Final Clinical Study Report
Protocol B9371039

CLINICAL STUDY REPORT SYNOPSISSYNOPSIS
Report Title: Final Report: A Phase 3, Single-Arm, Open-Label Study to Evaluate theImmunogenicity, Safety, and Tolerability of a Tick-Borne Encephalitis Vaccine in Healthy
Japanese Participants 1 Year of Age and Older
Study Number: B9371039
Regulatory Agency or Public Disclosure Identifier Number:
NCT04648241/jRCT2031200302
Study Phase: Phase 3
Name of Study Intervention: PF-06830414
Name of Sponsor/Company: Pfizer Inc.
CSR Version and Report Date: 1.0/ 20 January 2023
Number of Study Center(s) and Investigator(s): This study was conducted at 6 sites inJapan.
A list of study centers and investigators involved in this study is provided inAppendix 16.1.4.1.
Publications:NoneStudy Period:
This report covers the full study period from 18 January 2021 (first participant first visit)
through 21 February 2022 (last participant last visit).
This study was neither discontinued nor interrupted.
Rationale:
Tick-borne encephalitis (TBE) vaccine 0.5 and 0.25 mL are inactivated vaccines that areapproved for prevention of TBE in multiple European and other countries and are indevelopment in Japan for the prevention of TBE.
The purpose of the study was to evaluate the immunogenicity, safety, and tolerability of TBE
vaccine in healthy Japanese participants 1 year of age and older. Many clinical studies inadults and children have been conducted in the European Union, which have confirmed thesafety and immunogenicity of this vaccine in both adults and pediatric non-Japanese
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populations. The field effectiveness of this vaccine has also been demonstrated in endemic
countries where the vaccine has been approved.
The first TBE case in Japan was reported in Hokkaido in 1993. As of the end ofFebruary 2019, 4 additional cases have been reported in Hokkaido. Underdiagnosis is apossibility as there are no commercially available diagnostic enzyme-linked immunosorbent
assay (ELISA) kits for TBE currently available in Japan and patients with central nervous
system (CNS) symptoms in Japan are not routinely tested for TBE infection. Epizootiologicalsurveys report that the virus is circulating in nature in Japan.
As described above, there have recently been cases of TBE reported in Japan. In addition,
there is a medical need for immunization based on the World Health Organization (WHO)recommendation that travelers visiting various endemic areas be immunized if their visits
will include extensive outdoor activities. However, there is no TBE vaccine currentlyapproved in Japan. To address this situation, the Japanese Society of Travel and Health has
submitted to the Ministry of Health, Labour and Welfare (MHLW) a recommendation that adevelopment request for TBE vaccine be submitted in Japan, and the MHLW issued thisdevelopment request to Pfizer Japan Inc on 19 September 2019.
Objectives, Endpoints, and Statistical Methods:
Table S1. Study Objectives, Estimands, and Endpoints
Objectives
Estimands
Primary Immunogenicity
 To evaluate the In healthy Japanese adult participants
immunogenicity of
16 years of age and older who received
TBE vaccine 0.5 mL
3-dose TBE vaccine 0.5 mL inby NT.
compliance with the key protocol criteria(evaluable participants): The proportion
who are seropositive (achieving NT titer To evaluate the≥1:10) 4 weeks after the third dose.
immunogenicity ofTBE vaccine
0.25 mL by NT.
 In healthy Japanese pediatricparticipants ≥1 to <16 years of age who
received 3-dose TBE vaccine 0.25 mL incompliance with the key protocol criteria(evaluable participants): The proportion
who are seropositive (achieving NT titer≥1:10) 4 weeks after the third dose.
Primary Safety
 To evaluate thesafety profile of TBE
vaccine 0.5 mL.

In healthy Japanese participants from eachage group receiving at least 1 dose ofinvestigational product:
The percentage of participants reporting
local reactions within 7 days after eachvaccination.
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TBEV-neutralizing antibodytiters.



Prespecified localreactions (redness,swelling, and pain at theinjection site).



Prespecified systemic
events (fever, decreased

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Table S1. Study Objectives, Estimands, and Endpoints
Objectives

To evaluate thesafety profile of TBE
vaccine 0.25 mL.

Estimands
 The percentage of participants reporting
systemic events within 7 days after eachvaccination.
The percentage of participants reportingAEs within 1 month after each dose.

The percentage of participants reporting
SAEs during the study period.

Secondary Immunogenicity
In healthy Japanese adult participants To describe the16 years of age and older who received
immunogenicity ofTBE vaccine 0.5 mL 3-dose TBE vaccine 0.5 mL in compliancewith the key protocol criteria (evaluableby NT.
participants):

To describe theimmunogenicity ofTBE vaccine
0.25 mL by NT.

The proportion who are seropositive(achieving NT titer ≥1:10) 4 weeks afterthe second dose.

