SAFETY AND IMMUNOGENICITY STUDY OF VLA15, A MULTIVALENT RECOMBINANT OSPA BASED VACCINE CANDIDATE AGAINST LYME BORRELIOSIS: A RANDOMIZED, CONTROLLED, OBSERVER-BLIND PHASE 2 STUDY IN A HEALTHY PEDIATRIC AND ADULT STUDY POPULATION
Phase: PHASE2
Conditions: Lyme Borreliosis
Sponsor: Pfizer

VLA15 
Clinical Study Protocol VLA15-221 Final 11.0 
31-Jan-2024 
IND number: 
 
 
Valneva Austria GmbH                              
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Phase 2 Study 
Study Protocol VLA15-221 
IND number: 
 
 
Responsible Clinical 
Operations Manager 
 
 
 
phone 
 
e-mail  
 
address Campus Vienna Biocenter 3 
1030 Vienna, Austria  
 
 
Sponsor’s 
Collaboration Partner  
Valneva Austria GmbH 
 
  
 
  
 
e-mail  info@valneva.com 
address Campus Vienna Biocenter 3 
               1030 Vienna, Austria 
 
 
 
 
 
 
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CLINICAL STUDY PROTOCOL 
DRUG SUBSTANCE(S) 
VLA15
VERSION NO. 
Final 11.0
STUDY CODE 
VLA15-221
DATE 
31-Jan-2024
 SAFETY AND IMMUNOGENICITY STUDY OF VLA15, A MULTIVALENT RECOMBINANT 
OSPA BASED VACCINE CANDIDATE AGAINST LYME BORRELIOSIS: A RANDOMIZED,
CONTROLLED, OBSERVER-BLIND PHASE 2 STUDY IN A HEALTHY PEDIATRIC AND 
ADULT STUDY POPULATION 

VLA15 
Clinical Study Protocol VLA15-221 Final 11.0 
31-Jan-2024 
IND number: 
 
 
Valneva Austria GmbH                              
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INVESTIGATIONAL PRODUCT, dosage and mode of administration 
VLA15 is a multivalent Outer surface protein A (OspA) based vaccine candidate designed for the 
prevention of Lyme borreliosis. The vaccine targets the majority of Borrelia strains expressing 
clinically relevant OspA serotypes (STs) present in the U.S. (ST1) and Europe (ST1 to ST6). The 
vaccine includes three proteins, each containing the C-terminal half of two OspA serotypes linked 
to form three fusion proteins of ~35 kDa (ST1 and ST2, ST4 and ST3, and ST5 and ST6). VLA15 
is used in a formulation that contains aluminum hydroxide adjuvant.  
In this study, VLA15 is given at a dose of 180 µg total protein (i.e., 60 µg per fusion protein). This 
is the dose chosen for Phase 3 and licensure.  The dose selection for this study has been made 
based on safety and immunogenicity data from two previous Phase 2 studies (VLA15-201 and 
VLA15-202).  
A new VLA15 presentation is used in the VLA15-221 study. This presentation contains the same 
amounts of VLA15 (180 µg) and alum (0.5 mg) in a concentrated form (i.e., formulated in 0.5 mL 
instead of 1.0 mL of buffer). Hence, the antigen-alum ratio stays the same with the same 
concentration of buffer excipients.  
All injections will be administered intramuscularly (I.M.).  
COMPARATOR PRODUCT, dosage and mode of administration 
Placebo: Phosphate Buffered Saline (PBS) solution, 0.5 mL 
All injections will be administered intramuscularly (I.M.).  
STUDY OBJECTIVES 
Primary objectives: 
Safety:  
• 
To assess the safety and tolerability profile of VLA15, given in a three- or two dose primary 
immunization schedule (Month 0-2-6 or Month 0-6), in a healthy study population aged 5 
to 65 years up to Day 208 (Month 7). 
Immunogenicity:  
• 
To assess the immune response to VLA15, given in a three- or two dose primary 
immunization schedule (Month 0-2-6 or Month 0-6), in a healthy study population aged 5 
to 65 years at Day 208 (Month 7). 
 
CLINICAL STUDY PROTOCOL 
SYNOPSIS 
DRUG SUBSTANCE(S) 
VLA15
VERSION NO. 
Final 11.0
STUDY CODE 
VLA15-221
DATE 
31-Jan-2024
SAFETY AND IMMUNOGENICITY STUDY OF VLA15, A MULTIVALENT RECOMBINANT 
OSPA BASED VACCINE CANDIDATE AGAINST LYME BORRELIOSIS: A RANDOMIZED,
CONTROLLED, OBSERVER-BLIND PHASE 2 STUDY IN A HEALTHY PEDIATRIC AND
ADULT STUDY POPULATION 

VLA15 
Clinical Study Protocol VLA15-221 Final 11.0 
31-Jan-2024 
IND number: 
 
 
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Secondary objectives: 
Safety:  
• 
To assess the safety and tolerability profile of VLA15, given in a three- or two dose primary 
immunization schedule (Month 0-2-6 or Month 0-6), in a healthy study population aged 5 
to 65 years, up to one year after the last primary vaccination (Month 18).  
• 
To assess the safety and tolerability profile of VLA15 booster vaccinations (i.e., Booster 1 
at Month 18, one year after completion of the primary vaccination schedule, Booster 2 at 
Month 30 and Booster 3 at Month 42) until study end.  
Immunogenicity:  
• 
To assess the immune response to VLA15, applied in a three- or two dose primary 
immunization schedule (Month 0-2-6 or Month 0-6), in a healthy study population aged 5 
to 65 years, up to one year after the last primary vaccination (Month 18).  
• 
To assess the immune response of VLA15 booster vaccinations (i.e., Booster 1 at Month 
18, one year after completion of the primary vaccination schedule, Booster 2 at Month 30 
and Booster 3 at Month 42) until study end.  
 
Exploratory objective: 
• 
 
  
 
 

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STUDY DESCRIPTION 
VLA15-221 is a randomized, observer-blind (subject, sponsor and investigator/ site staff involved 
in clinical evaluation of subjects are blinded), placebo controlled, multicenter Phase 2 study in 
healthy subjects aged 5 to 65 years. The study is being conducted in two study parts (Part A: 
Main Study Phase, Part B: Booster Phase). VLA15-221 was initiated with an age de-escalation 
of sentinel cohorts. Subject enrollment into Part A started with the adult cohort to allow the 
generation and review of appropriate safety data before pediatric cohorts were initiated.  
 
Subject Enrollment into Part A (Main Study Phase):  
Enrollment was performed in an age-descending, staggered manner for the three age cohorts 
(see Figure 1). 
 
Figure 1 Subject enrollment process in Part A (Main Study Phase) 
 
Enrollment Cohort 1 (18-65 years): 
The enrollment started with 30 sentinel adult subjects aged 18-65 years (Cohort 1). Subjects were 
randomized 1:1:1 into one of three study groups to receive a vaccination of VLA15 (Groups 1 and 
2) or placebo (Group 3). After these 30 sentinel subjects had received the first vaccination and 
had completed a 7-day post vaccination safety follow up visit (Visit 1A) including review of 7-day 
eDiary data, safety data was reviewed in an unblinded manner by an independent Internal Review 
Committee (IRC). The IRC was composed of qualified personnel from Valneva’s collaboration 
partner Pfizer. Based on this data, the IRC made a recommendation on whether enrollment of the 
adolescent age cohort (12-17 years, Cohort 2) could be initiated. Enrollment of the remaining 270 
adult subjects of Cohort 1 continued without limitations during the IRC review.   
 

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Enrollment Cohort 2 (12-17 years): 
Upon IRC clearance, 30 sentinel adolescent subjects aged 12-17 years (Cohort 2) were enrolled. 
Subjects were randomized 1:1:1 into one of the three study groups to receive a vaccination of 
VLA15 (Groups 1 and 2) or placebo (Group 3).  Again, after these subjects had completed their 
safety follow up visit 7 days after the first vaccination (Visit 1A) including review of 7-day eDiary 
data, safety data was reviewed by the IRC. The IRC recommended whether enrollment of the 
youngest age cohort (5-11 years of age) could be initiated. In this age cohort, enrollment of the 
remaining 120 adolescent subjects was only initiated after IRC clearance.  
 
Enrollment Cohort 3 (5-11 years): 
Upon IRC clearance, 30 sentinel subjects aged 5-11 years (Cohort 3) were enrolled. Subjects 
were randomized 1:1:1 into one of the three study groups to receive a vaccination of VLA15 
(Groups 1 and 2) or placebo (Group 3). Again, after these 30 subjects had completed their safety 
follow up visit 7 days after the first vaccination (Visit 1A) including review of 7-day eDiary data, 
safety data was reviewed by the IRC. Enrollment of the remaining 120 subjects in this age cohort 
was initiated after IRC clearance.  
 
An external independent Data Monitoring Committee (DMC) reviews accruing safety data in an 
unblinded manner at regular intervals and might recommend adjusting, pausing or discontinuing 
the study at any time. Please refer to Section 8.6.2 for more details on the set-up and 
responsibilities of the DMC.  
Subject Enrollment into Part B (Booster Phase): 
VLA15 Booster (Group 1 and 2) 
• 
All eligible subjects within Group 1 and 2 will receive VLA15 booster doses at Months 18, 
30 and 42.  
Placebo (Group 3):  
• 
All eligible subjects within Group 3 will receive Placebo injections at Months 18,30 and 42.  
The study sponsor and study statisticians were unblinded at the time of the primary endpoint 
analysis, i.e., prior to subject enrollment into Part B. Study participants and investigators will 
remain blinded throughout the entire duration of study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY DESIGN 
 
The study is being conducted in two study parts (Part A: Main Study Phase, Part B: Booster 
Phase). Please refer to Figure 2 for the study design.  
 
 
Figure 2 Study Design 
In Part A (Main Study Phase) a total of approximately 600 subjects aged 5 to 65 years were 
randomized 1:1:1 into three study groups: Group 1 (approximately 200 subjects) received three 
I.M. vaccinations of VLA15 at Month 0-2-6. Group 2 (approximately 200 subjects) received two 
I.M. VLA15 vaccinations at Month 0-6 and a placebo injection at Month 2 in order to keep the 
blind. Group 3 (approximately 200 subjects) received three I.M. placebo injections at Month 0-2-
6. Within each study group subjects were enrolled 2:1:1 in three age cohorts (18-65 years, 12-17 
years and 5-11 years).  
In Part A, all subjects received three I.M. vaccinations at Month 0-2-6 (i.e., Day 1-57-180). On 
Day 8/Visit 1A (i.e., 7 days after the first vaccination) a safety visit was performed (phone call for 
subjects aged 18-65, in-person visit for subjects aged 5-17 years). In-person visits were 
scheduled for all age cohorts one month after each vaccination. Blood samples for 
immunogenicity assessments were collected at the screening visit, Day 85, Day 180, Day 194 (in 
a subset of adult subjects), Day 208, Day 365/Month 12 and at Month 18.  
In Part B (Booster Phase) all eligible subjects from Group 1 and 2 will receive a booster dose of 
VLA15 at Month 18, Month 30 and Month 42. Placebo injections will be administered to Group 3 
subjects at Month 18, Month 30 and Month 42. Subjects will be followed-up until Month 48 (i.e., 
2.5 years after start of Part B) with blood samples obtained at 1, 5, 8 and 12 months following the 
Month 18 booster dose (study months 19, 23, 26 and 30), at 1, 9 and 12 months following the 
Month 30 booster dose (study months 31, 39 and 42) and at 1 and 6 months following the Month 
42 booster dose (study months 43 and 48).   
 
 

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Table 1 provides an overview of study groups and treatments. 
 
 

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Table 1 Study Groups and Vaccinations 
 
Study Group 
Subjects 
Age Cohort  
(Age in years at 
Screening) 
Treatment 
Vaccination 
Schedule  
Part A: Main Study Phase 
Group 1 
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg 
Month 0-2-6 
Group 2 
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg  
Placebo 
Month 0-6 
Month 2* 
Group 3 
Total: 200 
100 
50 
50 
 
 
18-65 
12-17 
5-11 
 
Placebo 
Month 0-2-6 
Part B: Booster Phase  
Group 1  
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg 
Month 18,  
30 and 42 
Group 2 
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg 
Month 18,  
30 and 42 
Group 3 
 
Total: 200 
100 
50  
50 
 
18-65 
12-17 
5-11 
Placebo 
Month 18,  
30 and 42 
*In order to keep the blind, subjects assigned to Group 2 will receive a sham injection of placebo at Month 2.  
STUDY SPONSOR AND COLLABORATION PARTNERS 
The development of VLA15 is a collaboration between Valneva and Pfizer. At study initiation, 
Valneva served as study sponsor. Upon IND transfer (mid November 2021), Pfizer took over 
sponsorship; however, some sponsor responsibilities are delegated to Valneva and CROs for the 
continuity of this study. 
INVESTIGATOR AND SITES  
Multicenter study in Lyme borreliosis endemic areas in the U.S., in total 14 active study sites. 
STUDY START DATE 
• 
Main Study Phase (Part A): March 2021 
• 
Booster Phase (Part B): August 2022 

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STUDY DURATION 
Study duration per subject will be a maximum of 50 months per subject. Overall study duration 
(i.e., First-Subject-In to Last-Subject-Out) is estimated to be 4 years and 5 months. The end of 
the study is defined as the date of the last visit performed by the last subject. 
STUDY PARTICIPANTS 
A total of 715 subjects were screened and 625 healthy subjects aged 5 to 65 years were enrolled 
in this study: 320 subjects aged 18-65 years, 150 subjects aged 12-17 years and 155 subjects 
aged 5-11 years.  
CRITERIA FOR INCLUSION/EXCLUSION 
625 male or female subjects who met the inclusion and exclusion criteria listed below were 
enrolled in the study. 
Inclusion criteria: 
Subjects must meet ALL of the following criteria to be eligible for this study: 
 
1. Subject is aged 5 to 65 years* at the day of screening (Visit 0); 
2. Subject is of good general health as determined by medical history, physical examination, 
and judgement of the investigator; 
3. Parent(s)/legal representative(s) and subject who have an understanding of the study and 
its procedures as explained by the investigator and agree to its provisions:   
- 
For subjects aged 18-65 years†: Written informed consent prior to any study 
related procedures;  
- 
For subjects aged 5-17 years‡: Written informed consent by the subject’s legal 
representative(s), according to local requirements, and written informed assent of 
the subject, if applicable, prior to any study related procedures; 
4. If subject is of childbearing potential: 
a. Subject has a negative serum pregnancy test at screening (Visit 0); 
b. Subject agrees to employ adequate birth control measures according to the 
following timelines: 
- Main Study Phase: duration of entire study  
- Booster Phase: until 5 months after each booster vaccination (Booster 1 
until Month 23, Booster 2 until Month 35 and Booster 3 until Month 47).   
5. Subject is willing and able to comply with scheduled visits, treatment plan, and other study 
procedures; 
6. Subject is expected to be available for the duration of the study and can be contacted by 
telephone during study participation. 
 
* From the 5th birthday until the last day before the 66th birthday  
† From the 18th birthday until the last day before the 66th birthday  
‡ From the 5th birthday until the last day before the 18th birthday  

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Exclusion criteria (Main Study Phase): 
Subjects who meet ANY of the following criteria are NOT eligible for this study: 
1. Subject has a chronic illness related to Lyme borreliosis (LB), an active symptomatic LB 
as suspected or diagnosed by a physician, or received treatment for LB within the last 3 
months prior to Day 1/Visit 1; 
2. Subject received previous vaccination against LB; 
3. Subject had a tick bite within 4 weeks prior to Day 1/Visit 1; 
4. Subject has a medical history of or currently has a clinically relevant disease (e.g., 
cardiovascular, respiratory, neurologic, psychiatric conditions) which poses a risk for 
participation in the study, based on investigator’s judgement, such as individuals with 
poorly controlled or unstable disease, ongoing suspected or active inflammation, or poor 
compliance with pharmacologic treatment; 
5. Subject has a medical history of or currently has a neuro-inflammatory or autoimmune 
disease; 
6. Subject has a known thrombocytopenia, bleeding disorder, or received anticoagulants in 
the 3 weeks prior to Day 1/Visit 1, contraindicating I.M. vaccination as judged by the 
investigator; 
7. Subject has received an active or passive immunization within 4 weeks prior to Day 1/Visit 
1;  
8. Subject has received any other registered or non-registered medicinal product in another 
clinical trial within 4 weeks prior to vaccination at Day 1/Visit 1;  
9. Subject has a known or suspected defect of the immune system that would prevent an 
immune response to the vaccine, such as subjects with congenital or acquired 
immunodeficiency, including infection with human immunodeficiency virus (HIV), status 
post organ transplantation or immuno-suppressive therapy (e.g., radiation therapy, 
chemotherapy or glucocorticoid treatment) within 4 weeks prior to Day 1/Visit 1. 
Glucocorticoid immuno-suppressive therapy is defined as administration of chronic (longer 
than 14 days) prednisone or equivalent 0.05 mg/kg/day. Topical and inhaled steroids are 
allowed; 
10. Subject has a history of anaphylaxis of unknown cause or severe allergic reactions of 
unknown cause. Subjects with known hypersensitivity or allergic reactions to one of the 
components of the vaccine are to be excluded; 
11. Subject had any malignancy in the past 5 years. If treatment for cancer was successfully 
completed more than 5 years ago and the malignancy is considered to be cured, the 
subject may be enrolled. Subjects with history of squamous cell or basal cell skin cancer 
which has been successfully treated by surgical excision and treatment is considered to 
have achieved cure may be enrolled. Subjects with a history of skin cancer must not be 
vaccinated at the previous tumor site; 
12. Subject is pregnant (positive serum pregnancy test at Visit 0 or positive urine pregnancy 
test at Day 1/Visit 1), has plans to become pregnant during the course of the study or is 
lactating at the time of enrollment. Women of childbearing potential that are unwilling or 
unable to employ an adequate birth control measure during the course of the entire Main 
Study Phase;  
13. Subject has donated or plans to donate blood or blood-derived products (e.g. plasma) 
within 4 weeks prior to Day 1/V1 or subject received blood or blood-derived products (e.g. 
plasma or immunoglobulins) within 3 months prior to vaccination at Day 1/Visit 1 or plans 
to donate or use blood or blood products within 4 weeks after vaccination at Day 1/Visit 1; 

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14. Subject has any condition that, in the opinion of the investigator, may compromise the 
subject’s well-being, might interfere with evaluation of study endpoints, or would limit the 
subject’s ability to complete the study; 
15. Subject is in a dependent relationship with the sponsor, an investigator or other study 
team member, or the study center. Dependent relationships include close relatives and 
household members (i.e., children, partner/spouse, siblings, parents) as well as 
employees of the investigator or study center personnel. 
 
