Public Disclosure Synopsis
Protocol B3451003 – 18 July 2017 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
GENERIC DRUG NAME AND/OR COMPOUND NUMBER: Staphylococcus aureus
4-Antigen Vaccine (SA4Ag) / PF-06290510
PROTOCOL NO.: B3451003
PROTOCOL TITLE: A Phase 1/2a Placebo-Controlled, Randomized, Double-Blind,Sponsor-Unblinded Trial to Evaluate the Safety, Tolerability, and Immunogenicity of
Staphylococcus aureus 4-Antigen Vaccine (SA4Ag) in Japanese Adults
Study Center(s): Two (2) sites in Japan.
Study Initiation Date and Primary Completion or Final Completion Dates: 17 June 2015
to 02 September 2016
Phase of Development:
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Phase 1/2aStudy Objectives:
Primary Objectives:
The primary objectives of the study were as follows:
Primary Safety Objective:
To assess the safety and tolerability of a single administration of SA4Ag in Japanese adults
aged 20 to <65 years and 65 to <86 years by measuring local reactions, systemic events, andadverse events (AEs).
Primary Immunogenicity Objective:
To assess the immunogenicity of a single administration of SA4Ag in Japanese adults aged
20 to <65 years and 65 to <86 years by measuring antigen-specific antibody levels using acompetitive Luminex immunoassay (cLIA), fibrinogen-binding inhibition (FBI) assay, andopsonophagocytic activity (OPA) assays 1 month (Day 29 visit) after vaccination.

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Secondary Objective:
The secondary objective of the study was as follows:
Secondary Immunogenicity Objective:
To describe immune responses to specific antigens in Japanese adults aged 20 to <65 years
and 65 to <86 years, 10 days (Day 11 visit), 15 days (Day 15 visit), and 3 months(Month 3 visit) after vaccination.
METHODS
Study Design:This was a Phase 1/2a, multicenter, parallel-group, placebo-controlled, randomized,
double-blind, sponsor-unblinded study. Study subjects and all other study personnel,
including the principal investigator, were blinded. In particular, the individuals who
evaluated subject safety as well as the subject were blinded to their allocated vaccine group.

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)This study included Phase 1 and Phase 2 portions, with subjects enrolled in 2 age groups:
20 to <65 years and 65 to <86 years. The 20- to <65-year age group had 2 age substrata:
20 to <50 years and 50 to <65 years.
Subjects participated in the study for approximately 12 months. This study was completed inapproximately 18 months. The end of the study was the last visit of the last subject. Subjects
withdrawn from the study after randomization were not replaced, regardless of the reason forwithdrawal.
For the purposes of subject participation in the study, including data collection procedures,
enrollment in the study was considered to occur at the time of randomization.
Subjects enrolled in Phase 1 were required to attend a screening visit that included
hematology, coagulation, and blood chemistry assessments to confirm eligibility 2 to 14 days
prior to study vaccination.
Enrollment of subjects occurred in a sequential manner starting with the 20- to <50-year age
substratum. Enrollment of sequential age strata or groups was to begin at least 3 days
following completion of enrollment and vaccination of subjects from a younger age
substratum or group.
After Phase 1 enrollment was completed, the internal review committee (IRC) evaluated atleast 14 days of postvaccination safety data from all Phase 1 subjects, including all local
reactions and systemic events, all AEs, and all hematology, coagulation, and blood chemistrylaboratory results. Phase 2 did not commence until the IRC determined that it was safe to doso. Should the sponsor have decided not to proceed to Phase 2, the protocol was to beamended.

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Each subject enrolled in Phase 2 was screened and vaccinated on the same day when all
eligibility criteria were met. Hematology, coagulation, and blood chemistry laboratory tests
were not performed on Phase 2 subjects.
The enrollment process for Phase 1 and Phase 2 subjects is summarized in Table 1.
Table 1.

Enrollment Schematic

Phase 1 enrollment:
Sequential age substrata
or group enrollment
may open at least 3 days
after completion of theyounger age
substratum/group

20- to <65-Year Age Group
20- to <50-Year Age
50- to <65-Year Age
Substratum
Substratum
6 subjects
SA4Ag: 3
Placebo: 3
At least 3 days ↓65- to <86-Year AgeGroup

6 subjects
SA4Ag: 3
Placebo: 3
At least 3 days ↓090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

12 subjects
SA4Ag: 6
Placebo: 6

14 days ↓aPhase 2 enrollment
Subjects in each age
stratum/group are
randomized in parallel.

28 Subjects
SA4Ag: 14
Placebo: 14

28 Subjects
SA4Ag: 14
Placebo: 14

56 Subjects
SA4Ag: 28
Placebo: 28

Abbreviations: IRC = internal review committee.
a. IRC’s review of Phase 1 safety data up to the Day 15 visit determined whether Phase 2 enrollment could
open.

Following the screening visit (for Phase 1 subjects only), subject visits were to occur over the
12-month study as follows: Visits 1 (Day 1), 2 (Day 5), 3 (Day 11), 4 (Day 15), 5 (Day 29),
6 (Month 3), 7 (Month 6), and 8/End of Study (Month 12). For Phase 2 subjects, a visit was
not required for Day 5.
Number of Subjects (Planned and Analyzed):
Approximately 136 subjects were to participate in this study at 2 to 5 sites. The number ofsubjects enrolled at each site varied based on enrollment capabilities of each site.
Approximately 24 subjects (6 subjects aged 20 to <50 years, 6 subjects aged 50 to <65 years,
and approximately 12 subjects aged 65 to <86 years) in Phase 1 were to be sequentiallyrandomized in a 1:1 ratio to receive a single injection of SA4Ag or placebo. Approximately
112 subjects (28 subjects aged 20 to <50 years, 28 subjects aged 50 to <65 years, andapproximately 56 subjects aged 65 to <86 years) in Phase 2 were to be randomized in parallelin a 1:1 ratio to receive a single injection of either SA4Ag or placebo.

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Approximately 34 subjects were to be enrolled in each age substratum (20 to <50 years and
50 to <65 years), and 68 subjects in the 65- to <86-year age group. A total 91 subjects aged
20 to <65 years and 84 subjects aged 65 to <86 years were enrolled in this study,
respectively.
Diagnosis and Main Criteria for Inclusion and Exclusion:
The study included Japanese male and female adults aged 20 to <86 years at enrollment(confirmed by official identification document), determined by medical history, physicalexamination, and the clinical judgment of the investigator to be eligible for the study.
Subjects with preexisting chronic medical conditions determined to be stable were included.
Subjects were not included if they had bleeding diathesis or condition associated withprolonged bleeding time that may contraindicate intramuscular injection or blood draw, any
contraindication to vaccination or vaccine components, previous administration of an
Staphylococcus aureus vaccine, any infection proven or suspected to be caused by S aureus
within 6 months preceding study vaccination, receipt of blood products or immunoglobulins
within 12 months before enrollment or anticipated through conclusion of the study, or were
immunocompromised or were on immunosuppressive therapy or had a history of
immunosuppressive therapy.
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Study Treatment or Study Vaccine:
Study subjects received a single 0.5-mL dose of investigational product into the deltoid
muscle in the upper arm at Visit 1. As a standard practice of vaccination, the nondominantarm was recommended for the study vaccination unless medically contraindicated.
Subjects were randomized in a 1:1 ratio to 1 of 2 vaccine groups. Each subject received
either a single dose of SA4Ag or placebo at Visit 1.
Immunogenicity Evaluations and Endpoints:
Blood samples for immunogenicity assessments were collected from study subjects at Visit 1(prior to vaccination) and at applicable postvaccination visits for up to 1 year after
vaccination (Visits 3 to 8). Immunoassays (capsular polysaccharide serotype 5 [CP5] andcapsular polysaccharide serotype 8 [CP8] OPA assays, FBI assay for clumping factor A[ClfA], and cLIA for ClfA and manganese transporter C [MntC]) were performed on blood
samples from each blood sampling time point to measure the immune response to different
vaccine antigens.
The immunogenicity endpoints were as follows:
Primary Immunogenicity Endpoints:
The primary immunogenicity endpoints included the proportions of subjects achieving
antibody responses to specific antigens 1 month after vaccination (Day 29 visit) with results
greater than or equal to the thresholds listed in Table 2 in each age group.

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Table 2.
VaccineComponent
rmClfA

Thresholds for Primary Endpoints
ThresholdRationale for the Threshold

Approximately 100% of healthy adultsa (n=718) with antibody
titers below the LLOQ (121) prior to vaccination.
rP305A
4 × LLOQ (cLIA)
Approximately 51% of healthy adultsa (n=720) have antibody
titers below the LLOQ prior to vaccination.
CP5-CRM197
1000 (OPA)
This threshold titer represents approximately the 75th percentile
of baseline antibody titers in healthy adultsb (n=96).
CP8-CRM197
2000 (OPA)
This threshold titer represents approximately the 75th percentile
of baseline antibody titers in healthy adultsb (n=96).
Abbreviations: cLIA = competitive Luminex immunoassay; CP5-CRM197 = capsular polysaccharide
serotype 5 conjugated to cross-reactive material 197; CP8-CRM197 = capsular polysaccharide serotype 8
conjugated to cross-reactive material 197; FBI = fibrinogen-binding inhibition; LLOQ = lower limit ofquantitation; OPA = opsonophagocytic activity; rmClfA = recombinant clumping factor A mutant;rP305A = recombinant protein 305A.
a. Study B3451001 and B3451011 data.
b. Study B2251002 data.
121 (FBI)

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Secondary Immunogenicity Endpoints:•

Proportion of subjects achieving antibody responses to specific antigens with results
greater than or equal to the thresholds listed in the primary immunogenicity endpoints forthe Day 11, Day 15, and Month 3 visits after vaccination in each age group.

•

Immune responses to specific antigens listed below at the Day 11, Day 15, Day 29, andMonth 3 visits in each age group:•

Titers measured as geometric mean titers (GMTs) for ClfA and MntC using the cLIA.

•

OPA titers measured as GMTs against S aureus isolates (a CP5- and a
CP8-expressing strain of S aureus) for CP5-CRM197 and CP8-CRM197 (CP5 and CP8,
each conjugated to the nontoxic mutant form of diphtheria toxin, cross-reactive
material 197 [CRM197]), respectively.

•

FBI titers measured as GMTs for ClfA.

•

The immunoglobulin geometric mean fold rise (GMFR) from Day 1 to each
respective time point for ClfA and MntC using the cLIA.

•

GMFR from Day 1 to each respective time point on OPA titers for CP5-CRM197 and
CP8-CRM197 against S aureus clinical isolates (a CP5- and a CP8-expressing strain,
respectively).

•

GMFR from Day 1 to each respective time point on FBI titers for ClfA.

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Safety Evaluations:
Safety parameters included local reactions (size of redness and/or swelling and severity ofpain at the injection site) and systemic events (fever, fatigue, headache, vomiting, diarrhea,
muscle pain, and joint pain) that occurred in the 14 days after investigational productadministration at Visit 1. Subjects were issued an e-diary in order to monitor and record
local reactions and systemic events for 14 days following vaccination. Investigators
reviewed the e-diary data at frequent intervals as part of the ongoing safety review.
Acute reactions within the first 30 minutes after investigational product administration wereassessed and documented in the AE case report form (CRF) as immediate AEs. In addition,
AEs, serious adverse events (SAEs), and newly diagnosed chronic medical disorders wererecorded and reported.
For Phase 1 subjects only, hematologic, coagulation, and blood chemistry assessments were
performed at the screening visit prior to vaccination, and at the Day 5 and Day 15 visits.
Statistical Methods:

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A number of analysis populations were defined for the immunogenicity and safety analyses:
Full Analysis Set:
The intent-to-treat (ITT) population included all subjects who were enrolled and were notscreen failures.
Per Protocol Analysis Set:
The evaluable immunogenicity population was considered the primary population for the
analysis of immunogenicity data, and included subjects who:•

Were eligible for the study;•

Had been randomized;•

Had received investigational products as randomized;•

Had the Month 1 blood draw (Day 29, Visit 5) between Day 29 and Day 35, inclusive,
after vaccination (the algorithm for calculation will be [date of blood draw] – [date ofvaccination] +1);•

Had valid and determinate assay result for at least 1 antigen at Visit 5 (Day 29) for the
primary immunogenicity analysis;•

Had received no prohibited vaccines or treatment from Visit 1 (Day 1) to Visit 5(Day 29);•

Had no other major protocol deviations as determined by the clinicians from Visit 1(Day 1) to Visit 5 (Day 29).

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A major protocol deviation was a protocol deviation that, in the opinion of the clinicians,
would materially affect assessment of immunogenicity (eg, subject receipt of a prohibited
vaccine or medication that might affect immune response or a medication error withsuspected decrease or increase in potency of the vaccine).
For subjects who were not excluded from the evaluable immunogenicity population, if
subjects did not meet the criteria listed below, the subjects were excluded only from the visits
for analyses without excluding them from the evaluable immunogenicity population.
•

Had the blood draw at the blood draw visits, except Visit 5 (Day 29), within the window
as specified in the protocol (the algorithm for calculation will be [date of blooddraw] - [date of vaccination] +1);•

Had valid and determinate assay results at the blood draw visits, except Visit 5 (Day 29),
for the analyses.

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)The subjects who did not meet the criteria below may have been excluded only from thevisits or subsequent visits for analyses without excluding them from the evaluable
immunogenicity population as determined by the clinicians.
•

Had received no prohibited treatments after Visit 5 (Day 29);•

Had no other major protocol deviations as determined by the clinicians after Visit 5(Day 29).

Safety Analysis Set:
All subjects who received at least 1 dose of investigational product and had any safety data
after vaccination were to be included in the safety population. To include subjects in thesafety population, the subjects were to be included in the group according to the vaccine thatthey actually received.
Endpoints for AEs and laboratory parameters were analyzed based on the safety population.
Reactogenicity endpoints were also analyzed based on the safety population.
Other Analysis Sets:
No other analysis sets were analyzed.
Immunogenicity Analyses:
Immunogenicity results from subjects who received SA4Ag or placebo in Phase 1 andPhase 2 were combined in the analysis. Analyses for recombinant protein 305A (rP305A)
and recombinant clumping factor A mutant (rmClfA) were displayed as MntC and ClfA in
the tables, listings and figures.
Safety Analyses:

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Protocol B3451003 – 18 July 2017 – Final

The primary safety endpoints were as follows:•

Number and proportion of subjects reporting local reactions (size of redness and/or
swelling and severity of pain at the injection site) and severity of the local reactions as
self-reported on e-diaries for 14 days after vaccination.

