mediated immunity assays will be performed in approximately the first 10 subjects of 
each treatment group (no adjuvant, aluminum hydroxide, MF59, or placebo) enrolled in 
cohort 3 who sign an additional informed consent for the additional blood draws needed 
to perform these assays. Approximately 40 subjects total will be included in these assays. 
Blood samples from subjects in cohort 3 will be tested because these subjects will receive 
the highest dosage of vaccine (excluding placebo recipients) and are most likely to 
develop an immune response. Approximately 50 mL of blood will be drawn from subjects 
at Visit 1 before vaccination, Visit 2, Visit 5 before vaccination, and Visit 12. The blood 
volume drawn for cell mediated immunity assays will not exceed 50 mL at each time 
point in order to provide the necessary blood volume to collect peripheral blood 
mononuclear cells (PBMCs) for the cell mediated immunity assays. Additional blood 
samples may be drawn at these time points for safety labs and serology assays. 
 
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Please refer to the Laboratory Manual in the Investigator Site File for instructions on 
drawing and processing blood samples, including the minimum volume of blood required 
and what to do in the case of failed attempts at drawing blood. Please see section 6.8 for 
details on the cell mediated immunity assays and analysis of their data. 
 
Samples will be retained in accordance with regulatory guidance for retention of essential 
study documents as described in section 10. 
 
3.5.5 
Culture/PCR/Genotyping Assessments 
 
Not applicable. 
 
3.6 
Stopping/Pausing Guidelines 
 
Stopping/pausing guidelines are predefined criteria that halt the conduct of a study (either 
a vaccine group or the entire study). These guidelines are used to ensure the safety of 
study subjects. The following criteria, based on FDA guidance and with grading scales 
from the CBER Guidance for Industry “Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive vaccine Clinical Trials”, will be used for 
this study: 
 
1. If one or more subjects experience a Grade 4 AE (see Appendix D, E, and F), vital 
sign or laboratory abnormality that cannot be clearly attributed to another cause, 
vaccination will be suspended until a full safety review is performed. 
2. If six or more subjects experience a Grade 3 AE (see Appendix D, E, and F), vital 
sign or laboratory abnormality, dosage escalation will be suspended for that vaccine 
until a full safety review is performed. 
3. The study will be halted (no new enrollments and no further investigational product 
administered until a full safety review and consultation with the health authorities 
completed) if one of the following occurs 
a. One subject experiences a serious adverse event (SAE) assessed as possibly or 
probably related to investigational product or, 
b. There is a subject death assessed as possibly or probably related to the 
investigational product. 
 
If any of the halting rules are met, vaccination of subjects will be suspended until after 
full review of safety data by the DMC and health authorities. The investigator must 
inform the sponsor and the EC/IRB if any of the halting rules are met. The sponsor then 
must inform the DMC and health authorities. For further information on the DMC please 
see section 6.9 and the DMC Charter. 
 
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The sponsor or the investigator (following consultation with the sponsor) has the right to 
discontinue the study at any time. If the clinical study is prematurely terminated, the 
investigator must promptly inform the study subjects and must assure appropriate therapy 
and follow-up for the subjects. All procedures and requirements pertaining to the 
archiving of the documents must be followed. All other study materials (such as study 
vaccines) must be returned to the sponsor. 
 
3.7 
Premature Withdrawal and Early Study Termination 
 
A subject may discontinue study participation at any time prior to the last planned study 
visit. This is referred to as premature withdrawal from the study (see below for a 
description of withdrawal from study vaccine for subjects which refers to those subjects 
who do not receive additional vaccine doses but continue in the study for safety follow-up 
and/or other procedures). The reasons for premature withdrawal from the study include: 
 
▫ Adverse event 
▫ Death 
▫ Withdrawal of consent 
▫ Lost to follow-up 
▫ Administrative reason 
▫ Protocol deviation 
▫ Other 
NOTE: Before entering any alternate category as the reason for the subject’s 
discontinuation from the study, the investigator should make every effort to investigate 
whether or not safety concerns (adverse event or death) may have been related to the 
subject’s discontinuation from the study. If a safety concern has been associated with the 
subject’s discontinuation, this must be described on the Termination CRF page, even if it 
is not the primary reason for the subject’s discontinuation. 
 
 
For any subject withdrawing from study participation prior to the planned Termination 
visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the AE CRF page by indicating 
“Withdrawn from study due to AE”. 
 
For any subject withdrawn from study participation due to death, this should be noted on 
the Termination CRF page and the associated SAE that led to the death must be reported. 
 
 
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The subject can withdraw consent for participation in the study at any time without 
penalty or loss of benefit to which the subject is otherwise entitled. Reason for early 
termination should be deemed as “withdrawal of consent” if the subject withdraws from 
participation due to a non-medical reason (i.e., reason other than AE). If the subject 
intends to withdraw consent from the study, the investigator should clarify if the subject 
will withdraw completely from the study or if the subject will continue study participation 
for safety or a subset of other study procedures.  If complete withdrawal from the study 
by the subject is specified, no further study interventions will be performed with the 
subject. 
 
The date of termination is the date of the last contact (clinic visit or telephone) in which 
the subject’s health status was assessed or, in cases where the subject does not agree to 
any further safety follow-up; it is the date consent is withdrawn. 
 
For subjects who fail to show up for scheduled visits (clinic or telephone contacts), study 
staff are encouraged to make at least three documented attempts to contact the subject by 
telephone and at least one documented written attempt to contact the subject and 
encourage the completion of study termination procedures. These efforts to contact the 
subject should be recorded in the source documents. The termination date for the subject 
to be captured on the Termination CRF page is the date of the last successful visit (clinic 
or telephone) with the subject. 
 
For subjects who are withdrawn from the study due to sponsor decision (e.g., meeting 
pre-specified withdrawal criteria or termination of study by the sponsor), this reason 
should be noted in the Termination CRF page and any ongoing AEs at the time of study 
withdrawal must be followed until resolution/stabilization. 
 
In general, subjects associated with protocol deviations may remain in the study unless 
continuation in the study jeopardizes the subject’s health, safety, or rights. For subjects 
who are withdrawn from the study due to receipt of an excluded medication/vaccination 
or due to significant protocol non-compliance, this reason should be noted in the 
Termination CRF page. Any ongoing AEs at the time of study withdrawal must be 
followed until resolution/stabilization. See below for greater detail. 
 
If a subject is withdrawn prematurely from the study for a reason other than those 
outlined above, this reason must be documented in the Termination CRF page. 
In studies that involve more than 1 consecutive dose of study vaccine, a separate event is 
“withdrawal of study vaccination”. This event may occur if subjects are expected to 
receive more than 1 consecutive dose of vaccine as part of study participation. The act of 
withholding additional study vaccinations is referred to as withdrawal of study 
vaccination. Subjects may be withdrawn from study vaccination for several reasons 
 
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including but not limited to: AE related to earlier vaccinations, failure to meet criteria for 
revaccination (see section 4.4), or pregnancy. Subjects who are withdrawn from study 
vaccination should be encouraged to continue in the study for safety follow-up and 
other procedures as appropriate until the scheduled termination visit. If the subject 
is withdrawn from study vaccination(s) due to adverse event, this event must be linked to 
the withdrawal from vaccination on the AE CRF page. 
 
The sponsor or the investigator (following consultation with the sponsor) has the right to 
discontinue this study at any time. If the clinical study is prematurely terminated, the 
investigator is to promptly inform the study subjects and local EC/IRB and should assure 
appropriate therapy and follow up for the subjects. All procedures and requirements 
pertaining to the archiving of study documents should be followed. All other study 
materials (such as vaccines) must be returned to the sponsor. 
 
Any subject who, despite the requirement for adequate contraception, becomes pregnant 
during the trial will not receive further vaccination but should be encouraged to continue 
participation in the study. The site should complete a Pregnancy Report CRF (initial 
report) as soon as possible (see section 6.6.4 further details). If the subject withdraws 
from the study for any of the categories listed above except death, the site will obtain 
permission from the subject to continue to remain in contact with her until the outcome of 
the pregnancy is known, even if the outcome is not known until after the subject reaches 
the end of the routine study period. 
 
Withdrawn subjects will not be replaced. 
 
When a subject is withdrawn or withdraws from the study, the procedures described in 
section 3.8 Early Termination Visit should be completed if possible. 
 
3.8 
Early Termination Visit 
 
When a subject is withdrawn or withdraws from the study, the investigator will notify the 
sponsor and, when possible, will perform the procedures listed below: 
 
▫ Collect the diary card (if not already collected). 
▫ Review the subject’s solicited and unsolicited safety data. 
▫ Perform review of systems (see section 3.2.5 for explanation) and review of 
concomitant medications/vaccinations since last visit. 
▫ Collect vital sign measurements, including respiratory rate, blood pressure, pulse rate, 
and temperature (oral). 
 
 
 
 
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▫ Perform a directed physical examination including the respiratory system and any 
organ system warranting further examination based on reporting in the subject’s diary 
and review of system. 
▫ Draw a blood sample of approximately 10 mL for safety laboratory assessment. 
▫ Obtain a urine sample for safety assessment. 
▫ Perform a pregnancy test for female subjects of childbearing potential. 
 
The data for the early termination visit should be recorded on a designated early 
termination visit eCRF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.0 
SELECTION OF STUDY POPULATION 
 
4.1 
Inclusion Criteria 
In order to participate in this study, all subjects must meet ALL of the inclusion criteria 
described. 
 
1. Healthy males and non-pregnant females 18 to 45 years of age at time of enrollment. 
2. Individuals who have given written consent after the nature of the study has been 
explained according to local regulatory requirements. 
3. Individuals in good health as determined by the outcome of the medical history, 
physical examination and clinical judgment of the investigator. 
4. Individuals who can comply with the study procedures and are available for follow 
up. 
 
 
4.2 
Exclusion Criteria 
 
In order to participate in this study, all subjects must meet NONE of the exclusion criteria 
described. 
 
1. Individuals with any severe chronic or acute disease. 
2. Individuals with a history of illness or with an ongoing illness that may pose 
additional risk to the subject if he/she participates in the study, including the 
following: 
- 
History of any chronic respiratory illness, including current diagnosis of asthma 
within 2 years, exercise induced wheezing, reactive airway disease, emphysema, 
chronic bronchitis, cystic fibrosis or chronic obstructive pulmonary disease 
(COPD). 
- 
Any respiratory illness (e.g. cough, sore throat, dyspnea, wheezing or nocturnal 
awakenings to respiratory symptoms) within 7 days prior to receiving the first 
study injection. 
- 
Any active pulmonary infection or other inflammatory conditions, even in the 
absence of febrile episodes, within 14 days prior to the first study injection. 
- 
Hepatitis B or hepatitis C infection. 
3. Individuals who have had a malignancy (excluding nonmelanotic skin cancer) or 
lymphoproliferative disorder within the past 5 years. 
 