Exclusion criteria (Booster Phase): 
 
Subjects who meet ANY of the following criteria are NOT eligible for participation in the Booster 
Phase: 
1. Subject has developed a chronic illness related to Lyme borreliosis (LB) or an active 
symptomatic LB as suspected or diagnosed by a physician; 
2. Subject has developed a clinically relevant disease (e.g., cardiovascular, respiratory, 
neurologic, psychiatric conditions, malignancy) which poses a risk for further participation 
in the study, based on investigators judgement, such as individuals with poorly controlled 
or unstable disease, ongoing suspected or active inflammation, or poor compliance with 
pharmacologic treatment;  
3. Subject has developed a neuro-inflammatory or autoimmune disease; 
4. Subject has developed a thrombocytopenia or bleeding disorder, or is contraindicated for 
I.M. vaccination as judged by the investigator; 
5. Subject has developed a known or suspected defect of the immune system that would 
prevent an immune response to the vaccine, such as subjects with acquired 
immunodeficiency, including infection with human immunodeficiency virus (HIV) or status 
post organ transplantation; 
6. Subject has experienced an anaphylaxis of unknown cause or severe allergic reactions of 
unknown cause or has developed hypersensitivity or allergic reactions to one of the 
components of the vaccine;  
7. Subject is pregnant (positive urine pregnancy test), or is lactating or has plans to become 
pregnant up to 5 months after any booster vaccination (i.e., Booster 1 from Months 18 to 
23, Booster 2 from Months 30 to 35 and Booster 3 from Month 42 to 47).  Women of 
childbearing potential that are unwilling or unable to employ an adequate birth control 
measure for five months after any booster vaccination (i.e., Months 18 to 23, Months 30 
to 35 or Month 42 to 47);  
8. Subject has developed any condition that, in the opinion of the investigator, may 
compromise the subject’s well-being, might interfere with evaluation of study endpoints, 
or would limit the subject’s ability to complete the study; 
9. Subject is in a dependent relationship with the sponsor, an investigator or other study 
team member, or the study center. Dependent relationships include close relatives and 
household members (i.e., children, partner/spouse, siblings, parents) as well as 
employees of the investigator or study center personnel. 
Delay Criteria for Vaccination 
Vaccination will be delayed if: 
1. Subject has an acute illness with or without elevated body temperature (≥100.4 °F [38.0 
°C]) within 3 days prior to the scheduled vaccination. Subjects may be rescheduled for 
vaccination at a later date provided that the illness has resolved (body temperature <100.4 
°F [38.0 °C]). 

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2. Subject has received antipyretics within 4 hours prior to the scheduled time of vaccination. 
In this case the vaccination should be performed at a later date. 
Booster Phase: 
3. Subject has received an active or passive immunization within 4 weeks prior to any booster 
vaccination, except for influenza or pandemic vaccines which may be administered 
outside a 7-days interval before booster vaccination. 
4. Subject has received anticoagulants within 3 weeks prior to any booster vaccination. 
5. Subject received immuno-suppressive therapy (e.g., radiation therapy, chemotherapy or 
glucocorticoid treatment) within 4 weeks prior to any booster vaccination. Glucocorticoid 
immuno-suppressive therapy is defined as administration of chronic (longer than 14 days) 
prednisone or equivalent 0.05 mg/kg/day. Topical and inhaled steroids are allowed. 
6. Subject has donated or plans to donate blood or blood-derived products (e.g., plasma) 
within 4 weeks prior to any booster vaccination or received blood or blood-derived 
products (e.g., plasma or immunoglobulins) within 3 months prior to any booster 
vaccination in this study or plans to donate or use blood or blood products within 4 weeks 
after any booster dose. 
In addition, the following criteria must be met: 
1. For a rescheduled first vaccination: 
a. All inclusion and none of the exclusion criteria are met; In case not all of these criteria 
are met, the subject will be excluded from the study. 
b. The rescheduled visit should be within the specified time window (i.e., within 10 days 
after the screening visit). In case a first vaccination cannot be rescheduled within the 
specified time window (i.e., within 10 days after the screening visit), the subject might 
be invited for a rescreening. 
 
2. For a rescheduled second, third or booster vaccination: 
The rescheduled visit should be within the specified time window. In case a rescheduled 
booster vaccination has to occur outside the specified time window, the study team should 
be consulted before booster administration. 
 
Forbidden concomitant therapies during study conduct are described in Section 6.2.2. 
STUDY ENDPOINTS 
Primary Endpoints:  
Safety: 
+ Frequency of solicited local and solicited systemic AEs within 7 days after each and any 
vaccination of the primary vaccination series (Part A). 
Immunogenicity: 
+ GMTs (Geometric Mean Titers) for IgG against each OspA serotype ST1 to ST6, 
determined by an IgG binding assay, at Day 208/Month 7 (Part A). 
 
 
 
 

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Secondary Endpoints: 
Safety:  
+ Frequency of solicited local and solicited systemic AEs within 7 days after each booster 
dose administration (Part B);  
+ Frequency of SAEs during the entire study; 
+ Frequency of AESIs during the entire study; 
+ Frequency of unsolicited AEs within 28 days after each vaccination; 
+ Frequency of SAEs, AESIs, unsolicited and solicited AEs stratified by age cohort.  
 
Immunogenicity: 
Part A: Main Study Phase:  
+ GMTs for IgG against each OspA serotype (ST1 to ST6), determined by an IgG binding 
assay, at baseline (screening visit) and at Day 85, 180, 194*, 365 and Month 18; 
+ SCRs (Seroconversion Rate, defined as seroconversion from seronegative to seropositive 
or ≥four-fold increase in IgG titer compared to baseline if subject was tested OspA 
seropositive at baseline) for each OspA serotype specific IgG (ST1 to ST6), determined 
by an IgG binding assay, at Day 85, 180, 194*, 208, 365 and Month 18; 
+ GMFRs (Geometric Mean of the fold rise as compared to baseline) for IgG against each 
OspA serotype (ST1 to ST6), determined by an IgG binding assay, at Day 85 and 208;  
+ GMTs, SCRs and GMFRs for IgG against each OspA serotype (ST1 to ST6), determined 
by an IgG binding assay, at specified time-points, stratified by age cohort. 
 
Part B: Booster Phase:  
+ GMTs for IgG against each OspA serotype (ST1 to ST6), determined by an IgG binding 
assay, at Months 18, 19, 23, 26, 30, 31, 39, 42, 43 and 48; 
+ SCRs for each OspA serotype specific IgG (ST1 to ST6), determined by an IgG binding 
assay, at Months 18, 19, 23, 26, 30, 31, 39, 42, 43 and 48; 
+ GMFRs for IgG against each OspA serotype (ST1 to ST6), determined by an IgG binding 
assay, at Months 19, 31 and 43; 
+ GMTs, SCRs and GMFRs for IgG against each OspA serotype (ST1 to ST6), determined 
by an IgG binding assay, at specified time points, stratified by age cohort. 
 
Exploratory Endpoints: 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Visit 5A/Day194 data will be available for a subset of approximately 150 adult subjects.  
 
 
 
 
 
 

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SAMPLE SIZE JUSTIFICATION 
The sample size has been chosen to allow detection of common AEs. A total of 400 subjects in 
the VLA15 groups (Group 1 and Group 2) will provide 95% confidence that an AE not seen in the 
study would have a true incidence of not more than 0.75% across all age groups. In addition, the 
overall group size for the two VLA15 study groups has been selected to provide a sufficient safety 
database and for determining the optimal vaccination schedule before advancing the vaccine 
candidate into Phase 3. Upon completion of the study, the total number of subjects exposed to 
the final dose as used for upcoming Phase 3 studies would be a minimum of approximately 
N=710. The database would, thus, allow 95% confidence that a given reaction would not be 
observed at a higher rate than 1:(710/3) rate, i.e., 0.4%, if it is not observed in the studies 
preceding Phase 3. 
 
With respect to the primary endpoint, GMTs for ST1-6 specific IgGs on Day 208: In the absence 
of an established protective titer, sample size calculation is based on somewhat arbitrary 
differences in GMTs between VLA15 study groups to demonstrate which titer levels could be 
distinguished with the proposed sample size.  
 
Titers observed in the primary endpoint immunogenicity analysis (i.e., Day 208; one month after 
third vaccination) of 86 subjects receiving 180 µg of VLA15 in ongoing Phase 2 study VLA15-202 
were used as basis: In the 180 µg group (i.e. the dose chosen for further development of VLA15), 
an ELISA GMT of 274.7 was observed for ST1 (i.e. the serotype with lowest titers) with a Standard 
Deviation (LOG10) of 0.53. A total of 180 subjects per group (assuming 10% of the 200 subjects 
per study group are excluded from the primary PP analysis) will provide 80% power at a two-
sided alpha level of 5% to distinguish a GMT of 274.7 in one study group from a putative higher 
GMT of 394.3 in the other study group.   
 
The overall sample size of 200 subjects in the placebo group has been selected to allow for the 
internal validation of both safety and immunogenicity results. 
 
STATISTICAL METHODS 
The primary immunogenicity analysis will be an overall and group-wise comparison of the OspA 
serotype specific IgG GMTs in the per-protocol analysis set between study groups at Day 208 
(i.e., 28 days after the last vaccination) by ANOVA (factors treatment group, age group). In 
addition, GMTs and GMFRs (i.e., increase of IgG titers compared to respective titers at Day 1 
(baseline)) against each OspA serotype ST1 to ST6 will be compared overall and pair-wise 
between study groups on specified time points. For Part B, GMFRs at one month after each 
booster vaccination will be calculated and compared with respective titers at Day 208 (i.e., primary 
peak response) and pre-booster timepoints. SCRs will be compared overall and pair-wise 
between study groups by Fisher Freeman Halton test and Fisher exact test, respectively. Defined 
immunogenicity analyses will be repeated on the full analysis set and will be repeated by baseline 
B.b. s.l. serostatus and age cohort. 
 
All subjects entered into the study, who received at least one vaccination, will be included in the 
Safety Analysis Set (SAS) of Part A. The number and percentage of subjects with solicited local 
and solicited systemic AEs up to 7 days after each vaccination, after any active vaccination, and 
up to 7 days after any vaccination of the primary vaccination series (Month 0-2-6); as well as the 
number and percentage of subjects with unsolicited AEs, medically attended AEs, AESIs and 
SAEs will be presented for each study group overall and by body system/ preferred term. The 
same analyses will be performed for all subjects that received respective booster vaccinations 
(Booster Safety Analysis Set; BSAS) in Part B.  
Differences between the study groups will be assessed for significance using Fisher’s exact 
(Fisher Freeman Halton) test, whereby a significant overall test will be amended by pair-wise 
tests. Defined safety analyses will also be repeated stratified by baseline B.b. s.l. serostatus and 
age cohort. 

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DATA ANALYSES 
Analysis 1 included all safety and immunogenicity data from selected time points from Part A up 
to Day 208/ Month 7. This analysis was done in four parts. Every age cohort was analyzed 
separately as soon as data of this cohort was available (Analysis 1.1 (Cohort 1, aged 18-65 
years), Analysis 1.2 (Cohort 2, aged 12-17 years), Analysis 1.3 (Cohort 3, aged 5-11 years)). 
Pooled data from all three cohorts concluded Analysis 1.   
 
Analysis 2 included all safety and immunogenicity data from selected time points from Part A up 
to Month 12 (i.e., 6 months after the third immunization).   
 
Analysis 3 included all safety data and immunogenicity data from selected time points from Part 
A up to Month 18 and safety and immunogenicity data from Part B up to Month 19.  
 
Analysis 4 will include safety and immunogenicity data of Part B up to Month 31. 
Analysis 5 will include safety and immunogenicity data of Part B up to Month 43. 
Analysis 6 will include safety and immunogenicity data of Part B up to Month 48. 
 
In case analyses fall close in timing, they may be merged.  
STUDY REPORTS 
Clinical study report 1 compiles the data from Analysis 1. 
Clinical study report 2 will include the data compiled in Analysis 2 and 3. 
Clinical study report 3 will include the data compiled in Analysis 4. 
Clinical study report 4 will include the data compiled in Analysis 5. 
Clinical study report 5 will include the data compiled in Analysis 6. 
SAFETY AND DATA MONITORING 
All subjects will report all symptoms (solicited local and systemic AEs, unsolicited AEs) after each 
vaccination, as described below. The subjects/ legal representative(s) will be asked to complete 
electronic Subject Diaries (eDiaries).  
Solicited Adverse Events 
Solicited local and systemic adverse events will be assessed for absence, presence, severity and 
duration by the subjects themselves. The assessments will be recorded daily via an eDiary. 
Assessments by the subjects/ legal representative(s) will occur for a total of seven consecutive 
days, each day at the approximate same time, starting at the day of each vaccination. The 
subjects/ legal representative(s) will be instructed to carefully observe the injection site until all 
symptoms resolve. 
Solicited local Adverse Events (AEs) 
Solicited local adverse events include the following: pain, tenderness, induration/hardening, 
swelling and erythema/redness. 
Solicited systemic Adverse Events (AEs) 
Solicited systemic adverse events include: headache, myalgia (muscle pain), arthralgia (joint 
pain), fever (oral body temperature), nausea, vomiting and fatigue. 
Unsolicited Adverse Events 
Unsolicited AEs will be captured in the eDiary until 28 days after each vaccination. The eDiary 
entries will be verified by the study clinician together with the subject/ legal representative(s) at 
the subject’s next visit to the study site. Unsolicited AEs will be captured in the eCRF up to 28 
days after each vaccination. Thereafter, reporting of AEs in the eCRF will be limited to AESIs 

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(Adverse Events of Special Interest) and SAEs (Serious Adverse Events). AESIs and SAEs will 
be collected throughout the entire study period. SAEs need to be reported to Pfizer Safety and 
AESIs to 
 Safety Desk.   
Definition of Adverse Events of Special Interest (AESIs) 
An Adverse Event of Special Interest (serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might 
warrant further investigation in order to characterize and understand it.  
Collection and evaluation of Adverse Events of Special Interest (AESIs) 
Subjects will be carefully monitored for development of AESIs. Since a previous LB vaccine was 
accused of inducing auto-immune symptoms similar to those caused by disseminated LB 
infection, e.g., autoimmune arthritis, such events will constitute AESIs. In addition, the onset of 
any potentially autoimmune or neuro-inflammatory disorders will constitute AESIs. A subunit 
vaccine like VLA15 is not considered capable of inducing LB as such. Nevertheless, any potential 
LB cases are of relevance to development of the vaccine and will therefore receive particular 
attention and be captured as AESIs as well. Therefore, symptoms suggesting a LB-associated 
event and/ or onset of potentially autoimmune or neuro-inflammatory disorders will receive special 
attention. Identification of such events from a pre-defined list of AESIs and symptoms suggesting 
a Borrelia infection will be assessed in a guided approach as described below.  
 
The following symptoms will receive particular consideration: 
 
• 
Erythema migrans: an expanding red or bluish-red patch (≥5 cm in diameter) with or 
without central clearing; 
• 
Symptoms suggesting an arthritis (e.g., recurrent attacks or persisting objective joint 
swelling (synovitis) in one or a few large joints); 
• 
Neurological symptoms (e.g., meningo-radiculitis, meningitis, encephalitis, myelitis, 
cerebral vasculitis, facial palsy); 
• 
Cardiac symptoms (e.g., atrio-ventricular conduction disturbances, rhythm disturbances, 
myocarditis); 
• 
Immune-mediated disorders as proposed by competent authorities for previous clinical 
programs (please refer to APPENDIX 1). 
 
For avoidance of doubt, solicited AEs do not qualify as AESI and should not be reported 
as such. 
 
As part of unsolicited AE assessments, at each study visit starting from Visit 1A, the investigator 
will be guided through a scripted safety assessment (i.e., questionnaire) to enquire about 
symptoms that are consistent with Lyme borreliosis, allowing the investigator to assess whether 
there is a clinical suspicion for infection with Borrelia or a LB-associated event. In addition, 
presence of or symptoms suggesting one of the other AESIs from the pre-defined list will be 
determined by the investigator.  
 
In case there is clinical suspicion for Lyme borreliosis or a LB-associated event, investigators are 
asked to perform a clinical workup as described in APPENDIX 2, including specialist referral as 
needed. Subjects with suspected other AESIs (i.e., immune-mediated disorders) should also be 
referred to a respective clinical expert for full diagnostic work-up as needed. The investigator will 
request the medical records from the clinical expert, if applicable. In case an AESI is identified 
(by the investigator or a clinical specialist upon referral or without referral) the investigator will fill 
out the AESI Report Form with all available information, including information provided by the 

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clinical expert, if applicable, and will provide the AESI Report Form together with the medical 
records to the DMC through the 
 Safety Desk. For cases of Lyme borreliosis or LB-
associated events, the DMC will confirm the diagnosis. In case an AESI (LB or immune-mediated 
disorders as depicted in the pre-defined list) has already been diagnosed by a healthcare 
specialist prior to identification of a potential AESI by the investigator at the study visit, the 
investigator will also provide the AESI Report Form together with available medical records to the 
DMC through the 
 Safety Desk. In addition, the DMC will regularly review accruing AEs 
and can recommend specialist work-up to the investigator for any case they consider potential 
AESIs or cases of LB. The DMC will do a final adjudication of all AESIs and will assess whether 
cases were new in onset and whether there is any relationship to application of the study vaccine. 
Narratives with detailed case descriptions will be provided for all AESIs.   
INTERNAL REVIEW COMMITTEE (IRC) 
As VLA15-221 is the first study with VLA15 enrolling a pediatric study population, rigorous safety 
monitoring precautions were implemented to ensure well-being of all subjects. An independent 
Internal Review Committee (IRC) was installed at the sponsor’s collaboration partner Pfizer in 
order to review safety data of sentinel subjects in each age cohort prior to advancing the study 
into the next younger age cohort and prior to enrolling remaining subjects within each of the 
pediatric age cohorts (i.e., Cohort 2 and Cohort 3). The IRC was composed of qualified personnel 
from Pfizer, and included at least one pediatrician, statistician, vaccine safety expert and a senior 
member of the Pfizer Vaccine Research and Development organization. All IRC members were 
independent from the VLA15-221 study team. During the staggered subject enrollment phase, 
the IRC reviewed unblinded safety data and gave recommendation on whether enrollment of the 
next younger age cohorts as well as enrollment of remaining subjects of the current age cohort 
can be initiated as described in Section 4.2.1 (“Subject enrollment”). A written IRC charter was 
provided prior to the study start, including a detailed description of IRC set-up and processes.    
DATA MONITORING COMMITTEE (DMC) 
An external independent Data Monitoring Committee (DMC) comprising an experienced 
vaccinologist/pediatrician, a family practitioner/pediatrician, a rheumatologist and a neurologist, 
who are all experts in the field of Lyme borreliosis, is installed. The DMC reviews accruing safety 
data in an unblinded manner at regular intervals throughout the study and might recommend 
adjusting, pausing or discontinuing the study at any time. 
The DMC confirms diagnosis of potential LB cases based on medical records received from the 
investigator after clinical workup according to a standardized procedure on an ad-hoc basis. The 
DMC adjudicates AESIs and assesses whether cases were new in onset and whether there is 
any relationship to the study vaccine.  
 