•

Number and proportion of subjects reporting systemic events (fever, fatigue, headache,vomiting, diarrhea, muscle pain, and joint pain) and severity of systemic events as
self-reported on e-diaries for 14 days after vaccination.

•

Number and proportion of subjects reporting AEs, newly diagnosed chronic medical
disorders, and SAEs categorized according to the Medical Dictionary for Regulatory
Activities (MedDRA).

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)For Phase 1 subjects only:•

Number and proportion of Phase 1 subjects with grading shifts in hematology,
coagulation, and blood chemistry laboratory assessments.

•

Number and proportion of Phase 1 subjects with abnormal hematologic, coagulation, andblood chemistry assessments.

RESULTS
Subject Disposition and Demography:
The disposition of subjects aged 20 to <65 years is presented in Table 3.
A total of 91 subjects in this age group were screened for inclusion in the study. Of those,
68 subjects were randomized to 1 of 2 vaccine groups: 34 subjects to the placebo group and
34 subjects to the SA4Ag group. Of the 68 randomized subjects, all 68 were vaccinated. All
subjects received SA4Ag or placebo. No subjects were excluded from any of the analysis
populations.
The disposition of subjects aged 65 to <86 years is presented in Table 4.
A total of 84 subjects in this age group were screened for inclusion in the study. Of those,
68 subjects were randomized to 1 of 2 vaccine groups: 34 subjects to the placebo group and
34 subjects to the SA4Ag group. All subjects were vaccinated with either SA4Ag orplacebo. No subjects were excluded from any of the analysis populations.

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Table 3.

Disposition of Subjects – Subjects Aged 20 to <65 Years

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Vaccine Group (as Randomized)
Placebo
SA4Ag
Total
n
%
n
%
n
%
91
23
34
100.0
34
100.0
68
100.0
0
0.0
0
0.0
0
0.0
34
100.0
34
100.0
68
100.0

Screened
Screen failures
Randomizeda
Not vaccinatedVaccinatedInclusion in the following population:
Safety
34
100.0
34
100.0
mITT immunogenicity
34
100.0
34
100.0
Evaluable immunogenicity
34
100.0
34
100.0
mITT colonization
34
100.0
34
100.0
Completed Day 29 blood draw visit
34
100.0
34
100.0
Withdrawn before Day 29 blood draw visit
0
0.0
0
0.0
Withdrawn after Day 29 blood draw visit
1
2.9
0
0.0
Adverse event
1
2.9
0
0.0
Completed study
33
97.1
34
100.0
Abbreviations: mITT = modified intent-to-treat.
a. The values in this row are used as the denominators for percentages.
Program ID: Study B3451003 t_disp.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_disp_ag1.htm.

Table 4.

68
68
68
68
68
0
1
1
67

100.0
100.0
100.0
100.0
100.0
0.0
1.5
1.5
98.5

Disposition of Subjects – Subjects Aged 65 to <86 Years
Vaccine Group (as Randomized)
Placebo
SA4Ag
Total
n
%
n
%
n
%
84
16
34
100.0
34
100.0
68
100.0
0
0.0
0
0.0
0
0.0
34
100.0
34
100.0
68
100.0

Screened
Screen failures
Randomizeda
Not vaccinatedVaccinatedInclusion in the following population:
Safety
34
100.0
34
100.0
mITT immunogenicity
34
100.0
34
100.0
Evaluable immunogenicity
34
100.0
34
100.0
mITT colonization
34
100.0
34
100.0
Completed Day 29 blood draw visit
34
100.0
34
100.0
Withdrawn before Day 29 blood draw visit
0
0.0
0
0.0
Withdrawn after Day 29 blood draw visit
2
5.9
0
0.0
Adverse event
1
2.9
0
0.0
No longer willing to participate in study
1
2.9
0
0.0
Completed study
32
94.1
34
100.0
Abbreviations: mITT = modified intent-to-treat.
a. The values in this row are used as the denominators for percentages.
Program ID: Study B3451003 t_disp.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_disp_ag2.htm.

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68
68
68
68
68
0
2
1
1
66

100.0
100.0
100.0
100.0
100.0
0.0
2.9
1.5
1.5
97.1

Public Disclosure Synopsis
Protocol B3451003 – 18 July 2017 – Final

Demographics and smoking status for subjects aged 20 to <65 years are presented for thesafety population in Table 5.
Among randomized subjects in this age group, the mean age at vaccination was
47.0 (SD 12.1) years. Overall, the same number of males (34) and females (34) wereadministered the vaccine. In the SA4Ag group, 44.1% of subjects were female and 55.9%
were male; in the placebo group, 55.9% of subjects were female and 44.1% were male. All
subjects were Japanese. The mean body mass index (BMI) was 22.22 (SD 3.45) kg/m2 andthe majority of subjects (77.9%) had not used tobacco in the previous 6 months. Bothvaccine groups were generally balanced with regards to subject demographics, with a slight
imbalance in the sex of subjects across groups.

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Demographics and smoking status for subjects aged 65 to <86 years are presented for thesafety population in Table 6.
Among randomized subjects in this age group, the mean age at vaccination was
70.3 (SD 3.9) years. Overall, the same number of males (34) and females (34) wereadministered the vaccine. In the SA4Ag group, 38.2% of subjects were female and 61.8%
were male; in the placebo group, 61.8% of subjects were female and 38.2% were male. All
subjects were Japanese. The mean BMI was 23.45 (SD 3.83) kg/m2 and the majority ofsubjects (85.3%) had not used tobacco in the previous 6 months. Both groups were generally
balanced with regards to subject demographics, with an imbalance in the sex of subjects
across groups.

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Table 5.

Subject Demographics and Smoking Status – Subjects Aged 20 to <65 Years– Safety Population

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Vaccine Group (as Administered)Placebo
SA4Ag
Total
Na=34
Na=34
Na=68
n (%)
n (%)
n (%)
Sex
Female19 (55.9)
15 (44.1)
34 (50.0)Male
15 (44.1)
19 (55.9)
34 (50.0)
Race
Asian
34 (100.0)
34 (100.0)
68 (100.0)
Racial designation
Japanese
34 (100.0)
34 (100.0)
68 (100.0)
Ethnicity
Non-Hispanic/non-Latino
34 (100.0)
34 (100.0)
68 (100.0)
Age at vaccination (years)
Mean (SD)47.3 (12.2)
46.8 (12.1)
47.0 (12.1)
Median
49.5
50.0
49.5
Min, max
21, 6422, 6421, 64
BMI (kg/m2)
Mean (SD)22.35 (3.41)
22.08 (3.54)
22.22 (3.45)
Median
21.76
21.06
21.24
Min, max
17.0, 31.4
16.3, 32.6
16.3, 32.6
Used tobacco in the previous 6 months
Yes
7 (20.6)
8 (23.5)
15 (22.1)
No
27 (79.4)
26 (76.5)
53 (77.9)
Abbreviation: BMI = body mass index.
Note: "Racial designation" may be used to provide additional demographic information about subjects in the"Asian" category for race.
a. The values in this row are used as the denominators for percentages.
Program ID: Study B3451003 t_dm.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_dm_saf_ag1.htm.

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Table 6.

Subject Demographics and Smoking Status – Subjects Aged 65 to <86 Years– Safety Population

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Vaccine Group (as Administered)Placebo
SA4Ag
Total
Na=34
Na=34
Na=68
n (%)
n (%)
n (%)
Sex
Female21 (61.8)
13 (38.2)
34 (50.0)Male
13 (38.2)
21 (61.8)
34 (50.0)
Race
Asian
34 (100.0)
34 (100.0)
68 (100.0)
Racial designation
Japanese
34 (100.0)
34 (100.0)
68 (100.0)
Ethnicity
Non-Hispanic/non-Latino
34 (100.0)
34 (100.0)
68 (100.0)
Age at vaccination (years)
Mean (SD)70.6 (4.2)
70.0 (3.6)
70.3 (3.9)
Median
69.0
69.0
69.0
Min, max
65, 8065, 7865, 80
BMI (kg/m2)
Mean (SD)23.38 (3.63)
23.51 (4.07)
23.45 (3.83)
Median
22.38
22.83
22.56
Min, max
16.8, 32.4
16.8, 41.6
16.8, 41.6
Used tobacco in the previous 6 monthsYes
5 (14.7)
5 (14.7)
10 (14.7)
No
29 (85.3)
29 (85.3)
58 (85.3)
Abbreviations: BMI = body mass index, SD = standard deviation.
Note: "Racial designation" may be used to provide additional demographic information about subjects in the"Asian" category for race.
a. The values in this row are used as the denominators for percentages.
Program ID: Study B3451003 t_dm.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_dm_saf_ag2.htm.

Immunogenicity Results:
Of the 68 subjects randomized in each of the 20- to <65-year and 65- to <86-year age groups,
all subjects (100%) were included in the evaluable and modified intent-to-treat (mITT)
immunogenicity populations. All immunogenicity results are from the evaluable
immunogenicity population. Results from the evaluable and mITT populations were thesame because no subjects were excluded from either the evaluable or mITT analysis
populations.
Primary Immunogenicity Endpoint:
Subjects Achieving Antibody Threshold on Day 29 After Vaccination:
The proportions of subjects achieving defined antibody thresholds to each antigen on Day 29
after vaccination are presented in Table 7 for subjects aged 20 to <65 years in the evaluable
immunogenicity population. At Day 29, in the 20- to <65-year age group, all subjects(100%) in the SA4Ag group and 25.8% of subjects in the placebo group achieved the defined
OPA threshold for CP5. Similarly, 100% of subjects in the SA4Ag group and 17.6% ofTemplate version 1.7

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subjects in the placebo group achieved the defined OPA threshold response for CP8. A totalof 94.1% of subjects in the SA4Ag group achieved the defined threshold for ClfA using the
FBI assay compared with 8.8% of subjects in the placebo group. The majority of subjects(91.2%) in the SA4Ag group achieved the defined threshold for MntC using the cLIA
compared with 2.9% of subjects in the placebo group.
The proportions of subjects achieving defined antibody thresholds to the target antigens on
Day 29 after vaccination are presented in Table 8 for subjects aged 65 to <86 years in theevaluable immunogenicity population. In subjects aged 65 to <86 years, at Day 29 all
subjects (100%) in the SA4Ag group and 15.6% of subjects in the placebo group achieved
the defined threshold for CP5. Similarly, 94.1% of subjects in the SA4Ag group and 20.6%
of subjects in the placebo group achieved the defined threshold response for CP8. The
majority of subjects in the SA4Ag group (88.2%) achieved the defined threshold for ClfA
using the FBI assay compared with 5.9% of subjects in the placebo group. Almost all
subjects (94.1%) in the SA4Ag group achieved the defined threshold for MntC using thecLIA compared with 8.8% of subjects in the placebo group.

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Table 7.

Subjects Achieving Defined Antibody Thresholds to Target Antigens on
Day 29 After Vaccination – Subjects Aged 20 to <65 Years – Evaluable
Immunogenicity Population

Vaccine Group (as Randomized)
Placebo
SA4Ag
Assay Type
Target Antigen
Na nb%(95% CI)c
Na nb%(95% CI)c
OPA
CP5
31 8 25.8(11.9, 44.6) 34 34 100.0(89.7, 100.0)
CP8
34 6 17.6(6.8, 34.5)
34 34 100.0(89.7, 100.0)
FBI
ClfA
34 3
8.8
(1.9, 23.7)
34 32
94.1
(80.3, 99.3)
cLIA
MntC
34 1
2.9
(0.1, 15.3)
34 31
91.2
(76.3, 98.1)
Abbreviations: ClfA = clumping factor A; cLIA = competitive Luminex immunoassay; CP5 = capsularpolysaccharide serotype 5; CP8 = capsular polysaccharide serotype 8; FBI = fibrinogen-binding inhibition;
MntC = manganese transporter C; OPA = opsonophagocytic activity.
Note: The thresholds are 1000 and 2000 based on OPA assay for CP5 and CP8, respectively, 121 based on FBI
assay for ClfA, and 512 (4 times the lower limit of quantitation [LLOQ]) based on cLIA for MntC.
Note: The protocol-specified window for the Day 29 blood sample collection is Days 29 to 35 after vaccination.
a. N = number of subjects with blood drawn on Day 29 who have valid and determinate assay results.
b. n = Number of subjects with antibody response.
c. Exact 2-sided Clopper-Pearson confidence interval based upon the observed proportion of subjects.
Program ID: Study B3451003 t_im_ach_d29.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_ach_d29_eva_ag1.htm.

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Table 8.

Subjects Achieving Defined Antibody Thresholds to Target Antigens on
Day 29 After Vaccination – Subjects Aged 65 to <86 Years – Evaluable
Immunogenicity Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Vaccine Group (as Randomized)
Placebo
SA4Ag
Assay Type
Target Antigen
Na nb%(95% CI)c Na nb%(95% CI)c
OPA
CP5
32 5 15.6(5.3, 32.8)
34 34 100.0(89.7, 100.0)
CP8
34 7 20.6(8.7, 37.9)
34 32
94.1
(80.3, 99.3)
FBI
ClfA
34 2
5.9
(0.7, 19.7)
34 30
88.2
(72.5, 96.7)
cLIA
MntC
34 3
8.8
(1.9, 23.7)
34 32
94.1
(80.3, 99.3)
Abbreviations: ClfA = clumping factor A; cLIA = competitive Luminex immunoassay; CP5 = capsularpolysaccharide serotype 5; CP8 = capsular polysaccharide serotype 8; FBI = fibrinogen-binding inhibition;
MntC = manganese transporter C; OPA = opsonophagocytic activity.
Note: The thresholds are 1000 and 2000 based on OPA assay for CP5 and CP8, respectively, 121 based on FBI
assay for ClfA, and 512 (4 times the lower limit of quantitation [LLOQ]) based on cLIA for MntC.
Note: The protocol-specified window for the Day 29 blood sample collection is Days 29 to 35 after vaccination.
a. N = number of subjects with blood drawn on Day 29 who have valid and determinate assay results.
b. n = Number of subjects with antibody response.
c. Exact 2-sided Clopper-Pearson confidence interval based upon the observed proportion of subjects.
Program ID: Study B3451003 t_im_ach_d29.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_ach_d29_eva_ag2.htm.