 
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4. Individuals with known or suspected impairment of the immune system including but 
not limited to HIV, autoimmune disorders, immunosuppressive therapy, and diabetes 
mellitus. 
5. Individuals with any history of progressive or severe neurologic disorder, seizure 
disorder or Guillian-Barré syndrome. 
6. Individuals with a known bleeding diathesis, or any condition that may be associated 
with a prolonged bleeding time. 
7. Individuals with a BMI > 35 kg/m2. BMI is to be calculated by the following formula: 
subject weight at baseline divided by subject height in meters multiplied by the 
subject height in meters. The numerical result will be rounded to the nearest 0.1. 
8. Individuals who are allergic to any of the vaccine components, or with a history of 
anaphylaxis after vaccination. 
9. Individuals who during the 90 days prior to enrollment receive any medications or 
other treatments that may adversely affect the immune system such as allergy 
injections, immune globulin, interferon, immunomodulators, cytotoxic drugs or other 
drugs known to be frequently associated with significant major organ toxicity. 
10. Individuals who receive systemic immunosuppressive agents including steroids. Prior 
corticosteroid therapy should be discontinued 28 days prior to enrollment. Individuals 
using inhaled or topical corticosteroids will be permitted. 
11. Receipt or donation of blood or blood products 8 weeks prior to vaccination or 
planned receipt or donation during the study period. 
12. Individuals participating in any clinical trial with another investigational product 28 
days prior to receiving the first study vaccination or intent to participate in another 
clinical study at any time during the conduct of this study. 
13. Individuals who have received any vaccine 28 days prior to enrollment in this study, 
or who plan to receive any non-study vaccines within 28 days of the second dose of 
study vaccine. 
14. Individuals with any abnormal safety laboratory result at the screening visit. 
15. If female, ‘of childbearing potential’, sexually active and has not used any of the 
‘acceptable contraceptive methods’ for at least two months prior to study entry. 
Childbearing potential is defined as status post onset of menarche and not meeting any 
of the following conditions: menopausal for at least two years; sterile status after 
bilateral tubal ligation for at least one year, immediately after bilateral oophorectomy 
or after hysterectomy. 
Acceptable methods of birth control are defined as one or more of the following: 
 
 
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- 
Hormonal contraceptives (such as oral, injection, transdermal patch, implant, 
cervical ring). 
- 
Barrier (condom with spermicide or diaphragm with spermicide) each and every 
time during intercourse. 
- 
Intrauterine device (IUD). 
- 
Monogamous relationship with vasectomized partner. Partner must have been 
vasectomized for at least six months prior to subject’s study entry. 
16. If female subject of childbearing potential and have a positive urine pregnancy test 
prior to study vaccinations, or are currently lactating. 
17. If female of childbearing potential and sexually active, refusal to use an ‘acceptable 
contraceptive method’ through to three weeks after last study vaccination. 
18. Individuals with behavioral or cognitive impairment or psychiatric disease that, in the 
opinion of the investigator, may interfere with the subject's ability to participate in the 
study. 
19. Individuals with a history of drug or alcohol abuse within the past 2 years. 
20. Individuals who are acting as study personnel or immediate family members (brother, 
sister, child, parent) or the spouse of study personnel. 
21. Individuals with a body temperature ≥38 °C (≥100.4◦F) within 3 days of intended 
study vaccination. 
22. Individuals with any condition that, in the opinion of the investigator, would interfere 
with the primary study objectives. 
 
 
There may be instances when individuals meet all entry criteria except one that relates to 
transient clinical circumstances (e.g., body temperature elevation or recent use of 
excluded medication or vaccine). Under these circumstances, a subject may be 
considered eligible for study enrollment if the appropriate window for delay has passed, 
inclusion/exclusion criteria have been rechecked, and if the subject is confirmed to be 
eligible. 
 
4.3 
Criteria for Delay of Vaccination and/or Blood Sampling 
After enrollment, subjects may encounter clinical circumstances that warrant a delay in 
subsequent study vaccination. These situations are listed below. In the event that a 
subject meets a criterion for delay of vaccination, the subject may receive study 
vaccination once the window for delay has passed as long as the subject is otherwise 
eligible for study participation. 
 
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▫ Individuals with a body temperature >38.0° C (>100.4◦F) within 3 days of intended 
study vaccination. 
There are also circumstances under which repeat vaccination is a contraindication in this 
study. These circumstances include anaphylaxis or severe hypersensitivity reactions 
following vaccination. If these reactions occur, the subject must not receive additional 
vaccinations, but should be encouraged to continue in study participation. 
 
4.4 
Criteria for Repeat Vaccination in the Study 
 
Prior to receipt of second study vaccination, subjects must be evaluated to confirm that 
they are eligible for subsequent vaccination. If subjects meet any of the original exclusion 
criteria or the criteria listed below, they should not receive additional vaccinations. 
 
▫ Subjects who experience any serious adverse event judged to be possibly or probably 
related to study vaccine or non-study vaccines, including hypersensitivity reactions. 
▫ Subjects who develop any new condition which, in the opinion of the investigator, 
may pose additional risk to the subject if he/she continues to participate in the study. 
Subjects who meet any of these criteria must not receive further study vaccinations. 
However, these subjects should be encouraged to continue study participation, as 
discussed in section 3.7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.0 
TREATMENT OF SUBJECTS 
 
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects. 
 
5.1 
Study Vaccine(s) 
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccines specific to this study are 
described below. 
 
Three dosage levels of the RSV F subunit vaccine will be tested in this study, including 
formulations with and without adjuvant (see Table 5.1). Subjects will be randomized into 
three different cohorts, which will be assigned to receive one of the following dosage 
levels: 
 
1. Cohort 1: 45 µg 
2. Cohort 2: 90 µg 
3. Cohort 3: 135 µg 
Within each cohort subjects will be further randomized to receive the RSV F subunit 
vaccine without adjuvant, with 1 mg aluminum hydroxide, or with MF59 (which contains 
9.75 mg squalene and surfactants in 0.25 mL). Additionally, approximately 24 subjects in 
each cohort will be randomized to receive placebo (saline). 
 
Details of vaccine composition in each cohort are summarized in Table 5.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 5.1 
Study Vaccine Composition 
 
Cohort 
Vaccine 
Group 
Antigen Name 
(Dosage) 
Volume (Route of 
Administration) 
Adjuvant Name 
(Dosage) 
Excipients 
1 
A 
RSV F subunit 45 µg 
0.50 mL (IM) 
None 
Sucrose, 
Potassium 
phosphate 
B 
RSV F subunit 45 µg 
0.50 mL (IM) 
Aluminum hydroxide 
(1 mg) 
C 
RSV F subunit 45 µg 
0.50 mL (IM) 
MF59 (9.75 mg 
squalene) 
2 
D 
RSV F subunit 90 µg 
0.50 mL (IM) 
None 
E 
RSV F subunit 90 µg 
0.50 mL (IM) 
Aluminum hydroxide 
(1 mg) 
F 
RSV F subunit 90 µg 
0.50 mL (IM) 
MF59 (9.75 mg 
squalene) 
3 
G 
RSV F subunit 135 µg 
0.50 mL (IM) 
None 
H 
RSV F subunit 135 µg 
0.50 mL (IM) 
Aluminum hydroxide 
(1 mg) 
I 
RSV F subunit 135 µg 
0.50 mL (IM) 
MF59 (9.75 mg 
squalene) 
1-3 
Placebo 
Sterile saline 0.9% 
0.50 mL (IM) 
none 
 
5.2 
Non-Study Vaccines 
The term ‘non-study vaccine’ refers to those vaccines which will be intentionally given to 
study subjects but not formally included in the analysis of study objectives. No non-study 
vaccines are planned for this trial. Non-study vaccines which are given to subjects during 
the trial will be recorded in the Prior and Concomitant Medications/Blood Products 
eCRF. 
 
5.3 
Vaccines Preparation and Administration 
Detailed descriptions for vaccine handling and preparation will be placed in the 
Investigator Site File and the investigator must review these materials prior to study start. 
 
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the 
specific study site. 
 
 
 
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The RSV subunit vaccine will be provided as a lyophilized pellet at the 135 µg dosage. 
The lyophilized product is reconstituted with (a) sterile saline 0.9% NaCl to generate the 
non-adjuvanted RSV F subunit vaccine formulation, (b) aluminum hydroxide [Al(OH)3] 
to generate the RSV F subunit vaccine formulated in Al(OH)3, or (c) sterile saline 0.9% 
NaCl and adjuvant MF59 to generate the RSV F subunit vaccine formulated with MF59. 
In addition, the vaccine will need to be reconstituted in saline and diluted to the proper 
dosage for Cohort 1 and Cohort 2, and mixed with adjuvant as needed for each treatment 
group (for example, diluted and mixed with aluminum hydroxide for vaccine group E in 
Table 5.1), while also producing the correct final volume of 0.5 mL. Complete 
reconstitution and mixing instructions can be found in the Investigator Site File. The 
vaccine will be injected intramuscularly as a 0.5 mL dose using a standard syringe. A new 
syringe will be used for each subject. 
 
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE: 
 
Prior to vaccination, subjects must be determined to be eligible for study vaccination and 
it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to first study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol section 4.1 through 4.2. 
 
Eligibility for subsequent study vaccination is determined by following the criteria 
outlined in sections 4.3 and 4.4. 
 
Study vaccines should not be administered to individuals with known hypersensitivity to 
any component of the vaccines. 
 
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly. Before administering vaccine, the vaccination 
site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow the skin to dry. 
DO NOT inject intravascularly. 
 
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment should be readily available in case of anaphylactic reactions following vaccine 
administration. For example, epinephrine 1:1000, diphenhydramine, and/or other 
medications for treating anaphylaxis should be available. 
 
5.4 
Prior and Concomitant Medications and Vaccines 
 
All medications, vaccines and blood products taken or received by the subject within 28 
days prior to the start of the study are to be recorded on the Prior and Concomitant 
Medications/Blood Products eCRF. The use of antipyretics and/or analgesic medications 
within 24 hours prior to vaccination must be identified and the reason for their use 
 
 
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(prophylaxis versus treatment) must be described in the source documents and/or diary 
card and Concomitant Medications eCRF. 
 
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
 
In addition, the following are considered prior medications for this protocol: all 
medication/vaccines described in the inclusion and exclusion criteria of this protocol 
including those that may adversely affect the immune system. 
 
Concomitant medications include all medications (including vaccines) taken 
by/administered to the subject at and after enrollment and must be documented on the 
Concomitant Medications/Blood Products eCRF. 
 
When recording concomitant medications/vaccines, they should be checked against the 
study entry and continuation criteria in sections 4.1 through 4.4 to ensure that the subject 
should be enrolled/continue in the study. 
 
5.5 
Vaccine Supply, Labeling, Storage, and Tracking 
 
The sponsor will ensure the following: 
 
▫ supply the study vaccine 
▫ appropriate labeling of all study vaccines provided that complies with the legal 
requirements of each country where the study is to be performed 
The investigator must ensure the following: 
 
▫ acknowledge receipt of the study vaccines by a designated staff member at the site, 
including confirmation that the vaccines: 
- 
were received in good condition 
- 
remained within the appropriate temperature range during shipment from the 
sponsor to the investigator’s designated storage location 
- 
have been confirmed by the sponsor as authorized for use 
▫ proper storage of the study vaccines, including: 
- 
storage in a secure, locked, temperature-controlled location 
- 
proper storage according to the instructions specified on the labels 
 
 
 
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- 
appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature 
▫ appropriate use of the study vaccines, including: 
- 
use only in accordance with the approved protocol 
- 
proper handling, including confirmation that the vaccine has not expired prior to 
administration 
- 
appropriate documentation of administration of vaccines to study subjects 
including: 
▪ date, dosage, batch/serial numbers, expiration dates, unique identifying 
numbers assigned to subjects and study vaccines, and time of vaccine 
administration. This information will be maintained in an accountability log 
that will be reviewed by the site monitor. 
 
▪ proper reconciliation of all study and non-study vaccines received from the 
sponsor. Reconciliation is defined as maintaining records of which and how 
many vaccines were received, which vaccines (and volume thereof) were 
administered to subjects, which vaccines were destroyed at the site, and 
which vaccines were returned to the sponsor, as applicable. 
 
▫ proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 
▫ complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of: 
- 
copy of the site’s procedure for destruction of hazardous material 
- 
number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction 
Vaccines that have been stored differently from the sponsor’s instructions must not be 
used unless the sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the sponsor will make every effort to replace the vaccine supply. All 
vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical trial setting. 
 
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the trial as applicable dependent on the use of a 
computerized randomization system. 
 
 
 
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At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must return all unused study vaccines, packaging and supplementary labels to 
the sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.0 
MEASUREMENTS 
 
6.1 
Appropriateness of Measurements 
The measures of immunogenicity used in this study have been described based on 
scientific consensus and have been deemed appropriate to describe the immune response 
against RSV in this study. Exploratory immunogenicity assays will further understanding 
of the immune response to RSV and RSV vaccines. 
 
The measures of safety used in this study are based on previous study data and on 
comparable routine clinical and laboratory procedures. They include a close vigilance for, 
and stringent reporting of selected local and systemic adverse events routinely monitored 
in vaccine trials as indicators of reactogenicity. In addition, selected laboratory tests will 
be performed pre- and post-vaccination. 
 
6.2 
Demographics, Medical History and Physical Examination 
Prior to study enrollment, demographic data will be collected from the subject, including: 
gender, race, ethnicity, age, height, weight, and body mass index. 
 
Medical history will also be collected, including but not limited to any medical history 
that may be relevant to subject eligibility for study participation such as prior 
vaccinations, concomitant medications, and previous and ongoing illnesses or injuries. 
Relevant medical history can also include any medical history that contributes to the 
understanding of an adverse event that occurs during study participation, if it represents 
an exacerbation of an underlying disease/preexisting problem. 
 