During vaccination periods (i.e., Day 1 to Day 180 in Part A; Months 18, 30 and 42 in Part B), the 
DMC periodically reviews tables and listings of SAEs, Deaths, AESIs, medically attended AEs, 
solicited AEs, unsolicited AEs and AEs leading to withdrawal from further vaccination on a regular 
basis in scheduled meetings and via remote safety data reviews. SAE reports were provided to 
the DMC up to one year after first booster administration at Month 18. Thereafter, SAEs are 
reviewed on an ad-hoc basis by Pfizer up to end of the study. AESIs will be reviewed by the DMC 
on an ad-hoc basis until study end. A written DMC charter is provided including a detailed 
description of DMC set-up and processes.   

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Table 2 TABLE OF EVENTS – Part A: MAIN STUDY PHASE 
Visit 
V0 (1) 
V1 (2) 
V1A (3) 
V2 (4) 
V3 (2) 
V4 (4) 
V5 (2) 
V5A (5) 
V6 (4) 
V7 (4) 
V8 (4) 
Early 
Termination 
(4) (6) 
Timing Day (D) 
Month (M) 
D-10 
 
D1 
 
D8 
 
D29 
M1 
D57 
M2 
D85 
M3 
V3 + 28d 
D180 
M6 
D194 
M6.5 
V5 + 14d 
D208 
M7 
V5 + 28d 
D365 
M12 
D545 
M18 
< V8 
Time windows (D) 
-10 to 0 
0 
+2 
+2/- 4 
+/- 4 
+/- 4 
+4/-28 
+/-2  
+2/- 4 
+/- 14 
+/- 14 
n/a 
Visit type  
In-person 
In-person  
In-person  
or remotely 
In-person  
or remotely 
In-person 
In-person  
or remotely 
In-person 
In-person  
or remotely 
In-person  
or remotely 
In-person  
or remotely 
In-person  
or remotely 
In-person  
or remotely  
Informed consent/assent (7) 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
(Review) 
 
 
 
 
 
 
 
 
 
 
Vaccination delay criteria 
 
X 
 
 
X 
 
X 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history incl. vaccinations 
X 
X (8) 
 
 
 
 
 
 
 
 
 
 
Concomitant medications/ 
treatments incl. vaccinations 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination, ECG (9) 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (10) 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
Evaluation of oral body temperature 
X 
X (11) 
 
 
X (11) 
 
X (11) 
 
 
 
 
 
HIV test [3.0 mL] (12) 
X  
 
 
 
 
 
 
 
 
 
 
 
B.b. s.l. screening test [5.0 mL] (13) 
X  
 
 
 
 
 
 
 
 
 
X  
X (14) 
Serum Pregnancy test [2.0 mL] (15) 
X  
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy test (15) 
 
X (16) 
 
X 
X (16) 
X 
X (16) 
 
X 
X 
X 
X 
Immunogenicity blood sample 
[12.0 mL] (17) 
X 
 
 
 
 
X 
X  
X 
X 
X 
X 
 
Assay development sample  
[75.0 mL] (18) 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Randomization (19) 
 
X 
 
 
 
 
 
 
 
 
 
 
VACCINATION (20) 
 
X 
 
 
X 
 
X 
 
 
 
 
 
Check for AEs following vaccination 
 
X (21) 
 
 
X (21) 
 
X (21) 
 
 
 
 
 
Symptom-driven physical exam (22) 
 
X 
X (23) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inspection of injection site of previous 
vaccinations 
 
 
X (23) 
X 
 
X 
 
X 
X 
 
 
X (25) 
Explain eDiary (24) 
 
X 
 
 
 
 
 
 
 
 
 
 
Review eDiary 
 
 
X 
X 
 
X 
 
X 
X 
 
 
X (26) 
Check eDiary for SAEs/ AESIs 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Scripted Safety Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/ SAE/ AESI Assessment (27) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Volume [mL] 
17.0 (28); 
19.0 (29); 
20.0 (30); 
22.0 (31) 
 75.0 (32) 
0.0 
0.0 
0.0 
12.0 (33);  
87.0 (34) 
12.0 
12.0  
12.0 (33);  
87.0 (34) 
12.0 
17.0 
5.0 (14) 

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Table 3 TABLE OF EVENTS – Part B: BOOSTER PHASE 
Visit 
V8B (35) 
V9 
V10  
V11 
V12  
V13 
V14 
V15 
V16 
V17 
Early 
Termination 
(36)  
Month (M) 
M18 
M19 
V8B + 28d 
M23 
M26 
M30 
M31 
V12 + 28d 
M39 
M42 
M43 
V15 + 28d 
M48 
< V17 
Time windows (D) 
V8 +14 
+/-4 
+/-14 
+28/-14 
+/-28 
+/-4 
+/-14 
+/-28 
+/-4 
+/-14 
n/a 
Visit type  
In-person 
In-person 
In-person 
In-person 
In-person 
In-person 
In-person 
In-person 
In-person 
In-person 
In-person 
Inclusion/Exclusion criteria  
(Booster Phase) 
X (7) 
 
 
 
X (7) 
 
 
X (7) 
 
 
 
Vaccination delay criteria 
X 
 
 
 
X 
 
 
X 
 
 
 
Concomitant medications/ 
treatments incl. vaccinations 
X (37) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination (9) 
X 
 
 
 
X 
 
 
X 
 
 
 
Vital signs (10) 
X 
 
 
 
X 
 
 
X 
 
 
 
Evaluation of oral body temperature 
X (11) 
 
 
 
X (11) 
 
 
X (11) 
 
 
 
B.b. s.l. screening test [5.0 mL] (13) 
(38)  
 
 
 
 
X 
 
 
X 
 
X 
X 
Urine Pregnancy test (15)  
X (16) 
X 
X 
 
X (16) 
X 
 
X (16) 
X 
X 
X 
Immunogenicity blood sample 
[12.0 mL] (17) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assay development sample 
[75.0 mL] (18) 
 
X 
 
 
 
X 
 
 
X 
 
 
VACCINATION (20) 
X 
 
 
 
X 
 
 
X 
 
 
 
Check for AEs following vaccination 
X (21) 
 
 
 
X (21) 
 
 
X (21) 
 
 
 
Symptom-driven physical exam (22) 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
Inspection of injection site of 
previous vaccinations 
 
X 
 
 
 
X 
 
 
X 
 
X (25) 
Explain eDiary (24) 
X 
 
 
 
X 
 
 
X 
 
 
 
Review eDiary 
 
X 
 
 
 
X 
 
 
X 
 
X (26) 
Check eDiary for SAEs/ AESIs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Scripted Safety Assessment 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
AE/ SAE/ AESI Assessment (27) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Volume [mL] 
0.0 
12.0 (33); 
87.0 (34) 
12.0 
12.0 
17.0 
12.0 (33); 
87.0 (34) 
12.0 
17.0 
12.0 (33); 
87.0 (34) 
17.0 
5.0 
 
 

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(1) 
Re-screening of subjects is allowed once. Assessments, which have been performed during the first screening visit, remain valid for 14 days. In case re-screening occurs 
outside this time frame, already performed measures have to be repeated.  
(2) 
At on-site Visits, subjects will be supplied with urine pregnancy test kits to ensure that subjects can test for pregnancy at home in case the COVID-19 pandemic prohibits in-
person visits at subsequent scheduled visits (Visit 2, 4, 6, 7 and 8). Pregnancy test handling has to be explained to subjects by trained study site staff during Visit 1.   
(3) 
Visit 1A is a safety follow-up visit to be performed 7 days after the first vaccination (i.e., on Day 8). It is intended to perform Visit 1A remotely via a phone/video call in adult 
subjects (aged 18-65 years) and preferably as an in-person visit in adolescent subjects (aged 12-17 years) and children (5-11 years). If the COVID-19 pandemic prohibits 
in-person visits, Visit 1A may also be conducted remotely via a phone/video call in the younger age groups. For details on differences in respective study event procedures 
during in-person or remote visits, please refer to Section 4.2.1. 
(4) 
Visit should preferably be conducted as an in-person visit. If an in-person is not feasible due to COVID-19, e.g., travel restrictions, local recommendations, circumstances at 
the study site’s location that prohibit an in-person visit, or if the PI believes that the subject’s safety and well-being might be jeopardized with an in-person visit at the study 
site due to COVID-19, the visit should be conducted remotely. In case subject visit has to be performed remotely, a mobile nurse professional will come to the subject’s 
home and take the immunogenicity sample within the specified time window. Review of subject eDiary safety data will be performed by the study site via phone/video call. 
For details on differences in respective study event procedures during in-person or remote visits, please refer to Section 4.2.4. In order to perform urine pregnancy test at 
home, subjects will be supplied with additional test kits at the last on-site Visit.  
(5) 
Visit 5A will be performed in a subset of approximately 150 adult subjects only.  
(6) 
Every effort should be made to have discontinued subjects complete the early termination visit. If the subject is unwilling to perform an ET visit, a phone-call should be made 
to follow-up on Adverse Events and Concomitant Medications/ Vaccinations. Note: If a subject presents at a regular study visit and informs the site that it will discontinue 
the study after this visit, the study visit will not be performed as an ET visit, but as a regular study visit including all events that are described for the respective study and ET 
visit.   
(7) 
Informed consent/assent may be obtained within 10 days before Visit 1. For the Booster Phase, all subjects are asked to reconfirm the consent/assent latest at the respective 
booster vaccination visit.  
(8) 
Symptoms noted at Visit 1 (prior to first vaccination) are not considered AEs but will be recorded as medical history. 
(9) 
Physical examination on the following body systems: general appearance (including assessment of body weight and height), skin, head/ eyes /ears/ nose/ throat, chest, 
lungs, heart, abdomen, extremities and joints, lymph nodes, and neurological system. An ECG will be performed at Visit 0 only.  
(10) 
Vital signs (Systolic and diastolic blood pressure and pulse rate while seated and at rest) to be measured prior to vaccination and in addition prior to discharge in case 
subject reports any complaints. 
(11) 
To be performed prior to vaccination. 
(12) 
The results of negative HIV tests that were performed up to 4 weeks before Visit 0 are acceptable (blood: HIV test 3.0 mL). Positive HIV test obtained by ELISA will have to 
be confirmed by a second method (e.g., Western Blot or PCR). HIV tests only in subjects aged ≥ 12 years.   
(13) 
A commercially available Lyme borreliosis screening test will be performed (blood: 5.0 mL). Serum samples that are tested positive will have to be verified by a confirmatory 
immunoblot. Test result does not need to be available before randomization and remains valid for 4 weeks. 
(14) 
In case an ET Visit is performed remotely, the collection of the Lyme borreliosis screening sample will be omitted.  
(15) 
Female subjects aged ≥12 years and woman of childbearing potential. A woman is considered of childbearing potential if fertile and until becoming post-menopausal unless 
permanently sterile. A woman that is considered of non-childbearing potential must be e.g., surgically sterilized for at least 3 months prior to Visit 1 (e.g., by hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy, transcervical sterilization), or postmenopausal for at least one year prior to Visit 1. For serum pregnancy test: tests that were 
performed in study laboratory within visit window and where results are available at study visit are acceptable. Testing will only be performed in the 5 to 11 age cohort in 
female subjects after onset of menarche. 
(16) 
At vaccination visits, all samples have to be obtained before vaccination. Pregnancy results must be available before vaccination. 
(17) 
Blood will be collected for immunogenicity testing by an IgG binding assay 
.  
(18) 
Assay development sera will be collected in adult subjects (age cohort 18 to 65 years) only and will be used for further development of clinical assays.  
(19) 
To be performed by study staff otherwise not involved with study conduct to keep the study observer-blinded (i.e., un-blinded study staff) 
(20) 
Preparation of vaccination must be done by designated unblinded staff members (4.2.12) only. Administration of the vaccine can be performed by blinded OR unblinded 
staff. Vaccination with the assigned treatment has to be administered into the deltoid of the non-dominant arm. Subjects should be observed for at least 30 minutes for 
treatment of any immediate reactions. 
(21) 
If subject has any complaints after vaccination, a symptom-driven physical examination will be performed by the investigator prior to discharge. 

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(22) 
Except for Visit 1: Body systems for which the subject reports any symptoms should be evaluated and relevant abnormal findings documented as AEs. At vaccination days 
the symptom-driven physical exam is to be performed before administration of the vaccination. 
(23) 
At in-person visits for subjects aged 5-17 years.  
(24) 
At Visit 1, the subjects will be provided with thermometer and measuring tapes. The subjects will assess solicited local and systemic AEs themselves over a period of seven 
consecutive days after each vaccination. Subjects/ legal representative(s) will also be instructed to immediately inform the site in case of symptoms suggesting Lyme 
borreliosis, or any severe solicited AEs or other severe symptoms. 
(25) 
For Early Termination prior to Visit 6 in Part A or Visit 9/ Visit 17 in Part B, the previous injection site should be inspected.   
(26) 
Subject eDiary entries should be reviewed at the ET Visit if not done at previous visit. 
(27) 
Unsolicited AEs will be collected within 28 days after each vaccination. SAEs and AESIs will be collected throughout the entire study conduct and documented in the eCRF. 
Symptoms noted at Visit 1 prior to vaccination are not considered adverse events but will be recorded as medical history. 
(28) 
In females of non-childbearing potential (before onset of menarche) and male subjects aged <12 years i.e., without serum pregnancy and HIV test  
(29) 
In females aged <12 years and after onset of menarche i.e., with serum pregnancy test and without HIV test 
(30) 
In females of non-childbearing potential (surgically sterile or postmenopausal) and in males aged ≥12 years i.e., without serum pregnancy test and with HIV test  
(31) 
In females aged ≥12 years and of childbearing potential i.e., with serum pregnancy test and HIV test 
(32) 
A blood draw of in total 75.0 mL will be taken in subjects aged 18-65 years.  
(33) 
A blood draw of in total 12.0 mL will be taken in subjects from following age cohorts: 5-11 years and 12-17 years. 
(34) 
A blood draw of in total 87.0 mL (12.0 mL for immunogenicity and 75.0 mL for assay development) will be taken in subjects from age cohort 18-65 years. 
(35) 
Visit 8B should preferably be performed on the same day as Visit 8.  
(36) 
If the subject is unwilling to perform an ET visit, a phone call should be made to follow-up on Adverse Events and Concomitant Medications/Vaccinations. 
(37) 
Only to be performed if V8B is performed more than 14 days after V8, otherwise the assessment is already captured at Visit 8.  
(38) 
Test results do not need to be available before vaccination.  
 
 

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page 23 / 122 
 
SIGNATURE PAGE 
 
Title of Clinical Trial: 
SAFETY AND IMMUNOGENICITY STUDY OF VLA15, A MULTIVALENT 
RECOMBINANT OSPA BASED VACCINE CANDIDATE AGAINST LYME 
BORRELIOSIS: A RANDOMIZED, CONTROLLED, OBSERVER-BLIND 
PHASE 2 STUDY IN A HEALTHY PEDIATRIC AND ADULT STUDY 
POPULATION 
 
Study Code: 
VLA15-221 
IND number: 
 
 
With their signature, investigators and sponsor agree to conduct this study in accordance with 
the protocol, International Conference on Harmonization (ICH) and Good Clinical Practice 
(GCP) guidelines and with the applicable local regulatory requirements. Moreover, the site will 
keep all information obtained from the participation in this study confidential unless otherwise 
agreed in writing. 
 