Secondary Immunogenicity Endpoints:
The secondary immunogenicity endpoints describe the immune responses from baseline
through Month 3 visit using antibody threshold responses other than the primary endpoint, in
addition to GMT and GMFRs.
Threshold Response to Specific Antigens:
The proportions of subjects achieving defined antibody thresholds to each antigen (evaluable
immunogenicity population) are presented in Table 9 for subjects aged 20 to <65 years. In
subjects aged 20 to <65 years, all subjects (100%) in the SA4Ag group achieved thepredefined OPA thresholds for both antigens (CP5 and CP8) at Day 11, Day 15 and Month 3.
Almost all subjects in the SA4Ag group achieved the predefined FBI assay threshold for
ClfA and the cLIA threshold for MntC at Day 11 (97.1% and 94.1%, respectively) and the
proportion remained high at Day 15 and Month 3 (Table 9). In contrast, the proportion ofsubjects in the placebo group who achieved the predefined thresholds for each antigen did
not differ substantially from baseline.
The proportions of subjects achieving defined antibody thresholds to each antigen (evaluable
immunogenicity population) are presented in Table 10 for subjects aged 65 to <86 years. As
with the younger age group, at Day 11 almost all subjects aged 65 to <86 years in the
SA4Ag group achieved the predefined threshold for CP5 and CP8 (100% and 94.1%,
respectively) and the proportions remained high at Day 15 and Month 3. The majority ofsubjects in the SA4Ag group achieved the predefined FBI assay threshold for ClfA and thecLIA threshold for MntC at Day 11 (82.4% and 97.1%, respectively) and the proportions
remained high at Day 15 and Month 3. In contrast, the proportions of subjects in the placebo

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group who achieved the predefined thresholds for each antigen at each time point did not
differ substantially from baseline.

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Table 9.

Subjects Achieving Defined Antibody Thresholds to Target Antigens at
Each Sampling Time Point – Subjects Aged 20 to <65 Years – Evaluable
Immunogenicity Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Vaccine Group (as Randomized)
Placebo
SA4Ag
Sampling
Nb nc % (95% CI)d Nb nc%(95% CI)dAssay Type Target Antigen
Timea
OPA
CP5
Baseline
34 7 20.6 (8.7, 37.9) 34 8
23.5
(10.7, 41.2)
Day 1134 7 20.6 (8.7, 37.9) 33 33 100.0 (89.4, 100.0)
Day 1533 7 21.2 (9.0, 38.9) 34 34 100.0 (89.7, 100.0)
Day 2931 8 25.8 (11.9, 44.6) 34 34 100.0 (89.7, 100.0)
Month 332 6 18.8 (7.2, 36.4) 34 34 100.0 (89.7, 100.0)
Month 632 6 18.8 (7.2, 36.4) 34 34 100.0 (89.7, 100.0)
Month 1230 2 6.7 (0.8, 22.1) 34 33 97.1
(84.7, 99.9)
CP8
Baseline
33 5 15.2 (5.1, 31.9) 33 11 33.3
(18.0, 51.8)
Day 1133 6 18.2 (7.0, 35.5) 34 34 100.0 (89.7, 100.0)
Day 1532 6 18.8 (7.2, 36.4) 34 34 100.0 (89.7, 100.0)
Day 2934 6 17.6 (6.8, 34.5) 34 34 100.0 (89.7, 100.0)
Month 334 7 20.6 (8.7, 37.9) 34 34 100.0 (89.7, 100.0)
Month 633 5 15.2 (5.1, 31.9) 34 32 94.1
(80.3, 99.3)
Month 1231 5 16.1 (5.5, 33.7) 34 29 85.3
(68.9, 95.0)
FBI
ClfA
Baseline
34 4 11.8 (3.3, 27.5) 34 0
0.0
(0.0, 10.3)
Day 1134 4 11.8 (3.3, 27.5) 34 33 97.1
(84.7, 99.9)
Day 1534 4 11.8 (3.3, 27.5) 34 33 97.1
(84.7, 99.9)
Day 2934 3 8.8 (1.9, 23.7) 34 32 94.1
(80.3, 99.3)
Month 334 1 2.9 (0.1, 15.3) 34 30 88.2
(72.5, 96.7)
Month 633 1 3.0 (0.1, 15.8) 34 26 76.5
(58.8, 89.3)
Month 1232 1 3.1 (0.1, 16.2) 34 21 61.8
(43.6, 77.8)
cLIA
MntC
Baseline
34 1 2.9 (0.1, 15.3) 34 8
23.5
(10.7, 41.2)
Day 11
34 1 2.9 (0.1, 15.3) 34 32 94.1
(80.3, 99.3)
Day 1534 1 2.9 (0.1, 15.3) 34 32 94.1
(80.3, 99.3)
Day 2934 1 2.9 (0.1, 15.3) 34 31 91.2
(76.3, 98.1)
Month 334 1 2.9 (0.1, 15.3) 34 26 76.5
(58.8, 89.3)
Month 633 2 6.1 (0.7, 20.2) 34 25 73.5
(55.6, 87.1)
Month 1232 1 3.1 (0.1, 16.2) 34 17 50.0
(32.4, 67.6)
ClfA
Day 1134 0 0.0 (0.0, 10.3) 34 27 79.4
(62.1, 91.3)
Day 1534 0 0.0 (0.0, 10.3) 34 30 88.2
(72.5, 96.7)
Day 2934 0 0.0 (0.0, 10.3) 34 30 88.2
(72.5, 96.7)
Month 334 0 0.0 (0.0, 10.3) 34 27 79.4
(62.1, 91.3)
Month 633 0 0.0 (0.0, 10.6) 34 23 67.6
(49.5, 82.6)
Month 1232 0 0.0 (0.0, 10.9) 34 19 55.9
(37.9, 72.8)
Abbreviations: ClfA = clumping factor A; cLIA = competitive Luminex immunoassay; CP5 = capsularpolysaccharide serotype 5; CP8 = capsular polysaccharide serotype 8; FBI = fibrinogen-binding inhibition;
MntC = manganese transporter C; OPA = opsonophagocytic activity.
Note: The thresholds are 1000 and 2000 based on OPA assay for CP5 and CP8, respectively, 121 based on FBI
assay for ClfA, 512 (4 times the lower limit of quantitation [LLOQ]) based on cLIA for MntC, and ≥4-fold risefrom baseline based on cLIA for ClfA.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, for Month 3 is Days 84 to 98, for Month 6 is Days 168 to 196, and for Month 12 is Days 345 to
375 after vaccination.
b. N = number of subjects with valid and determinate assay results at the specified visit.
c. n = Number of subjects with antibody response.
d. Exact 2-sided Clopper-Pearson confidence interval based upon the observed proportion of subjects.

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Table 9.

Subjects Achieving Defined Antibody Thresholds to Target Antigens at
Each Sampling Time Point – Subjects Aged 20 to <65 Years – Evaluable
Immunogenicity Population
Vaccine Group (as Randomized)
Placebo
SA4Ag

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)Sampling
Nb nc % (95% CI)d Nb nc%(95% CI)dAssay Type Target Antigen
Timea
Program ID: Study B3451003 t_im_ach_allvis.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 28FEB2017 14:01. File ID: t_im_ach_allvis_eva_ag1.htm.

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Table 10. Subjects Achieving Defined Antibody Thresholds to Target Antigens at
Each Sampling Time Point – Subjects Aged 65 to <86 Years – Evaluable
Immunogenicity Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Vaccine Group (as Randomized)
Placebo
SA4Ag
Sampling
Nb nc % (95% CI)d Nb nc%(95% CI)dAssay Type Target Antigen
Timea
OPA
CP5
Baseline
34 4 11.8 (3.3, 27.5) 34 5
14.7
(5.0, 31.1)
Day 1133 6 18.2 (7.0, 35.5) 34 34 100.0 (89.7, 100.0)
Day 1533 3 9.1 (1.9, 24.3) 34 34 100.0 (89.7, 100.0)
Day 2932 5 15.6 (5.3, 32.8) 34 34 100.0 (89.7, 100.0)
Month 334 7 20.6 (8.7, 37.9) 34 34 100.0 (89.7, 100.0)
Month 633 5 15.2 (5.1, 31.9) 33 33 100.0 (89.4, 100.0)
Month 1230 3 10.0 (2.1, 26.5) 34 33 97.1
(84.7, 99.9)
CP8
Baseline
34 7 20.6 (8.7, 37.9) 34 9
26.5
(12.9, 44.4)
Day 1134 7 20.6 (8.7, 37.9) 34 32 94.1
(80.3, 99.3)
Day 1534 7 20.6 (8.7, 37.9) 34 33 97.1
(84.7, 99.9)
Day 2934 7 20.6 (8.7, 37.9) 34 32 94.1
(80.3, 99.3)
Month 334 5 14.7 (5.0, 31.1) 34 30 88.2
(72.5, 96.7)
Month 633 7 21.2 (9.0, 38.9) 33 24 72.7
(54.5, 86.7)
Month 1232 7 21.9 (9.3, 40.0) 34 24 70.6
(52.5, 84.9)
FBI
ClfA
Baseline
34 1 2.9 (0.1, 15.3) 34 0
0.0
(0.0, 10.3)
Day 11
34 1 2.9 (0.1, 15.3) 34 28 82.4
(65.5, 93.2)
Day 1534 2 5.9 (0.7, 19.7) 34 30 88.2
(72.5, 96.7)
Day 2934 2 5.9 (0.7, 19.7) 34 30 88.2
(72.5, 96.7)
Month 334 1 2.9 (0.1, 15.3) 34 28 82.4
(65.5, 93.2)
Month 633 1 3.0 (0.1, 15.8) 33 24 72.7
(54.5, 86.7)
Month 1232 0 0.0 (0.0, 10.9) 34 16 47.1
(29.8, 64.9)
cLIA
MntC
Baseline
34 3 8.8 (1.9, 23.7) 34 4
11.8
(3.3, 27.5)
Day 11
34 3 8.8 (1.9, 23.7) 34 33 97.1
(84.7, 99.9)
Day 1534 6 17.6 (6.8, 34.5) 34 33 97.1
(84.7, 99.9)
Day 2934 3 8.8 (1.9, 23.7) 34 32 94.1
(80.3, 99.3)
Month 334 5 14.7 (5.0, 31.1) 34 28 82.4
(65.5, 93.2)
Month 633 4 12.1 (3.4, 28.2) 33 25 75.8
(57.7, 88.9)
Month 1232 3 9.4 (2.0, 25.0) 34 19 55.9
(37.9, 72.8)
ClfA
Day 1134 0 0.0 (0.0, 10.3) 34 30 88.2
(72.5, 96.7)
Day 1534 0 0.0 (0.0, 10.3) 34 31 91.2
(76.3, 98.1)
Day 2934 0 0.0 (0.0, 10.3) 34 29 85.3
(68.9, 95.0)
Month 334 0 0.0 (0.0, 10.3) 34 26 76.5
(58.8, 89.3)
Month 633 0 0.0 (0.0, 10.6) 33 23 69.7
(51.3, 84.4)
Month 1232 0 0.0 (0.0, 10.9) 34 19 55.9
(37.9, 72.8)
Abbreviations: ClfA = clumping factor A; cLIA = competitive Luminex immunoassay; CP5 = capsularpolysaccharide serotype 5; CP8 = capsular polysaccharide serotype 8; FBI = fibrinogen-binding inhibition;
MntC = manganese transporter C; OPA = opsonophagocytic activity.
Note: The thresholds are 1000 and 2000 based on OPA assay for CP5 and CP8, respectively, 121 based on FBI
assay for ClfA, 512 (4 times the lower limit of quantitation [LLOQ]) based on cLIA for MntC, and ≥4-fold risefrom baseline based on cLIA for ClfA.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, for Month 3 is Days 84 to 98, for Month 6 is Days 168 to 196, and for Month 12 is Days 345 to
375 after vaccination.
b. N = number of subjects with valid and determinate assay results at the specified visit.
c. n = Number of subjects with antibody response.
d. Exact 2-sided Clopper-Pearson confidence interval based upon the observed proportion of subjects.

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Table 10. Subjects Achieving Defined Antibody Thresholds to Target Antigens at
Each Sampling Time Point – Subjects Aged 65 to <86 Years – Evaluable
Immunogenicity Population
Vaccine Group (as Randomized)
Placebo
SA4Ag
Sampling
Nb nc % (95% CI)d Nb nc%(95% CI)dAssay Type Target Antigen
Timea
Program ID: Study B3451003 t_im_ach_allvis.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 28FEB2017 14:01. File ID: t_im_ach_allvis_eva_ag2.htm.

OPA Titers and GMTs:

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)OPA assay GMTs for CP5 and CP8 in the evaluable immunogenicity population arepresented in Table 11 for subjects aged 20 to <65 years. For subjects aged 20 to <65 years,
high OPA GMTs for CP5 and CP8 were observed in the SA4Ag group at each time pointfrom Day 11 through Month 3. In the placebo group, OPA GMTs remained similar at eachtime point from baseline through Month 3.
OPA assay GMTs for CP5 and CP8 in the evaluable immunogenicity population arepresented in Table 12 for subjects aged 65 to <86 years. Similar patterns were observed in
the 65- to <86-year age group, whereby high OPA GMTs for CP5 and CP8 were observed in
the SA4Ag group at each time point from Day 11 through Month 3. In the placebo group,
OPA GMTs remained similar from baseline through Month 3.