A general physical examination is to be performed by a qualified health care practitioner 
and will include, at a minimum, measurement of the following vital signs: respiratory 
rate, heart rate, blood pressure, and body temperature (oral). It will also include 
assessment of general appearance; examination of the head, ears, eyes, nose and throat 
(HEENT); examination of skin; auscultation of heart and lungs; palpation of the 
abdomen; and examination of extremities. “Qualified health care practitioner” refers to 
any licensed health care professional who is permitted by institutional policy to perform 
physical examinations and who is identified within the site’s roles and responsibilities 
log. 
 
At clinic visits after enrollment subjects will undergo a symptom-directed physical 
examination. This is a physical examination that will include at a minimum measurement 
of vital signs (respiratory rate, heart rate, and blood pressure), body temperature (oral), a 
check of general appearance, as well as examination of organ systems that are relevant to 
 
 
 
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the investigator based on review of the subject’s reported adverse events, review of 
systems, or concomitant medication use. 
 
Data on subject demographics, medical history, and physical exams will be recorded in 
the source documents and in the associated eCRFs as included in the eCRF instructions 
provided by NVD. 
 
6.3 
Immunogenicity Measurements 
Serum anti-RSV neutralizing antibody titers will be evaluated for all subjects by plaque 
reduction neutralization assay (PRNA). Samples will be collected at the following time 
points: 
 
▫ Visit 1 (baseline, pre-vaccination) 
▫ Visit 5 (28 days after the first dose) 
▫ Visit 9 (28 days after  the second dose) 
▫ Visit 12 (6 months after the  first dose) 
Binding antibody to the RSV proteins F, G (Ga and Gb), and N by a microsphere-based 
fluorescence linked immunosorbent assay, multiplexed using Luminex® technology will 
be evaluated using the same samples. 
 
The binding assays are needed to (i) distinguish immune responses following 
immunization versus natural infection, and (ii) assess the ratio of neutralizing antibodies 
(NAb) and non-NAb to the F protein. 
 
All testing will be conducted by qualified and certified laboratories. See section 3.5.1 and 
the Laboratory Manual in the Investigator Site File for more information. For assays not 
performed internally by NVD, data will be provided by external laboratories by EDT to 
NVD (see section 9). 
 
6.4 
Efficacy Measurements 
 
This study has no efficacy measurements. 
 
6.5 
Solicited Safety Measurements 
The term “reactogenicity” refers to selected signs and symptoms (“adverse events”) 
occurring in the hours and days following a vaccination, to be collected by the subject for 
7 consecutive days, using a pre-defined checklist in a diary card (i.e., solicited adverse 
events). 
 
 
 
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The following adverse events are included in the diary check list. Each adverse event is to 
be assessed using the scoring system shown in Appendix B (local AEs) and Appendix C 
(systemic AEs). 
 
Solicited local adverse events: 
Solicited local AEs include: 
 
▫ injection site induration 
▫ injection site swelling 
▫ injection site erythema 
▫ injection site pain 
AEs will be recorded as absent, mild, moderate, or severe. Please see Appendix B for 
grading scales. 
 
Solicited systemic adverse events: 
Solicited systemic AEs include: 
 
▫ body temperature (oral preferred) 
▫ chills 
▫ nausea 
▫ generalized myalgia 
▫ generalized arthralgia 
▫ headache 
▫ fatigue 
▫ diarrhea 
▫ loss of appetite 
▫ cough 
▫ rhinorrhea 
▫ wheezing 
AEs will be recorded as absent, mild, moderate, or severe. Please see Appendix C for 
grading scales. 
 
Other solicited reactions: 
 
 
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Use of analgesics/antipyretics will be recorded as absent or present, and it will be 
indicated if they were used for treatment or for prophylaxis. 
 
Solicited local and systemic AEs and unsolicited AEs will be collected using diary cards 
for 7 days following any dose of vaccine or placebo. Subjects will be asked to take an oral 
temperature for the first 7 days after each dose and to record other systemic and local AEs 
that may develop, as well as any medications subjects have received. Reminder telephone 
calls at two and four days after each dose of vaccine or placebo will be used to remind the 
subject to record AEs in the diary cards and bring the diary cards to their next clinic visit. 
Telephone calls at 14 and 21 days after each dose of vaccine or placebo will be used to 
collect unsolicited AEs occurring since the last study contact, as well as any solicited AEs 
continuing beyond the 7 day period after vaccination. 
 
All AEs necessitating a non-scheduled physician visit, medical attention, or leading to 
withdrawal from the study will also be collected throughout the study, and all AEs will be 
monitored until resolution or, if the AE becomes chronic, a cause is identified.  If an AE 
is unresolved at the conclusion of the study, a clinical assessment will be made by the 
investigator and the medical monitor to determine whether or not continued follow-up of 
the AE is warranted. The relationship of the study treatment to any AE and any SAE will 
be determined by the investigator as probably related, possibly related, or not related. Any 
SAEs will further be reported as related/suspected or not related. All AEs resulting in 
withdrawal of the subjects from the study will be summarized. 
 
In addition, all SAEs, NOCDs, and AESIs will be collected from the date of signed 
informed consent and at scheduled periodic reviews and will be followed up until the end 
of the study (approximately 393 days after the first dose of vaccine or placebo [saline]). 
This may include a period before and after an active treatment of investigational product. 
On an individual basis, SAE follow-up may take longer than the study duration, if the 
SAE is not resolved at the completion of the study. Monitoring for AESIs (see section 
6.6.1.1 and Appendix A) will be extended through 12 months after the second vaccination 
and will be accomplished by clinic visits or telephone follow-up calls as detailed in Table 
2. All AESIs will be reported in the same manner as SAEs. A tabulation of all AESIs, 
categorized by MedDRA preferred terms and assessed relationship to study vaccine will 
be performed. 
 
The study staff must review the diary card with the subject at the next clinic visit (see 
section 3.2.5) and must directly record the solicited local and systemic adverse events, 
and other solicited reactions on the appropriate Local and Systemic Reactions eCRF. As 
described in Section 3.4.1, all solicited adverse events that are legible must be recorded 
verbatim in the eCRFs, even if the values do not appear to be plausible (see section 
3.2.5.3 and section 8.1 for more detail). 
 
 
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If a solicited local or systemic adverse event continues beyond day 7 after vaccination, it 
will also be recorded as an Adverse Event on the Adverse Events eCRF. 
 
6.6 
Unsolicited Safety Measurements 
 
6.6.1 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
 
NOTE: Every effort should be made by the investigator to evaluate new safety 
information reported by a subject (solicited and unsolicited AEs) for an underlying 
diagnosis and to capture this diagnosis as the event in the AE page. In other words, the 
practice of reporting only symptoms (e.g., “cough” or “ear pain”) are better reported 
according to the underlying cause (e.g., “asthma exacerbation” or “otitis media”). 
 
All AEs will be monitored until resolution or, if the AE becomes chronic, a cause 
identified. If an AE is unresolved at the conclusion of the study, a clinical assessment 
will be made by the investigator and medical monitor whether continued follow-up of the 
AE is warranted. 
 
The severity of events reported on the Adverse Events eCRF will be determined by the 
investigator as: 
 
Mild: 
transient with no limitation in normal daily activity. 
Moderate: 
some limitation in normal daily activity. 
Severe: 
unable to perform normal daily activity. 
 
The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions: 
 
1. Not Related 
 
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation.  If the subject has not received the vaccine, the 
timing of the exposure to the vaccine and the onset of the AE are not reasonably related in 
 
 
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time, or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related. 
 
2. Possibly Related 
 
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes. 
 
3. Probably Related 
 
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified. 
 
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator. Solicited AEs will not be evaluated for relationship to study vaccine and 
severity of solicited AEs is defined as described in section 6.5. 
 
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions: 
 
▫ “Medically attended adverse event”: an adverse event that leads to an unscheduled 
visit to a healthcare practitioner. 
▫ “New onset of chronic disease”: an adverse event that represents a new diagnosis of a 
chronic medical condition that was not present or suspected in a subject prior to study 
enrollment. 
▫ “New onset of autoimmune disorder”: an adverse event that represents a new 
diagnosis of an autoimmune disease that was not present or suspected in a subject 
prior to study enrollment. 
 
Please note: any solicited adverse event that meets any of the following criteria must also 
be entered as an adverse event on the Adverse Event eCRF: 
 
▫ Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator. 
▫ Solicited local or systemic adverse event lasting beyond 7 days’ duration. 
▫ Solicited local or systemic adverse events that lead to subject withdrawal from study 
vaccination. 
▫ Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see section 6.6.2). 
 
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6.6.1.1 
Adverse Events of Special Interest 
 
Certain adverse events of special interest (AESIs) are monitored for after the 
administration of immunostimulatory agents. All subjects enrolled in the study will be 
monitored for AESIs for the entire follow-up period. The AESIs will be defined 
according to the MedDRA preferred terms listed in Appendix A. The occurrence of any 
of these adverse events will be treated as a serious adverse event (SAE), meeting the 
criterion of a “medically important event.” 
 
Subjects will be assessed for diagnosis of an AESI at the following clinic visits: 
 
▫ Visit 1 (baseline,  pre-vaccination) 
▫ Visit 2 (7 days after  the first dose) 
▫ Visit 5 (28 days after the first dose; pre-second dose) 
▫ Visit 6 (7 days after the second dose) 
▫ Visit 9 (28 days after the second dose) 
▫ Visit 10 (56 days after the second dose) 
▫ Visit 11 (4 months after the first  dose) 
▫ Visit 12 (6 months after the first  dose) 
▫ Visit 13 (6 months after the second dose) 
At these visits a qualified health care practitioner listed on the site’s responsibilities and 
delegation logs will conduct a review of organ systems and a targeted physical exam, and 
will evaluate subjects for any new signs or symptoms that could indicate one of the AESIs 
listed in Appendix A. They will also interview the subject about recent medical history 
and any new diagnosis that could indicate an AESI. Medical records related to any new 
medical event or diagnosis will be requested, reviewed by the site staff, and recorded in 
the subject’s source documents. 
 
In addition, subjects will be interviewed by phone at the following time points: 
 
▫ Visit 3 (14 days after  the first dose) 
▫ Visit 4 (21 days after  the first dose) 
▫ Visit 7 (14 days after the second  dose) 
▫ Visit 8 (21 days after the second  dose) 
▫ Visit 14 (9 months after the first  dose) 
▫ Visit 15 (1 year after the first dose) 
 
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▫ Visit 16 (1 year after the second  dose) 
These phone calls will include a scripted interview to determine if the subject has had a 
new medical issue for which they visited a doctor, and if they had any new diagnosis 
since the last clinic visit. Any new diagnosis deemed to potentially be an AESI will be 
recorded in the subject’s source documents, and the subject will be instructed to visit the 
site within the next 7 days. The subject will be instructed to bring any new medical 
records with them to the clinic for review. 
 
A diagnosis of an AESI will be reported in the same manner and time frame as an SAE 
using the VSAE form. The investigator must notify NVD within 24 hours. The AESI 
diagnosis, as well as any medications taken to treat the condition, will be recorded in the 
subject’s source documents and on the Adverse Events eCRF. 
 
6.6.1.2 
New Onset of Chronic Disease 
New onset of chronic disease is defined as an illness that starts during the course of the 
study that did not exist prior to enrollment into the study and is likely to persist 
throughout the lifetime of the subject. A chronic disease is one that can be treated but for 
which no cure exists.  For example, a new onset of asthma (occurs for the first time 
during the study and has been evaluated longitudinally to ensure that a diagnosis of 
asthma is appropriate) is classified as a New Onset of Chronic Disease (NOCD). This is 
applicable for any chronic disease affecting any organ class that arises during the study 
that is likely to persist throughout the subject’s lifetime (even if in remission). Infectious 
diseases, such as Hepatitis C virus or tuberculosis, are not considered NOCDs as there are 
antibiotics and antivirals that are potentially able to cure such diseases (this is a 
generalizable cure and not specific to the subject). In case of doubt, diagnoses of new 
onset of chronic disease should be discussed with the study medical monitor. 
 
Any NOCD will be described in the medical chart/source documents and entered into the 
Adverse Events eCRF. 
 
6.6.2 Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following: 
 
▫ Death. 
▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
▫ Required or prolonged hospitalization. 
 
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▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
▫ Congenital anomaly or birth defect. 
▫ An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above. 
Adverse events which do not fall into these categories are defined as non-serious. 
 
It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe. 
 