 
Principal Investigator 
 
 
 
 
  
  
Print Name 
 Signature 
Date 
 
  
  
 
 
 
 
 

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 Signature 
 
Date 
Valneva Austria GmbH 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
Valneva Austria GmbH 
 Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 Signature 
 
Date 
Valneva Austria GmbH 
  
 
 
 
 
 

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LIST OF RESPONSIBLE PERSONNEL 
Responsible Medical / Safety Officer: 
 
Valneva Austria GmbH 
Phone:
  
Mobile Phone: 
 
Fax:
 
Email:
 
 
Monitoring: 
 
 
 
Phone:
 
Fax:
 
 
Serious Adverse Event (SAE) reporting by fax within 24 hours  
after discovery:  
Pfizer Safety 
SAE fax number:  
 
 
AESI reporting by email to: 
 Safety Desk 
 
 
  
Phone:
 
AESI e-mail: 
   
  
Study Medical Monitor: 
 
 
 
  
Phone:
 
Fax:
 
E-mail: 
 
 
 
 
 
 

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Laboratories: 
Immunological Assays:  
Valneva Austria GmbH 
Clinical Serology 
 
 
Phone:
 
Fax:
 
 
Pfizer Vaccine Research and Development 
 
 
 
 
 
  
 
  
 
 
Statistical Analysis: 
 
 
 
Phone: 
 
Email: 
 
 
Data Management: 
 
 
 
Phone: 
 
Email: 
 

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TABLE OF CONTENTS 
 
1 
INTRODUCTION ......................................................................................................31 
 
DISEASE BACKGROUND ............................................................................................................... 31 
 
LYME BORRELIOSIS VACCINES ..................................................................................................... 31 
 
VACCINE CANDIDATE VLA15 ....................................................................................................... 32 
 
PREVIOUS RESULTS .................................................................................................................... 32 
1.4.1 
Repeat dose toxicology study in rabbits .........................................................................................32 
1.4.2 
In vivo efficacy studies in mice........................................................................................................33 
1.4.3 
Clinical studies with VLA15 .............................................................................................................33 
1.4.3.1 
Phase 1 Study VLA15-101 ................................................................................................... 36 
1.4.3.2 
Phase 2 Studies VLA15-201, VLA15-202 and VLA15-221................................................... 36 
 
STUDY RATIONALE ...................................................................................................................... 43 
 
RISK - BENEFIT ANALYSIS ........................................................................................................... 43 
2 
STUDY OBJECTIVES ..............................................................................................46 
 
PRIMARY OBJECTIVE ................................................................................................................... 46 
 
SECONDARY OBJECTIVES............................................................................................................ 46 
 
EXPLORATORY OBJECTIVE: ......................................................................................................... 46 
3 
SELECTION OF STUDY POPULATION ...................................................................47 
4 
INVESTIGATIONAL PLAN ........................................................................................51 
 
STUDY ENDPOINTS ..................................................................................................................... 51 
 
STUDY DESIGN AND PLAN ........................................................................................................... 52 
4.2.1 
Study Description ............................................................................................................................52 
4.2.2 
Study Design ..................................................................................................................................54 
4.2.3 
Discussion of study design .............................................................................................................56 
4.2.4 
Study events description .................................................................................................................58 
4.2.5 
Number of subjects and study centres ............................................................................................77 
4.2.6 
Timely conduct of the study ............................................................................................................77 
4.2.7 
Study duration.................................................................................................................................77 
4.2.8 
Assignment of subjects to study groups .........................................................................................77 
4.2.9 
Subject Identification .......................................................................................................................77 
4.2.10 Re-screening ..................................................................................................................................78 
4.2.11 Randomization ................................................................................................................................78 
4.2.12 Blinding ...........................................................................................................................................78 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS .........................................................79 
 
DESCRIPTION OF IMP ................................................................................................................. 79 
5.1.1 
VLA15 Presentation for primary vaccination series and first booster ..............................................79 
5.1.2 
VLA Placebo for primary vaccination series and first booster .........................................................80 
5.1.3 
Condition of storage of IMP for primary vaccination series and first booster ..................................80 
5.1.4 
VLA15 presentation for subsequent booster vaccinations ..............................................................80 
5.1.5 
Placebo for subsequent booster vaccinations.................................................................................81 
5.1.6 
Condition of storage of IMP for subsequent booster vaccinations ..................................................81 
5.1.7 
Packaging & labelling of IMP ..........................................................................................................81 
6 
TREATMENT OF SUBJECTS ...................................................................................82 
 
INVESTIGATIONAL TREATMENT ..................................................................................................... 82 
6.1.1 
Dose and dosing schedule .............................................................................................................82 
6.1.2 
Preparation and method of administration for primary vaccination series and first booster 
vaccination ...................................................................................................................................................82 
6.1.3 
Preparation and method of administration for subsequent booster vaccinations ............................83 
6.1.4 
Treatment duration .........................................................................................................................83 
 
PRIOR AND CONCOMITANT THERAPY ........................................................................................... 83 
6.2.1 
Permitted prior and concomitant therapy ........................................................................................83 
6.2.2 
Forbidden concomitant therapy ......................................................................................................83 
 
TREATMENT COMPLIANCE ........................................................................................................... 84 
6.3.1 
Drug dispensing and accountability ................................................................................................84 
 
PREGNANCY TESTING AND BIRTH CONTROL .................................................................................. 84 
7 
ASSESSMENT OF IMMUNOGENICITY ...................................................................85 
 
IMMUNOGENICITY MEASUREMENTS .............................................................................................. 85 
7.1.1 
OspA serotype specific IgG binding assay .....................................................................................85 
 
 
7.1.3 
Additional Testing Procedures ........................................................................................................86 
8 
ASSESSMENT OF SAFETY .....................................................................................86 

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PHYSICAL EXAMINATION .............................................................................................................. 86 
 
VITAL SIGNS, ECG AND ORAL BODY TEMPERATURE .................................................................... 87 
 
SOLICITED AES AND SUBJECT DIARY ........................................................................................... 87 
8.3.1 
Collection, assessment and documentation of solicited AEs ..........................................................87 
8.3.2 
Severity of solicited AEs .................................................................................................................88 
 
UNSOLICITED AES ...................................................................................................................... 90 
8.4.1 
Collection, follow-up and documentation of unsolicited AEs ...........................................................91 
8.4.2 
Evaluation of unsolicited AEs..........................................................................................................92 
8.4.2.1 
Definition of medically attended AEs .................................................................................... 92 
8.4.2.2 
Definition of Serious Adverse Events (SAEs) ....................................................................... 92 
8.4.2.3 
SAE reporting procedure ...................................................................................................... 92 
8.4.2.4 
Definition of Adverse Events of Special Interest (AESIs) ..................................................... 93 
8.4.2.5 
Collection and evaluation of Adverse Events of Special Interest (AESIs) ............................ 93 
8.4.2.6 
Severity of unsolicited AEs ................................................................................................... 94 
8.4.2.7 
Causality assessment .......................................................................................................... 95 
8.4.2.8 
Outcome ............................................................................................................................... 95 
8.4.2.9 
Actions taken ........................................................................................................................ 95 
8.4.3 
Timeframe for reporting of unsolicited AEs .....................................................................................96 
8.4.4 
Environmental Exposure, Exposure During Pregnancy or Breastfeeding and Occupational 
Exposure reporting procedures ....................................................................................................................96 
8.4.4.1 
Exposure During Pregnancy (EDP) ...................................................................................... 96 
8.4.4.2 
Exposure During Breastfeeding ........................................................................................... 98 
8.4.4.3 
Occupational Exposure ........................................................................................................ 98 
8.4.5 
Medication Errors ............................................................................................................................98 
8.4.6 
Lack of Efficacy ...............................................................................................................................99 
 
LABORATORY PARAMETERS ........................................................................................................ 99 
 
SAFETY MONITORING ................................................................................................................ 100 
8.6.1 
Internal Review Committee (IRC) .................................................................................................100 
8.6.2 
Data Monitoring Committee (DMC) ...............................................................................................100 
8.6.3 
Sponsor ........................................................................................................................................101 
9 
STATISTICAL METHODS AND SAMPLE SIZE ....................................................... 101 
 
GENERAL ASPECTS ................................................................................................................... 101 
 
ANALYSIS SETS ........................................................................................................................ 102 
 
IMMUNOGENICITY ANALYSIS ...................................................................................................... 103 
 
SAFETY ANALYSIS ..................................................................................................................... 104 
 
GENERAL CONSIDERATIONS FOR THE DETERMINATION OF THE OPTIMAL SCHEDULE ....................... 105 
 
DETERMINATION OF SAMPLE SIZE .............................................................................................. 105 
 
DATA ANALYSES ....................................................................................................................... 106 
10 
DEVIATIONS FROM THE PROTOCOL .................................................................. 106 
 
RELEVANT PROTOCOL DEVIATIONS............................................................................................ 106 
 
PREMATURE SUBJECT WITHDRAWAL FROM STUDY OR TREATMENT ............................................. 106 
10.2.1 Individual stopping criteria ............................................................................................................107 
 
DOCUMENTATION OF PREMATURE WITHDRAWAL ........................................................................ 107 
 
SUBSEQUENT THERAPY ............................................................................................................ 108 
11 
ETHICAL AND REGULATORY ASPECTS .............................................................. 108 
 
ETHICAL/ REGULATORY FRAMEWORK ........................................................................................ 108 
 
INSTITUTIONAL REVIEW BOARD ................................................................................................. 108 
 
SUBJECT INFORMATION AND INFORMED CONSENT/ASSENT ......................................................... 108 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 108 
 
SOURCE DATA AND RECORDS ................................................................................................... 108 
 
PERIODIC MONITORING ............................................................................................................. 109 
 
AUDIT AND INSPECTION ............................................................................................................. 109 
 
CONFIDENTIALITY OF SUBJECT’S DATA ...................................................................................... 109 
13 
DATA HANDLING AND RECORD KEEPING .......................................................... 109 
 
INFORMATION FOR INVESTIGATORS ............................................................................................ 109 
 
ELECTRONIC CASE REPORT FORMS (ECRFS) ............................................................................ 109 
13.2.1 eCRF entries.................................................................................................................................109 
13.2.2 Changes to eCRF data .................................................................................................................110 
13.2.3 eCRF entry validation ...................................................................................................................110 
13.2.4 Data collection ..............................................................................................................................110 
 
CODING OF ADVERSE EVENTS, DRUGS AND DISEASES ............................................................... 110 
 
INVESTIGATOR FILE ................................................................................................................... 110 
13.4.1 Maintenance .................................................................................................................................110 

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13.4.2 Archiving and destruction .............................................................................................................110 
 
PROVISION OF ADDITIONAL INFORMATION .................................................................................. 111 
14 
CHANGES IN THE CONDUCT OF THE STUDY .................................................... 111 
 
PROTOCOL AMENDMENTS ......................................................................................................... 111 
 
STUDY TERMINATION – STUDY STOPPING RULES ....................................................................... 111 
 
STUDY CHANGES IN RESPONSE TO THE COVID-19 PANDEMIC SITUATION .................................. 111 
15 
REPORTING AND PUBLICATION .......................................................................... 112 
 
CLINICAL STUDY REPORT .......................................................................................................... 112 
 
PUBLICATION POLICY ................................................................................................................ 112 
16 
LIABILITIES AND INSURANCE .............................................................................. 112 
17 
APPENDIX 1 .......................................................................................................... 113 
18 
APPENDIX 2 .......................................................................................................... 114 
19 
REFERENCES ....................................................................................................... 117 
  
LIST OF TABLES 
Table 1 Study Groups and Vaccinations ................................................................................................. 7 
Table 2 TABLE OF EVENTS – Part A: MAIN STUDY PHASE ............................................................. 18 
Table 3 TABLE OF EVENTS – Part B: BOOSTER PHASE .................................................................. 19 
Table 4 Overview of the VLA15 Clinical Development Program ........................................................... 34 
Table 5 Solicited Local Adverse Events after any Vaccination (primary vaccination series) by 
Symptom, Safety Population .................................................................................................. 40 
Table 6 Solicited Systemic Adverse Events after any Vaccination (primary vaccination series) by 
Symptom, Safety Population .................................................................................................. 41 
Table 7 Solicited Local Adverse Events after Month 18 Booster Vaccination by Symptom, Safety 
Population .............................................................................................................................. 42 
Table 8 Solicited Systemic Adverse Events after Month 18 Booster Vaccination by Symptom, Safety 
Population .............................................................................................................................. 42 
Table 9 Overview of components of 180 µg VLA15 presentation ......................................................... 80 
Table 10 Grading of Solicited Adverse Events ...................................................................................... 89 
Table 11 Early disseminated or late disseminated Lyme borreliosis .................................................. 115 
 
LIST OF FIGURES 
Figure 1 Subject enrollment process in Part A (Main Study Phase) ....................................................... 4 
Figure 2 Study Design ............................................................................................................................. 6 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
Alum 
ANOVA 
Al(OH)3, Aluminum Hydroxide 
Analysis of variance 
ATC 
Anatomical Therapeutic Chemical 
B.b. s.l. 
Borrelia burgdorferi sensu lato  
BFAS 
Booster Full Analysis Set  
BPPAS 
Booster Per-Protocol Analysis Set  
BSAS 
Booster Safety Analysis Set 
BSL2 
Biological Safety Level 2 
CA 
Competent Authority 
CI 
Confidence Interval 
CR 
Clinically Relevant 
CRA 
Clinical Research Associate 
CMO 
eCRF 
Contract Manufacturing Organization  
Electronic Case Report Form 
CSR 
Clinical Study Report  
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
e.g. 
For Example 
EC 
Ethics Committee 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EMA 
European Medicines Agency 
EudraCT 
European Clinical Trials Database 
ET 
Early Termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GCLP 
Good Clinical Laboratory Practice 
GLP 
Good Laboratory Practice 
GMFR 
Geometric Mean Fold Rise 
GMT 
Geometric Mean Titer 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonization 
i.e. 
That Is 
I.M. 
Intramuscular 
IgG 
Immunoglobulin G 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
kDa 
Kilo Dalton 
IRC 
Internal Review Board  
ITT 
Intent-to-Treat 
LB 
Lyme borreliosis 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram 
M 
Month 
mm 
Millimeter(s) 
mg 
Milligram(s) 
min 
Minute(s) 
mL 
Milliliter(s) 
N/A 
Not Applicable 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
No. 
Number(s) 
OspA 
Outer surface protein A 
PBS 
Phosphate Buffered Saline 
PCR 
Polymerase Chain Reaction 

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PFS 
Pre-filled syringe 
PP 
Per Protocol 
PPAS 
Per-Protocol Analysis Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
 
 
SCR 
Seroconversion Rate 
SOP 
Standard Operating Procedures 
ST 
Serotype 
ULN 
Upper Limit of Normal 
V 
Visit 
WBC 
White blood cell 
WHO 
World Health Organization 
w/ 
With 
w/o 
Without 
yrs 
Years 
 

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1 
INTRODUCTION 
 
Disease Background 
Lyme borreliosis (LB) is an emerging, tick-borne zoonotic disease caused by several 
genospecies of the spirochete Borrelia burgdorferi sensu lato (s.l.). It is recognized as the most 
common vector-borne disease in both Europe and North America1. In Europe, incidence based 
on notified cases report about 85,000 cases per year2, however, due to inconsistent case 
reporting and the fact that LB is often undiagnosed, this number is largely underestimated3,4. 
In the US, the Center for Disease Control and Prevention (CDC) estimates about 300,000 
cases annually with a  ≈62% rise in median Lyme disease diagnose incidences during 2010-
2018 compared to 2005-20105,6. The incidence of LB has a bimodal distribution with respect 
to age. Two target populations are mainly affected: children aged 5-14 years and the adult 
population aged 50-64 years3,7. 
In Europe, most human infections are caused by four genospecies, presenting six serotypes 
(STs): B. afzelii (ST2), B. garinii (ST3, ST5 and ST6), B. burgdorferi sensu stricto (s.s.) (ST1) 
and B. bavariensis (ST4). In the US, B. burgdorferi s.s. (ST1) is found in almost 100% of cases. 
Recently, a new genospecies named Borrelia mayonii has been described, which was found 
in few clinical specimens isolated in the Upper Midwest of the US8. 
The most common clinical manifestation of LB is a gradually expanding erythematous skin 
rash called erythema migrans (EM), a distinct sign of early localized Borrelia infection. An EM 
appears within days to weeks at the location of the tick bite and is often accompanied by 
symptoms of fatigue, fever, headache, mild stiff neck, arthralgia, or myalgia1. In approximately 
70% - 80% of LB cases patients develop an EM9,10. 
If untreated or treated inadequately, the infection can disseminate to other parts of the body 
and can cause serious late stage manifestations affecting the nervous system (facial palsy, 
meningitis, myelitis, and encephalitis), joints (recurrent or persistent large joint synovitis), or 
heart (e.g., conduction abnormalities and carditis). 
The most common late stage clinical manifestations of LB that develops in about 30% of 
patients include musculoskeletal manifestations, such as Lyme arthritis. Lyme arthritis 
comprises recurrent attacks or long-lasting joint swelling (synovitis), usually in one or a few 
joints most commonly the knee, which develops months after a tick bite. Nervous system 
manifestations include Lyme neuroborreliosis, most commonly presented as cranial 
neuropathy with facial nerve palsy, possibly with bilateral involvement (bilateral Bell’s palsy), 
within a few weeks of infection. In adults, the disease typically presents as painful 
meningoradiculoneuritis and facial palsy. In contrast, children most frequently develop 
headache due to meningitis, and facial palsy. In children there are shorter lasting symptoms 
and better outcomes. Cardiac manifestations in LB appear to be uncommon, and Lyme carditis 
usually presents within two months of infection as myocarditis with acute intermittent 
atrioventricular heart block. In Europe, more severe skin manifestations (e.g., acrodermatitis 
chronica atrophicans (ACA), borrelial lymphocytoma) can result from disseminated infection 
as late complications9. 
 
Lyme borreliosis vaccines 
Two OspA based Lyme borreliosis vaccines have previously shown to be efficacious to prevent 
Lyme borreliosis in humans: LYMErix (Smith Kline Beecham) and ImuLyme (Pasteur Mérieux 
Connaught). Both vaccines contained Outer surface protein A (OspA) from B. burgdorferi 
(ST1) as antigen, a surface exposed lipoprotein of 28.5 kDa. OspA is one of the dominant 
antigens expressed by the spirochetes when present in an unfed tick. During tick feeding the 
incoming blood signals the downregulation of OspA expression, allowing the spirochetes to 
migrate to the salivary glands and further into the blood of the host. OspA-based LB vaccines 

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act on spirochetes in the tick gut, where spirochetes are neutralized by anti-OspA antibodies 
in a complement independent manner, before they can infect the human. 
In LYMErix, OspA was absorbed to aluminum hydroxide and demonstrated vaccine efficacy of 
49% in the first tick season (i.e., after 2 vaccine doses) and of 76% in the second tick season 
(i.e. after 3 doses) in clinical Phase III testing11. ImuLyme was tested in a non-adjuvanted 
formulation of OspA in clinical Phase III and conferred protection in 68% and in 92% of subjects 
in the first and second tick season, respectively (after 2 and 3 vaccine doses)12. 
LYMErix has been licensed and marketed in the US from 1998 to 2002, when it was voluntarily 
withdrawn from the market. A relationship between the Lyme borreliosis vaccine and joint 
reactions was hypothesized because of partial homology of OspA ST1 in the vaccine with 
hLFA-1 antigen (human leukocyte function-associated antigen-1) that was claimed to induce 
antibiotic-refractory Lyme arthritis in a subset of naturally infected patients. The hypothesis 
could not be proven. On the contrary, a retrospective study of joint complaints after vaccination 
reported to the Vaccine Adverse Event Reporting System showed no unusual number of such 
complaints. In the Phase III study of the vaccine, the incidence of transient arthralgia was non-
significantly increased in vaccinees, but the incidence of arthritis was not increased as 
compared to the placebo group13. 
ImuLyme (Pasteur Mérieux Connaught) was never marketed based on a commercial decision. 
In Europe, no Lyme borreliosis vaccine has been licensed until now. 
More recently, a clinical Phase I/II study has been performed by Baxter BioScience. Similar to 
the vaccine candidate VLA15, the vaccine candidate is a multivalent OspA based LB vaccine, 
designed to provide protection against the most prevalent OspA ST1 to ST614,15. Overall, it 
could be shown that the vaccine candidate was safe and well tolerated and induced substantial 
antibody responses against all six OspA serotypes. 
 