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Table 11. Anti–Staphylococcus aureus Antigen-Specific OPA Assay GMTs – Subjects
Aged 20 to <65 Years – Evaluable Immunogenicity Population
Vaccine Group (as Randomized)
Placebo
SA4Ag
Target Antigen Sampling Timea nb GMTc
(95% CI)dnb
GMTc(95% CI)dCP5
Baseline
34 355.1(227.7, 553.8) 34
301.7(197.4, 461.0)
Day 1134 360.6(231.7, 561.1) 33 37617.8(27863.0, 50787.8)
Day 1533 354.9(236.9, 531.9) 34 26677.0(20149.0, 35319.9)
Day 2931 432.6(275.3, 679.8) 34 25026.5(18911.3, 33119.1)
Month 332 410.0(266.1, 631.8) 34 14679.2(11032.9, 19530.7)
Month 632 400.1(269.7, 593.5) 34
9032.0(6590.8, 12377.5)
Month 1230 274.3(184.8, 407.2) 34
4797.2(3400.8, 6766.9)
CP8
Baseline
33 512.9(338.4, 777.5) 33
702.5(407.8, 1210.1)
Day 1133 567.9(372.3, 866.3) 34 27501.3(19669.7, 38451.2)
Day 1532 514.7(333.8, 793.5) 34 25403.8(18448.2, 34981.9)
Day 2934 544.5(362.0, 819.1) 34 23453.9(16904.7, 32540.3)
Month 334 504.1(327.4, 776.2) 34 11856.2(8663.2, 16226.1)
Month 633 452.9(300.9, 681.6) 34
7508.5(5416.8, 10407.9)
Month 1231 509.5(327.8, 791.8) 34
5600.3(3959.2, 7921.7)
Abbreviations: CP5 = capsular polysaccharide serotype 5; CP8 = capsular polysaccharide serotype 8; GMT =geometric mean titer; OPA = opsonophagocytic activity.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, for Month 3 is Days 84 to 98, for Month 6 is Days 168 to 196, and for Month 12 is Days 345 to
375 after vaccination.
b. n = Number of subjects with valid and determinate OPA assay titers to the given antigen at the specified
visit.
c. GMTs were calculated using all subjects with available data for the specified blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for means of the titers on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmt.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmt_opa_eva_ag1.htm.

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Table 12. Anti–Staphylococcus aureus Antigen-Specific OPA Assay GMTs – Subjects
Aged 65 to <86 Years – Evaluable Immunogenicity Population
Vaccine Group (as Randomized)
Placebo
SA4Ag
Target Antigen Sampling Timea nb GMTc
(95% CI)dnb
GMTc(95% CI)dCP5
Baseline
34 349.0(249.2, 488.9) 34
332.9(223.9, 495.1)
Day 1133 342.0(231.1, 506.2) 34 31066.0(20279.0, 47591.1)
Day 1533 331.3(231.2, 474.9) 34 31706.4(21585.9, 46571.8)
Day 2932 350.1(241.8, 506.9) 34 29639.2(20983.3, 41865.7)
Month 334 339.8(238.9, 483.4) 34 16000.3(11448.0, 22362.8)
Month 633 333.1(234.1, 474.0) 33 10470.1(7202.3, 15220.4)
Month 1230 277.2(189.5, 405.4) 34
5963.8(4281.5, 8307.2)
CP8
Baseline
34
337.3(195.7, 581.3) 34
388.6(222.6, 678.3)
Day 1134 351.2(205.9, 598.9) 34 16214.6(8218.2, 31991.7)
Day 1534 326.6(193.6, 551.1) 34 24039.8(13014.0, 44407.0)
Day 2934 336.4(195.7, 578.3) 34 16542.0(9489.2, 28836.7)
Month 334 308.5(187.1, 508.7) 34
7881.5(4521.6, 13738.1)
Month 633 322.6(193.2, 538.7) 33
4384.9(2461.8, 7810.3)
Month 1232 341.9(198.6, 588.8) 34
3545.5(2076.8, 6052.9)
Abbreviations: CP5 = capsular polysaccharide serotype 5; CP8 = capsular polysaccharide serotype 8;
GMT = geometric mean titer; OPA = opsonophagocytic activity.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, for Month 3 is Days 84 to 98, for Month 6 is Days 168 to 196, and for Month 12 is Days 345 to
375 after vaccination.
b. n = Number of subjects with valid and determinate OPA assay titers to the given antigen at the specified
visit.
c. GMTs were calculated using all subjects with available data for the specified blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for means of the titers on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmt.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmt_opa_eva_ag2.htm.

OPA GMFRs From Baseline Titers:
OPA assay GMFRs are presented for the evaluable immunogenicity population in Table 13
for subjects aged 20 to <65 years. In the 20- to <65-year age group, substantial rises in OPA
GMTs for CP5 and CP8 from baseline to each time point from Day 11 (GMFRs of 125.0 and
38.7, respectively) through Month 3 (GMFRs of 48.7 and 16.2, respectively) were observedin the SA4Ag group. No rises were observed in the placebo group.
OPA assay GMFRs are presented for the evaluable immunogenicity population in Table 14
for subjects aged 65 to <86 years. Similarly, in the 65- to <86-year age group, substantial
rises in OPA GMTs for CP5 and CP8 from baseline to each time point from Day 11 (GMFRs
of 93.3 and 41.7, respectively) through Month 3 (GMFRs of 48.1 and 20.3, respectively)
were observed in the SA4Ag group. No rises were observed in the placebo group.

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Table 13. Anti–Staphylococcus aureus OPA Assay GMFRs From Baseline to Each
Sampling Time Point After Vaccination – Subjects Aged 20 to <65 Years –Evaluable Immunogenicity Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

TargetAntigen
CP5

Vaccine Group(as Randomized)
PlaceboSampling Timeanb
GMFRc(95% CI)d
Day 1134
1.0(0.8, 1.2)
Day 1533
1.0(0.9, 1.2)
Day 2931
1.1(1.0, 1.2)
Month 332
1.1
(1.0, 1.3)
SA4Ag
Day 1133
125.0(78.5, 198.9)
Day 1534
88.4(59.4, 131.6)
Day 2934
83.0(54.2, 126.9)
Month 33448.7
(34.2, 69.2)
CP8
PlaceboDay 1132
1.1(1.0, 1.3)
Day 1531
1.0(0.9, 1.1)
Day 2933
1.1(1.0, 1.2)
Month 333
1.0
(0.9, 1.2)
SA4Ag
Day 1133
38.7(21.0, 71.3)
Day 1533
35.2(19.1, 64.8)
Day 2933
32.2(17.4, 59.5)
Month 333
16.2
(9.6, 27.6)
Abbreviations: CP5 = capsular polysaccharide serotype 5; CP8 = capsular polysaccharide serotype 8;
GMFR = geometric mean fold rise; OPA = opsonophagocytic activity.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, and for Month 3 is Days 84 to 98 after vaccination.
b. n = Number of subjects with determinate OPA assay titers to the given antigen at both the baseline andindicated sampling time blood draws.
c. GMFRs (indicated sampling time/baseline) were calculated using all subjects with available data from boththe baseline and indicated sampling time blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for the mean fold rise on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmfr.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmfr_opa_eva_ag1.htm.

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Table 14. Anti–Staphylococcus aureus OPA Assay GMFRs From Baseline to Each
Sampling Time Point After Vaccination – Subjects Aged 65 to <86 Years –Evaluable Immunogenicity Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

TargetAntigen
CP5

Vaccine Group(as Randomized)
PlaceboSampling Timeanb
GMFRc(95% CI)d
Day 1133
0.9(0.8, 1.0)
Day 1533
0.9(0.8, 1.0)
Day 2932
0.9(0.8, 1.1)
Month 334
1.0
(0.9, 1.1)
SA4Ag
Day 11
34
93.3(56.7, 153.5)
Day 1534
95.2(61.5, 147.5)
Day 2934
89.0(58.6, 135.2)
Month 334
48.1
(32.1, 71.9)
CP8PlaceboDay 1134
1.0(0.9, 1.1)
Day 1534
1.0(0.9, 1.0)
Day 2934
1.0(1.0, 1.0)
Month 334
0.9
(0.8, 1.0)
SA4Ag
Day 1134
41.7(20.6, 84.6)
Day 1534
61.9(30.8, 124.4)
Day 2934
42.6(22.6, 80.4)
Month 334
20.3
(11.5, 35.8)
Abbreviations: CP5 = capsular polysaccharide serotype 5; CP8 = capsular polysaccharide serotype 8;
GMFR = geometric mean fold rise; OPA = opsonophagocytic activity.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, and for Month 3 is Days 84 to 98 after vaccination.
b. n = Number of subjects with determinate OPA assay titers to the given antigen at both the baseline andindicated sampling time blood draws.
c. GMFRs (indicated sampling time/baseline) were calculated using all subjects with available data from boththe baseline and indicated sampling time blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for the mean fold rise on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmfr.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmfr_opa_eva_ag2.htm.

FBI Titers and GMTs:
FBI assay GMTs in the evaluable immunogenicity population are presented in Table 15 forsubjects aged 20 to <65 years. For subjects aged 20 to <65 years, high FBI GMTs for ClfA
were observed in the SA4Ag group at each time point from Day 11 through Month 3. In theplacebo group, FBI GMTs were similar at each time point from baseline through Month 3.
FBI assay GMTs in the evaluable immunogenicity population are presented in Table 16 forsubjects aged 65 to <86 years. In the 65- to <86-year age group, high FBI GMTs wereobserved in the SA4Ag group for ClfA at each time point from Day 11 through Month 3. In
the placebo group, FBI GMTs remained similar at each time point from baseline throughMonth 3.

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Table 15. Anti–Staphylococcus aureus Antigen-Specific FBI Assay GMTs – Subjects
Aged 20 to <65 Years – Evaluable Immunogenicity Population
Vaccine Group (as Randomized)
Placebo
SA4Ag
Target Antigen
Sampling Timea
nb GMTc(95% CI)d nb GMTc
(95% CI)dClfA
Baseline
34
67.2(60.5, 74.7) 34
60.5
NEDay 11
34
68.4(59.7, 78.3) 34 755.5(468.1, 1219.2)
Day 1534
69.9(60.2, 81.2) 34 868.5(544.1, 1386.3)
Day 2934
68.1(59.1, 78.5) 34 748.4(473.0, 1184.4)
Month 334
64.0
(57.1, 71.8) 34 474.5(309.7, 726.9)
Month 633
63.8
(57.3, 71.0) 34 327.4(216.3, 495.8)
Month 1232
63.2
(57.8, 69.2) 34 177.4(123.7, 254.4)
Abbreviations: ClfA = clumping factor A; FBI = fibrinogen-binding inhibition; GMT = geometric mean titer;
NE = not estimable.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, for Month 3 is Days 84 to 98, for Month 6 is Days 168 to 196, and for Month 12 is Days 345 to
375 after vaccination.
b. n = Number of subjects with valid and determinate FBI assay titers to the given antigen at the specified
visit.
c. GMTs were calculated using all subjects with available data for the specified blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for means of the titers on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmt.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmt_fbi_eva_ag1.htm.

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Table 16. Anti–Staphylococcus aureus Antigen-Specific FBI Assay GMTs – Subjects
Aged 65 to <86 Years – Evaluable Immunogenicity Population
Vaccine Group (as Randomized)
Placebo
SA4Ag
Target Antigen
Sampling Timeanb
GMTc(95% CI)d nb
GMTc(95% CI)dClfA
Baseline
34
63.3(57.7, 69.4) 34
60.5
NEDay 11
34
63.3(57.7, 69.4) 34
620.1(367.8, 1045.6)
Day 1534
64.6(58.7, 71.1) 34
706.8(421.2, 1185.9)
Day 2934
65.2(58.6, 72.5) 34
620.7(396.5, 971.8)
Month 334
63.1
(57.9, 68.8) 34
384.8(256.1, 578.3)
Month 633
62.6
(58.4, 67.2) 33
249.1(168.7, 367.8)
Month 12
32
60.5
NE
34
135.6
(96.4, 190.7)
Abbreviations: ClfA = clumping factor A; FBI = fibrinogen-binding inhibition; GMT = geometric mean titer;
NE = not estimable.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, for Month 3 is Days 84 to 98, for Month 6 is Days 168 to 196, and for Month 12 is Days 345 to
375 after vaccination.
b. n = Number of subjects with valid and determinate FBI assay titers to the given antigen at the specified
visit.
c. GMTs were calculated using all subjects with available data for the specified blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for means of the titers on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmt.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmt_fbi_eva_ag2.htm.

FBI GMFRs From Baseline Titers:
FBI assay GMFRs are displayed for the evaluable immunogenicity population in Table 17
for subjects aged 20 to <65 years. In the 20- to <65-year age group, substantial rises in FBI
GMTs for ClfA from baseline to each time point from Day 11 (GMFR of 12.5) throughMonth 3 (GMFR of 7.8) were observed in the SA4Ag group. No rises were observed in theplacebo group.
FBI assay GMFRs are presented for the evaluable immunogenicity population in Table 18
for subjects aged 65 to <86 years. Similarly, in the 65- to <86-year age group, substantial
rises in FBI GMTs for ClfA from baseline to each time point from Day 11 (GMFR of 10.3)
through Month 3 (GMFR of 6.4) were observed in the SA4Ag group. No rises wereobserved in the placebo group.

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Protocol B3451003 – 18 July 2017 – Final

Table 17. Anti–Staphylococcus aureus FBI Assay GMFRs From Baseline to Each
Sampling Time Point After Vaccination – Subjects Aged 20 to <65 Years –Evaluable Immunogenicity Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

TargetAntigen
ClfA

Vaccine Group(as Randomized)
PlaceboSampling Timeanb
GMFRc(95% CI)d
Day 1134
1.0(0.9, 1.1)
Day 1534
1.0(0.9, 1.2)
Day 2934
1.0(0.9, 1.1)
Month 334
1.0
(0.9, 1.0)
SA4Ag
Day 1134
12.5(7.7, 20.2)
Day 1534
14.4(9.0, 22.9)
Day 2934
12.4(7.8, 19.6)
Month 334
7.8
(5.1, 12.0)
Abbreviations: ClfA = clumping factor A; FBI = fibrinogen-binding inhibition; GMFR = geometric mean fold
rise.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, and for Month 3 is Days 84 to 98 after vaccination.
b. n = Number of subjects with determinate FBI assay titers to the given antigen at both the baseline andindicated sampling time blood draws.
c. GMFRs (indicated sampling time/baseline) were calculated using all subjects with available data from boththe baseline and indicated sampling time blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for the mean fold rise on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmfr.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmfr_fbi_eva_ag1.htm.