Serious adverse events will be captured both on the VSAE form as well as on the AE 
eCRF. All SAEs will be evaluated by the investigator for relationship of the event to 
study vaccine. SAEs that are judged to be possibly or probably related to the study 
vaccine should be reported to the sponsor as related (i.e., suspected) events. 
 
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions: 
 
1. Related/suspected 
 
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the AE CRF page (see section 6.6.1). 
 
2. Not Related 
 
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship. 
 
The relationship of the study vaccine to an SAE will be determined by the investigator. 
 
In addition, SAEs will be evaluated by the sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the Investigator’s Brochure or an event that is 
by nature more specific or more severe than a listed event. 
 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the Medical History eCRF. If the onset of an event occurred before the 
subject entered the trial (e.g., any pre-planned hospitalization for conditions like cosmetic 
 
 
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treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
trial or was necessary due to a worsening of the pre-existing condition. 
 
6.6.3 Methods for Assessing and Recording AEs and SAEs 
 
The period of observation for AEs extends from the time the subject signs informed 
consent until he or she completes the specified safety follow-up period of approximately 1 
year after receipt of the second dose of vaccine or terminates the study early (whichever 
comes first). AEs occurring after the informed consent form is signed but prior to 
receiving study vaccine/product will be documented as an adverse event and recorded on 
the Adverse Events eCRF and on source documents. However, AEs occurring prior to 
receipt of any study vaccine will be analyzed separately from “treatment emergent” AEs 
(AEs occurring after administration of the first study vaccine). 
 
All AEs meeting criteria for reporting, regardless of severity, will be monitored by the 
investigator until resolution or stabilization. All subjects experiencing AEs - whether 
considered associated with the use of the study vaccine or not - must be monitored until 
symptoms subside and any abnormal laboratory values have returned to baseline, or until 
there is a satisfactory explanation for the changes observed, or until death, in which case a 
full pathologist’s report should be supplied, if possible. All findings must be reported on 
an Adverse Events CRF and on the VSAE form, if necessary, which is part of the 
Investigator Site File. All findings in subjects experiencing AEs must be reported also in 
the subject's medical records. 
 
All SAEs which occur during the course of the trial, whether considered to be associated 
with the study vaccination or not, must be reported within 24 hours of the site becoming 
aware of the event by telephone or fax to NVD. Contact details for submitting SAEs to 
NVD or its designee and instructions for completion of documentation will be provided in 
a handout located in the Investigator Site File. 
 
All SAEs are also to be documented on the Adverse Events eCRF. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
eCRF(s) in addition to the outcome of the AE. 
 
After receipt of the initial report, representatives of NVD will contact the investigator if it 
is necessary to obtain further information for assessment of the event. 
 
All SAEs must be reported by the investigator to his/her corresponding EC or IRB and 
applicable regulatory authorities in accordance with institutional policy/regulatory 
 
 
 
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requirements and adequate documentation of this notification must be provided to the 
sponsor. 
 
NVD or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of unexpected serious and non-serious adverse vaccine reactions 
(also referred to as “SUSARs”) to the regulatory authority(ies) and the IRB/EC. If a 
SUSAR or other safety signal relating to use of one of the study vaccines is reported to 
NVD or its designee, the sponsor will communicate the information to the investigator 
and the investigator will be responsible for submitting this information to the EC or IRB 
and other relevant authorities. 
 
Post-Study Events 
Any suspected SAE that occurs outside of the protocol-specified follow-up period or after 
the end of the study but considered to be caused by the study vaccine must be reported to 
Novartis or its designee. These SAEs will be processed by Novartis or its designee as 
during the course of the study, until 3 months after the last scheduled study visit. 
Instructions and contact details for collecting and reporting these suspected SAEs will be 
provided to the investigator. 
 
 
6.6.4 Pregnancies 
 
To ensure subjects’ safety, each pregnancy in a subject on study vaccine must be reported 
to NVD within 24 hours of the site learning of its occurrence. If the subject agrees to 
submit this information, the pregnancy must be followed to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of 
any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
This follow-up should occur even if intended duration of safety follow-up for the study 
has ended. 
Pregnancy data must be recorded on a Pregnancy Report CRF (initial report) and 
Pregnancy Follow-Up CRF (outcome report) and reported to NVD. Contact details for 
submitting the case report forms will be described in the Investigator Site File. 
 
Any pregnancy outcome meeting the definition of a SAE (see section 6.6.2) must also be 
reported on the VSAE Report Form. 
 
 
 
 
 
 
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6.7 
Safety Laboratory Measurements 
 
To assess laboratory AEs, blood and urine samples will be collected for each subject at 
Screening and Visits 1, 2, 5, 6, and 9 as outlined in Table 2 and in section 3.5.3 to 
perform blood chemistry, hematology, and urine analyses for all subjects. 
 
Safety laboratory assessments from serum will include sodium, potassium, chloride, 
bicarbonate (or CO2), glucose, blood urea nitrogen (BUN), calcium, magnesium, 
phosphorous, creatinine, creatine phosphokinase (CPK), albumin, total protein, alkaline 
phosphatase, liver function tests (ALT, AST, γGT), total bilirubin, direct bilirubin, 
indirect bilirubin, cholesterol, LDH, and pancreatic enzymes (amylase, lipase). 
Hematology tests will include CBC test (WBC, WBC differential, RBC, RBC indices, 
hemoglobin, hematocrit, platelets, and mean platelet volume [MPV]), fibrinogen, 
prothrombin time (PT), partial thromboplastin time (PPT), INR, C-reactive protein 
(CRP), D-dimer. 
 
Safety laboratory assessments from urine will include at a minimum protein, glucose, and 
presence of red blood cells. 
 
All testing will be conducted by qualified and certified laboratories as outlined in the 
Laboratory Manual. Abnormal laboratory values will be defined following the FDA 
CBER Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive vaccine Clinical Trials” dated September 2007, or the 
institution’s normal ranges if they differ from CBER guidance. Please see Appendix D, E, 
and F. Retesting will not be performed in the case of abnormal values. 
 
 
6.8 
Other Measurements 
The serum neutralizing antibody (NAb) and binding antibody responses against additional 
RSV strains and native or engineered RSV antigens at baseline and following vaccination 
will be performed in a subset of subjects, following evaluation of the primary and 
secondary immunogenicity evaluations and depending on the volume of serum remaining 
for additional testing. The predominant isotype of the RSV-specific serum antibody may 
be determined and the RSV-specific immune response against different RSV subgroup A 
and subgroup B strains may be evaluated. RSV group A and group B strains could 
include those with engineered alterations in the F and G glycoproteins and strains that lack 
the G glycoprotein. Different RSV antigens may include engineered, recombinant RSV 
antigens, such as an F antigen in which one or more known neutralizing epitopes has been 
blocked by the addition of a glycosylation site or F antigens locked in a defined 
conformation, such as a pre-fusion conformation. To make this determination, the serum 
 
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samples may be mixed with a recombinant RSV antigen (potentially an antigen with 
engineered changes) before use in a neutralization assay. Alternatively, the serum may be 
bound to an immobilized recombinant RSV antigen and then eluted before use in a 
neutralization assay or binding assay, or the fraction of serum that does not bind to an 
immobilized recombinant RSV antigen may be used in a neutralization assay or binding 
assay. 
 
These data will be entered into Source Documents if the assays are conducted internally 
at NVD, or will be transferred via EDT if the assays are conducted by external 
laboratories (see section 9.1). Testing and analyses to characterize the serum neutralizing 
antibody (NAb) to additional RSV strains may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
 
The serum NAb and binding Ab assays described above will be performed in 
approximately the first 10 subjects enrolled in each of the four treatment groups of cohort 
3 (135 µg of RSV F subunit vaccine without adjuvant, with MF59, or with aluminum 
hydroxide; or placebo), who agree to a separate Informed Consent and additional 
collection of blood samples. The time points for blood collection will be: 
 
▫ Visit 1 (baseline, pre-vaccination) 
▫ Visit 2 (seven days after the first dose) 
▫ Visit 5 (28 days after the first dose) 
▫ Visit 12 (six months after the first dose) 
 
 
In addition, cell mediated immunity assays will be performed. The frequency of B cells 
specific for RSV proteins will be determined by enzyme-linked immunosorbent spot 
(ELISPOT) at the same time points, in order to evaluate the peak of plasmablast 
responses (Visit 2), the B cell memory responses (Visit 5), and for persistence of antibody 
responses (Visit 12). 
 
Subsequently, the analysis of the RSV-specific B-cell repertoire to explore the baseline 
immunity to RSV and the immune response to the RSV F subunit vaccine will be 
performed in a subset of these subjects, including those with the most pronounced 
response to the RSV F subunit vaccine in the non-adjuvanted, aluminum hydroxide- 
adjuvanted, and MF59-adjuvanted treatment groups. The samples for the exploratory B 
cell repertoire analysis will be chosen based on the levels of baseline immunity and the 
level of response to the vaccine (as determined serologically and by ELISPOT), and on 
the distribution of samples between subjects who received placebo, unadjuvanted vaccine, 
 
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aluminum hydroxide-adjuvanted vaccine, or MF59-adjuvanted vaccine. The selection 
will be based on the goal of the exploratory objective to understand the differences in the 
RSV-specific B cell repertoires elicited by natural infection and by the adjuvanted or 
unadjuvanted vaccine. Testing and analyses of the RSV-specific B-cell repertoire may be 
or may not be performed after the Clinical Study Report (CSR) has been completed, and 
these data will be submitted as an addendum to the CSR. 
 
B cells secreting RSV-specific antibodies will be enumerated by ELISPOT according to 
treatment group and time point evaluated for subjects in cohort 3 only. The diversity of 
the elicited B-cell receptors will be accomplished through sequence analysis of 
complementary DNA (cDNA) from immunoglobulin (Ig) messenger RNA (mRNA) and 
functional, binding, and epitope mapping analyses of antibodies or antibody fragments 
expressed from those cDNAs. The Ig cDNAs will be cloned from plasmablasts obtained 
approximately one week after dosing and from memory B cells obtained at Visit 1 and at 
time points more than one week after dosing. 
 
6.9 
Data Monitoring Committee 
 
A Data Monitoring Committee (DMC) will be implemented to review safety data during 
scheduled periodic reviews. DMC membership will consist of a minimum of 3 individuals 
who are external to the site and sponsor, including at least 1 statistician. Subjects will be 
enrolled in a stepwise manner in each of the three vaccine dosage cohorts (cohort 1: low 
dosage of RSV F subunit vaccine [45 µg], cohort 2: middle dosage of RSV F subunit 
vaccine [90 µg], and cohort 3: high dosage of RSV F subunit vaccine [135 µg]). The 
DMC will review safety data, as described in the DMC charter and in the statistical 
analysis plan, after enrollment of the first 12 subjects in each cohort, and shortly after 
Visit 2 (seven days after the first dose), before proceeding with enrollment of the 
remaining subjects in each cohort. In addition, the DMC will review safety data, as 
described in the DMC charter and in the statistical analysis plan, after enrollment of each 
cohort has been completed before proceeding with enrollment of the subsequent cohort. 
Preferably, the DMC will firstly receive blinded data and only in case it is deemed 
necessary to evaluate unblinded data (either at group or subject level), unblinded 
information will be released to the DMC members only. In such a circumstance, an NVD 
independent statistician and a randomization programmer will have access to unblinded 
data. 
 
Criteria to assess safety will include, but may not be limited to, immediate AEs within 30 
minutes, solicited and unsolicited AEs within 7 days and 28 days after each vaccination, 
respectively, SAEs (including AESI and NOCD), and clinical laboratory safety 
parameters. The specific roles and responsibilities of the DMC members and other 
personnel involved will be documented in the DMC charter. The DMC charter will be 
 
 
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finalized before the start of the study and will pre-define all safety criteria to be met, as 
well as any stopping rules set by the DMC, if necessary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.0 
ENDPOINTS AND STATISTICAL ANALYSES 
 
7.1 
Endpoints 
For the immunogenicity evaluation: 
 
▫ Values below the detection limit (1:100) will be set at 1:50. 
▫ Antibody concentrations will be logarithmically transformed (base 10). 
 
 
7.1.1 Primary Endpoint(s) 
 
Primary Immunogenicity Endpoints: 
1. Geometric mean titer (GMT) of the serum anti-RSV neutralizing antibody (NAb) titer 
at Day 57 (28 days after the second dose). 
2. Proportion of subjects with a ≥4-fold increase in serum anti-RSV NAb titer from Day 
1 (baseline) to Day 57 (28 days after the second dose). 
 