Vaccine Candidate VLA15 
Valneva’s VLA15 vaccine candidate is composed of three ~35 kDa fusion proteins (designated 
as Lip-D1B2B, Lip-D4Bva3B and Lip-D5B6B), each containing the C-terminal part of two OspA 
serotypes representing the serotype dominating in the USA and the six serotypes that are 
prevalent in Europe. Each fusion protein is built of two subunits containing the C-terminal half 
of two OspA serotypes, fused together via a linker. The C-terminal half of OspA is the exposed 
part of OspA on the surface of spirochetes and therefore readily accessible for antibodies. In 
order to stabilize the OspA subunits at physiological temperatures and preserve the structure 
needed to induce protective immunity, one disulfide bond per subunit has been introduced. 
The 21 amino acids linker used to fuse the two subunits is derived from two N-terminal loops 
from B. burgdorferi OspA (ST1) and designed to induce flexibility and distance between the 
subunits to keep epitopes accessible. Each protein is fused to an N-terminal lipid moiety which 
results in higher immunogenicity as shown in preclinical tests. 
Further, the putative T cell epitope in OspA ST1, which presents homology to human leukocyte 
function-associated antigen-1 (hLFA-1) and previously claimed to induce antibiotic-refractory 
Lyme arthritis in a subset of naturally infected patients has been replaced with the 
corresponding sequence from OspA ST2. The design of the VLA15 vaccine has been chosen 
in order to induce a strong serotype specific immunity needed for protection against infection 
by Borrelia expressing OspA ST1 to ST6. 
 
Previous Results 
1.4.1 Repeat dose toxicology study in rabbits 
Safety and tolerability of VLA15 was tested in a repeated dose toxicology study in male and 
female New Zealand White rabbits. The study was performed under GLP conditions and 
according to respective guidelines from WHO and EMA. Animals were dosed with 4 

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intramuscular injections (each dose 90 μg of antigen) administered at two weeks intervals. 
VLA15 was administered with or without an aluminium hydroxide adjuvant (alum). Results from 
this study were supportive for clinical use and are summarized in the VLA15 Investigator’s 
Brochure. 
1.4.2 In vivo efficacy studies in mice 
The efficacy of VLA15 was demonstrated for five of the six OspA serotypes in two mouse 
challenge models: a tick challenge model for ST1, ST2 and ST4, where immunized mice were 
challenged with ticks harboring B. burgdorferi (ST1), B. afzelii (ST2) or B. bavariensis (ST4) 
and a needle challenge model, where immunized mice were challenged subcutaneously with 
in vitro grown B. garinii (ST5 or ST6). Groups of mice immunized with the corresponding full-
length OspA; Lip-OspA1-His (ST1), Lip-OspA2-His (ST2), Lip-OspA4-His (ST4), Lip-OspA5-
His (ST5) or Lip-OspA6-His (ST6) were included as positive control in the respective 
experiment.  
In summary, it was shown that VLA15 is highly immunogenic and produces a long-lasting 
immune response. Protective efficacy against four Borrelia species (B. burgdorferi, B. afzelii, 
B. bavariensis and B. garinii) including five clinically relevant OspA serotypes (1, 2, 4, 5 and 6) 
could be demonstrated in mouse models using either infected ticks or in vitro grown 
spirochetes for challenge. 
For more details on immunogenicity and efficacy, please refer to VLA15 Investigator’s 
Brochure. 
1.4.3 Clinical studies with VLA15 
At the time of release date of this CSP Version 11.0, the clinical development program of 
VLA15 comprises one completed Phase 1 study (VLA15-101), two completed and one ongoing 
Phase 2 studies (VLA15-201, VLA15-202 and VLA15-221, respectively) and two ongoing 
Phase 3 studies (C4601003 and C4501012). Table 4 summarizes the VLA15 Clinical 
Development Program: 
 
 

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Table 4 Overview of the VLA15 Clinical Development Program 
 
Study Title 
Vaccination 
Schedule 
(Month) 
Number 
of 
Subjects 
Randomization 
Treatment 
Study 
Region 
Study Status 
Phase 1 
VLA15-101 
Study assessing the safety, immunogenicity 
and dose response of VLA15, a new 
multivalent 
recombinant 
OspA 
vaccine 
candidate against Lyme borreliosis, in healthy 
adults aged below 40 years 
0-1-2 
179 
1:1:1 
12 µg w/ or w/o Alum 
Non-endemic 
Europe & US 
Completed 
48 µg w/ or w/o Alum 
90 µg w/ or w/o Alum 
Booster Extension of Study VLA15-101 
13 
64 
1:1 
48 µg w/ or w/o Alum 
Non-endemic 
Europe 
Completed 
90 µg w/ or w/o Alum 
Phase 2* 
VLA15-201 
Immunogenicity and safety study of VLA15, a 
multivalent recombinant OspA based vaccine 
candidate against Lyme borreliosis, in healthy 
adults aged 18 to 65 years - A randomized, 
controlled, observer-blind Phase 2 study  
 
0-1-2 
 
Run-In Phase: 
120 
Main Study 
Phase: 
452 
1:1:1:1 
 
 
2:2:1 
(90 µg)†  
Endemic 
Europe & US 
 
Completed 
 
135 µg 
180 µg 
Placebo 
VLA15-202 
Alternative schedule study for VLA15, a 
multivalent recombinant OspA based vaccine 
candidate against Lyme borreliosis, in healthy 
adults aged 18 to 65 years – A randomized, 
controlled, observer-blind Phase 2 study. 
0-2-6 
246 
2:2:1 
135 µg  
Endemic 
US 
Completed 
180 µg  
Placebo 
Booster Extension of Study VLA15-202 
18 
58 
2:1 
180 µg 
Completed 
Placebo 
VLA15-221 
Safety and immunogenicity study of VLA15, a 
multivalent recombinant OspA based vaccine 
candidate 
against 
Lyme 
Borreliosis: 
A 
randomized, controlled, observer-blind Phase 
2 study in a healthy pediatric and adult study 
population  
0-2-6  
or  
0-6 
625 
2:1 
180 µg 
Endemic 
US 
Completed 
Placebo 
 
 
 
 
* In Phase 2 only alum adjuvanted VLA15 presentations are administered.  
† Run-In Phase only 

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Phase 2* 
VLA15-221 
Booster Phase of Study VLA15-221 
18 
~600 
2:1 
180 µg 
Endemic  
US 
Completed 
Placebo 
30 
~400 
2:1 
180 µg 
Ongoing 
Placebo 
42 
~300 
2:1 
180 µg 
Planned Start: 
August 2024 
Placebo 
Phase 3* 
C4601003 
A Phase 3, multicenter, placebo-controlled, 
randomized, observer-blinded trial to evaluate 
the 
efficacy, 
safety, 
tolerability, 
immunogenicity, and lot consistency of a 
6valent OspA-based Lyme disease vaccine in 
healthy participants ≥5 years of age 
 
0-2-5 to 9 
and 
18 
~9000 
1:1 
180 µg  
Endemic 
Europe & NA 
Ongoing 
Placebo 
C4601012 
A Phase 3 randomized, placebo-controlled, 
observer-blinded trial to evaluate the safety of 
a 6-valent OspA-based Lyme disease vaccine 
(VLA15) in healthy children 5 through 17 
years of age 
 
0-2-6  
and 
18 
~3550 
3:1 
180 µg  
US 
Ongoing 
Placebo 
 
* In Phase 2 and 3 only alum adjuvanted VLA15 presentations are administered.  

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1.4.3.1 Phase 1 Study VLA15-101 
The first clinical study with VLA15 was conducted in 179 healthy adults aged 18 to <40 years 
in Belgium and in the US. As this Phase 1 study was the first-in-human study with VLA15, 
special safety measures were implemented, and the first 24 subjects were vaccinated open-
label and in a staggered dose escalation approach. Thereafter the study was conducted in an 
observer-blinded manner. The remaining 155 subjects were randomized into six study groups 
to receive either VLA15 12 µg w/ Alum, VLA15 12 µg w/o Alum, VLA15 48 µg w/ Alum, VLA15 
48 µg w/o Alum, VLA15 90 µg w/ Alum or VLA15 90 µg w/o Alum. The vaccinations were 
administered I.M. at 28 days apart (i.e., at Month 0-1-2). 
Data from the primary vaccination series revealed that VLA15 was generally safe and well 
tolerated in all study groups with no associated safety concerns. In addition, this part of the 
study showed that VLA15 was immunogenic in all doses and formulations tested with 
adjuvanted formulations being more immunogenic than non-adjuvanted formulations of the 
same dose level.  
Subjects that were enrolled in Belgium, who completed the primary immunization schedule 
(three vaccinations) and were assigned in the 48 µg or 90 µg dose groups, were asked to 
participate in a Booster Extension. In total, 64 subjects (out of 179 subjects from the Initial 
Study) participated in the Booster Extension and received a booster dose approximately one 
year after the first vaccination. The administration of a booster dose was also generally safe 
and well tolerated in all study groups. In addition, the booster vaccination resulted in a 
pronounced antibody titer increase for all doses and formulations tested and all for OspA 
serotypes (ST1-ST6).   
Safety and immunogenicity results of the Phase 1 study VLA15-101 are described in more 
detail in the Clinical Study Report, dated 24 April 2019. Safety and Immunogenicity results of 
the Booster Extension of the VLA15-101 study are described in more detail in the Clinical Study 
Report, dated 05 December 2019. In addition, summarized safety and immunogenicity data of 
Phase 1 can be found in the current version of the Investigator’s Brochure. 
1.4.3.2 Phase 2 Studies VLA15-201, VLA15-202 and VLA15-221 
Two Phase 2 studies (VLA15-201 and VLA15-202) have been completed. Both studies were 
investigating higher VLA15 dose levels in adjuvanted forms as compared to Phase 1 as well 
as two different immunization schedules (Month 0-1-2 and Month 0-2-6). In both studies, 
subjects received in total three injections of either 135 µg VLA15, 180 µg VLA15 or placebo. 
Further on, eligible subjects receiving the VLA15 180 µg dose in study VLA15-202 were re-
randomized to receive a booster dose of VLA15 180 µg or placebo at Month 18. A DSMB (Data 
Safety Monitoring Board; same DSMB for both studies) has reviewed unblinded accruing 
safety information of both studies in parallel at regular intervals. The DSMB did not identify a 
safety concern. Present Phase 2 study (VLA15-221) is currently ongoing; safety and 
immunogenicity data up to Month 12 are available. At finalization date of this CSP, Month 18 
booster vaccinations are completed. Until now, the DMC has not identified a safety concern 
and recommended to continue the study as planned.  
 
VLA15-201 Phase 2 Clinical Study  
VLA15-201 was an observer-blinded, randomized, multicenter Phase 2 study. Main objective 
was to determine the optimal dose of VLA15 in healthy adults aged 18 to 65 years. The study 
started with a 120 subjects (18-40 years) Run-In Phase to evaluate safety of the higher dose 
levels of VLA15 w/ alum initially in a smaller population (90 µg: N=29; 135 µg: N=31; 180 µg: 
N= 30; Placebo: N=30). After review of safety data by an independent DSMB, 452 subjects 
(135 µg: N=183; 180 µg=175; Placebo: N=94) aged 18-65 years were enrolled in the Main 
Study Phase to receive according to the allocated study group three injections of either VLA15 
or placebo at Month 0-1-2. Subjects were followed for safety and immunogenicity up to one 
year after administration of the first vaccination.  

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Overall, 517 of 572 subjects (90.4%) reported any solicited or unsolicited AE. Most AEs were 
mild to moderate in severity. A total of 18 subjects (3.1%) experienced severe related AEs, all 
of them were solicited AEs and as such counted per definition as related: nine subjects (4.2%) 
in the 135 µg group and nine subjects (4.4%) in the 180 µg group. Solicited local AEs were 
reported by 89.7% (90 µg group), 93.0% (135 µg group) and 96.1% (180 µg group) of subjects, 
compared to 29.8% of subjects in the placebo group. The most common solicited local AEs 
were pain (84.6%, pooled VLA15 groups) and tenderness (92.2%, pooled VLA15 groups). 
Solicited systemic AEs were reported by 62.1% (90 µg group), 67.8% (135 µg group) and 
71.7% (180 µg group) of subjects, compared to 42.7% of subjects in the placebo group. The 
most common solicited systemic AEs were headache (35.7%, pooled VLA15 groups), fatigue 
(33.9%, pooled VLA15 groups) and myalgia (47.8%, pooled VLA15 groups). In general, rates 
of solicited local and systemic AEs declined with subsequent vaccinations. An overview of 
solicited AEs is shown in Table 5 and Table 6.  
No vaccine related severe unsolicited Adverse Event and no related Serious Adverse Event 
was reported. One case of osteoarthritis (135 µg group) was reported as AESI. This case was 
initially reported as suspected symptomatic borreliosis and assessed as possibly being related 
by the investigator. After detailed clinical workup including diagnostic serology testing and x-
ray analysis by a rheumatologist, the DSMB concluded that this case is an osteoarthritis and 
not related to study vaccination. Diagnosis of osteoarthritis was agreed by the investigator. In 
addition, three cases (1.4%) of Lyme disease/Erythema migrans were reported in the 135 µg 
group and one case (0.5%) of Polyarthritis was reported in the 180 µg group as AESI. All of 
these were assessed as unrelated to study vaccine.  
VLA15 was immunogenic at all dose levels tested and induced significant IgG antibody levels 
by Day 85 (i.e., 1 month after completion of the vaccination series). A dose response was 
observed, with lowest IgG titers being observed in the 90 µg dose group and highest titers 
being observed in the 180 µg dose group for all serotypes. At Day 85, in the 90 µg group, the 
GMTs ranged from 74.3 (ST1) to 267.4 (ST3). In the 135 µg group the GMTs reached levels 
of 101.9 (ST1) to 283.2 (ST3), whereas in the 180 µg group GMTs were 115.8 (ST1) to 308.6 
(ST3). Differences in GMTs between VLA15 dose groups were not significant.  
More details on safety and immunogenicity results of the VLA15-201 study are described in 
the latest version of the Investigator Brochure.  
 
VLA15-202 Phase 2 Clinical Study  
VLA15-202 was an observer-blinded, randomized, multicentre Phase 2 study. Main objective 
of this study was the investigation of the immune response of three primary vaccinations 
applied at an alternative immunization schedule, i.e., Month 0-2-6 (Main Study Phase). Further 
on, eligible subjects receiving the VLA15 180 µg dose were re-randomized to receive a booster 
dose of VLA15 180 µg or placebo at Month 18 (Booster Phase).  
A total of 246 healthy adults aged 18-65 years were randomized 2:2:1 to receive three VLA15 
vaccinations of either 135 µg w/ alum (N=97), 180 µg w/ alum (N=98) or placebo (N=51) at 
Month 0, 2 and 6. Thereof, 58 subjects from the VLA15 180 µg group were re-randomized to 
receive a booster vaccination of VLA15 180 µg (N=39) or placebo (N=19) at Month 18 and 
were followed-up until one year after booster administration (i.e., Month 30).   
In the Main Study Phase, a total of 234 of 246 subjects (95.1%) reported any solicited or 
unsolicited AE up to Month 18 (i.e., one year after the last dose of the primary vaccination 
series). Most AEs were mild or moderate in severity. A total of 15 subjects (6.1%) experienced 
severe related AEs; 14 (5.7%) subjects experienced at least one severe solicited AEs of Grade 
3, as such counted per definition as related: 6 subjects (6.2 %) in the 135 µg group, 7 subjects 
(7.1%) in the 180 µg group, and 1 subject (2.0 %) in the placebo group. One subject in the 135 
µg group experienced a severe unsolicited event of Ventricular extrasystoles which was 

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assessed as possibly related to study vaccine by the investigator. Subject had a history of 
benign premature ventricular contractions. The event occurred 13 days after the second 
vaccination and was treated with Propranolol. The event recovered after 39 days.   
Solicited local AEs after the primary vaccination series were reported by 95.9% (135 µg group) 
and 98.0% (180 µg group) of subjects, compared to 45.1% of subjects in the placebo group. 
The most common solicited local AEs were pain (89.2%, pooled VLA15 groups) and 
tenderness (95.9%, pooled VLA15 groups). Solicited systemic AEs were reported by 78.4% 
(135 µg group) and 69.4% (180 µg group) of subjects, compared to 51.0% of subjects in the 
placebo group. The most common solicited systemic AEs were myalgia (54.9%, pooled VLA15 
groups), headache (44.6%, pooled VLA15 groups) and fatigue (31.8%, pooled VLA15 groups). 
Rates of solicited local and systemic AEs declined after the first vaccination. Most solicited 
AEs were mild or moderate. An overview of solicited AEs after the primary vaccination series 
is shown in Table 5 and Table 6.  
After administration of a booster dose of VLA15 180 µg at Month 18, 89.7% of subjects 
reported any solicited local AE: 63.2 % pain, 89.5% tenderness, 19.4% erythema, 7.9% 
swelling, 5.3% induration. Further on, 51.3% of subjects reported any solicited systemic AE: 
21.1% headache, 2.7% flu like symptoms, 7.9% nausea, 2.7% vomiting, 18.4% fatigue, 10.5% 
arthralgia and 28.9% myalgia.  
No related serious AEs were reported for the duration of the study. During the Main Study 
Phase two events were reported as AESI (Adverse Event of Special Interest): One case of 
Lyme disease (135 µg group): erythematous rash (approximately 2 cm), developed 
approximately 2 weeks after 1st vaccination. One case of ventricular extrasystoles (135 µg 
group) which was assessed as possibly related to study vaccine by the Investigator. The 
subject had a history of benign premature ventricular contractions. During the Booster Phase, 
one case of a suspected Lyme disease, which developed approx. 2 months after booster 
vaccination, was reported. No other cases of predefined AESIs, e.g., arthritis, rheumatoid 
arthritis or facial paralysis, were observed. 
VLA15 was immunogenic at both dose levels (135 µg, 180 µg) tested. GMTs at Day 208 (i.e., 
1 months after the third vaccine dose) ranged from 278.5 (ST1) to 545.2 (ST2) in the 135 µg 
group and from 274.7 (ST1) to 596.8 (ST3) in the 180 µg group. There was a trend that the 
180 µg dose induces a faster onset of immunity. Functionality of antibodies could be 
demonstrated using a 
 for all serotypes with GMTs ranging from 30.9 
(ST5) to 1201.8 (ST3) in the 135 µg group and from 36.8 (ST5) to 1408.0 (ST3) in the 180 µg 
group at Day 208. Respective seroconversion rates (SCRs) ranged from 41.9% (ST5) to 94.8% 
(ST3) in the 135 µg group and from 44.7% (ST5) to 97.5% (ST3) in the 180 µg group. 
 