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Table 18. Anti–Staphylococcus aureus FBI Assay GMFRs From Baseline to Each
Sampling Time Point After Vaccination – Subjects Aged 65 to <86 Years –Evaluable Immunogenicity Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

TargetAntigen
ClfA

Vaccine Group(as Randomized)
PlaceboSampling Timeanb
GMFRc(95% CI)d
Day 1134
1.0
NEDay 1534
1.0(1.0, 1.1)
Day 2934
1.0(1.0, 1.1)
Month 334
1.0
(1.0, 1.0)
SA4Ag
Day 11
34
10.3(6.1, 17.3)
Day 1534
11.7(7.0, 19.6)
Day 2934
10.3(6.6, 16.1)
Month 334
6.4
(4.2, 9.6)
Abbreviations: ClfA = clumping factor A; FBI = fibrinogen-binding inhibition; GMFR = geometric mean foldrise; NE = not estimable.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, and for Month 3 is Days 84 to 98 after vaccination.
b. n = Number of subjects with determinate FBI assay titers to the given antigen at both the baseline andindicated sampling time blood draws.
c. GMFRs (indicated sampling time/baseline) were calculated using all subjects with available data from boththe baseline and indicated sampling time blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for the mean fold rise on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmfr.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmfr_fbi_eva_ag2.htm.

cLIA Titers and GMTs:
cLIA GMTs for ClfA and MntC in the evaluable immunogenicity population are presented inTable 19 for subjects aged 20 to <65. For subjects aged 20 to <65 years, high cLIA GMTs
for ClfA and MntC were observed in the SA4Ag group at each time point from Day 11
through Month 3. In the placebo group, cLIA GMTs remained similar at each time pointfrom baseline through Month 3.
cLIA GMTs for ClfA and MntC in the evaluable immunogenicity population are presented inTable 20 for subjects aged 65 to <86 years. Similar patterns were observed in the 65- to<86-year age group, whereby high cLIA GMTs were observed in the SA4Ag group for ClfA
and MntC at each time point from Day 11 through Month 3. In the placebo group, cLIA
GMTs remained similar at each time point from baseline through Month 3.

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090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Table 19. Anti–Staphylococcus aureus Antigen-Specific cLIA GMTs – Subjects Aged
20 to <65 Years – Evaluable Immunogenicity Population
Vaccine Group (as Randomized)
Placebo
SA4Ag
Target Antigen
Sampling Timea nb GMTc
(95% CI)dnb GMTc(95% CI)dClfA
Baseline
34
200.7(177.6, 226.8) 34
218.1(196.7, 241.7)
Day 1134
190.7(166.1, 218.9) 34 4105.2(2389.4, 7053.0)
Day 1534
198.7(172.2, 229.2) 34 4706.0(2802.7, 7902.1)
Day 2934
198.4(173.7, 226.6) 34 3815.0(2288.8, 6359.0)
Month 334
201.6
(177.3, 229.2) 34 2309.3(1492.9, 3572.3)
Month 633
218.2
(195.1, 244.1) 34 1715.3(1134.7, 2592.8)
Month 1232
158.8
(138.4, 182.2) 34
990.8(670.5, 1464.1)
MntC
Baseline
34349.4(306.8, 398.0) 34
376.8(316.5, 448.5)
Day 11
34358.5(312.2, 411.6) 34 5019.6(3207.2, 7856.2)
Day 1534351.4(312.2, 395.6) 34 4431.7(2896.0, 6781.7)
Day 2934326.9(287.2, 371.9) 34 2920.8(1947.4, 4380.8)
Month 334316.3(275.6, 363.0) 34 1273.5(912.1, 1778.0)
Month 633394.0
(361.5, 429.4) 34
865.0(669.8, 1117.1)
Month 1232
260.6(226.0, 300.5) 34
512.2(390.2, 672.3)
Abbreviations: ClfA = clumping factor A; cLIA = competitive Luminex immunoassay; GMT = geometric mean
titer; MntC = manganese transporter C.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, for Month 3 is Days 84 to 98, for Month 6 is Days 168 to 196, and for Month 12 is Days 345 to
375 after vaccination.
b. n = Number of subjects with valid and determinate cLIA titers to the given antigen at the specified visit.
c. GMTs were calculated using all subjects with available data for the specified blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for means of the titers on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmt.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmt_clia_eva_ag1.htm.

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090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Table 20. Anti–Staphylococcus aureus Antigen-Specific cLIA GMTs – Subjects Aged
65 to <86 Years – Evaluable Immunogenicity Population
Vaccine Group (as Randomized)
Placebo
SA4Ag
Target Antigen
Sampling Timea nb GMTc
(95% CI)dnb GMTc(95% CI)dClfA
Baseline
34
216.6(179.7, 261.0) 34
174.0(150.3, 201.4)
Day 1134
203.7(172.2, 241.0) 34 3394.1(2029.3, 5676.8)
Day 1534231.9(199.1, 270.1) 34 4571.3(2883.1, 7248.1)
Day 2934
182.5(149.4, 223.1) 34 3313.6(2155.0, 5095.3)
Month 334
224.8
(190.8, 264.8) 34 2054.8(1348.3, 3131.6)
Month 633243.7(211.3, 281.1) 33 1418.0(947.2, 2122.8)
Month 1232
168.7
(137.0, 207.7) 34
762.1(509.1, 1140.8)
MntC
Baseline
34
321.4(270.6, 381.7) 34
334.8(291.6, 384.3)
Day 1134313.6(260.9, 377.0) 34 6712.9(4385.4, 10275.6)
Day 1534356.0(297.8, 425.5) 34 5710.0(3816.9, 8541.9)
Day 2934281.4(235.8, 335.7) 34 3471.0(2397.3, 5025.5)
Month 334384.1
(329.9, 447.2) 34 1528.7(1112.2, 2101.1)
Month 633415.0(360.7, 477.5) 33 1043.6(815.8, 1334.9)
Month 1232
255.6
(215.0, 303.9) 34
568.3(425.6, 758.8)
Abbreviations: ClfA = clumping factor A; cLIA = competitive Luminex immunoassay; GMT = geometric mean
titer; MntC = manganese transporter C.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, for Month 3 is Days 84 to 98, for Month 6 is Days 168 to 196, and for Month 12 is Days 345 to
375 after vaccination.
b. n = Number of subjects with valid and determinate cLIA titers to the given antigen at the specified visit.
c. GMTs were calculated using all subjects with available data for the specified blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for means of the titers on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmt.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmt_clia_eva_ag2.htm.

cLIA GMFRs From Baseline Titers:cLIA GMFRs are presented for the evaluable immunogenicity population in Table 21 forsubjects aged 20 to <65 years. In the 20- to <65-year age group, substantial rises in cLIA
GMTs for ClfA and MntC from baseline to each time point from Day 11 (GMFRs of
18.8 and 13.3, respectively) through Month 3 (GMFRs of 10.6 and 3.4, respectively) wereobserved in the SA4Ag group. No rises were observed in the placebo group.
cLIA GMFRs are presented for the evaluable immunogenicity population in Table 22 forsubjects aged 65 to <86 years. In the 65- to <86-year age group, substantial rises in cLIA
GMTs for ClfA and MntC from baseline to each time point from Day 11 (GMFRs of
19.5 and 20.1, respectively) through Month 3 (GMFRs of 11.8 and 4.6, respectively) wereobserved in the SA4Ag group. No rises were observed in the placebo group.

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Protocol B3451003 – 18 July 2017 – Final

Table 21. Anti–Staphylococcus aureus cLIA GMFRs From Baseline to Each Sampling
Time Point After Vaccination – Subjects Aged 20 to <65 Years – Evaluable
Immunogenicity Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

TargetAntigen
ClfA

Vaccine Group(as Randomized)
PlaceboSampling Timeanb
GMFRc(95% CI)d
Day 1134
1.0(0.9, 1.0)
Day 1534
1.0(0.9, 1.1)
Day 2934
1.0(0.9, 1.1)
Month 334
1.0
(0.9, 1.1)
SA4Ag
Day 1134
18.8(11.0, 32.1)
Day 1534
21.6(13.0, 35.7)
Day 2934
17.5(10.7, 28.7)
Month 334
10.6
(7.0, 16.1)
MntC
PlaceboDay 1134
1.0(0.9, 1.1)
Day 1534
1.0(0.9, 1.1)
Day 2934
0.9(0.8, 1.1)
Month 334
0.9
(0.8, 1.0)
SA4Ag
Day 1134
13.3(9.0, 19.8)
Day 1534
11.8(8.1, 17.1)
Day 2934
7.8(5.5, 10.9)
Month 334
3.4
(2.6, 4.4)
Abbreviations: ClfA = clumping factor A; cLIA = competitive Luminex immunoassay; GMFR = geometricmean fold rise; MntC = manganese transporter C.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, and for Month 3 is Days 84 to 98 after vaccination.
b. n = Number of subjects with determinate cLIA titers to the given antigen at both the baseline and indicatedsampling time blood draws.
c. GMFRs (indicated sampling time/baseline) were calculated using all subjects with available data from boththe baseline and indicated sampling time blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for the mean fold rise on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmfr.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmfr_clia_eva_ag1.htm.

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Table 22. Anti–Staphylococcus aureus cLIA GMFRs From Baseline to Each Sampling
Time Point After Vaccination – Subjects Aged 65 to <86 Years – Evaluable
Immunogenicity Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

TargetAntigen
ClfA

Vaccine Group(as Randomized)
PlaceboSampling Timeanb
GMFRc(95% CI)d
Day 1134
0.9(0.9, 1.0)
Day 1534
1.1(1.0, 1.2)
Day 2934
0.8(0.8, 0.9)
Month 334
1.0
(1.0, 1.1)
SA4Ag
Day 1134
19.5(12.0, 31.8)
Day 1534
26.3(17.0, 40.5)
Day 2934
19.0(12.8, 28.4)
Month 334
11.8
(8.0, 17.5)
MntC
PlaceboDay 1134
1.0(0.9, 1.1)
Day 1534
1.1(1.0, 1.3)
Day 2934
0.9(0.8, 1.0)
Month 334
1.2
(1.1, 1.4)
SA4Ag
Day 11
34
20.1(13.2, 30.5)
Day 1534
17.1(11.5, 25.3)
Day 2934
10.4(7.3, 14.7)
Month 334
4.6
(3.4, 6.1)
Abbreviations: ClfA = clumping factor A; cLIA = competitive Luminex immunoassay; GMFR = geometricmean fold rise; MntC = manganese transporter C.
a. Protocol-specified timing for blood sample collection. The baseline blood sample was drawn at Day 1 forall subjects. The blood sample window for Day 11 is Days 10 to 12, for Day 15 is Days 15 to 17, for Day 29 isDays 29 to 35, and for Month 3 is Days 84 to 98 after vaccination.
b. n = Number of subjects with determinate cLIA titers to the given antigen at both the baseline and indicatedsampling time blood draws.
c. GMFRs (indicated sampling time/baseline) were calculated using all subjects with available data from boththe baseline and indicated sampling time blood draws.
d. Confidence intervals are computed by back transforming the CIs generated for the mean fold rise on thelog scale based on the Student t distribution.
Program ID: Study B3451003 t_im_gmfr.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_im_gmfr_clia_eva_ag2.htm.

Safety Results:
Local Reaction:
The incidences and maximum severities of local reactions (defined as pain, swelling, andredness) at the injection site reported by subjects within 14 days after vaccination arepresented in Table 23 for subjects aged 20 to <65 years.
In the 20- to <65-year age group, 1 (2.9%) subject in both the SA4Ag and placebo groups
reported redness, reported as being mild. Seven (7) (20.6%) subjects reported pain at the
injection site in the SA4Ag group and no subjects reported pain at the injection site in theplacebo group. These reactions were mild for all but 1 subject, which was moderate. No
subjects in either the SA4Ag or placebo groups reported any swelling at the injection site.
No severe local reactions were reported by any subjects in this age group.

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Table 23. Summary of Local Reactions and Maximum Severity Within 14 Days –Subjects Aged 20 to <65 Years – Safety Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)dLocal Reaction

Na

Vaccine Group (as Administered)PlaceboSA4Ag
nb (%)(95% CI)cNanb (%)(95% CI)c

RednessAny34
1 (2.9)(0.1, 15.3)
34
1 (2.9)(0.1, 15.3)
Mild34
1 (2.9)(0.1, 15.3)
34
1 (2.9)(0.1, 15.3)
Moderate34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Swellingd
Any34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Mild34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Moderate34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Pain at injection siteeAny34
0 (0.0)(0.0, 10.3)
34
7 (20.6)(8.7, 37.9)
Mild
34
0 (0.0)(0.0, 10.3)
34
6 (17.6)(6.8, 34.5)
Moderate34
0 (0.0)(0.0, 10.3)
34
1 (2.9)(0.1, 15.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Any local reactionf34
1 (2.9)(0.1, 15.3)
34
7 (20.6)(8.7, 37.9)
a. N = number of subjects reporting "yes" or "no" for at least 1 day.
b. n = Number of subjects reporting severity of mild, moderate, or severe based on the severity scales in theinterval.
c. Exact 2-sided Clopper-Pearson confidence interval based upon the observed proportion of subjects.
d. Mild = 2.5 to 5.0 cm, moderate = 5.5 to 10.0 cm, severe = ≥10.5 cm.
e. Mild = does not interfere with activity, moderate = interferes with activity, severe = prevents daily activity.
f. Any local reaction = any redness, any swelling, or any pain at the injection site.
Program ID: Study B3451003 t_lr_max.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_lr_max_ag1.htm.

The incidences and maximum severities of local reactions (defined as pain, swelling, andredness) at the injection site reported by subjects within 14 days after vaccination arepresented in Table 24 for subjects aged 65 to <86 years.
In the 65- to <86-year age group, 5 (14.7%) subjects in the SA4Ag group and 1 (2.9%)
subject in the placebo group reported redness; these were mild to moderate except 1 subject
who reported severe redness in the SA4Ag group which resulted in an unscheduled visit.
Swelling was reported by 3 (8.8%) subjects in the SA4Ag group (moderate in severity) and2 (5.9%) subjects in the placebo group (mild in severity). Pain at the injection site wasreported in 7 (20.6%) subjects in the SA4Ag group and 1 (2.9%) subject in the placebogroup. These reactions were mostly mild.