 
7.1.2 Secondary Immunogenicity Endpoints 
1. GMT of the serum anti-RSV NAb titer at Day 1 (baseline), Day 29 (28 days after the 
first dose), and Day 181 (six months after the first dose). 
2. Proportion of subjects with a ≥4-fold increase in serum anti-RSV NAb titer from Day 
1 (baseline) to all other time points (Day 29 [28 days after the first dose] and Day 181 
[six months after the first dose]). 
3. Proportion of subjects at Day 29 (28 days after the first dose), Day 57 (28 days after the 
second dose), and Day 181 (six months after the first dose) who achieve serum anti- 
RSV NAb titers greater than the 3rd quartile of serum anti-RSV NAb titers at Day 1 
(baseline). 
4. Reverse cumulative distribution of serum anti-RSV NAb titers at Day 1 (baseline), 
Day 29 (28 days after the first dose), Day 57 (28 days after the second dose), and Day 
181 (six months after the first dose). 
5. GMT of the serum total binding antibody to each of the RSV proteins F, G and N at 
Day 1 (baseline), Day 29 (28 days after the first dose), Day 57 (28 days after the 
second dose), and Day 181 (six months after the first dose). 
 
 
 
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6. Proportion of subjects with a ≥4-fold increase in serum total binding antibody titers to 
each of the RSV proteins F, G and N from Day 1 (baseline) to all time points (Day 29 
[28 days after the first dose], Day 57 [28 days after the second dose], and Day 181 [six 
months after the first dose]). 
7. Proportion of subjects at Day 29 (28 days after the first dose), Day 57 (28 days after 
the second dose), and Day 181 (six months after the first dose) who achieve serum 
total binding antibody titers to each of the RSV proteins F, G, and N greater than the 
3rd quartile of serum total binding antibody titers to RSV protein F at Day 1 
(baseline). 
8. Reverse cumulative distribution of serum total binding antibody to each of the RSV 
proteins F, G, and N at Day 1 (baseline), Day 29 (28 days after the first dose), Day 57 
(28 days after the second dose) and Day 181 (six months after the first dose). 
9. Ratio of RSV F subunit serum neutralizing antibody (NAb) titer to each of the RSV F 
subunit serum total binding antibody titers to RSV proteins F, G and N at Day 1 
(baseline), Day 29 (28 days after the first dose), Day 57 (28 days after the second 
dose), and Day 181 (six months after the first dose). 
 
 
7.1.3 Secondary Efficacy Endpoints 
 
There are no secondary efficacy endpoints for this study. 
 
7.1.4 Safety Endpoints 
 
Safety will be assessed by measuring the frequency of local and systemic solicited 
adverse events (AEs), unsolicited AEs, serious adverse events (SAEs), new onset of 
chronic diseases (NOCD), adverse event of special interest (AESIs), and safety laboratory 
data for all subjects. 
 
▫ Reactogenicity will be assessed by the percentage and frequency of subjects with 
solicited local and solicited systemic adverse events up to 7 days after each 
vaccination and calculated for four time intervals after each vaccination: 30 minutes, 
Days 1-3 (without 30 min), Days 4-7 (without 30 min), Days 1-7 (without 30 min). 
▫ Unsolicited AEs will be assessed by the percentage and frequency of subjects with 
any unsolicited AEs for 28 days after each vaccination. 
▫ Percentage and frequency of subjects with SAEs, non-scheduled physician visits, 
unsolicited medically attended AEs, unsolicited AEs leading to study withdrawal, 
NOCDs, and AESIs will be collected from study start until study completion. 
 
 
 
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7.1.5 Other Endpoints 
 
No other endpoints are included in this study. 
 
7.1.6 Exploratory Endpoints 
 
1. Predominant isotype of the RSV-specific serum antibody at multiple time points. 
2. RSV-specific immune response against different RSV group A and group B strains or 
engineered RSV antigens at multiple time points. 
3. Frequency of B cells secreting RSV-specific antibodies at Day 1 (baseline), Day 8 
(seven days after the first dose), Day 29 (28 days after the first dose), and Day 181 
(six months after the first dose). 
4. Diversity of the B-cell repertoire at Day 1 (baseline), Day 8 (seven days after the first 
dose), Day 29 (28 days after the first dose), and Day 181 (six months after the first 
dose). 
 
 
7.2 
Success Criteria 
In the absence of formal statistical hypotheses, the study will not be declared positive or 
negative according to given rules. The selection of an appropriate vaccine dosage and 
adjuvant for future studies will be determined by the joint evaluation of the 
immunogenicity and safety profiles of each dosage/adjuvant group. 
 
7.2.1 Success Criteria for Primary Objectives 
Not applicable. 
 
7.2.2 Success Criteria for Secondary Immunogenicity Objectives 
Not applicable. 
 
7.2.3 Success Criteria for Secondary Efficacy Objectives 
There are no secondary efficacy objectives in this study. 
 
7.2.4 Success Criteria for Safety Objectives 
Not applicable. 
 
 
 
 
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7.3 
Analysis Sets 
 
7.3.1 All Enrolled Set 
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments, regardless of the subject’s randomization and treatment 
status in the trial. 
 
7.3.2 
Exposed Set 
All subjects in the Enrolled Population who receive a study vaccination. 
 
7.3.3 Full Analysis Set (FAS) Immunogenicity Set 
All subjects in the Enrolled Population who: 
 
▫ receive a study vaccination AND provide immunogenicity data at relevant time 
points. 
Subjects will be included in the FAS if they have any evaluable serum samples at pre- and 
post-baseline. 
 
FAS populations will be analyzed “as randomized” (i.e., according to the vaccine a 
subject was designated to receive, which may be different from the vaccine the subject 
actually received). 
 
7.3.4 Per Protocol (PP) Population, Immunogenicity Set 
All subjects in the FAS Immunogenicity Population who: 
 
▫ Are not excluded due to reasons (see section 7.3.8) defined prior to unblinding or 
analysis 
▫ Examples for subjects excluded due to other reasons than major protocol deviations 
are: 
- 
Subjects who withdrew informed consent 
- 
Premature withdrawals due to adverse events 
▫ Exclusions need to be considered by objective/time point, i.e., sometimes not all data 
of a subject but only part of the subject's data will be removed from the PPS analysis. 
If a subject shows evidence of natural RSV infection during the trial they may not be 
part of the PPS. However, if evidence of natural RSV infection occurs at Visit 9 or 
 
 
 
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later, that subject will be included in the PPS analysis through Visit 5, but will not be 
included in the PPS analysis from Visit 9 through the end of the study. 
The complete list of all PPS, based on objective and time points, will be provided in the 
Statistical Analysis Plan. 
 
7.3.5 Safety Set 
 
Safety Set (solicited adverse events and other solicited reactions) 
All subjects in the Exposed Population who: 
 
▫ Provide post-vaccination reactogenicity data 
Safety Set (unsolicited adverse events) 
 
All subjects in the Exposed Population who: 
 
▫ Have post-vaccination unsolicited adverse event records 
Safety Set (overall) 
All subjects in the Exposed Population who: 
 
▫ Have either post-vaccination adverse event or reactogenicity records 
Subjects will be analyzed as "treated" (i.e., according to the vaccine a subject received, 
rather than the vaccine to which the subject may have been randomized). 
 
7.3.6 Other Analysis Sets 
All subjects who are screened, i.e., consented but not yet randomized/enrolled. 
 
7.3.7 Subgroups 
The subgroup of subjects undergoing additional evaluations for exploratory objectives 
will not be part of this analysis. Results will be available after the Clinical Study Report is 
issued. 
 
7.3.8 Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. An exclusion refers to a protocol deviation that is used to 
remove data from an analysis population at the time of analysis. Relevant protocol 
 
 
 
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deviations will be defined as exclusionary from the analysis according to protocol 
objectives and endpoints, which will be specified in the statistical analysis plan. 
 
Any deviation that affects the subject's rights, safety, or well- being and/or the 
completeness, accuracy and reliability of the study data constitutes a major protocol 
deviation. Changes or alterations in the conduct of the trial which do not have a major 
impact on the subject's rights, safety or well-being, or the completeness, accuracy and 
reliability of the study data are considered minor protocol deviations. Major and minor 
deviations will be reviewed to determine the final list of deviations that will be used for 
exclusion from the analysis set(s). This will be defined in the statistical analysis plan prior 
to unblinding. 
 
The following deviations are considered major: 
 
▫ A subject received incorrect study vaccine or dose of study vaccine 
▫ A subject met withdrawal criteria during the study but was not withdrawn 
▫ A subject received an excluded medication or vaccine 
▫ A subject was enrolled but does not meet the protocol's eligibility criteria 
▫ A subject with no safety data 
▫ Inadvertent loss of samples or data that support the analysis of primary objectives 
▫ Failure to obtain informed consent prior to initiation of study-related procedures 
▫ Falsifying research or medical records. 
Subjects who terminate study participation prematurely for reasons such as withdrawal of 
consent, adverse event (including death), or administrative reason do not represent 
protocol deviations, nor are the missing assessments that should otherwise have been 
collected for that subject later in the study considered protocol deviations. 
 
Pre-specified reasons for delay or cancellation of study vaccination as reflected in 
sections 4.3 and 4.4 do not constitute protocol deviations. 
 
All protocol deviations will be classified into major and minor. Major protocol deviations 
will be summarized by vaccine, center (overall) and grouped into the different categories 
as defined above. The site monitor will keep the investigator informed of minor and 
major protocol deviations, so that the investigator can comply with reporting these 
deviations to the local EC/IRB according to their institutional policy. 
 
Prior to unblinding, designated staff at the Sponsor will develop a memo that describes 
the selected deviations that are identified as exclusions from analysis populations. This 
memo will be included in the trial master file. 
 
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7.4 
Analysis Plan 
 
7.4.1 Analysis of Demographic and Baseline Characteristics 
Descriptive statistics (mean, standard deviation, median, minimum and maximum) for 
age, height and weight at enrollment will be calculated by overall and by vaccine group. 
 
Distributions of subjects by sex and ethnic origin will be summarized. 
 
7.4.2 Analysis of Primary Objectives 
 
7.4.2.1 
Statistical Hypotheses for Primary Objectives 
 
There are no statistical hypotheses being tested in the study. 
 
7.4.2.2 
Analysis Populations for Primary Objectives 
 
PPS will be used for the primary objective analyses. The primary immunogenicity 
analyses will be based on the per-protocol set. If the full analysis set (FAS) and PP differ 
by more than 10%, primary immunogenicity analyses will also be conducted on the FAS. 
 
7.4.2.3 
Statistical Methods for Primary Objectives 
 
For the primary immunogenicity analyses the following statistical methods will be 
applied: 
 
GMTs: For each treatment group within each cohort, GMTs of the serum anti-RSV NAb 
along with their associated 95% confidence intervals (CIs) will be computed by 
exponentiation of the corresponding log-transformed means and 95% CIs. 
 
The statistical analyses for GMTs will be conducted using an ANCOVA model with 
dosage and adjuvant as factors and baseline antibody level as covariate. Interactions 
between factors will be investigated and further described in the statistical analysis plan to 
be finalized and approved before the start of the trial. 
 
Fold-rise: Proportions of subjects with a ≥4-fold increase in serum anti-RSV NAb titer 
from baseline will be presented, for each treatment group within each cohort, together 
with their two-sided 95% Clopper-Pearson CIs. 
 
7.4.2.4 
Sample Size and Power Considerations of Primary Objectives 
 
Sample size is not driven by statistical assumptions for formal hypothesis testing as 
previous clinical trial data are not available and clinically meaningful group differences 
 
 
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are not established. In addition, values for a correlate of protection are not known at 
present stage. Nevertheless, some information from the neutralization assay for human 
serum was provided. 
 
Hence, the number of proposed subjects will be sufficient to provide a descriptive 
summary of the safety and immunogenicity of the RSV F subunit vaccine. 
 
 
Safety 
 
With 24 subjects in each active vaccine group of each cohort, the probability of observing 
at least one adverse event per group is 90%, if the actual rate of the event is 9.1%. For 
placebo, with 72 subjects, for the same actual rate of the event, the probability to detect at 
least one event increases to 99.9%. 
 
When the frequency of an adverse event is greater than 17.5%, there is 99% probability of 
observing one or more subjects presenting with such an AE in each of the active vaccine 
groups. 
 