. At Month 19, one month after 
booster dose administration, GMTs increased by factor 2.9 (ST3) to 4.2 (ST1, ST4) as 
compared to Day 208 (peak levels after primary vaccination series) and ranged from 1253.6 
(ST1) to 2160.4 (ST2) in the 180 µg with booster group. At Month 30, GMTs sustained at a 
higher level approx. in the range of 2.4 [ST1] to 5 [ST3]-fold one year after booster dose (Month 
30) compared to one year after primary immunization (Month 18). 
More details on safety and immunogenicity results of the VLA15-202 study are described in 
the latest version of the IB.  
VLA15-221 Phase 2 Clinical Study  
In the Main Study Phase, 625 subjects (320 subjects aged 18-65 years, 150 aged 12-17 years 
and 155 aged 5-11 years) were randomized 1:1:1 to receive 180 µg of VLA15 at a two or three 
dose schedule (Month 0-2-6 or Month 0-6) or placebo. At Booster Phase initiation, 449 subjects 
were eligible to receive the first booster vaccination at Month 18 (247 subjects aged 18-65 
years, 98 aged 12-17 years and 104 subjects aged 5-11 years).  
 

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Data available up to Month 19 has revealed that the overall safety profile between the three 
age groups was similar and the vaccine was well tolerated by all three age cohorts regardless 
of the primary vaccination schedule.  
Up to Month 19, 552 of 625 subjects (88.3%) reported any solicited or unsolicited AE. Most 
AEs were mild to moderate in severity. A total of 22 subjects (3.5%) experienced severe related 
AEs, all of them were solicited AEs and as such, counted per definition as related: twenty 
subjects (4.8%) that received any VLA15 vaccination (5 subjects aged 18-65 years, 2 subjects 
aged 12-17 years and 13 subjects aged 5-11 years) vs. two subjects (1.0%) that received 
placebo (both subjects aged 18-65 years).   
After any vaccination, solicited local AEs were reported by 96.6% subjects in the Month 0-2-
6+18 group and 96.5% subjects in the Month 0-6+18 group, compared to 41.1% placebo group 
subjects. The most common solicited local AEs in subjects who received any VLA15 
vaccination were tenderness (91.9%) and pain (81.6%). Solicited systemic AEs were reported 
by 80.4% subjects in the Month 0-2-6+18 group and 75.5% subjects in the Month 0-6+18 
group, compared to 56.0% placebo group subjects. The most common solicited systemic AEs 
in subjects who received any VLA15 vaccination were muscle pain (51.9%), headache (41.9%) 
and fatigue (34.4%). With regards to solicited AEs, no clinically relevant differences were 
observed between age cohort. An overview of solicited AEs is shown in Table 5 and Table 6.  
Up to Month 19, no vaccine related severe unsolicited AEs and no related SAEs occurred. 
Overall, 11 unrelated AESIs, all of which occurred in VLA15 treatment groups, were reported. 
Five of these events were experienced by subjects who did not complete their primary 
vaccination schedule: two erythema migrans cases (one subject aged 18-65 years and one 
aged 5-11 years), one Lyme disease case (subject aged 5-11 years), one optic neuritis 
diagnosis (subject aged 18-65 years) and one Diabetes mellitus Type 1 diagnosis (subject 
aged 12-17 years). In addition, one 9-year-old subject, who completed the Month 0-6 schedule, 
developed Lyme disease 5 months after the last vaccination, one 14-year-old subject, who 
completed the M0-6 schedule, developed Diabetes mellitus Type 1 8 months after last 
vaccination, one 59-year-old subject, who completed the Month 0-2-6 schedule, developed 
osteoarthritis two months after the last vaccination, one 66-year-old subject, who completed 
the Month 0-2-6 schedule, developed Lyme disease 10 months after the last vaccination and 
one 45-year-old subject, who completed the Month 0-2-6 schedule, developed Lyme disease 
9.5 months after the last vaccination. After performing Analysis 3, one Lyme disease event in 
an adult subject was recalled as the event did not meet specified AESI criteria. No AESIs were 
reported between the Month 18 booster vaccination and the Month 19 folllow-up visit.   
VLA15 was immunogenic at both primary vaccination schedules tested and induced significant 
IgG antibody levels by Day 208 (i.e., 1 month after completion of the primary vaccination 
series). The number of VLA15 vaccinations within the primary series influenced the immune 
response. Across all age groups, at Day 208/ Month 7 GMTs ranged from 333.2 U/mL [ST1] 
to 656.0 U/mL [ST2] in the Month 0-2-6 and from 197.3 U/mL [ST1] to 460.3 U/mL [ST2] in the 
Month 0-6 schedule group. When stratified by age, the immunogenicity analyses revealed age-
dependent vaccine responses with higher antibody titers in adolescents and children in 
comparison to adults for all six serotypes at Day 208/ Month 7. At Month 18 (i.e., twelve months 
post priming completion), GMTs were substantially reduced for both primary vaccination 
schedules, with ranges from 27.3 [ST1] to 35.4 [ST2] in the Month 0-2-6 and from 22.7 [ST1] 
to 33.8 [ST3] in the Month 0-6 group. The Month 18 booster vaccination induced a strong 
anamnestic response in all three age groups with titers ranging between 1057.0 [ST1] to 
1807.9 [ST2] in the Month 0-2-6+18 group and 830.0 [ST1] to 1603.1 [ST2] in the Month 0-
6+18 group. Data showing the effect of a Month 30 and 42 booster is pending.  
More details on available safety and immunogenicity results of the VLA15-221 study are 
described in the latest version of the IB.  
 
 

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Table 5 Solicited Local Adverse Events after any Vaccination (primary vaccination 
series) by Symptom, Safety Population 
 
VLA15-201 Study 
VLA15-202 Study 
 
VLA15-221 Study 
 
Month 0-1-2  
Schedule 
Month 0-2-6 
Schedule 
Month 0-2-6 
Schedule 
Month 0-6 
Schedule 
90 µg  
w Alum 
N=29 
n (%) 
135 µg  
w Alum 
N=214 
n (%) 
180 µg  
w Alum 
N=205 
n (%) 
135 µg  
w Alum  
N=97 
n (%) 
180 µg  
w Alum 
N=98 
n (%) 
180 µg  
w Alum 
N=190 
n (%) 
180 µg  
w Alum 
N=187 
n (%) 
Solicited 
local AE 
after any 
vacc. 
26 (89.7)a  
199 (93.0)a  
197 (96.1)a  
93 (95.9)c 
96 (98.0)c 
178 (93.7)e 
177 (94.7)f 
 Pain 
22 (75.9)a  
176 (82.2)a  
181 (88.3)a  
87 (89.7)c 
87 (88.8)c 
153 (80.5)e 
144 (77.0)f 
Tenderness 
25 (86.2)a  
194 (90.7)a  
194 (94.6)a  
92 (94.8)c 
95 (96.9)c 
176 (92.6)e 
173 (92.5)f 
Erythema 
8 (27.6)a  
68 (31.8)a  
72 (35.1)a  
28 (28.9) 
41 (41.8)d 
51 (26.8)e 
35 (18.7)f 
Swelling 
4 (13.8)a  
57 (26.6)a  
68 (33.2)a  
24 (24.7)c 
32 (32.7)c  
39 (20.5)e 
31 (16.6)f 
Induration 
3 (10.3)a,b  
64 (29.9)a,b  
65 (31.7)a,b  
27 (27.8)c 
29 (29.6)c 
37 (19.5)e 
27 (14.4)f 
n: number of subjects with event 
N: number of subjects studied in treatment group 
a significant pairwise comparison Placebo vs. 90 µg, Placebo vs. 135 µg, Placebo vs. 180 µg  
b significant pairwise comparison: 90 µg vs. 135 µg, 90 µg vs. 180 µg 
c significant pairwise comparison Placebo vs. 135 µg, Placebo vs. 180 µg  
d significant pairwise comparison Placebo vs. 180 µg 
e significant pairwise comparison Placebo vs. Month 0-2-6 
f significant pairwise comparison Placebo vs. Month 0-6 
 
 

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Table 6 Solicited Systemic Adverse Events after any Vaccination (primary vaccination 
series) by Symptom, Safety Population 
 
  
VLA15-201 Study  
VLA15-202 Study  
VLA15-221 Study 
 
Month 0-1-2  
Schedule 
Month 0-2-6  
Schedule 
Month 0-2-6 
Schedule 
Month 0-6 
Schedule 
90 µg  
w Alum 
N=29 
n (%) 
135 µg  
w Alum 
N=214 
n (%) 
180 µg  
w Alum 
N=205 
n (%) 
135 µg  
w Alum  
N=97 
n (%) 
180 µg  
w Alum 
N=98 
n (%) 
180 µg  
w Alum 
N=190 
n (%) 
180 µg  
w Alum 
N=187 
n (%) 
Solicited 
sys. AE 
after any 
vacc. 
18 (62.1)  
145 (67.8)b  
147 (71.7)b 
76 (78.4)b 
68 (69.4)b 
128 (67.4)e 
128 (68.4)f 
 Headache 
10 (34.5)  
69 (32.2)  
81 (39.5)  
45 (46.4) 
42 (42.9) 
73 (38.4) 
68 (36.4) 
Fever 
2 (6.9)  
5 (2.3)  
5 (2.4)  
7 (7.2) 
4 (4.1) 
6 (3.2) 
3 (1.6) 
Flu like  
symptoms 
3 (10.3)  
23 (10.7)  
33 (16.1)  
17 (17.5) 
7 (7.1) 
n/a* 
n/a* 
Nausea 
4 (13.8)  
23 (10.7)  
32 (15.6)  
17 (17.5) 
15 (15.3) 
16 (8.4) 
21 (11.2) 
Vomiting 
1 (3.4)  
4 (1.9)  
6 (2.9)  
2 (2.1) 
3 (3.1) 
6 (3.2) 
6 (3.2) 
Fatigue 
8 (27.6)  
65 (30.4)  
79 (38.5)c  
30 (30.9) 
32 (32.7) 
63 (33.2) 
56 (29.9) 
Arthralgia 
2 (6.9)  
35 (16.4)  
35 (17.1)  
20 (20.6) 
21 (21.4) 
29 (15.3) 
18 (9.6) 
Myalgia 
14 (48.3)a  
103 (48.1)a 
97 (47.3)a  
53 (54.6)b 
54 (55.1)b 
87 (45.8)e 
90 (48.1)f 
n: number of subjects with event 
N: number of subjects studied in treatment group 
* Not assessed in study VLA15-221 
a significant pairwise comparison Placebo vs 90 µg, Placebo vs 135 µg, Placebo vs 180 µg 
b significant pairwise comparison Placebo vs 135 µg, Placebo vs 180 µg 
c significant pairwise comparison: Placebo vs 180 µg 
e significant pairwise comparison Placebo vs. Month 0-2-6 
f significant pairwise comparison Placebo vs. Month 0-6 
 
 
 

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Table 7 Solicited Local Adverse Events after Month 18 Booster Vaccination by 
Symptom, Safety Population 
 
VLA15-
202 
Study 
VLA15-221 Study 
Month 0-2-6+18 Schedule 
Month 0-6+18 Schedule 
N(18-65 
yrs)=39 
n/Nm (%) 
N(18-65 
yrs)=79 
n/Nm (%) 
N(12-17 
yrs)=32 
n/Nm (%) 
N(5-11 
yrs)=37 
n/Nm (%) 
N(18-65 
yrs)=77 
n/Nm (%) 
N(12-17 
yrs)=35 
n/Nm (%) 
N(5-11 
yrs)=31 
n/Nm (%) 
Solicited 
local AE 
after any 
vacc. 
35 /38 
(92.1)a 
62 /76 
(81.6)a 
24 /32 
(75.0)a 
28 /36 
(77.8)a 
65 /76 
(85.5)a 
25 /35 
(71.4)a 
27 /31 
(87.1)a 
 Pain 
24 /38 
(63.2)a 
44 /75 
(58.7)a 
13 /31 
(41.9)a 
17 /35 
(48.6)a 
41 /75 
(54.7)a 
18 /35 
(51.4)a 
20 /29 
(69.0)a 
Tenderness 
34 /38 
(89.5)a 
60 /75 
(80.0)a 
20 /32 
(62.5)a 
26 /36 
(72.2)a 
63 /76 
(82.9)a 
23 /35 
(65.7)a 
25 /30 
(83.3)a 
Erythema* 
2 /36  
(5.6) 
4 /73  
(5.5)  
0 /32 
(0.0) 
6 /35 
(17.1) 
4 /76  
(5.3)  
1 /33 
(3.0) 
7 /30 
(23.3) 
Swelling* 
1 /38  
(2.6) 
4 /73  
(5.5)  
2 /32  
(6.3) 
4 /35 
(11.4) 
4 /76  
(5.3) 
1 /33 
(3.0) 
8 /29 
(27.6) 
Induration* 
2 /38  
(5.3) 
2 /75  
(2.7) 
0 /32 
(0.0) 
4 /35 
(11.4) 
2 /76  
(2.6) 
1 /33 
(3.0) 
6 /29 
(20.7) 
n...number of subjects, percentages are based on Nm, Nm...number of subjects with non-missing observations 
*above grading scale 
a: significant pairwise comparison between VLA15 and placebo group 
 
Table 8 Solicited Systemic Adverse Events after Month 18 Booster Vaccination by 
Symptom, Safety Population 
 
VLA15-
202 
Study 
VLA15-221 Study 
Month 0-2-6+18 Schedule 
Month 0-6+18 Schedule 
N(18-65 
yrs)=39 
n/Nm 
(%) 
N(18-65 
yrs)=79 
n/Nm (%) 
N(12-17 
yrs)=32 
n/Nm 
(%) 
N(5-11 
yrs)=37 
n/Nm 
(%) 
N(18-65 
yrs)=77 
n/Nm 
(%) 
N(12-17 
yrs)=35 
n/Nm 
(%) 
N(5-11 
yrs)=31 
n/Nm 
(%) 
Solicited sys. 
AE after any 
vacc. 
20 /34  
(58.8) 
32 /70 
(45.7) 
9 /30 
(30.0) 
12 /33 
(36.4) 
36 /75 
(48.0) 
18 /35 
(51.4) 
15 /30 
(50.0) 
 Headache 
8 /38  
(21.1) 
13 /73 
(17.8) 
4 /30 
(13.3) 
6 /35 
(17.1) 
7 /76 
(9.2) 
9 /34 
(26.5) 
3 /29 
(10.3) 
Fever 
0 /32  
(0.0) 
0 /67  
(0.0) 
0 /31 
(0.0) 
1 /33 
(3.0) 
0 /71 
(0.0) 
0 /33 
(0.0) 
0 /27 
(0.0) 
Nausea 
3 /38  
(7.9) 
6 /73 
(8.2)a 
0 /31 
(0.0) 
5 /35 
(14.3) 
2 /75 
(2.7) 
1 /34 
(2.9) 
2 /28 
(7.1) 
Vomiting 
1 /37 
(2.7) 
0 /73  
(0.0) 
0 /31 
(0.0) 
2 /35 
(5.7) 
1 /75 
(1.3) 
0 /34 
(0.0) 
0 /28 
(0.0) 
Fatigue 
7 /38 
(18.4) 
10 /73 
(13.7) 
3 /31 
(9.7) 
7 /35 
(20.0) 
14 /75 
(18.7) 
2 /34 
(5.9) 
5 /29 
(17.2) 
Arthralgia 
4 /38 
(10.5) 
5 /73 
(6.8)a 
1 /31 
(3.2) 
1 /35 
(2.9) 
2 /75 
(2.7) 
0 /34 
(0.0) 
0 /28 
(0.0) 
Myalgia 
11 /38 
(28.9)a 
19 /74 
(25.7)a 
5 /31 
(16.1)a,b 
5 /35 
(14.3) 
25 /75 
(33.3)a 
16 /35 
(45.7)a,b 
11 /29 
(37.9) 

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n...number of subjects, percentages are based on Nm, Nm...number of subjects with non-missing observations 
a: significant pairwise comparison between VLA15 and placebo group 
b: significant pairwise comparison between VLA15 groups  
In summary, the safety and immunogenicity data of Phase 1 and Phase 2 are encouraging, 
with a positive Benefit Risk profile for all age groups and all doses and schedules (incl. one 
booster dose) tested. The AE profile of VLA15 is comparable to licensed lipidated recombinant 
vaccines or lipid-containing formulations. Moreover, to date, an independent DMC has not 
identified a safety concern. Higher VLA15 doses and a broader immunization schedule 
investigated in the Phase 2 studies led to a further optimized immune response. In addition, 
administration of a booster dose led to a substantial anamnestic response. Available data 
supported the decision to advance the 180 µg dose into Phase 3. 
For more detailed information on available data, please refer to the current version of the 
Investigator’s Brochure.  
 
Study Rationale 
Study VLA15-221 is conducted to compare two different vaccination schedules of VLA15 and 
to generate a sufficient safety database for advancing the vaccine candidate into Phase 3. 
VLA15-221 is the first study to involve children and adolescents.  
Therefore, as a safety precaution, subject enrollment at study start of the Main Study Phase 
(Part A) was performed in an age-descending, staggered manner (see Figure 1 and Section 
4.2.1) with in total 90 sentinel subjects (30 subjects per age cohort). Staggered enrollment of 
younger age cohorts (12-17 years and 5-11 years, respectively) only started upon review of 7-
day safety data incl. 7-day eDiary data of the previous age cohort and positive recommendation 
by an independent Internal Review Committee (IRC). During the enrollment process, no safety 
concern was identified by the IRC and thus, enrollment could proceed according to plan and 
without any limitations.  
Overall, 625 subjects aged 5-65 years were enrolled and randomized 1:1:1 into three study 
groups to receive either VLA15 at Month 0-2-6 or Month 0-6, respectively, or placebo. In Part 
B, all eligible subjects will receive a booster vaccination of either VLA15 (Group 1 and 2) or 
Placebo (Group 3) at Month 18, Month 30 and Month 42. VLA15 will be administered at a dose 
of 180 µg. This dose has been selected based on available safety and immunogenicity data 
from Phase 2 studies VLA15-201 and VLA15-202.  
The VLA15 presentation used in this study is in a more concentrated form as compared to the 
presentation used in previous studies. It contains the same amount of antigen and aluminum 
adjuvant, and the same concentration of other excipients as the 1 mL presentation used 
previously. Thus, 0.5 mL of the new presentation contains 180 µg VLA15 and 0.5 mg of alum. 
This presentation is currently being administered in the ongoing Phase 3 study and is planned 
to be final for product commercialization. Hence, there were a total of approximately 400 
subjects who have received VLA15 in the final presentation before advancing the vaccine into 
Phase 3.  
Immunogenicity assessment is being done using an IgG binding assay. 
 
.  
 