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Table 24. Summary of Local Reactions and Maximum Severity Within 14 Days –Subjects Aged 65 to <86 Years – Safety Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)dLocal Reaction

Na

Vaccine Group (as Administered)PlaceboSA4Ag
nb (%)(95% CI)cNanb (%)(95% CI)c

RednessAny34
1 (2.9)(0.1, 15.3)
34
5 (14.7)(5.0, 31.1)
Mild
34
1 (2.9)(0.1, 15.3)
34
2 (5.9)(0.7, 19.7)
Moderate34
0 (0.0)(0.0, 10.3)
34
2 (5.9)(0.7, 19.7)
Severe34
0 (0.0)(0.0, 10.3)
34
1 (2.9)(0.1, 15.3)
Swellingd
Any34
2 (5.9)(0.7, 19.7)
34
3 (8.8)(1.9, 23.7)
Mild
34
2 (5.9)(0.7, 19.7)
34
0 (0.0)(0.0, 10.3)
Moderate34
0 (0.0)(0.0, 10.3)
34
3 (8.8)(1.9, 23.7)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Pain at injection siteeAny34
1 (2.9)(0.1, 15.3)
34
7 (20.6)(8.7, 37.9)
Mild
34
1 (2.9)(0.1, 15.3)
34
5 (14.7)(5.0, 31.1)
Moderate34
0 (0.0)(0.0, 10.3)
34
2 (5.9)(0.7, 19.7)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Any local reactionf
34
2 (5.9)(0.7, 19.7)
34
10 (29.4)(15.1, 47.5)
a. N = number of subjects reporting "yes" or "no" for at least 1 day.
b. n = Number of subjects reporting severity of mild, moderate, or severe based on the severity scales in theinterval.
c. Exact 2-sided Clopper-Pearson confidence interval based upon the observed proportion of subjects.
d. Mild = 2.5 to 5.0 cm, moderate = 5.5 to 10.0 cm, severe = ≥10.5 cm.
e. Mild = does not interfere with activity, moderate = interferes with activity, severe = prevents daily activity.
f. Any local reaction = any redness, any swelling, or any pain at the injection site.
Program ID: Study B3451003 t_lr_max.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_lr_max_ag2.htm.

Systemic Events:
The incidences and severities of the systemic events of fever, fatigue, headache, diarrhea,
vomiting, muscle pain, and joint pain within 14 days after vaccination, as recorded by e-diaryfor safety population, are presented for subjects aged 20 to <65 years in Table 25.
For subjects aged 20 to <65 years, 10 (29.4%) subjects reported at least 1 systemic event inboth the SA4Ag and placebo groups. The most commonly reported systemic events were
fatigue and headache (11.8% and 11.8% of subjects, respectively) in the SA4Ag group andfatigue and diarrhea (14.7% and 14.7% of subjects, respectively) in the placebo group. All
systemic events reported by subjects in this age group were mild or moderate in severity.

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Protocol B3451003 – 18 July 2017 – Final

Table 25. Summary of Systemic Events and Maximum Severity Within 14 Days –Subjects Aged 20 to <65 Years – Safety Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Systemic Event

Na

Vaccine Group (as Administered)PlaceboSA4Ag
nb (%)(95% CI)cNanb (%)(95% CI)c

Fever
Any
34
0 (0.0)(0.0, 10.3)
34
2 (5.9)(0.7, 19.7)
37.5°C-38.4°C
34
0 (0.0)(0.0, 10.3)
34
2 (5.9)(0.7, 19.7)
38.5°C-38.9°C
34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
39.0°C-40.0°C
34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)>40.0°C
34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
FatiguedAny34
5 (14.7)(5.0, 31.1)
34
4 (11.8)(3.3, 27.5)
Mild
34
3 (8.8)(1.9, 23.7)
34
3 (8.8)(1.9, 23.7)
Moderate
34
2 (5.9)(0.7, 19.7)
34
1 (2.9)(0.1, 15.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
HeadachedAny34
4 (11.8)(3.3, 27.5)
34
4 (11.8)(3.3, 27.5)
Mild
34
2 (5.9)(0.7, 19.7)
34
4 (11.8)(3.3, 27.5)
Moderate
34
2 (5.9)(0.7, 19.7)
34
0 (0.0)(0.0, 10.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Vomitinge
Any34
1 (2.9)(0.1, 15.3)
34
0 (0.0)(0.0, 10.3)
Mild34
1 (2.9)(0.1, 15.3)
34
0 (0.0)(0.0, 10.3)
Moderate34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
DiarrheafAny34
5 (14.7)(5.0, 31.1)
34
2 (5.9)(0.7, 19.7)
Mild34
5 (14.7)(5.0, 31.1)
34
2 (5.9)(0.7, 19.7)
Moderate34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Muscle paind
Any34
0 (0.0)(0.0, 10.3)
34
1 (2.9)(0.1, 15.3)
Mild34
0 (0.0)(0.0, 10.3)
34
1 (2.9)(0.1, 15.3)
Moderate34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Joint paind
Any34
0 (0.0)(0.0, 10.3)
34
1 (2.9)(0.1, 15.3)
Mild34
0 (0.0)(0.0, 10.3)
34
1 (2.9)(0.1, 15.3)
Moderate34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Any systemic eventg
34
10 (29.4)(15.1, 47.5)
34
10 (29.4)(15.1, 47.5)
Abbreviation: IV = intravenous.
a. N = number of subjects reporting ''yes'' or ''no'' for at least 1 day.
b. n = Number of subjects reporting severity of mild, moderate, or severe based on the severity scales in theinterval.
c. Exact 2-sided Clopper-Pearson confidence interval based upon the observed proportion of subjects.
d. Mild: does not interfere with activity; moderate: some interference with activity; severe: significant,prevents daily routine activity.
e. Mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; severe: requires IV hydration.
f. Mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; severe: 6 or more stools in
24 hours.
g. Any systemic event = any fever ≥37.5°C, any fatigue, any headache, any vomiting, any diarrhea, anymuscle pain, and any joint pain.

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Protocol B3451003 – 18 July 2017 – Final

Table 25. Summary of Systemic Events and Maximum Severity Within 14 Days –Subjects Aged 20 to <65 Years – Safety Population
Vaccine Group (as Administered)Placebo
SA4Ag
Systemic EventNanb (%)(95% CI)cNanb (%)(95% CI)c
Program ID: Study B3451003 t_se_max.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_se_max_ag1.htm.

The incidences and severities of the systemic events of fever, fatigue, headache, diarrhea,
vomiting, muscle pain, and joint pain within 14 days after vaccination, as recorded by e-diaryfor safety population, are presented for subjects aged 65 to <86 years in Table 26.

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

For subjects aged 65 to <86 years, 12 (35.3%) subjects in the SA4Ag group and 6 (17.6%)
subjects in the placebo group reported at least 1 systemic event. In both the SA4Ag andplacebo groups, fatigue (17.6% and 5.9% of subjects, respectively) and muscle pain
(14.7% and 8.8% of subjects, respectively) were the most commonly reported systemic
events. All systemic events reported by subjects in this age group were mild or moderate inseverity.

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Protocol B3451003 – 18 July 2017 – Final

Table 26. Summary of Systemic Events and Maximum Severity Within 14 Days –Subjects Aged 65 to <86 Years – Safety Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Systemic Event

Na

Vaccine Group (as Administered)PlaceboSA4Ag
nb (%)(95% CI)cNanb (%)(95% CI)c

Fever
Any
34
1 (2.9)(0.1, 15.3)
34
2 (5.9)(0.7, 19.7)
37.5°C-38.4°C
34
1 (2.9)(0.1, 15.3)
34
2 (5.9)(0.7, 19.7)
38.5°C-38.9°C
34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
39.0°C-40.0°C
34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)>40.0°C
34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
FatiguedAny34
2 (5.9)(0.7, 19.7)
34
6 (17.6)(6.8, 34.5)
Mild
34
2 (5.9)(0.7, 19.7)
34
4 (11.8)(3.3, 27.5)
Moderate34
0 (0.0)(0.0, 10.3)
34
2 (5.9)(0.7, 19.7)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
HeadachedAny34
1 (2.9)(0.1, 15.3)
34
3 (8.8)(1.9, 23.7)
Mild34
1 (2.9)(0.1, 15.3)
34
2 (5.9)(0.7, 19.7)
Moderate34
0 (0.0)(0.0, 10.3)
34
1 (2.9)(0.1, 15.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Vomitinge
Any34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Mild34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Moderate34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Diarrheaf
Any34
0 (0.0)(0.0, 10.3)
34
2 (5.9)(0.7, 19.7)
Mild34
0 (0.0)(0.0, 10.3)
34
2 (5.9)(0.7, 19.7)
Moderate34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Muscle paind
Any34
3 (8.8)(1.9, 23.7)
34
5 (14.7)(5.0, 31.1)
Mild
34
3 (8.8)(1.9, 23.7)
34
3 (8.8)(1.9, 23.7)
Moderate34
0 (0.0)(0.0, 10.3)
34
2 (5.9)(0.7, 19.7)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Joint paind
Any34
0 (0.0)(0.0, 10.3)
34
3 (8.8)(1.9, 23.7)
Mild34
0 (0.0)(0.0, 10.3)
34
2 (5.9)(0.7, 19.7)
Moderate34
0 (0.0)(0.0, 10.3)
34
1 (2.9)(0.1, 15.3)
Severe34
0 (0.0)(0.0, 10.3)
34
0 (0.0)(0.0, 10.3)
Any systemic eventg34
6 (17.6)(6.8, 34.5)
34
12 (35.3)(19.7, 53.5)
Abbreviation: IV = intravenous.
a. N = number of subjects reporting ''yes'' or ''no'' for at least 1 day.
b. n = Number of subjects reporting severity of mild, moderate, or severe based on the severity scales in theinterval.
c. Exact 2-sided Clopper-Pearson confidence interval based upon the observed proportion of subjects.
d. Mild: does not interfere with activity; moderate: some interference with activity; severe: significant,prevents daily routine activity.
e. Mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; severe: requires IV hydration.
f. Mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; severe: 6 or more stools in
24 hours.
g. Any systemic event = any fever ≥37.5°C, any fatigue, any headache, any vomiting, any diarrhea, anymuscle pain, and any joint pain.

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Protocol B3451003 – 18 July 2017 – Final

Table 26. Summary of Systemic Events and Maximum Severity Within 14 Days –Subjects Aged 65 to <86 Years – Safety Population
Vaccine Group (as Administered)Placebo
SA4Ag
Systemic EventNanb (%)(95% CI)cNanb (%)(95% CI)c
Program ID: Study B3451003 t_se_max.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_se_max_ag2.htm.

Adverse Events:
Summary of Adverse Events From Day 1 to the Day 29 Visit:
All AEs (serious and non serious, including newly diagnosed chronic medical disorders)were collected from the time that the subject provides informed consent to Day 29 visit.

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

A summary of AEs from Day 1 to the Day 29 visit (safety population) is presented in Table
27 for subjects aged 20 to <65 years.
For subjects aged 20 to <65 years, the proportions of subjects reporting AEs from Day 1 to
Day 29 visit were similar in the SA4Ag and placebo groups (2.9% and 5.9%, respectively).
Three (3) subjects reported AEs: 1 in the SA4Ag group and 2 in the placebo group. None of
the events were considered to be related to investigational product. No SAEs, severe AEs,
life-threatening AEs, immediate AEs, AEs leading to withdrawal or deaths were reported byany subjects in this age group.

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Table 27. Number (%) of Subjects With Adverse Events – Subjects Aged 20 to<65 Years – Day 1 to the Day 29 Visit – Safety Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Vaccine Group (asAdministered)Placebo
SA4Ag
Na=34
Na=34
b
c
b
n
%
n
%c
2
5.9
1
2.9
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0

Category of Adverse Events
RelationshipAdverse events
RelatedSerious adverse events
RelatedSevere adverse events
RelatedLife-threatening adverse events
RelatedImmediate adverse events
Adverse events leading to withdrawal
RelatedDeathsRelateda. The values in this row are used as the denominators for percentages.
b. Number of subjects reporting at least 1 event of the type specified.
c. Percentage of subjects reporting at least 1 event of the type specified.
Program ID: Study B3451003 t_ae_num.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_ae_num_d29_ag1.htm.

A summary of AEs from Day 1 to the Day 29 visit (safety population) is presented Table 28
for subjects aged 65 to <86 years.
For subjects aged 65 to <86 years, the proportions of subjects reporting AEs from Day 1 after
vaccination to Day 29 were 5.9% in both the SA4Ag and placebo groups. Four (4) subjects
reported AEs: 2 in the SA4Ag group and 2 in the placebo group. One (1) event in each group
was considered to be related to investigational product. No SAEs, severe AEs,
life-threatening AEs, immediate AEs, AEs leading to withdrawal or deaths were reported byany subjects in this age group.

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Table 28. Number (%) of Subjects With Adverse Events – Subjects Aged 65 to<86 Years – Day 1 to the Day 29 Visit – Safety Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Vaccine Group (asAdministered)Placebo
SA4Ag
Na=34
Na=34
b
c
b
n
%
n
%c
2
5.9
2
5.9
1
2.9
1
2.9
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0

Category of Adverse Events
RelationshipAdverse events
RelatedSerious adverse events
RelatedSevere adverse events
RelatedLife-threatening adverse events
RelatedImmediate adverse events
Adverse events leading to withdrawal
RelatedDeathsRelateda. The values in this row are used as the denominators for percentages.
b. Number of subjects reporting at least 1 event of the type specified.
c. Percentage of subjects reporting at least 1 event of the type specified.
Program ID: Study B3451003 t_ae_num.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_ae_num_d29_ag2.htm.

Summary of Adverse Events After the Day 29 Visit to the Month 12 Visit:
After the Day 29 visit to the Month 12 visit, only newly diagnosed chronic medical disorders
and SAEs were collected.
A summary of AEs from Day 29 to the Month 12 visit is presented in Table 29 for subjects
aged 20 to <65 years.
For subjects aged 20 to <65 years, no subjects reported AEs in any category after the Day 29
to Month 12 visit in the SA4Ag group. In the placebo group, 1 subject reported an SAE
which was determined to be severe, and led to withdrawal. No subjects reported AEs
considered to be related to the investigational product in this time period. No deaths orlife-threatening AEs were reported through Month 12 in either group.