 
Immunogenicity 
 
With 22 evaluable subjects per group, a two-sided 95% confidence interval (CI) for a 
single GMT of the anti-RSV NAb will extend 0.167 from the observed mean, assuming a 
standard deviation of 0.400 (in log scale). Analogously, with an observed proportion of 
subjects with ≥4-fold increase in NAb titers from Visit 1 (baseline) to Visit 9 (28 days 
after the second dose) equal to 50%, the 95% CI around that value will be from 28.2% to 
71.8% (Clopper-Pearson method). 
 
7.4.2.5 
Analysis of Safety Objectives 
 
7.4.2.5.1 
Analysis of Extent of Exposure 
 
The number of subjects who received one and two doses of vaccine will be summarized 
by vaccine group. 
 
7.4.2.5.2 
Analysis of Solicited Local and Systemic Adverse Events and Other 
Reactions 
 
All solicited adverse events will be summarized according to defined severity grading 
scales. 
 
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Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented. 
 
Post-vaccination solicited adverse events reported from day 1 to day 7 will be 
summarized for the intervals day 1-3, day 4-7, day 1-7 by maximal severity and by 
vaccine group, excluding the 30 minute measurement, which will be summarized 
separately. The severity of solicited local adverse events, including injection site 
induration, swelling, and erythema will be summarized according to categories based on 
linear measurement: 25 to 50 mm, 51 to 100 mm, >100 mm. 
 
Injection site pain and systemic reactions (except fever) occurring up to 7 days after each 
vaccination will be summarized according to “mild”, “moderate” or “severe”. 
 
Each solicited local and systemic adverse event will also be further summarized as “none” 
versus “any”. 
 
Implausible measurements (for further definition see analysis plan) will be left out of the 
analysis. 
 
Use of antipyretics and analgesics will be summarized by frequency, by type of use 
(prophylactic versus treatment), and percentage of subjects reporting use. The influence 
of antipyretics and analgesics use on the occurrence of specific adverse events (e.g., 
fever) will be assessed. 
 
Body temperature will be summarized by 0.5 °C increments from 36.0 °C up to ≥40 °C 
and will be broken down according by route of measurement. 
 
7.4.2.5.3 
Analysis of Spontaneously Reported Adverse Events 
 
All the adverse events occurring during the study, judged either as probably related, 
possibly related, or not related to vaccination by the investigator, will be recorded. 
 
The original verbatim terms used by investigators to identify adverse events in the CRFs 
will be mapped to preferred terms using the MedDRA dictionary. The adverse events 
will then be grouped by MedDRA preferred terms into frequency tables according to 
system organ class. All reported adverse events, as well as adverse events judged by the 
investigator as at least possibly related to study vaccine, will be summarized according to 
system organ class and preferred term within system organ class. These summaries will 
be presented by vaccination group. When an adverse event occurs more than once for a 
subject, the maximal severity and strongest relationship to the vaccine group will be 
counted. 
 
 
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Separate summaries will be produced for the following categories: 
 
▫ serious adverse events 
▫ adverse events that are possibly or probably related to vaccine 
▫ adverse events of special interest 
▫ new onset of chronic disease adverse event leading to withdrawal 
▫ adverse events leading to a medically attended visit 
▫ adverse event by data source 
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data. 
 
7.4.2.5.4 
Analysis of Safety Laboratory Values 
The investigator must assess all safety laboratory results (see section 3.5.3). Clinically 
significant modifications in blood chemistry, hematology, and urinalysis test values will 
be assessed by medical judgment based on interpretation of deviations from the 
institution’s normal values and, whenever possible, graded according to the criteria 
included in CBER Guidance for Industry “Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” dated September 
2007 (see Appendix D, E, and F). 
 
The following information will be displayed: 
 
▫ Change in absolute laboratory values from Visit 1 (baseline)to Visit 2 (seven days 
after the first dose), Visit 5 (28 days after the first dose), Visit 6 (seven days after the 
second dose), and Visit 9 (28 days after the second dose) 
▫ 3 x 3 shift tables by visit, using the categorization of low, normal, and high 
 
 
7.4.3 Analysis of Key Secondary Immunogenicity Objectives 
 
This study does not include key secondary immunogenicity objectives. 
 
7.4.4 Analysis of Key Secondary Efficacy Objectives 
 
This study does not include key secondary efficacy objectives. 
 
 
 
 
 
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7.4.5 Analysis of Key Secondary Other Objectives 
 
This study does not include key secondary efficacy objectives. 
 
7.4.6 Analysis of Non-Key Objectives 
 
The same statistical methods as described for primary objectives will be applied to the 
secondary objectives, which are either GMTs or proportions. 
 
Reverse cumulative distribution plots for antibody titers will be provided by treatment 
group. 
 
Non-Key Immunogenicity Objectives 
Not applicable. 
 
Non-Key Exploratory Objectives 
Not applicable. 
 
7.5 
Planned Interim Analysis 
An Interim Analysis will be performed on the immunogenicity and safety data collected 
from all subjects at Visits 1, 5, and 9. 
 
There will not be any statistical penalties applied as the interim analysis will not trigger 
changes in the study conduct (e.g. sample size re-estimation, cancellation of vaccine 
groups, early stop). The site staff will remain blinded through the end of the study and 
will not have access to unblinded information. 
 
The study statistician and the statistical programmer will be the only NVD people to be 
unblinded at subject level (i.e. full unblinding) for the interim analysis. Other NVD 
personnel will only receive grouped unblinded information with no possibility to guess 
the treatment allocation for a single subject. 
 
A thorough description of how data will be secured will be reported in the Data Security 
Plan (DSP). 
 
Details on the interim analysis conduct will be described in the Statistical Analysis Plan. 
An interim CSR will not be produced. 
 
 
 
 
 
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8.0 
SOURCE DOCUMENTATION, STUDY MONITORING, AND AUDITING 
 
Study monitoring and auditing will be standardized and performed in accordance with the 
sponsor’s or delegated contract research organization’s (CRO) standard operating 
procedures and applicable regulatory requirements (e.g., FDA, EMA, and ICH 
guidelines). 
 
Prior to enrollment of the first study subject, NVD or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices (including signing of the source data agreement (SDA, see 
section 8.1) and all electronic systems. CRFs supplied by the sponsor must be completed 
for each enrolled subject (see section 7.3.1 for definition of enrolled subject). 
Documentation of screened but not enrolled subjects must be maintained at the site and 
made available for review by the site monitor. All data entries as well as study related 
documents will be checked by the sponsor and/or site monitor. In addition, the 
investigator and site staff will be made aware of the plans to monitor the data collected at 
the site. 
 
8.1 
Source Documentation 
Prior to the start of the study, the site staff participating in the study conduct will be 
trained on what documents will be required for review as source documentation (i.e., 
original records, laboratory reports, medical records, subject diaries). The kinds of 
documents that will serve as source documents will be specified in the SDA. The SDA 
will be finalized and available for further review prior to first subject, first visit. 
 
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject, and date of completion and reason. 
 
The subject or the subject’s parents or legal guardian(s) must also allow access to the 
subject’s medical records. Each subject, or the subject’s parent(s) or legal guardian(s), 
must be informed of this prior to the start of the study and consent for access to medical 
records may be required in accordance with local regulations. 
 
All safety data reported by subjects must be written down on source documents prior to 
entry of the data into CRFs. If there are multiple sources of information (e.g., diary card, 
verbal report of the subject, telephone contact details, medical chart) supporting the 
diagnosis of an adverse event, these sources must be identified in the source documents, 
 
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discrepancies between sources clarified, the ultimate diagnosis must be justified and 
written in the source documents, and this diagnosis must be captured in the adverse event 
CRF (AE CRF). The AE CRF must also capture which source(s) of information were 
used to determine the adverse event (e.g., subject recall, medical chart, diary card, and/or 
other sources). 
 
8.2 
Study Monitoring and Source Data Verification 
A contract research organization (CRO) may be involved in the monitoring of protocol 
conduct and data entry. If a CRO is involved in study oversight, the name and address of 
this CRO will be located in the investigator site file. Prior to enrollment of the first study 
subject, NVD will develop a Clinical Monitoring Plan to specify how monitoring will be 
performed for the study. 
 
Study progress will be monitored by NVD or its representative (e.g., a CRO) as 
frequently as necessary to ensure: 
 
▫ that the rights and well-being of human subjects are protected 
▫ the reported trial data are accurate, complete, and verifiable from the source 
documents and 
▫ the conduct of the trial is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements 
Contact details for the team involved in study monitoring will be identified in a handout 
located in the Investigator Site File. Study data recorded on CRFs will be verified by 
checking the CRF entries against source documents in order to ensure data completeness 
and accuracy as required by study protocol. Additional documents such as the investigator 
site file, pharmacy records, and informed consent documentation must also be available 
for review if requested. Arrangements for monitoring visits will be made in advance in 
accordance with the monitoring plan, except in case of emergency. 
 
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection by NVD or its representative at the time of each monitoring 
visit. These documents must also be available for inspection, verification and copying, as 
required by regulations, by officials of the regulatory health authorities (e.g., FDA, EMA 
and others) and/or ECs/IRBs. The investigator and study site staff must comply with 
applicable privacy, data protection and medical confidentiality laws for use and disclosure 
of information related to the study and enrolled subjects. 
 
 
 
 
 
 
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9.0 
DATA MANAGEMENT 
 
9.1 
Data Entry and Management 
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), reactogenicity data, and 
immunogenicity data will be entered onto electronic case report forms (eCRFs) in a 
timely fashion by the investigator and/or the investigator’s dedicated site staff. Data 
entered onto eCRFs are stored on a secure website. The data collected on this secure 
website are assimilated into an electronic data capture (EDC) system, which is compliant 
with 21 Part 11 policies of the Code of Federal Regulations. The data system includes 
password protection and internal quality checks. The EDC will be designed and validated 
by NVD prior to activation for data entry by sites. The investigator or designated delegate 
must review data entered and electronically sign the eCRFs to verify their accuracy. 
 
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within EDC, to which the sponsor and site monitors have exclusively “read only” access. 
eCRF data will be reviewed routinely by study personnel from NVD and clinical 
monitors. 
 
All serology results produced by Clinical Serology, NVD will be entered into the Seroad 
database by NVD’s Clinical Serology Laboratory, Marburg. All results will be checked in 
the laboratory for validity and completeness. 
 
Electronic Data Transfer (EDT) is one method used by NVD for collecting laboratory 
data. The full-service laboratory (i.e., central laboratory) will send data as electronic files 
by a secured method (e.g., via diskette, CD, as an encrypted file attachment on electronic 
mail, or as a direct transfer into a specified server directory) to NVD’s BCDM 
department. The data file is pre-processed and loaded by a member of the BCDM team 
into the study database. The laboratory will submit a results file containing the tests and 
the results as specified in the protocol. If the laboratory provides the service, it will also 
submit a Demography (DEMOG) file containing the subject’s demographic information. 
If the file includes results of data blinded to personnel in clinical research, the source will 
provide a separate results file that will be loaded into a separate laboratory table. 
 
For this protocol, immunology laboratory data and/or safety laboratory data from external 
laboratories will be transmitted via EDT. 
 
 
 
 
 
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9.2 
Data Clarification 
 
As part of the conduct of the trial, NVD may have questions about the data entered by the 
site, referred to as queries. The monitors and the sponsor are the only parties that can 
generate a query. 
 
For eCRF trials, all corrections and clarifications will be entered into the EDC and will be 
identified by the person entering the information, the reason for the change, as well as the 
time of the changes made. If changes are made to a previously and electronically signed 
CRF, the investigator must confirm and endorse the changes. 
 
9.3 
Data Coding Procedures 
 
Coding of Adverse Events, Medical History, and Prior and Concomitant Medications will 
be performed using standard dictionaries as described in the Data Management Plan. 
 
9.4 
Data Protection 
NVD respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 
 
The sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data [95/46/EC] confirms herewith compliance to Directive 95/46/EC in all stages of 
Data Management. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.0 
RECORD RETENTION 
 
Investigators must retain all study records required by NVD and by the applicable 
regulations in a secure and safe facility. The investigator must consult a NVD 
representative before disposal of any study records, and must notify the sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained until at least 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in 
an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. “Essential documents” are defined as 
documents that individually and collectively permit evaluation of the conduct of a trial 
and the quality of the data produced. These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement 
with the sponsor. The Committee for Human Medicinal Products for Human Use 
(CHMP) requires retention for the maximum period of time permitted by the institution, 
but not less than 15 years (ICH E6, 4.9.5). It is the responsibility of the sponsor to inform 
the investigator/institution as to when these documents no longer need to be retained (ICH 
E6, 5.5.12). 
 