Risk - Benefit Analysis 
Risks:  
The safety of OspA based vaccines has previously been shown16,17. A theoretical risk put 
forward for the previously licensed OspA vaccine LYMErix, although never proven, has been 
eliminated in the design of VLA15: the putative T cell epitope in OspA ST1 presenting 
homology to human leukocyte function-associated antigen-1 (hLFA-1) and claimed to induce 
antibiotic-refractory Lyme arthritis in a subset of naturally infected patients, has been 
eliminated through the replacement by corresponding sequence from OspA ST2. 

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Results from a GLP repeat dose toxicity and local tolerance study in rabbits with four bi-weekly 
intramuscular injections of 90 µg VLA15 w/ or w/o alum were supportive for clinical use.  
Safety data in humans are available from a Phase 1 first-in-human study (VLA15-101), from 
two completed Phase 2 studies (VLA15-201, and VLA15-202) and from this study (VLA15-
221) for the primary endpoint analysis. Most AEs were reported to be mild or moderate and 
comprised typical vaccine reactions: solicited injection site reactions (mainly injection site pain 
(67.0 %, 84.6%, 89.2% and 77.0% for pooled VLA15 groups in study 101/201/202/221 
,respectively) and injection site tenderness (84.4%, 92.2%, 95.9% and 90.6%for pooled VLA15 
groups in study 101/201/202/221, respectively)) or solicited systemic reactions (mainly 
headache (44.7%, 35.7%, 44.6% and 37.4%, for pooled VLA15 groups in study 
101/201/202/221, respectively), fatigue (25.1%, 33.9% , 31.8% and 31.4%, for pooled VLA15 
groups in study 101/201/202/221, respectively) and myalgia (25.1%, 47.8% ,54.9% and 46.8%, 
for pooled VLA15 groups in study 101/201/202/221,respectively)).  
Subjects aged 5 to 65 years were enrolled during the VLA15-221 clinical study. The study 
assesses the safety and immunogenicity of VLA15 in children and adolescents for the first 
time. Children aged 5-15 years are one of the main target populations for a vaccine against 
Lyme borreliosis and therefore early inclusion of this age group into the clinical development 
of VLA15 is of importance. In order to ensure the safety in all age groups, a staggered 
enrollment process with limited recruitment rates was planned to establish initial safety data in 
adults, before initiating enrollment in adolescents and further on in children and prior to 
progressing to a larger study population. Enrollment was rigorously monitored and could 
continue without any limitations. Preliminary safety data revealed that VLA15 was safe across 
all age groups during primary vaccination series. Reactogenicity did vary to a small degree by 
age cohort for some events, but no differences were attributable to having received 3 doses 
compared with 2 doses of vaccine. 
Reactogenicity after administration of a booster dose (study VLA15-202 and VLA15-221) was 
comparable to the primary series. Few severe related AEs were reported, all of them 
comprised solicited AEs, as such counted per definition as related. Also, rates of fever, a sign 
for inflammatory reactions, were low, ranging from 1.7% in VLA15-101 to 5.6% (pooled VLA15 
groups) in VLA15-202. No related SAE was reported and no case of rheumatoid arthritis or 
other immune-mediated events was reported in any study. During vaccination periods of all 
studies, safety data have been reviewed regularly by an independent DMC. The DMC did not 
identify a safety concern to date. 
Overall, the AE profile of VLA15 appeared comparable to licensed lipidated recombinant 
vaccines or lipid-containing formulations (e.g., Trumenba®18 or Bexsero®19) that might be 
associated with an increased inflammatory response through interaction with Toll-like 
receptors20.  
To date, the overall safety profile of VLA15 including a booster dose is well tolerated and 
favorable. Available data support advancing the vaccine development with the 180 µg dose. 
For more detailed information on available data, please refer to the current version of the 
Investigator’s Brochure.  
 
As with any vaccine, the VLA15 vaccine might induce allergic and anaphylactic reactions, the 
process of vaccination may also trigger syncope. The needle pricks for blood sampling may 
also cause local reactions such as edema. In addition, possible triggering of an autoimmune 
disease in predisposed subjects cannot be excluded. 
Benefits: 
From previous OspA ST1 based vaccines have shown to be protective against LB in humans.  
VLA15 was effective in animal models and immunogenic in humans. However, as VLA15 is a 
new multivalent construct that has not yet been tested for clinical efficacy, the subjects might 
not directly benefit from vaccination with VLA15. In addition, a portion of subjects is receiving 
placebo injections and will therefore not benefit from the vaccinations.  

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In view of the positive safety profile observed so far with VLA15 and the usually limited risks 
associated with vaccinations, the risk benefit ratio for VLA15 is assessed to be positive. 

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2 
STUDY OBJECTIVES 
 
Primary Objective 
Safety:  
• 
To assess the safety and tolerability profile of VLA15, given in a three- or two dose 
primary immunization schedule (Month 0-2-6 or Month 0-6), in a healthy study 
population aged 5 to 65 years up to Day 208 (Month 7). 
Immunogenicity:  
• 
To assess the immune response to VLA15, given in a three- or two dose primary 
immunization schedule (Month 0-2-6 or Month 0-6), in a healthy study population aged 
5 to 65 years at Day 208 (Month 7). 
 
Secondary Objectives 
Safety:  
• 
To assess the safety and tolerability profile of VLA15, given in a three- or two dose 
primary immunization schedule (Month 0-2-6 or Month 0-6), in a healthy study 
population aged 5 to 65 years, up to one year after the last primary vaccination (Month 
18).  
• 
To assess the safety and tolerability profile of VLA15 booster vaccinations (i.e., Booster 
1 at Month 18, one year after completion of the primary vaccination schedule, Booster 
2 at Month 30 and Booster 3 at Month 42) until study end.  
Immunogenicity:  
• 
To assess the immune response to VLA15, applied in a three- or two dose primary 
immunization schedule (Month 0-2-6 or Month 0-6), in a healthy study population aged 
5 to 65 years, up to one year after the last primary vaccination (Month 18).  
• 
To assess the immune response of VLA15 booster vaccinations (i.e., Booster 1 at 
Month 18, one year after completion of the primary vaccination schedule, Booster 2 at 
Month 30 and Booster 3 at Month 42) until study end.  
 
Exploratory Objective: 
 
 
  
 
 

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3 
SELECTION OF STUDY POPULATION 
CRITERIA FOR INCLUSION/EXCLUSION 
625 male or female subjects who met the inclusion and exclusion criteria listed below were 
enrolled in the study. 
Inclusion criteria: 
Subjects must meet ALL of the following criteria to be eligible for this study: 
 
1. Subject is aged 5 to 65 years* at the day of screening (Visit 0); 
2. Subject is of good general health as determined by medical history, physical 
examination, and judgement of the investigator; 
3. Parent(s)/legal representative(s) and subject who have an understanding of the study 
and its procedures as explained by the investigator and agree to its provisions:   
- 
For subjects aged 18-65 years†: Written informed consent prior to any study 
related procedures;  
- 
For subjects aged 5-17 years‡: Written informed consent by the subject’s legal 
representative(s), according to local requirements, and written informed assent 
of the subject, if applicable, prior to any study related procedures; 
4. If subject is of childbearing potential: 
a. Subject has a negative serum pregnancy test at screening (Visit 0); 
b. Subject agrees to employ adequate birth control measures according to 
following timelines: 
- Main Study Phase: duration of entire study  
- Booster Phase: until 5 months after each booster vaccination (Booster 
1 until Month 23, Booster 2 until Month 35 and Booster 3 until Month 
47).   
5. Subject is willing and able to comply with scheduled visits, treatment plan, and other 
study procedures; 
6. Subject is expected to be available for the duration of the study and can be contacted 
by telephone during study participation. 
 
* From the 5th birthday until the last day before the 66th birthday  
† From the 18th birthday until the last day before the 66th birthday  
‡ From the 5th birthday until the last day before the 18th birthday  

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Exclusion criteria (Main Study Phase): 
Subjects who meet ANY of the following criteria are NOT eligible for this study: 
1. Subject has a chronic illness related to Lyme borreliosis (LB), an active symptomatic 
LB as suspected or diagnosed by a physician, or received treatment for LB within the 
last 3 months prior to Day 1/Visit 1; 
2. Subject received previous vaccination against LB; 
3. Subject had a tick bite within 4 weeks prior to Day 1/Visit 1; 
4. Subject has a medical history of or currently has a clinically relevant disease (e.g., 
cardiovascular, respiratory, neurologic, psychiatric conditions) which poses a risk for 
participation in the study, based on investigator’s judgement, such as individuals with 
poorly controlled or unstable disease, ongoing suspected or active inflammation, or 
poor compliance with pharmacologic treatment; 
5. Subject has a medical history of or currently has a neuro-inflammatory or autoimmune 
disease; 
6. Subject has a known thrombocytopenia, bleeding disorder, or received anticoagulants 
in the 3 weeks prior to Day 1/Visit 1, contraindicating I.M. vaccination as judged by the 
investigator; 
7. Subject has received an active or passive immunization within 4 weeks prior to Day 
1/Visit 1;  
8. Subject has received any other registered or non-registered medicinal product in 
another clinical trial within 4 weeks prior to vaccination at Day 1/Visit 1;  
9. Subject has a known or suspected defect of the immune system that would prevent an 
immune response to the vaccine, such as subjects with congenital or acquired 
immunodeficiency, including infection with human immunodeficiency virus (HIV), status 
post organ transplantation or immuno-suppressive therapy (e.g., radiation therapy, 
chemotherapy or glucocorticoid treatment) within 4 weeks prior to Day 1/Visit 1. 
Glucocorticoid immuno-suppressive therapy is defined as administration of chronic 
(longer than 14 days) prednisone or equivalent 0.05 mg/kg/day. Topical and inhaled 
steroids are allowed; 
10. Subject has a history of anaphylaxis of unknown cause or severe allergic reactions of 
unknown cause. Subjects with known hypersensitivity or allergic reactions to one of the 
components of the vaccine are to be excluded; 
11. Subject had any malignancy in the past 5 years. If treatment for cancer was 
successfully completed more than 5 years ago and the malignancy is considered to be 
cured, the subject may be enrolled. Subjects with history of squamous cell or basal cell 
skin cancer which has been successfully treated by surgical excision and treatment is 
considered to have achieved cure may be enrolled. Subjects with a history of skin 
cancer must not be vaccinated at the previous tumor site; 
12. Subject is pregnant (positive serum pregnancy test at Visit 0 or positive urine pregnancy 
test at Day 1/Visit 1), has plans to become pregnant during the course of the study or 
is lactating at the time of enrollment. Women of childbearing potential that are unwilling 
or unable to employ an adequate birth control measure during the course of the entire 
Main Study Phase;  
13. Subject has donated or plans to donate blood or blood-derived products (e.g., plasma) 
within 4 weeks prior to Day 1/V1 or subject received blood or blood-derived products 
(e.g., plasma or immunoglobulins) within 3 months prior to vaccination at Day 1/Visit 1 
or plans to donate or use blood or blood products within 4 weeks after vaccination at 
Day 1/Visit 1; 

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14. Subject has any condition that, in the opinion of the investigator, may compromise the 
subject’s well-being, might interfere with evaluation of study endpoints, or would limit 
the subject’s ability to complete the study; 
15. Subject is in a dependent relationship with the sponsor, an investigator or other study 
team member, or the study center. Dependent relationships include close relatives and 
household members (i.e., children, partner/spouse, siblings, parents) as well as 
employees of the investigator or study center personnel. 
 
Exclusion criteria (Booster Phase): 
 
Subjects who meet ANY of the following criteria are NOT eligible for participation in the 
Booster Phase: 
1. Subject has developed a chronic illness related to Lyme borreliosis (LB) or an active 
symptomatic LB as suspected or diagnosed by a physician; 
2. Subject has developed a clinically relevant disease (e.g., cardiovascular, respiratory, 
neurologic, psychiatric conditions, malignancy) which poses a risk for further 
participation in the study, based on investigators judgement, such as individuals with 
poorly controlled or unstable disease, ongoing suspected or active inflammation, or 
poor compliance with pharmacologic treatment;  
3. Subject has developed a neuro-inflammatory or autoimmune disease; 
4. Subject has developed a thrombocytopenia or bleeding disorder, or is contraindicated 
for I.M. vaccination as judged by the investigator; 
5. Subject has developed a known or suspected defect of the immune system that would 
prevent an immune response to the vaccine, such as subjects with acquired 
immunodeficiency, including infection with human immunodeficiency virus (HIV) or 
status post organ transplantation; 
6. Subject has experienced an anaphylaxis of unknown cause or severe allergic reactions 
of unknown cause or has developed hypersensitivity or allergic reactions to one of the 
components of the vaccine;  
7. Subject is pregnant (positive urine pregnancy test), or is lactating or has plans to 
become pregnant up to 5 months after any booster vaccination (i.e., Booster 1 from 
Months 18 to 23, Booster 2 from Months 30 to 35 and Booster 3 from Month 42 to 47).  
Women of childbearing potential that are unwilling or unable to employ an adequate 
birth control measure for five months after any booster vaccination (i.e., Months 18 to 
23, Months 30 to 35 or Month 42 to 47);  
8. Subject has developed any condition that, in the opinion of the investigator, may 
compromise the subject’s well-being, might interfere with evaluation of study endpoints, 
or would limit the subject’s ability to complete the study; 
9. Subject is in a dependent relationship with the sponsor, an investigator or other study 
team member, or the study center. Dependent relationships include close relatives and 
household members (i.e., children, partner/spouse, siblings, parents) as well as 
employees of the investigator or study center personnel. 
Delay Criteria for Vaccination 
Vaccination will be delayed if: 
1. Subject has an acute illness with or without elevated body temperature (≥100.4 °F [38.0 
°C]) within 3 days prior to the scheduled vaccination. Subjects may be rescheduled for 

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vaccination at a later date provided that the illness has resolved (body temperature 
<100.4 °F [38.0 °C]). 
2. Subject has received antipyretics within 4 hours prior to the scheduled time of 
vaccination. In this case the vaccination should be performed at a later date. 
Booster Phase: 
3. Subject has received an active or passive immunization within 4 weeks prior to any 
booster vaccination, except for influenza or pandemic vaccines which may be 
administered outside a 7-days interval before booster vaccination. 
4. Subject has received anticoagulants within 3 weeks prior to any booster vaccination. 
5. Subject received immuno-suppressive therapy (e.g., radiation therapy, chemotherapy 
or glucocorticoid treatment) within 4 weeks prior to any booster vaccination. 
Glucocorticoid immuno-suppressive therapy is defined as administration of chronic 
(longer than 14 days) prednisone or equivalent 0.05 mg/kg/day. Topical and inhaled 
steroids are allowed. 
6. Subject has donated or plans to donate blood or blood-derived products (e.g., plasma) 
within 4 weeks prior to any booster vaccination or received blood or blood-derived 
products (e.g., plasma or immunoglobulins) within 3 months prior to any booster 
vaccination in this study or plans to donate or use blood or blood products within 4 
weeks after any booster dose. 
In addition, the following criteria must be met: 
1. For a rescheduled first vaccination: 
a. All inclusion and none of the exclusion criteria are met; In case not all of these 
criteria are met, the subject will be excluded from the study. 
b. The rescheduled visit should be within the specified time window (i.e., within 10 
days after the screening visit). In case a first vaccination cannot be rescheduled 
within the specified time window (i.e., within 10 days after the screening visit), the 
subject might be invited for a rescreening. 
 
2. For a rescheduled second, third or booster vaccinations: 
The rescheduled visit should be within the specified time window. In case a 
rescheduled booster vaccination has to occur outside the specified time window, the 
study team should be consulted before booster administration. 
 
Forbidden concomitant therapies during study conduct are described in Section 6.2.2. 
 
 

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4 
INVESTIGATIONAL PLAN 
 
Study Endpoints 
Primary Endpoints:  
Safety: 
+ Frequency of solicited local and solicited systemic AEs within 7 days after each and 
any vaccination of the primary vaccination series (Part A). 
Immunogenicity: 
+ GMTs (Geometric Mean Titers) for IgG against each OspA serotype ST1 to ST6, 
determined by an IgG binding assay, at Day 208/Month 7 (Part A). 
 
Secondary Endpoints: 
Safety:  
+ Frequency of solicited local and solicited systemic AEs within 7 days after each booster 
dose administration (Part B);  
+ Frequency of SAEs during the entire study; 
+ Frequency of AESIs during the entire study; 
+ Frequency of unsolicited AEs within 28 days after each vaccination; 
+ Frequency of SAEs, AESIs, unsolicited and solicited AEs stratified by age cohort.  
 
Immunogenicity: 
Part A: Main Study Phase:  
+ GMTs for IgG against each OspA serotype (ST1 to ST6), determined by an IgG binding 
assay, at baseline (screening visit) and at Day 85, 180, 194*, 365 and Month 18; 
+ SCRs (Seroconversion Rate, defined as seroconversion from seronegative to 
seropositive or ≥four-fold increase in IgG titer compared to baseline if subject was 
tested OspA seropositive at baseline) for each OspA serotype specific IgG (ST1 to 
ST6), determined by an IgG binding assay, at Day 85, 180, 194*, 208, 365 and Month 
18; 
+ GMFRs (Geometric Mean of the fold rise as compared to baseline) for IgG against each 
OspA serotype (ST1 to ST6), determined by an IgG binding assay, at Day 85 and 208;  
+ GMTs, SCRs and GMFRs for IgG against each OspA serotype (ST1 to ST6), 
determined by an IgG binding assay, at specified time-points, stratified by age cohort. 
 
Part B: Booster Phase:  
+ GMTs for IgG against each OspA serotype (ST1 to ST6), determined by an IgG binding 
assay, at Months 18, 19, 23, 26, 30, 31, 39, 42, 43 and 48; 
+ SCRs for each OspA serotype specific IgG (ST1 to ST6), determined by an IgG binding 
assay, at Months 18, 19, 23, 26, 30, 31, 39, 42, 43 and 48; 
+ GMFRs for IgG against each OspA serotype (ST1 to ST6), determined by an IgG 
binding assay, at Months 19, 31 and 43; 
 
* Visit 5A/Day194 data will be available for a subset of approximately 150 adult subjects.  

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+ GMTs, SCRs and GMFRs for IgG against each OspA serotype (ST1 to ST6), 
determined by an IgG binding assay, at specified time points, stratified by age cohort. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design and Plan 
4.2.1 Study Description  
VLA15-221 is a randomized, observer-blind (subject, sponsor and investigator/ site staff 
involved in clinical evaluation of subjects are blinded), placebo controlled, multicenter Phase 2 
study in healthy subjects aged 5 to 65 years. The study is being conducted in two study parts 
(Part A: Main Study Phase, Part B: Booster Phase). VLA15-221 was initiated with an age de-
escalation of sentinel cohorts. Subject enrollment into Part A started with the adult cohort to 
allow the generation and review of appropriate safety data before pediatric cohorts were 
initiated.  
 