NT GMTs 4 weeks after the second and4 weeks after the third dose.

NT GMFRs 4 weeks after the second
and 4 weeks after the third dose ascompared to baseline.

NT GMFR 4 weeks after the third doseas compared to 4 weeks after the seconddose.

In healthy Japanese pediatric participants 1
through 15 years of age who received 3-dose
TBE vaccine 0.25 mL in compliance with thekey protocol criteria (evaluable participants):The proportion who are seropositive(achieving NT titer ≥1:10) 4 weeks after
the second dose.

NT GMTs 4 weeks after the second and4 weeks after the third dose.
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Endpoints
appetite, drowsiness,and irritability forparticipants 1 to≤2 years of age; fever,fatigue, headache,vomiting, diarrhea,
muscle pain, and joint
pain for participants>2 years of age).
AEs within 1 monthafter vaccination.

SAEs throughout thestudy.

TBEV-neutralizing antibodytiters.

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Protocol B9371039

CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives, Estimands, and Endpoints
Objectives

Estimands
 NT GMFRs 4 weeks after the second
and 4 weeks after the third dose ascompared to baseline.

NT GMFR 4 weeks after the third doseas compared to 4 weeks after the second
dose.

PPD

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Table S1. Study Objectives, Estimands, and Endpoints
Objectives

EstimandsEndpoints

Abbreviations: AE = adverse event;
GMFR = geometric meanfold rise; GMT = geometric mean titer;; NT = neutralization test; SAE = serious adverse event; TBE = tick-borne encephalitis;
TBEV = tick-borne encephalitis virus.
Source: Appendix 16.1.1, Protocol Section 3

Methodology:
This Phase 3, multicenter, single-arm, open-label study was conducted at investigator sites inJapan. This study was part of the Phase 3 clinical development plan to support use of TBE
vaccine 0.5 and 0.25 mL in healthy Japanese adults (≥16 years of age) and the pediatricpopulation (≥1 and <16 years of age). The purpose of this study was to provide key safety
and immunogenicity data in Japanese participants.
Estimations for the immunogenicity and safety objects, estimands, and endpoints for thisstudy are presented in Table S1.
The primary immunogenicity objective of the study was to assess the immunogenicity of theinvestigational product by neutralization test (NT) in samples collected from Japanese
healthy adults and children when administered as a 3-dose schedule. The null hypothesis
tested concerns the seropositivity rate for the primary endpoint in each age group. The
immune response induced by TBE vaccine was evaluated in each age group, testing thehypotheses H0: seropositivity rate ≤90% vs H1 seropositivity rate >90%. These hypotheses
were tested separately for each age group and no adjustment of multiplicity was considered.
For each age group, if the lower bound of the 95% confidence interval (CI) on the NT
seropositivity rate among the evaluable population was >90%, the objective was achieved.
The primary safety objective was evaluated for each vaccine group by descriptive summary
statistics for reactogenicity events (local reactions and systemic events collected through anelectronic diary [e-diary]), adverse events (AEs), and serious adverse events (SAEs).
The secondary

endpoints were analyzed by descriptive summary statistics.

Number of Participants (planned and analyzed):
Approximately 100 adult (≥16 years of age at the time of consent) and 65 pediatricparticipants (≥1 to <16 years of age at the time of consent) were planned and exactly
100 adult and 65 pediatric participants were enrolled in the study.

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Of the 100 adult participants and 65 pediatric participants enrolled in the study, 99 (99%)
adult participants and 65 (100%) pediatric participants completed the study. One adultparticipant completed the blood draw after Dose 2 but was lost to follow-up prior to theblood draw before Dose 3.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Key eligibility criteria for participants in this study are briefly summarized below.
Inclusion criteria: male or female, healthy Japanese participants ≥16 years of age forGroup 1 (adults) or ≥1 to <16 years of age for Group 2 (pediatric) at time of consent(Visit 1).

Exclusion criteria: medical or psychiatric conditions that may have increased the risk ofstudy participation or, in the investigator’s judgment, made the participant inappropriate
for the study (including immunocompromised individuals with known or suspected
immunodeficiency); known prior history of flavivirus infection, receipt of certain
prior/concomitant therapies, which included immunosuppressive therapy and prior TBEvaccine.