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Protocol B3451003 – 18 July 2017 – Final

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Table 29. Number (%) of Subjects With Adverse Events – Subjects Aged 20 to<65 Years – After the Day 29 Visit to the Month 12 Visit – Safety Population
Vaccine Group (asAdministered)Placebo
SA4Ag
Category of Adverse Events
Na=34
Na=34
b
c
b
Relationshipn%n%cAdverse events
1
2.9
0
0.0
Related00.0
00.0
Serious adverse events
1
2.9
0
0.0
Related00.0
00.0
Severe adverse events
1
2.9
0
0.0
Related00.0
00.0Life-threatening adverse events
0
0.0
0
0.0
Related00.0
00.0
Adverse events leading to withdrawal
1
2.9
0
0.0
Related00.0
00.0
Deaths00.0
0
0.0
Related00.0
00.0
Note: After the Day 29 visit, only newly diagnosed chronic medical disorders and serious adverse events werecollected.
a. The values in this row are used as the denominators for percentages.
b. Number of subjects reporting at least 1 event of the type specified.
c. Percentage of subjects reporting at least 1 event of the type specified.
Program ID: Study B3451003 t_ae_num.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_ae_num_m12_ag1.htm.

A summary of AEs from Day 29 visit to the Month 12 visit is presented in Table 30 for
subjects aged 65 to <86 years.
For subjects aged 65 to <86 years, 4 subjects in the SA4Ag group and 2 subjects in theplacebo group reported AEs after the Day 29 to Month 12 visit. Among these, SAEs werereported by 3 subjects and severe AEs were reported by 2 subjects in the SA4Ag group. In
the placebo group, SAEs were reported by 2 subjects and 1 subject reported a severe AE
which resulted in study withdrawal. No subjects reported AEs considered to be related to theinvestigational product in this time period. No deaths or life-threatening AEs were reported
through Month 12.

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090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Table 30. Number (%) of Subjects With Adverse Events – Subjects Aged 65 to<86 Years – After the Day 29 Visit to the Month 12 Visit – Safety Population
Vaccine Group (asAdministered)Placebo
SA4Ag
Category of Adverse Events
Na=34
Na=34
b
c
b
Relationshipn%n%cAdverse events
2
5.9
4
11.8
Related00.0
00.0
Serious adverse events
2
5.9
3
8.8
Related00.0
00.0
Severe adverse events
1
2.9
2
5.9
Related00.0
00.0Life-threatening adverse events
0
0.0
0
0.0
Related00.0
00.0
Adverse events leading to withdrawal
1
2.9
0
0.0
Related00.0
00.0
Deaths00.0
0
0.0
Related00.0
00.0
Note: After the Day 29 visit, only newly diagnosed chronic medical disorders and serious adverse events werecollected.
a. The values in this row are used as the denominators for percentages.
b. Number of subjects reporting at least 1 event of the type specified.
c. Percentage of subjects reporting at least 1 event of the type specified.
Program ID: Study B3451003 t_ae_num.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_ae_num_m12_ag2.htm.

Non Serious AEs Throughout the Study:
Treatment-emergent non serious AEs reported in subjects by MedDRA system organ class(SOC) and preferred term throughout the study for subjects aged 20 to <65 years are
summarized in Table 31.
The most frequently reported non serious AEs (>5% of subjects) were events that werecollected by systematic assessment in the e-diary. For subjects aged 20 to <65 years, theseincluded pain at the injection site, fatigue, headache, diarrhea and fever (20.6%, 11.8%,
11.8%, 5.9% and 5.9% of subjects, respectively) in the SA4Ag group, and diarrhea, fatigue
and headache (14.7%, 14.7% and 11.8% of subjects, respectively) in the placebo group.

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Table 31. Treatment-Emergent Non Serious Adverse Events by System Organ Classand Preferred Term (All Causalities) – Subjects Aged 20 to <65 Years –Safety Population

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Vaccine Group (as Administered)Placebo
SA4Ag
11/34(32.4)
13/34(38.2)

Total # participants affected/at risk
Gastrointestinal disorders
Diarrhoea (Diarrhea)†2# participants affected /at risk
5/34(14.7)
2/34(5.9)
Vomiting†2# participants affected /at risk
1/34(2.9)0/34(0.0)
General disorders and administration site conditions
Fatigue†2# participants affected /at risk
5/34(14.7)
4/34(11.8)
Injection site erythema (Redness)†1# participants affected /at risk
1/34(2.9)
1/34(2.9)
Injection site pain (Pain at the injection site)†1# participants affected /at risk
0/34(0.0)
7/34(20.6)
Pyrexia (Fever >=37.5°C)†2# participants affected /at risk
0/34(0.0)
2/34(5.9)
Infections and infestations
Nasopharyngitis*# participants affected /at risk
1/34(2.9)0/34(0.0)
Upper respiratory tract infection*# participants affected /at risk
0/34(0.0)
1/34(2.9)
Musculoskeletal and connective tissue disorders
Arthralgia (Joint pain)†2# participants affected /at risk
0/34(0.0)
1/34(2.9)
Myalgia (Muscle pain)†2# participants affected /at risk
0/34(0.0)
1/34(2.9)
Nervous system disorders
Headache†2# participants affected /at risk
4/34(11.8)
4/34(11.8)
Migraine*# participants affected /at risk
1/34(2.9)0/34(0.0)
Note: Preferred Terms from vocabulary, MedDRA 19.0
*Events collected by non-systematic assessment†Events collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0 (Term from vocabulary, Local Reactions if different from MedDRA)
2
Term from vocabulary, MedDRA 19.0 (Term from vocabulary, Systemic Events if different from MedDRA)
Program ID: Study B3451003 t_ae_sum_br.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 18APR2017 10:06. File ID: t_ae_sum_br_nonser_ag1.htm.

Treatment-emergent non serious AEs reported in subjects by MedDRA SOC and preferredterm throughout the study for subjects aged 65 to <86 years are summarized in Table 32.
The most frequently reported non serious AEs (>5% of subjects) were events that werecollected by systematic assessment in the e-diary. For subjects aged 65 to <86 years, theseincluded pain at the injection site, fatigue, muscle pain, injection site swelling, joint pain,
headache, diarrhea and fever (20.6%, 17.6%, 14.7%, 8.8%, 8.8%, 8.8%, 5.9% and 5.9% ofTemplate version 1.7

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subjects, respectively) in the SA4Ag group, and muscle pain, fatigue and injection site
swelling (8.8%, 5.9% and 5.9% of subjects, respectively) in the placebo group.
Table 32. Treatment-Emergent Non Serious Adverse Events by System Organ Classand Preferred Term (All Causalities) – Subjects Aged 65 to <86 Years –Safety Population
Vaccine Group (as Administered)PlaceboSA4Ag
8/34(23.5)
17/34(50.0)

Total # participants affected/at risk

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Gastrointestinal disorders
Diarrhoea (Diarrhea)†2# participants affected /at risk
0/34(0.0)
2/34(5.9)
General disorders and administration site conditions
Fatigue†2# participants affected /at risk
2/34(5.9)
6/34(17.6)
Injection site erythema (Redness)†1# participants affected /at risk
1/34(2.9)
5/34(14.7)
Injection site pain (Pain at the injection site)†1# participants affected /at risk
1/34(2.9)
7/34(20.6)
Injection site pain*# participants affected /at risk
0/34(0.0)
1/34(2.9)
Injection site swelling (Swelling)†1# participants affected /at risk
2/34(5.9)
3/34(8.8)
Pyrexia (Fever >=37.5°C)†2# participants affected /at risk
1/34(2.9)
2/34(5.9)
Infections and infestations
Bronchitis*# participants affected /at risk
1/34(2.9)0/34(0.0)
Cystitis*# participants affected /at risk
0/34(0.0)
1/34(2.9)
Musculoskeletal and connective tissue disorders
Arthralgia (Joint pain)†2# participants affected /at risk
0/34(0.0)
3/34(8.8)
Myalgia (Muscle pain)†2# participants affected /at risk
3/34(8.8)
5/34(14.7)
Nervous system disorders
Headache†2# participants affected /at risk
1/34(2.9)
3/34(8.8)
Headache*# participants affected /at risk
1/34(2.9)0/34(0.0)
Renal and urinary disorders
Hypertonic bladder*# participants affected /at risk
0/34(0.0)
1/34(2.9)
Reproductive system and breast disorders
Benign prostatic hyperplasia*# participants affected /at risk
0/34(0.0)
1/34(2.9)
Note: Preferred Terms from vocabulary, MedDRA 19.0
*Events collected by non-systematic assessment†Events collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0 (Term from vocabulary, Local Reactions if different from MedDRA)
2
Term from vocabulary, MedDRA 19.0 (Term from vocabulary, Systemic Events if different from MedDRA)
Program ID: Study B3451003 t_ae_sum_br.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 18APR2017 10:06. File ID: t_ae_sum_br_nonser_ag2.htm.

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Deaths, SAEs and AEs That Led to Withdrawal:
No subjects died during the study.
No SAEs were reported by subjects in either age group from Day 1 through the Day 29 visit(Table 27; Table 28).
A summary of SAEs reported after the Day 29 visit to the Month 12 visit (safety population)
for subjects aged 20 to <65 years is presented in Table 33.
For subjects aged 20 to <65 years, no SAEs were reported by subjects in the SA4Ag group.
One (1) SAE (bladder cancer) was reported by 1 subject in the placebo group and wasconsidered by the investigator to be unrelated to investigational product.

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Table 33. Summary of Serious Adverse Events – Subjects Aged 20 to <65 Years –After the Day 29 Visit to the Month 12 Visit – Safety Population

System Organ Classb
Preferred TermbAny eventf

Vaccine Group (as Administered)Placebo
SA4Ag
Na=34
Na=34
No. ofNo. ofNo. ofNo. of
Subjectsc %d Eventse Subjectsc %d Eventse
1
2.9
1
0
0.0
0

Neoplasms benign, malignant and unspecified (incl
1
2.9
1
0
0.0
0
cysts and polyps)
Bladder cancer
1
2.9
1
0
0.0
0
Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities.
Note: After the Day 29 visit, only newly diagnosed chronic medical disorders and serious adverse events werecollected.
a. The values in this row are used as the denominators for percentages.
b. Adverse events are as specified in the database. The MedDRA (v19.0) coding dictionary was applied.
c. Number of subjects reporting at least 1 event of the type specified.
d. Percentage of subjects reporting at least 1 event of the type specified.
e. The total number of events of the type specified.
f. "Any event" represents the number of subjects reporting at least 1 event of any kind.
Program ID: Study B3451003 t_ae_sum.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_ae_sum_ser_m12_ag1.htm.

A summary of SAEs reported after the Day 29 visit to the Month 12 visit (safety population)
for subjects aged 65 to <86 years is presented in Table 34.
For subjects aged 65 to <86 years, in the SA4Ag group 7 SAEs were reported by 3 subjects.
Four (4) SAEs were reported by 2 subjects in the placebo group. None of the events wereconsidered by the investigator to be related to the investigational product.

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Table 34. Summary of Serious Adverse Events – Subjects Aged 65 to <86 Years –After the Day 29 Visit to the Month 12 Visit – Safety Population
Vaccine Group (as Administered)Placebo
SA4Ag
Na=34
Na=34
No. ofNo. ofNo. ofNo. of
Subjectsc %d Eventse Subjectsc %d Eventse
2
5.9
4
3
8.8
7

System Organ Classb
Preferred TermbAny eventf
Eye disorders
Cataract
Hyalosis asteroid
Macular fibrosis

0
0
0
0

0.0
0.0
0.0
0.0

0
0
0
0

1
1
1
1

2.9
2.9
2.9
2.9

3
1
1
1

Injury, poisoning and procedural complications
Contusion
Rib fracture

1
1
1

2.9
2.9
2.9

2
1
1

0
0
0

0.0
0.0
0.0

0
0
0

1

2.9

1

0

0.0

0

1

2.9

1

0

0.0

0

Nervous system disorders
Carotid artery aneurysm
Cerebral infarction
Intracranial aneurysm

0
0
0
0

0.0
0.0
0.0
0.0

0
0
0
0

1
1
1
1

2.9
2.9
2.9
2.9

3
1
1
1

Reproductive system and breast disorders
Prostatitis

0
0

0.0
0.0

0
0

1
1

2.9
2.9

1
1

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Neoplasms benign, malignant and unspecified (inclcysts and polyps)
Breast cancer

Respiratory, thoracic and mediastinal disorders
1
2.9
1
0
0.0
0
Vocal cord disorder
1
2.9
1
0
0.0
0
Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities.
Note: After the Day 29 visit, only newly diagnosed chronic medical disorders and serious adverse events werecollected.
a. The values in this row are used as the denominators for percentages.
b. Adverse events are as specified in the database. The MedDRA (v19.0) coding dictionary was applied.
c. Number of subjects reporting at least 1 event of the type specified.
d. Percentage of subjects reporting at least 1 event of the type specified.
e. The total number of events of the type specified.
f. "Any event" represents the number of subjects reporting at least 1 event of any kind.
Program ID: Study B3451003 t_ae_sum.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_ae_sum_ser_m12_ag2.htm.

No subjects in either age group were withdrawn from the study due to AEs from Day 1 to the
Day 29 visit. One (1) subject aged 20 to <65 years in the placebo group withdrew from thestudy to focus on treatment for the SAE of bladder cancer. The event was determined by theinvestigator to be unrelated to the investigational product. One (1) subject aged 65 to<86 years in the placebo group withdrew from the study to focus on treatment for the SAE ofbreast cancer. The event was determined by the investigator to be unrelated to theinvestigational product.

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Clinical Laboratory Evaluation (Phase 1 Subjects Only):
Clinical laboratory evaluations were performed only in Phase 1 subjects. Data were
evaluated for a total of 24 subjects (12 subjects aged 20 to <65 years, and 12 subjects aged
65 to <86 years) at baseline, Day 5, and Day 15. For subjects aged 20 to <65 years and 65 to<86 years, a summary of normal/abnormal laboratory results are presented for hematology inTable 35 and Table 36, respectively, for coagulation in Table 37 and Table 38, respectively,
and for blood chemistry in Table 39 and Table 40, respectively.

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Results of clinical laboratory evaluations did not suggest any impact of SA4Ag on
hematology parameters, coagulation profile, and blood chemistry. Of the abnormal values
reported, all were minor shifts from baseline and determined as not clinically significant by
the investigator. No AEs associated with abnormal laboratory values were reported.