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11.0 
USE OF INFORMATION AND PUBLICATION 
 
NVD assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations. 
 
NVD also assures that key results of this clinical trial will be posted in a publicly 
accessible database within the required time-frame from the last subject’s last study visit 
as dictated by applicable regulations. 
 
Further to legislated data disclosure, NVD will ensure that as far as possible results of this 
study will be published as scientific/clinical papers in high-quality peer-reviewed 
journals. Preparation of such manuscripts will be made with full collaboration of principal 
investigators and in accordance with the current guidelines of Good Publication Practice 
(Graf 2009). 
 
NVD must be notified of any intent to publish data collected from the study and prior 
approval from NVD must be obtained prior to publication. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12.0 
ETHICS 
 
12.1 
Regulatory and Ethical Compliance 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations including European Directive 2001/20/EC, US Code of 
Federal Regulations Title 21, Novartis codes on protection of human rights, and with the 
ethical principles laid down in the Declaration of Helsinki (European Council 2001, US 
Code of Federal Regulations, ICH 1997). 
 
12.2 
Informed Consent Procedures 
 
Eligible subjects may only be included in the study after providing written informed 
consent or assent, as described in section 3.2.1. Before the start of the trial, the 
investigator will have the informed consent and any other materials that will be provided 
to the subjects reviewed and approved by the IRB/EC. This review and approval will be 
documented and stored with other study documents. The investigator or designee must 
fully inform the subject or legal guardian of all pertinent aspects of the trial. A copy of the 
written informed consent will be given to the subject or the designee. The 
subject/designee must be allowed ample time to ask about the details of the trial and to 
make a decision as to whether or not to participate in the study. The subject and/or legal 
guardian must sign the consent form indicating their agreement to participate in the study 
before any study-related procedures are conducted. If the subject and/or legal guardian is 
unable to read and write, a witness must be present during the informed consent 
discussion and at the time of informed consent signature. 
 
Prior to the start of the study, NVD will provide to investigators a separate document with 
a proposed informed consent form that complies with the ICH GCP guideline and 
regulatory requirements and is considered appropriate for this study. Any changes to the 
proposed consent form suggested by the investigator must be agreed to by NVD before 
submission to the IRB/EC and a copy of the approved version must be provided to the 
NVD monitor after IRB/EC approval. 
 
Women of child bearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study and 
agree that in order to participate in the study they must adhere to the contraception 
requirements indicated in the protocol for the duration of the study. If case of doubts on 
the ability of a subject to adhere to these requirements, that subject should not be allowed 
in the study 
 
 
 
 
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12.3 
Responsibilities of the Investigator and IRB/EC 
 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined 
in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH 1997). A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/EC must be given to NVD before study initiation. Prior to study start and at any time 
the protocol is amended during study conduct, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to NVD monitors, auditors, Novartis 
Clinical Quality Assurance representatives, designated agents of NVD, IRBs/ECs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform NVD immediately that this request has 
been made. 
 
The investigator is also responsible for the following: 
 
▫ maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant trial-related duties 
▫ demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period 
▫ demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed trial period 
▫ ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions 
▫ ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study 
▫ if permission to do so is given by the subject, ensuring that the subject’s primary 
healthcare provider is informed of the subject’s participation in the study. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the sponsor and prior review and documented approval/favourable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or 
administrative aspects of the trial (e.g., change in monitor(s), change of telephone 
number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol. 
 
 
 
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The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC 
approval/favourable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted: 
 
(a) to the IRB/IEC for review and approval/favourable opinion, 
 
(b) to the sponsor for agreement and, if required, 
 
(c) to the regulatory authority(ies). 
 
12.4 
Protocol Adherence 
 
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact NVD or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as no authorized deviations are permitted. 
If the investigator feels a change to the protocol would improve the conduct of the study 
this must be considered a protocol amendment, and unless such an amendment is agreed 
upon by NVD and approved by the IRB/EC it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the Clinical Study Report. 
 
12.5 
Protocol Amendments 
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (e.g., change of telephone number(s), logistical changes). 
Protocol amendments must be approved by NVD, Health Authorities where required, and 
the IRB/EC. In cases when the amendment is required in order to protect the subject 
safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding 
the need for formal approval of a protocol amendment, the investigator is expected to take 
any immediate action required for the safety of any subject included in this study, even if 
this action represents a deviation from the protocol. In such cases, NVD should be notified 
of this action, the IRB/EC at the study site, and, if required by local regulations, the 
relevant health authority) should be informed within 10 working days. 
 
 
 
 
 
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13.0 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX A: ADVERSE EVENTS OF SPECIAL INTEREST (AESI) 
 
AEs of special interest (AESI) will include those listed in below. The AESIs will be 
defined according to the following MedDRA preferred terms (underlined). 
 
Neuroinflammatory disorders: optic neuritis, uveitis, multiple sclerosis, demyelinating 
disease, transverse myelitis, Guillain-Barre syndrome, myasthenia gravis, encephalitis, 
ADEM, neuritis, Bell’s palsy 
 
Musculoskeletal and connective tissue disorders: rheumatoid arthritis, juvenile 
rheumatoid arthritis, polymyalgia rheumatica, psoriatic arthropathy, ankylosing 
spondylitis, systemic lupus erythematosis, cutaneous lupus, Sjogren’s syndrome, 
scleroderma, dermatomyositis, polymyositis, mixed connective tissue disease, reactive 
arthritis 
 
Vasculidites: temporal arteritis, Wegener’s granulomatosis, mixed connective tissue 
disease 
 
Gastrointestinal disorders: Crohn’s disease, ulcerative colitis, inflammatory bowel disease 
(non-specific), celiac disease, autoimmune hepatitis, primary sclerosing cholangitis, 
primary biliary cirrhosis 
 
Renal disorders: glomerulonephritis, nephritis, renal vasculitis 
Cardiac disorders: carditis, pericarditis, myocarditis, cardiomyopathy 
Skin disorders: psoriasis, vitiligo, Raynaud’s phenomenon, erythema nodosum, 
autoimmune bullous skin diseases, Stevens-Johnson syndrome 
 
Hematologic disorders: autoimmune hemolytic anemia, idiopathic thrombocytopenic 
purpura, antiphospholipid syndrome, pernicious anemia 
 
Metabolic disorders: autoimmune thyroiditis, Grave’s or Basedow’s disease, Hashimoto 
thyroiditis, insulin-dependent diabetes mellitus, Addison’s disease 
 
Others: sarcoidosis 
 
 
 
 
 
 
 
 
 
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APPENDIX B: TOXICITY GRADING SCALES FOR SOLICITED LOCAL 
ADVERSE EVENTS 
(Adapted from CBER 2007b) 
 
Adverse event Following 
Administration of 
Injectable Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Pain 
Present but does not 
interfere with activity 
Interferes with activity 
Prevents daily activity 
Induration / Swelling / 
Erythema1 
25 – 50 mm 
51 – 100 mm 
> 100 mm 
* This toxicity grading scale is adapted from CBER 2007 to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events. This toxicity grading scale is an NVD 
standard that is used for patient reporting. ‘Grade 4’ is not listed here but will be defined in the statistical 
analysis plan as necessary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 These ranges will be included in analyses, summarized: 1 to 2.4 cm, 2.5 to 5.0 cm, 5.1 to 10.0 cm, > 10.0 cm. 
 
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APPENDIX C: TOXICITY SCALES FOR SOLICITED SYSTEMIC ADVERSE 
EVENTS 
(Adapted from CBER 2007b) 
 
Systemic 
Adverse event 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Fever 
°C 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 - 102 
39.0 – 40 
102.1 - 104 
°F 
Chills 
Present but does not 
interfere with activity 
Interferes with activity 
Prevents daily activity 
Nausea 
Nausea present but not 
interfering with oral intake 
Nausea leading to 
decreased oral intake 
Nausea leading to minimal 
to no oral intake 
Myalgia 
Present but does not 
interfere with activity 
Interferes with activity 
Prevents daily activity 
Arthralgia 
Present but does not 
interfere with activity 
Interferes with activity 
Prevents daily activity 
Headache 
Present but does not 
interfere with activity 
Interferes with activity 
Prevents daily activity 
Fatigue 
Present but does not 
interfere with activity 
Interferes with activity 
Prevents daily activity 
Diarrhea 
2-3 loose stools /24 hours 
4-5 loose stools /24 hours 
6 or more watery stools /24 
hours or requires outpatient 
IV hydration 
Loss of 
appetite 
Loss of appetite without 
decrease in oral intake 
Decreased oral intake 
without weight loss 
Decreased oral intake with 
weight loss 
Cough 
Present but does not 
interfere with activity 
Interferes with activity 
Prevents daily activity 
Rhinorrhea 
Present but does not 
interfere with activity 
Interferes with activity 
Prevents daily activity 
Wheezing 
Present but does not 
interfere with activity 
Interferes with activity 
Prevents daily activity 
* This toxicity grading scale is adapted from CBER 2007b to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events. This toxicity grading scale is an NVD 
standard that is used for patient reporting. ‘Grade 4’ is not listed here but will be defined in the statistical 
analysis plan as necessary 
 
 
 
 
 
 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 1 / Version Date: August, 20 2012 
Doc Number: 60686169 

Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 111 of 115 
Confidential 
 
 
APPENDIX D: TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(SERUM) 
 
Serum * 
Mild (Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Sodium – Hyponatremia 
mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium – Hypernatremia 
mEq/L 
144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium – Hyperkalemia 
mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium – Hypokalemia 
mEq/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Glucose – Hypoglycemia 
mg/dL 
65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose – Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL 
100 – 110 
110 – 125 
111 – 125 
126 – 200 
>125 
>200 
Insulin 
requirements or 
hyperosmolar 
coma 
Blood Urea Nitrogen 
BUN mg/dL 
23 – 26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires 
dialysis 
Calcium – hypocalcemia 
mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium – hypercalcemia 
mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
> 12.0 
Magnesium – 
hypomagnesemia mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous – 
hypophosphatemia mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL 
1.25 – 1.5 x 
ULN*** 
1.6 – 3.0 x ULN 
3.1 –10 x ULN 
> 10 x ULN 
Albumin – 
Hypoalbuminemia g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
-- 
Total Protein – 
Hypoproteinemia g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
-- 
Alkaline phosphate – 
increase by factor 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
73.1 – 10 x 
ULN 
> 10 x ULN 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 1 / Version Date: August, 20 2012 
Doc Number: 60686169 

Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 112 of 115 
Confidential 
 
 
Serum * 
Mild (Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Liver Function Tests – 
ALT, AST 
increase by factor 
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
> 10 x ULN 
Bilirubin – when 
accompanied 
by any increase in Liver 
Function Test 
increase by factor 
1.1 – 1.25 x 
ULN 
1.26 – 1.5 x 
ULN 
1.51 – 1.75 x 
ULN 
> 1.75 x ULN 
Bilirubin – when Liver 
Function Test is normal; 
increase by factor 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
Cholesterol 
201 – 210 
211 – 225 
> 226 
--- 
Pancreatic enzymes – 
amylase, lipase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization 
of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value 
that falls within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if 
the subject had a new seizure associated with the low sodium value. 
*** ULN” is the upper limit of the normal range. 
**** Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 1 / Version Date: August, 20 2012 
Doc Number: 60686169 

Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 113 of 115 
Confidential 
 
 
APPENDIX E: TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(HEMATOLOGY) 
 
Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin (Female) - 
gm/dL 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) 
change from baseline 
value - gm/dL 
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - 
gm/dL 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (Male) 
change from baseline 
value – gm/dL 
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm3 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25, 000 
> 25,000 
WBC Decrease - 
cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 
Lymphocytes Decrease - 
cell/mm3 
750 – 1,000 
500 – 749 
250 – 499 
< 250 
Neutrophils Decrease - 
cell/mm3 
1,500 – 2,000 
1,000 – 1,499 
500 – 999 
< 500 
Eosinophils - cell/mm3 
650 – 1500 
1501 - 5000 
> 5000 
Hypereosinophilic 
Platelets Decreased - 
cell/mm3 
125,000 – 
140,000 
100,000 – 
124,000 
25,000 – 99,000 
< 25,000 
PT – increase by factor 
(prothrombin time) 
1.0 – 1.10 x 
ULN** 
71.11 – 1.20 x 
ULN 
1.21 – 1.25 x 
ULN 
> 1.25 ULN 
PTT – increase by factor 
(partial thromboplastin 
time) 
1.0 – 1.2 x ULN 
1.21 – 1.4 x 
ULN 
1.41 – 1.5 x 
ULN 
> 1.5 x ULN 
Fibrinogen increase - 
mg/dL 
400 – 500 
501 – 600 
> 600 
-- 
Fibrinogen decrease - 
mg/dL 
150 – 200 
125 – 149 
100 – 124 
< 100 or 
associated 
with gross 
bleeding 
or disseminated 
intravascular 
coagulation (DIC) 
 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 1 / Version Date: August, 20 2012 
Doc Number: 60686169 

Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 114 of 115 
Confidential 
 
 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
** “ULN” is the upper limit of the normal range. 
*** Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 1 / Version Date: August, 20 2012 
Doc Number: 60686169 

Novartis Vaccines and Diagnostics 
08 JAN 14 Final Version 1.0 
Protocol V122_01 
Page 115 of 115 
Confidential 
 
 
APPENDIX F: TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(URINE) 
 
Urine * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization 
or 
dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization 
for 
hyperglycemia 
Blood (microscopic) – 
red blood cells per 
high power field 
(rbc/hpf) 
1 - 10 
11 – 50 
> 50 and/or gross 
blood 
Hospitalization 
or 
packed red blood 
cells (PRBC) 
transfusion 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
** Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 1 / Version Date: August, 20 2012 
Doc Number: 60686169 

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Novartis Vaccines 
24 JUN 14 
Clinical Study Protocol V122_01 Amendment 1 
Confidential 
Page 1 of 3 
 
 
 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
 
 
 
 
 
Study Number: V122_01 
 
Protocol Title: A Phase 1 Randomized, Observer Blind, Placebo Controlled, Dosage- 
Escalation Single Center Study to Evaluate the Safety and Immunogenicity of an RSV 
Fusion Glycoprotein (F) Subunit Vaccine in Healthy Adults 
 
Amendment Number 1 
 
Revised Protocol version 2.0 issued on 24 JUN 14 
 
 
The present amendment reflects changes to the Revised Protocol version 1.0 issued 
on 08 JAN 14 
 
 
 
 
Property of Novartis Vaccines 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of Novartis Vaccines 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Doc Number: 64823943 

Novartis Vaccines 
24 JUN 14 
Clinical Study Protocol V122_01 Amendment 1 
Confidential 
Page 2 of 3 
 
 
DESCRIPTION OF CHANGE(S) AND RATIONALE: 
 
 
 
CHANGE 
LOCATION(S) OF 
CHANGE 
RATIONALE FOR 
CHANGE 
Removal of BB-IND 
Title page, Synopsis header 
Decision taken that 
V122_01 will not be 
conducted under IND. 
Updated description of 
randomization. Changed to 
enrolling all 288 subjects in 
one of three cohorts, 
followed by allocation to 
one of four treatment 
groups. Combined placebo 
subjects within each cohort. 
Clarified wording on 
enrollment and 
randomization. 
Synopsis Methodology 
section, Table 1, Section 
3.1, Table 3.1-1, Section 
3.2.3, Section 3.2.4 
Modified wording to more 
accurately describe how 
enrollment and 
randomization will actually 
be performed. 
Removal of “loss of 
appetite” as a solicited 
systemic reaction. 
Synopsis Safety 
Measurements section, 
Section 6.5, Appendix B 
Nausea is already included 
as a solicited AE, and is a 
better measure than loss of 
appetite. Including both 
may be confusing to 
subjects completing the 
diary. 
Updated list of 
abbreviations to remove 
those no longer applicable. 
List of Abbreviations 
Abbreviations for removed 
safety labs needed to be 
deleted. 
 
 
 
 
 
 
 
 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Doc Number: 64823943 

Novartis Vaccines 
24 JUN 14 
Clinical Study Protocol V122_01 Amendment 1 
Confidential 
Page 3 of 3 
 
 
CHANGE 
LOCATION(S) OF 
CHANGE 
RATIONALE FOR 
CHANGE 
Updated list of Safety labs 
to remove unnecessary tests. 
The following tests were 
deleted: cholesterol, LDH, 
pancreatic enzymes, 
fibrinogen, PT, PPT, and D- 
dimer. 
Section 3.5.3, Section 6.7, 
Appendix C, Appendix D 
The removed safety labs did 
not provide critical 
information related to 
subject safety, and added 
cost and logistical 
complexity. The list of 
safety labs has now been 
reduced to those that 
provide the most important 
and useful information for 
assessing subject safety. 
Removed the list of AESIs 
as an appendix. It will 
instead be included in the 
Investigator Site File. 
Appendix A, references to 
Appendix A, and renaming 
of other appendices 
The previous list included in 
Appendix A was outdated. 
Moving forward the list of 
AESIs will be provided 
outside of the protocol to 
avoid the need for future 
amendments. 
Added the following 
statement: 
“The analysis of the B-cell 
receptor diversity does not 
have the intent or the 
capability to identify or rule 
out any genetic 
modifications in the RNA 
or DNA that are presumably 
linked to disease or 
predisposition to disease.” 
Section 6.8 
This statement is intended 
as a clarification that no 
genetic testing is being 
performed that would 
provide information related 
to health status of the 
subjects. 
 
 
 
 
 
 
 
 
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Date: Thursday, 03 July 2014, 17:11 GMT 
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Novartis Vaccines 
26 AUG 14 
Clinical Study Protocol V122_01 Amendment 2 
Confidential 
Page 1 of 3 
 
 
 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
 
 
 
 
 
Study Number: V122_01 
 
Protocol Title: A Phase 1 Randomized, Observer Blind, Placebo Controlled, Dosage- 
Escalation Single Center Study to Evaluate the Safety and Immunogenicity of an RSV 
Fusion Glycoprotein (F) Subunit Vaccine in Healthy Adults 
 
Amendment Number 2 
 
Revised Protocol version 3.0 issued on 26 AUG 14 
 
 
The present amendment reflects changes to the Revised Protocol version 2.0 issued 
on 24 JUN 14 
 
 
 
 
Property of Novartis Vaccines 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of Novartis Vaccines 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Doc Number: 66185819 

Novartis Vaccines 
26 AUG 14 
Clinical Study Protocol V122_01 Amendment 2 
Confidential 
Page 2 of 3 
 
 
DESCRIPTION OF CHANGE(S) AND RATIONALE: 
 
 
 
CHANGE 
LOCATION(S) OF 
CHANGE 
RATIONALE FOR 
CHANGE 
Name of Sponsor updated 
Synopsis header 
Study conducted in EU, so 
to Novartis Pharma Services 
sponsor needs to be 
AG 
Novartis Pharma Services 
AG 
Visit windows updated in 
Time and Events Table: 
Screening window extended 
to -28 days, -1/+1 windows 
applied to Reminder Calls 
and Phone Calls for Visits 
3, 4, 7, and 8 
Time and Events Table 
(Table 2) 
Site requested additional 
screening time and windows 
for phone calls to better 
facilitate scheduling of 
subjects. 
INR removed as safety lab 
Table of Contents, Section 
INR was erroneously kept 
assay. 
3.5.3, Section 6.7 
in list of safety labs; it is 
linked to PT, which was 
previously removed. 
Clarified Stopping/Pausing 
Guidelines: 
Section 3.6 
Clarified guidelines so they 
are more easily understood. 
Reordered so SAEs are 
listed first, then Grade 4 
AEs, then Grade 3 AEs. 
Added that review of SAEs 
will be done by DMC, 
IRB/EC, and health 
authorities. Review of 
Grade 4 AEs and Grade 3 
AEs will be done by the 
DMC. 
Grade 3 AEs guideline now 
also refers to Appendix A 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Doc Number: 66185819 

Novartis Vaccines 
26 AUG 14 
Clinical Study Protocol V122_01 Amendment 2 
Confidential 
Page 3 of 3 
 
 
CHANGE 
LOCATION(S) OF 
CHANGE 
RATIONALE FOR 
CHANGE 
and Appendix B. 
Vaccine Group names 
Table 5.1 
Updating Vaccine Groups 
updated to align with other 
to 1A, 1B, 1C, 1D, 2A, 2B, 
study documents. All three 
2C, 2D, 3A, 3B, 3C, and 3D 
cohorts now have Groups 
allowed for simplified kit 
A, B, and C. All placebo 
design and aligned with 
groups (in all three cohorts) 
other documentation. 
are named Group D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Novartis Vaccines 
16 DEC 14 
Clinical Study Protocol V122_01 Amendment 3 
Confidential 
Page 1 of 2 
 
 
 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
 
 
 
 
 
Study Number: V122_01 
 
Protocol Title: A Phase 1 Randomized, Observer Blind, Placebo Controlled, Dosage- 
Escalation Single Center Study to Evaluate the Safety and Immunogenicity of an RSV 
Fusion Glycoprotein (F) Subunit Vaccine in Healthy Adults 
 
Amendment Number 3 
 
Revised Protocol version 4.0 issued on 16 DEC 14 
 
 
The present amendment reflects changes to the Revised Protocol version 3.0 issued 
on 26 AUG 14 
 
 
 
 
Property of Novartis Vaccines 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of Novartis Vaccines 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Doc Number: 69058108 

Novartis Vaccines 
16 DEC 14 
Clinical Study Protocol V122_01 Amendment 3 
Confidential 
Page 2 of 2 
 
 
DESCRIPTION OF CHANGE(S) AND RATIONALE: 
 
CHANGE 
LOCATION(S) OF 
CHANGE 
RATIONALE FOR CHANGE 
Exclusion criteria #14 has 
been updated from 
“Individuals with any 
abnormal safety laboratory 
result at the screening visit” 
to “Individuals with any 
clinically significant 
abnormal safety laboratory 
result, as judged by the 
investigator.” 
Section 4.2 
The investigator must be able to 
decide if an abnormal safety lab 
result (based on standard toxicity 
tables) in an otherwise healthy 
individual is clinically significant 
and therefore should exclude the 
subject from the study. This 
language is similar to what has 
been used in other trials. 
Safety review of data by the 
DMC has been changed 
from Visit 9 to Visit 6, prior 
to proceeding with 
enrollment of the 
subsequent cohort. 
Section 3.2.3 
As a precedent, DMC reviews 
within and between cohorts will be 
performed based on safety data 
from 7 days after each vaccination. 
The Stopping/Pausing guidelines 
defined in Section 3.6 will of 
course still apply. 
Reference to “28 days after 
each vaccination” has been 
removed. 
Section 6.9 
As described above for Section 
3.2.3, the DMC review will be 
performed at 7 days after each 
vaccination. 
In the Times and Events 
Table, Visit Number row 
was moved up so it is next 
to Study Day row. 
Table 2 
The rows were reordered to make 
the table easier to read. 
References to “major” and 
“minor” protocol deviations 
have been updated to 
“reportable” and “not 
reportable,” respectively. 
Section 7.3.8 
Novartis SOP now defines protocol 
deviations as either CSR reportable 
or non-reportable. 
 
 
 
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GSK 
12 APR 16 
Clinical Study Protocol V122_01 Amendment 4 
Confidential 
Page 1 of 2 
 
 
 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
 
 
 
 
 
Study Number: V122_01 
 
Protocol Title: A Phase 1 Randomized, Observer Blind, Placebo Controlled, Dosage- 
Escalation Single Center Study to Evaluate the Safety and Immunogenicity of an RSV 
Fusion Glycoprotein (F) Subunit Vaccine in Healthy Adults 
 
Amendment Number 4 
 
Revised Protocol version 5.0 issued on 12 APR 16 
 
 
The present amendment reflects changes to the Revised Protocol version 4.0 issued 
on 16 DEC 14 
 
 
 
 
Property of GlaxoSmithKline Biologicals S.A. (hereafter referred to as GSK) 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GSK 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
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Doc Number: 79231633 

GSK 
12 APR 16 
Clinical Study Protocol V122_01 Amendment 4 
Confidential 
Page 2 of 2 
 
 
DESCRIPTION OF CHANGE(S) AND RATIONALE: 
 
CHANGE 
LOCATION(S) OF 
CHANGE 
RATIONALE FOR CHANGE 
Update to sponsor name 
Throughout the 
entire document 
Sponsorship change due to 
acquisition of Novartis Vaccines 
by GSK 
Removal of reference to 
interim analysis 
Synopsis (page 13) 
Section 3.1 
Alignment with internal decision 
made within organization 
Section 3.3 
Section 7.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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