Study Interventions, Dose, Mode of Administration, and Batch Number(s):TBE vaccine was supplied as a suspension for injection in a pre-filled syringe. Participantsreceived 1 dose of TBE vaccine at each vaccination visit (Visits 1, 2, and 4) in accordancewith the protocol schedule of activities.
In participants ≥16 years of age, TBE vaccine 2.4 µg/0.5 mL was administeredintramuscularly by injecting into the deltoid muscle of the right or left arm. In participants<16 years of age, TBE vaccine 1.2 µg/0.25 mL was administered intramuscularly by
injecting into the deltoid muscle of the right or left arm. For children ≤18 months of age,
TBE vaccine 1.2 µg/0.25 mL was administered intramuscularly by injecting into theanterolateral thigh muscle of the leg.
Investigational product lot numbers are provided in Table S2.
Table S2. Investigational Product Lot Numbers – Final
Investigational Product

Manufacturer

TBE vaccine (FSME-IMMUN)
0.25 mL

Pfizer

0.5 mL

Vendor Lot Number(Manufacturer)

Lot Numbera(Pfizer)

CY4872
DT732920-004443
21-AE-00088

CW4626
DP289020-004444
21-AE-00169

Abbreviation: TBE = tick-borne encephalitis.
a. Lot number assigned to the investigational product by Pfizer Global Clinical Supply.
Protocol B9371039 Investigational Product Lot Numbers Table – Final, Final, Version 1.0, 21Apr2022.
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Duration of Study Intervention:
Study duration was approximately between 7 to 15 months for each participant.
Summary of Results:
Demographic and Other Baseline Characteristics:
Demographic characteristics in the adult group were broadly similar with a balanced numberof male and female participants. Pediatric participants were predominantly male (70.8%). All
participants were non-Hispanic/non-Latino (100%) and Asian (100%). Adult participants age
ranged from 16 through 75 years (mean age 44.3 years) while the pediatric population age
ranged from 1 through 15 years (mean age 6.9 years).
Demographic characteristics of the immunogenicity population were similar to the safety
population.
Exposure:
Of the 100 adult participants, 99 received 3 doses and 1 participant received 2 doses of TBE
vaccine. All 65 pediatric participants received all 3 doses of TBE vaccine.
Immunogenicity Results:
The primary immunogenicity objective was achieved for both adult and pediatric participants
4 weeks after Dose 3 of TBE vaccine with 98.0% (95% CI: 92.9, 99.8) of adult participants
and 100.0% (95% CI: 94.5, 100.0) of pediatric participants achieving tick-borne encephalitis
virus (TBEV) neutralization seropositivity. Both age groups met the protocol-defined criteriaof the lower bound of the 95% CI on the NT seropositivity rate being >90% for the evaluable
immunogenicity population.
The reverse cumulative distribution curves (RCDCs) of TBEV neutralization titers increased
4 weeks after Dose 2 then decreased before Dose 3 and increased again 4 weeks after Dose 3.
TBEV NT geometric mean titers (GMTs) followed the same pattern as the TBEV
neutralization titers with all participants starting BLQ before Dose 1, increasing 4 weeks after
Dose 2, decreasing before Dose 3, and reaching maximum values 4 weeks after Dose 3.
TBEV NT geometric mean fold rise (GMFRs) were higher for pediatric participants (93.2[95% CI: 75.2, 115.6]) than adult participants (32.0 [95% CI: 26.0, 39.4]). The age groups
were similar after Dose 2 but a greater increased response was observed for pediatricparticipants after Dose 3. Both adult and pediatric participants had higher TBEV NT GMFRs
from 4 weeks after Dose 2 to 4 weeks after Dose 3.

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Safety Results:
Reactogenicity (local reactions and systemic events) were typically mild to moderate andshort-lived. AEs were mild to moderate with only 1 reported severe AE (colitis ischaemic[adult]) and no reported life-threatening AEs. None of the AEs were considered related to theInvestigational product by the investigator.
In the adult population, 2.0% to 6.1% of participants reported any AE within 1 month of eachdose. AEs were most frequently reported in the system organ class (SOC) of infections andinfestations (range of 1.0% to 4.0%).
In the pediatric population, 10.8% to 29.2% of participants reported any AE within 1 monthof each dose. AEs within 1 month of each dose were most frequently reported in the SOC ofinfections and infestations (range of 7.7% to 18.5%). AEs reported after any dose and before
the 1-month blood draw after any dose were most frequently reported in the SOC ofinfections and infestations and were more frequently reported in the younger age groups(50.0% for 1-2 years of age and 53.6% for 3 6 years of age) than the older age group (6.9%for 7-15 years of age).
No immediate AEs were reported. No AEs leading to discontinuation were reported and nodeaths were reported.
SAEs were reported for 2 adult participants (abdominal pain and colitis ischaemic) and 1
pediatric participant (diarrhea)..
Overall, the safety results showed no new safety issues and were consistent with the known
safety and tolerability profile of TBE vaccine.
Conclusions:
The 3-dose series of TBE vaccine was observed to elicit a robust immune response by TBEV
neutralization in Japanese adult and pediatric participants. There was a ≥98% TBEV
neutralization seropositivity rate demonstrated in both adult and pediatric populations
4 weeks after Dose 3.
The safety and tolerability of TBE vaccine in Japanese adult and pediatric participants was
acceptable and consistent with the known profile of TBE vaccine.
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