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Table 35. Summary of Normal/Abnormal Laboratory Results by Visit: Hematology –Phase 1 Subjects Aged 20 to <65 Years – Safety Population

Parameter (Units)
HEMOGLOBIN (g/dL)

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

WHITE BLOOD CELLS (109/L)

NEUTROPHILS (ABSOLUTE) (109/L)c

PLATELETS (109/L)

Visit
Baseline

Grade
Nb
NormalVaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)
66
6 (100.0)
6 (100.0)

Day 5

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)65 (83.3)
1 (16.7)

Day 15

Nb
NormalAbnormal6
5 (83.3)
1 (16.7)

6
3 (50.0)
3 (50.0)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)65 (83.3)
1 (16.7)

Day 15

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)6
4 (66.7)
2 (33.3)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)6
4 (66.7)
2 (33.3)

Day 15

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)6
4 (66.7)
2 (33.3)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Note: Baseline is the measurement at screening (or from repeat testing if the value at screening was abnormal).
Laboratory abnormalities were assessed relative to the grading scales derived from the Food and Drug
Administration (FDA) guidelines on toxicity grading scales for healthy adult volunteers enrolled in preventive
vaccine clinical trials, where present, and relative to local laboratory reference ranges otherwise.
a. n = Number of subjects in the specified category.
b. N = number of subjects with a measurement at the specified visit. The value is used as the denominators

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Table 35. Summary of Normal/Abnormal Laboratory Results by Visit: Hematology –Phase 1 Subjects Aged 20 to <65 Years – Safety Population
Vaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Parameter (Units)
Visit
Grade
for percentages.
c. Individual data of absolute neutrophil count are truncated to 2 decimal places after calculation by whiteblood cell count*neutrophils (%), and displayed in listings. The truncated data will be used to summarize
results.
Program ID: Study B3451003 t_lb_abn.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_lb_abn_hem_ag1.htm.

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Table 36. Summary of Normal/Abnormal Laboratory Results by Visit: Hematology –Phase 1 Subjects Aged 65 to <86 Years – Safety Population

Parameter (Units)
HEMOGLOBIN (g/dL)

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

WHITE BLOOD CELLS (109/L)

NEUTROPHILS (ABSOLUTE) (109/L)c

PLATELETS (109/L)

Visit
Baseline

Grade
Nb
NormalVaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)
66
6 (100.0)
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)65 (83.3)
1 (16.7)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)65 (83.3)
1 (16.7)

Day 15

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)65 (83.3)
1 (16.7)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Note: Baseline is the measurement at screening (or from repeat testing if the value at screening was abnormal).
Laboratory abnormalities were assessed relative to the grading scales derived from the Food and Drug
Administration (FDA) guidelines on toxicity grading scales for healthy adult volunteers enrolled in preventive
vaccine clinical trials, where present, and relative to local laboratory reference ranges otherwise.
a. n = Number of subjects in the specified category.
b. N = number of subjects with a measurement at the specified visit. The value is used as the denominators
for percentages.
c. Individual data of absolute neutrophil count are truncated to 2 decimal places after calculation by whiteblood cell count*neutrophils (%), and displayed in listings. The truncated data will be used to summarize

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Table 36. Summary of Normal/Abnormal Laboratory Results by Visit: Hematology –Phase 1 Subjects Aged 65 to <86 Years – Safety Population
Vaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Parameter (Units)
Visit
Grade
results.
Program ID: Study B3451003 t_lb_abn.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_lb_abn_hem_ag2.htm.

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Table 37. Summary of Normal/Abnormal Laboratory Results by Visit: Coagulation –Phase 1 Subjects Aged 20 to <65 Years – Safety Population

Parameter (Units)
PROTHROMBIN TIME (sec)090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

PROTHROMBIN TIME INR (No Unit)

ACTIVATED PARTIAL THROMBOPLASTIN TIME
(sec)

PLATELET AGGREGATION WITH ADP (%)

PLATELET AGGREGATION WITH ARACHIDONIC
ACID (%)

PLATELET AGGREGATION WITH COLLAGEN (%)

Visit
Baseline

Grade
Nb
NormalVaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)
66
6 (100.0)
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

BaselineNb

6

6

Normal6 (100.0)

6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

BaselineNb

6

6

Normal6 (100.0)

6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

BaselineNb

66

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Table 37. Summary of Normal/Abnormal Laboratory Results by Visit: Coagulation –Phase 1 Subjects Aged 20 to <65 Years – Safety Population

Parameter (Units)

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)FIBRINOGEN ACTIVITY (mg/dL)

Visit

Grade
NormalVaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)
6 (100.0)
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Abbreviations: ADP = adenosine diphosphate; INR = international normalized ratio.
Note: Baseline is the measurement at screening (or from repeat testing if the value at screening was abnormal).
Laboratory abnormalities were assessed relative to the grading scales derived from the Food and Drug
Administration (FDA) guidelines on toxicity grading scales for healthy adult volunteers enrolled in preventive
vaccine clinical trials, where present, and relative to local laboratory reference ranges otherwise.
a. n = Number of subjects in the specified category.
b. N = number of subjects with a measurement at the specified visit. The value is used as the denominators
for percentages.
Program ID: Study B3451003 t_lb_abn.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_lb_abn_coa_ag1.htm.

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Table 38. Summary of Normal/Abnormal Laboratory Results by Visit: Coagulation –Phase 1 Subjects Aged 65 to <86 Years – Safety Population

Parameter (Units)
PROTHROMBIN TIME (sec)090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

PROTHROMBIN TIME INR (No Unit)

Visit
Baseline

Grade
Nb
NormalVaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)
66
6 (100.0)
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

66

Normal6 (100.0)

6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

66

NormalAbnormal

6 (100.0)
0 (0.0)5 (83.3)
1 (16.7)

Day 5

Nb
NormalAbnormal6
4 (66.7)
2 (33.3)

6
6 (100.0)
0 (0.0)Day 15

Nb
Normal66 (100.0)

65 (83.3)

ACTIVATED PARTIAL THROMBOPLASTIN TIME
Baseline(sec)

PLATELET AGGREGATION WITH ADP (%)

PLATELET AGGREGATION WITH ARACHIDONIC
Baseline
ACID (%)

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Nb

Nb

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Protocol B3451003 – 18 July 2017 – Final

Table 38. Summary of Normal/Abnormal Laboratory Results by Visit: Coagulation –Phase 1 Subjects Aged 65 to <86 Years – Safety Population

Parameter (Units)

Grade
AbnormalVaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)
0 (0.0)1 (16.7)

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)65 (83.3)
1 (16.7)

Day 5

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)65 (83.3)
1 (16.7)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Visit

PLATELET AGGREGATION WITH COLLAGEN (%) Baseline

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)FIBRINOGEN ACTIVITY (mg/dL)

Abbreviations: ADP = adenosine diphosphate; INR = international normalized ratio.
Note: Baseline is the measurement at screening (or from repeat testing if the value at screening was abnormal).
Laboratory abnormalities were assessed relative to the grading scales derived from the Food and Drug
Administration (FDA) guidelines on toxicity grading scales for healthy adult volunteers enrolled in preventive
vaccine clinical trials, where present, and relative to local laboratory reference ranges otherwise.
a. n = Number of subjects in the specified category.
b. N = number of subjects with a measurement at the specified visit. The value is used as the denominators
for percentages.
Program ID: Study B3451003 t_lb_abn.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_lb_abn_coa_ag2.htm.

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Protocol B3451003 – 18 July 2017 – Final

Table 39. Summary of Normal/Abnormal Laboratory Results by Visit: Blood
Chemistry – Phase 1 Subjects Aged 20 to <65 Years – Safety Population

Visit
Baseline

Grade
Nb
NormalVaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)
66
6 (100.0)
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

ASPARTATE AMINOTRANSFERASE (AST) (U/L) Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)65 (83.3)
1 (16.7)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
Normal65 (83.3)

6
6 (100.0)

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Parameter (Units)
ALANINE AMINOTRANSFERASE (ALT) (U/L)

ALKALINE PHOSPHATASE (U/L)

BILIRUBIN (TOTAL) (mg/dL)

CREATININE (mg/dL)

LACTATE DEHYDROGENASE (U/L)

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Protocol B3451003 – 18 July 2017 – Final

Table 39. Summary of Normal/Abnormal Laboratory Results by Visit: Blood
Chemistry – Phase 1 Subjects Aged 20 to <65 Years – Safety Population

Parameter (Units)

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

CREATINE KINASE (U/L)

Visit

Grade
AbnormalVaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)
1 (16.7)
0 (0.0)

Day 5

Nb
NormalAbnormal6
5 (83.3)
1 (16.7)

65 (83.3)
1 (16.7)

Day 15

Nb
NormalAbnormal6
5 (83.3)
1 (16.7)

6
6 (100.0)
0 (0.0)Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)6
4 (66.7)
2 (33.3)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Note: Baseline is the measurement at screening (or from repeat testing if the value at screening was abnormal).
Laboratory abnormalities were assessed relative to the grading scales derived from the Food and Drug
Administration (FDA) guidelines on toxicity grading scales for healthy adult volunteers enrolled in preventive
vaccine clinical trials, where present, and relative to local laboratory reference ranges otherwise.
a. n = Number of subjects in the specified category.
b. N = number of subjects with a measurement at the specified visit. The value is used as the denominators
for percentages.
Program ID: Study B3451003 t_lb_abn.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_lb_abn_bche_ag1.htm.

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Protocol B3451003 – 18 July 2017 – Final

Table 40. Summary of Normal/Abnormal Laboratory Results by Visit: Blood
Chemistry – Phase 1 Subjects Aged 65 to <86 Years – Safety Population

Visit
Baseline

Grade
Nb
NormalVaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)
66
6 (100.0)
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

ASPARTATE AMINOTRANSFERASE (AST) (U/L) Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)65 (83.3)
1 (16.7)

Day 15

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)65 (83.3)
1 (16.7)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
NormalAbnormal6
5 (83.3)
1 (16.7)

6
6 (100.0)
0 (0.0)Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
Normal66 (100.0)

6
6 (100.0)

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Parameter (Units)
ALANINE AMINOTRANSFERASE (ALT) (U/L)

ALKALINE PHOSPHATASE (U/L)

BILIRUBIN (TOTAL) (mg/dL)

CREATININE (mg/dL)

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Protocol B3451003 – 18 July 2017 – Final

Table 40. Summary of Normal/Abnormal Laboratory Results by Visit: Blood
Chemistry – Phase 1 Subjects Aged 65 to <86 Years – Safety Population

Parameter (Units)
LACTATE DEHYDROGENASE (U/L)

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

CREATINE KINASE (U/L)

Visit
Baseline

Grade
Nb
NormalVaccine Group (asAdministered)PlaceboSA4Ag
na (%)
na (%)
66
6 (100.0)
6 (100.0)

Day 5

Nb
NormalAbnormal6
6 (100.0)
0 (0.0)65 (83.3)
1 (16.7)

Day 15

Nb
NormalAbnormal6
5 (83.3)
1 (16.7)

65 (83.3)
1 (16.7)

Baseline

Nb
Normal66 (100.0)

6
6 (100.0)

Day 5

Nb
Normal66 (100.0)

6
6 (100.0)

Day 15

Nb
NormalAbnormal6
5 (83.3)
1 (16.7)

6
6 (100.0)
0 (0.0)Note: Baseline is the measurement at screening (or from repeat testing if the value at screening was abnormal).
Laboratory abnormalities were assessed relative to the grading scales derived from the Food and Drug
Administration (FDA) guidelines on toxicity grading scales for healthy adult volunteers enrolled in preventive
vaccine clinical trials, where present, and relative to local laboratory reference ranges otherwise.
a. n = Number of subjects in the specified category.
b. N = number of subjects with a measurement at the specified visit. The value is used as the denominators
for percentages.
Program ID: Study B3451003 t_lb_abn.sas. Date of Data Extraction: 10FEB2017. Runtime
ID: 27FEB2017 15:21. File ID: t_lb_abn_bche_ag2.htm.

CONCLUSIONS:
The results of this study confirm that the final selected dose level of SA4Ag elicits rapid androbust CP5, CP8, ClfA, and MntC immune responses in healthy Japanese adults aged
20 to <65 years and 65 to <86 years.
In the SA4Ag group, almost all subjects aged 20 to <65 years (>91%) and 65 to <86 years(>88%) achieved the defined antibody thresholds for each antigen on Day 29 after
vaccination. Peak titers were generally observed at Days 11 and 15. The majority ofsubjects (>82%) in the SA4Ag group achieved the thresholds for each antigen for both age
groups by Day 11, and the proportions remained high through Month 3. In contrast, theproportions of subjects in the placebo group who achieved the predefined thresholds for eachantigen did not differ substantially from baseline at any blood sampling time point.

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In both age groups, substantial increases in GMTs were observed at each time point fromDay 11 through Month 3 for each antigen measured using functional OPA assays for CP5
and CP8, FBI assay for ClfA, and cLIA for MntC and ClfA in the SA4Ag group. At Day 29,
OPA GMFRs for CP5 and CP8 were >80 and >32, respectively, and FBI GMFRs for ClfA
were >10, demonstrating robust functional immune responses compared with baseline ineach age group. cLIA GMFRs for ClfA and MntC were >17 and >7 in SA4Ag recipients, ineach age group.
Local reactions reported within the first 14 days after vaccination were more common in the
SA4Ag group for both age groups, and were mostly mild in severity. Systemic events were
all mild or moderate in severity and there were no clear differences in the incidences andseverities of systemic events among SA4Ag and placebo recipients.

090177e18c5c2c5b\Approved\Approved On: 20-Jul-2017 05:31 (GMT)

Overall, few AEs were reported in this study and there were no notable differences infrequencies between the SA4Ag group and the placebo group for both age groups. FromDay 1 to Day 29, no SAEs or AEs leading to withdrawal were reported across the age groups.
From Day 29 to the Month 12 visit, no SAEs or AEs were considered by the investigator tobe related to the investigational product. No subjects died during the study and there were nolife-threatening events reported for both age groups in this study.
Results of clinical laboratory evaluations did not suggest any impact of SA4Ag on
hematology parameters, coagulation profile, and blood chemistry.
Overall, SA4Ag was well-tolerated with an acceptable safety profile in healthy Japanese
adults. The results support continued development of SA4Ag for the prevention of invasive
S aureus disease in Japanese adults.

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