Subject Enrollment into Part A (Main Study Phase):  
Enrollment was performed in an age-descending, staggered manner for the three age 
cohorts (see Figure 1). 
 
 
 
 
 
 
 
 

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Figure 1 Subject enrollment process in Part A (Main Study Phase) 
 
Enrollment Cohort 1 (18-65 years): 
The enrollment started with 30 sentinel adult subjects aged 18-65 years (Cohort 1). Subjects 
were randomized 1:1:1 into one of three study groups to receive a vaccination of VLA15 
(Groups 1 and 2) or placebo (Group 3). After these 30 sentinel subjects had received the first 
vaccination and had completed a 7-day post vaccination safety follow up visit (Visit 1A) 
including review of 7-day eDiary data, safety data was reviewed in an unblinded manner by an 
independent Internal Review Committee (IRC). The IRC was composed of qualified personnel 
from Valneva’s collaboration partner Pfizer. Based on this data, the IRC made a 
recommendation on whether enrollment of the adolescent age cohort (12-17 years, Cohort 2) 
could be initiated. Enrollment of the remaining 270 adult subjects of Cohort 1 continued without 
limitations during the IRC review.   
Enrollment Cohort 2 (12-17 years): 
Upon IRC clearance, 30 sentinel adolescent subjects aged 12-17 years (Cohort 2) were 
enrolled. Subjects were randomized 1:1:1 into one of the three study groups to receive a 
vaccination of VLA15 (Groups 1 and 2) or placebo (Group 3).  Again, after these subjects had 
completed their safety follow up visit 7 days after the first vaccination (Visit 1A) including review 
of 7-day eDiary data, safety data was reviewed by the IRC. The IRC recommended whether 
enrollment of the youngest age cohort (5-11 years of age) could be initiated. In this age cohort, 
enrollment of the remaining 120 adolescent subjects was only initiated after IRC clearance.  
 
 

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Enrollment Cohort 3 (5-11 years): 
Upon IRC clearance, 30 sentinel subjects aged 5-11 years (Cohort 3) were enrolled. Subjects 
were randomized 1:1:1 into one of the three study groups to receive a vaccination of VLA15 
(Groups 1 and 2) or placebo (Group 3). Again, after these 30 subjects had completed their 
safety follow up visit 7 days after the first vaccination (Visit 1A) including review of 7-day eDiary 
data, safety data was reviewed by the IRC. Enrollment of the remaining 120 subjects in this 
age cohort was only initiated after IRC clearance.  
 
An external independent Data Monitoring Committee (DMC) reviews accruing safety data in 
an unblinded manner at regular intervals and might recommend adjusting, pausing or 
discontinuing the study at any time. Please refer to Section 8.6.2 for more details on the set-
up and responsibilities of the DMC.  
 
Subject Enrollment into Part B (Booster Phase): 
VLA15 Booster (Group 1 and 2) 
• 
All eligible subjects within Group 1 and 2 will receive VLA15 booster doses at Months 
18, 30 and 42.  
Placebo (Group 3):  
• 
All eligible subjects within Group 3 will receive Placebo injections at Months 18, 30 and 
42.  
The study sponsor and study statisticians were unblinded at the time of the primary endpoint 
analysis, i.e., prior to subject enrollment into Part B. Study participants and investigators will 
remain blinded throughout the entire duration of study.   
4.2.2 Study Design  
The study is being conducted in two study parts (Part A: Main Study Phase, Part B: Booster 
Phase). Please refer to Figure 2 for the study design.  
 
 
 
Figure 2 Study Design 
 
In Part A (Main Study Phase) a total of approximately 600 subjects aged 5 to 65 years were 
randomized 1:1:1 into three study groups: Group 1 (approximately 200 subjects) received three 
I.M. vaccinations of VLA15 at Month 0-2-6. Group 2 (approximately 200 subjects) received two 
I.M. VLA15 vaccinations at Month 0-6 and a placebo injection at Month 2 in order to keep the 
blind. Group 3 (approximately 200 subjects) received three I.M. placebo injections at Month 0-

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2-6. Within each study group subjects were enrolled 2:1:1 in three age cohorts (18-65 years, 
12-17 years and 5-11 years).  
In Part A, all subjects received three I.M. vaccinations at Month 0-2-6 (i.e., Day 1-57-180). On 
Day 8/Visit 1A (i.e., 7 days after the first vaccination) a safety visit was performed (phone call 
for subjects aged 18-65, in-person visit for subjects aged 5-17 years). In-person visits were 
scheduled for all age cohorts one month after each vaccination. Blood samples for 
immunogenicity assessments were collected at the screening visit, Day 85, Day 180, Day 194 
(in a subset of adult subjects), Day 208, Day 365/Month 12 and at Month 18.  
In Part B (Booster Phase) all eligible subjects from Group 1 and 2 will receive a booster dose 
of VLA15 at Month 18, Month 30 and Month 42. Placebo injections will be administered to 
Group 3 subjects at Month 18, Month 30 and Month 42. Subjects will be followed-up until Month 
48 (i.e., 2.5 years after start of Part B) with blood samples obtained at 1, 5, 8 and 12 months 
following the Month 18 booster dose (study months 19, 23, 26 and 30), at 1, 9 and 12 months 
following the Month 30 booster dose (study months 31, 39 and 42) and at 1 and 6 months 
following the Month 42 booster dose (study months 43 and 48).   
 
 
 
 

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Table 1 provides an overview of study groups and treatments. 
 
 

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Table 1 Study Groups and Vaccinations 
 
Study 
Group 
Subjects 
Age Cohort  
(Age in years at 
Screening) 
Treatment 
Vaccination 
Schedule  
Part A: Main Study Phase 
Group 1 
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg 
Month 0-2-6 
Group 2 
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg  
Placebo 
Month 0-6 
Month 2* 
Group 3 
Total: 200 
100 
50 
50 
 
 
18-65 
12-17 
5-11 
 
Placebo 
Month 0-2-6 
Part B: Booster Phase  
Group 1 
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg 
Month 18,  
30 and 42 
Group 2 
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg 
Month 18,  
30 and 42 
Group 3 
 
Total: 200 
100 
50  
50 
 
18-65 
12-17 
5-11 
Placebo 
Month 18,  
30 and 42 
*In order to keep the blind, subjects assigned to Group 2 will receive a sham injection of placebo at Month 2.  
4.2.3 Discussion of study design 
Rationale for dose/ presentations 
The dose and formulation used in this study were decided based on data from Phase 1 and 
Phase 2 development with VLA15. Phase 1 data revealed that adjuvanted VLA15 formulations 
were more immunogenic compared with non-adjuvanted formulations with a comparable 
safety profile. Hence only adjuvanted formulations were tested in Phase 2. Data from two 
completed Phase 2 studies (VLA15-201 and VLA15-202), where higher vaccine doses and a 
broader immunization schedule were investigated, revealed, that VLA15 demonstrated a good 
safety profile for all dose groups and schedules tested. Based on safety and immunogenicity 
results obtained from precedent Phase 2 studies, the 180 μg dose was selected to be used in 
this study. This is the highest dose investigated in the development program and is 
demonstrating a good safety profile and immune response. Sustained high levels of antibodies 

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are of utmost importance for an OspA based vaccine to confer protection. Hence, the 180 µg 
dose is administered in and the ongoing Phase 3 studies.   
This dose is well in the range of other lipidated recombinant proteins that have been tested in 
clinical development and that are now licensed (e.g. for Trumenba®, a 200 µg dose was tested 
down to the age of 18 months in clinical studies and was considered to be well tolerated by the 
authors21).  
Rationale for immunization schedule 
Data from study VLA15-202 have demonstrated that a Month 0-2-6 schedule induced 1.7 
(ST6) to 2.4-fold (ST1) higher antibody levels in the 180 µg dose group, depending on the 
serotype, compared with levels obtained in study VLA15-201 using the 180 µg dose group in 
an immunization schedule of Month 0-1-2. Therefore, the Month 0-2-6 schedule will be used 
in further development as obtaining high circulating antibody levels is of utmost importance for 
an OspA based vaccine.  
On the other hand, the magnitude and durability of the immune response may be determined 
by the spacing between the first and last dose of the primary series, with possibly limited 
additional benefit of a dose in between22,23. If both primary vaccination schedules (Month 0-6 
or Month 0-2-6) are similarly immunogenic, in general the schedule with the lowest number of 
vaccinations will be selected for further clinical development. Hence, the primary vaccination 
series investigated in present study VLA15-221 consists of either three VLA15 vaccinations at 
Month 0-2-6 or two VLA15 vaccinations at Month 0-6.  
In Part B, subjects that received VLA15 vaccinations at Month 0-2-6 (Group 1) or Month 0-6 
(Group 2), will receive booster doses of VLA15 at Month 18, 30 and 42. This will allow to 
assess the immunogenic effect of booster vaccinations after two or three primary vaccinations. 
The booster vaccinations are anticipated to induce even higher antibody levels and improve 
antibody sustainability. The efficacy of previous OspA based Lyme vaccines LYMErix and 
ImuLyme was shown to be substantially increased after a booster vaccination administered 
prior to the second tick season characterized by a significant increase in anti-OspA antibodies, 
which is seen as a prerequisite for protection11,12,24.  
Data generated in the study group receiving placebo (Group 3) will serve to compare the safety 
and tolerability profile of the VLA15 booster doses with placebo. 
Rationale for study population 
The proposed study population consists of healthy subjects aged 5 to 65 years, who live in LB 
endemic regions in the US. Major exclusion criteria include chronic illness related to Lyme 
borreliosis (LB), an active symptomatic LB as suspected or diagnosed by a physician, history 
of a neuro-inflammatory or autoimmune disease, history of immunodeficiency or ongoing 
immunosuppressive therapy (incl. infection with HI virus), known history of anaphylaxis, 
pregnancy and lactation or any active or passive vaccination within 4 weeks prior to first study 
vaccination.  
This study is the first study which includes a pediatric population. Early involvement of children 
is crucial for the development of a vaccine against Lyme borreliosis as children aged 5-15 
years are one of the age groups at highest risk to get LB. Hence it is important to provide a 
vaccine for this age group as early as possible.  
Subjects with a positive serology test result for Borrelia burgdorferi sensu lato (B.b. s.l.) 
antibodies (i.e., subjects that were previously infected with B.b. s.l.) were also enrolled. As a 
previous Borrelia infection does not confer protection against new infection, this study 
population is also a target population for a Lyme vaccine and hence included in this Phase 2 
study.  
The rationale for selecting this study population is to evaluate the final vaccine dose and 
presentation and the most appropriate schedule in all anticipated target populations to 
establish efficacy of the LB vaccine in a Phase 3 study, which will include healthy subjects 

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aged ≥5 years who live in Lyme borreliosis endemic areas. The results of both VLA15 
schedules from this study VLA15-221 were used as basis for selecting the optimal primary 
immunization schedule (i.e., Month 0-2-6) for use in Phase 3 studies in adults and children, 
who are, besides older adults, the target populations that are mainly affected by Lyme 
borreliosis.  
This study was designed according to the Note for Guidance on Clinical Evaluation of New 
Vaccines (CHMP/VWP/164653/2005), where applicable. Feedback that was obtained from 
Competent Authority in an End-of-Phase 1 meeting on 29 May 2018 and from scientific advice 
procedures with EMA on 18 Oct 2018 and on 26 Mar 2020 has been taken into consideration 
in the design of the protocol. 
4.2.4 Study events description 
For an outline of procedures required at each visit, please refer to the Tables of Events (Table 
2 for Part A, Table 3 for Part B, respectively). 
 
Part A started with a Screening Visit within 10 days prior to the first administration of the 
investigational medicinal product (IMP).  
The experimental part involves following visits:  
• 
Main Study Phase: nine to ten study visits (Days 1, 8*, 29, 57, 85, 180, 194†, 208, 365, 
545)  
• 
Booster Phase: ten study visits (Months 18, 19, 23, 26, 30, 31, 39, 42, 43, 48) 
Vaccinations will be performed at following time-points:  
• 
Main Study Phase: Days 1-57-180 (Month 0-2-6) 
• 
Booster Phase: Month 18, 30 and 42 
 
In order to observe immediate reactions, sentinel subjects of all age cohorts (18-65 years, 12-
17 years and 5-11 years) were observed for at least 30 minutes after each vaccination prior to 
discharge from study site.  
In the visit descriptions below, all tasks not explicitly mentioned to be performed by unblinded 
study staff are performed by blinded study staff.  
For all study visits, subjects do not have to be in a fasted state. 
In the Main Study Phase (Part A) following procedures are performed for all subjects: 
 
Visit 0, Screening Visit (-10 to 0 days prior to Visit 1): 
This visit is performed as an in-person visit at the study site. 
 
Signed and dated informed consent/assent must be obtained before any study specific 
procedures are undertaken 
 
• 
Check of inclusion and exclusion criteria. 
• 
Document demographic data, complete medical history, vaccination history covering 
the last three years prior to screening, concomitant medications/treatments.  
 
* Visit 1A (i.e. on Day 8) is to be performed as an in-person visit for subjects aged 5-17 years only. 
Due to the COVID-19 pandemic exceptions can be made according to the Table of Events (i.e. Table 
2). For adults (18-65 years) this visit will routinely be performed via phone/video call.  
† Visit 5A is to be performed by a subset of approximately 150 adult subjects only. Subjects will be 
asked prior to study start, if they would like to perform this additional visit.  

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• 
Perform physical examination (general appearance including assessment of body 
weight and height, skin, head/ eyes /ears/ nose/ throat, chest, lungs, heart, abdomen, 
extremities and joints, lymph nodes, and neurological system), measure ECG and vital 
signs (systolic and diastolic blood pressure, pulse rate) in seated position and at rest, 
measure oral body temperature.  
• 
Laboratory tests:  
− 
HIV Test: HIV testing will only be performed in subjects aged ≥12 years. The 
results of negative HIV tests that were performed up to 4 weeks before Visit 0 
are acceptable. Positive HIV tests obtained by ELISA will have to be confirmed 
by a second method (e.g., Western blot or PCR).  
− 
B.b. s.l. screening Test: For serological screening of previous infection with 
Lyme borreliosis, a commercially available Lyme borreliosis screening test will 
be performed. Serum samples that are tested positive will have to be verified 
by a confirmatory immunoblot. Test result does not need to be available before 
randomization and remains valid for 4 weeks. 
− 
Serum Pregnancy Test: A serum pregnancy test has to be performed for each 
female subject aged ≥ 12 years and woman of childbearing potential*. If the test 
is positive, the subject must be excluded from the study.  
• 
Collect immunogenicity sample: Blood will be collected for immunogenicity testing by 
an IgG binding assay 
 
 
 
Visit 1, Day 1: 
 
This visit is performed as an in-person visit at the study site. 
• 
Review inclusion and exclusion criteria. 
• 
Check vaccination delay criteria. 
• 
Document any changes to medical history and concomitant medication/treatments 
including vaccination(s) since the previous study visit. Symptoms noted at Visit 1 
prior to first vaccination are not considered AEs but are recorded as medical history. 
• 
Perform symptom-driven physical examination, measure vital signs (systolic and 
diastolic blood pressure, pulse rate) in seated position and at rest, measure oral body 
temperature (vaccination should be postponed in case of an acute febrile illness). 
• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). Pregnancy test result must be obtained 
prior to vaccination. 
• 
Collect assay development sample (prior to vaccination): Assay development sera 
will be collected from subjects in age group 18 to 65 years only. 
• 
Designated unblinded staff member only (Section 4.2.12): Randomize subject to 
treatment group as described in Section 4.2.11. Prepare vaccination according to 
assigned treatment group. As this study is performed observer-blind, subjects and 
 
* A woman is considered of childbearing potential if fertile and until becoming post-menopausal unless 
permanently sterile. A female that is considered of non-childbearing potential must be e.g. surgically 
sterilized for at least 3 months prior to Visit 1 (e.g. by hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, transcervical sterilization), or postmenopausal for at least one year prior to Visit 1. 

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study staff involved in general study conduct and safety assessments must not be 
informed about the treatment group allocation. 
• 
Administration of vaccination according to assigned treatment group can be 
performed by blinded OR unblinded staff. Vaccine is to be administrated into 
deltoid of the non-dominant arm. 
− 
Blinded staff member: Observe subject for at least 30 minutes after 
vaccination for immediate treatment of possible AEs. Record any AEs and 
local and systemic tolerability following vaccination, if applicable. 
− 
If the subject has any complaints after vaccination, perform a symptom-driven 
physical examination and record vital signs prior to discharge. Only discharge 
subject if in the opinion of the investigator no further concerns exist. 
• 
Explain eDiary: Instruct subject/ legal representative(s) how and when to complete 
the eDiary. Distribute thermometer and measuring tape. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
• 
Supply subjects with urine pregnancy test kits to ensure that subjects can test for 
pregnancy at home in case the COVID-19 pandemic prohibits in-person visits at 
subsequent scheduled visits.  
 
Visit 1A, Day 8 (+ 2 days):  
 
This safety follow-up visit is to be performed remotely (phone/video call) for subjects aged 18-
65 years. For subjects aged 5-17 years, Visit 1A will be performed as an in-person visit. If an 
in-person visit for adolescents or children cannot be done or is inacceptable due to COVID-19, 
e.g. travel restrictions, local recommendations, circumstances at the study site’s location that 
prohibit an in-person visit, or if the PI believes that the subject’s safety and well-being might 
be jeopardized with an in-person visit at the study site due to COVID-19, the visit should be 
conducted remotely (e.g., phone/ video call).  
 
For in-person visits:    
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
In subjects aged 5-17 years:  
− 
Perform symptom-driven physical examination. 
− 
Inspect vaccination site for (ongoing) Adverse Events. 
• 
Perform scripted safety assessment. 
• 
Review eDiary: including verification of entries with the subject. Clinician to re-assess 
severity of reported solicited local and systemic AEs. In addition, re-assess causality 
for any reported medically attended or severe solicited local and systemic AEs. 
Record any unsolicited AEs, any AESI or SAE since last study visit. Instruct subject/ 
legal representative(s) to continue using the eDiary for documenting AEs. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  

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− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
For remote visits:  
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Review eDiary: verify entries with subject. Instruct subject/ legal representative(s) to 
continue using the eDiary for documenting AEs.  
• 
Perform scripted safety assessment. 
• 
Record any unsolicited AEs, any AESI or SAE since last study visit. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
 
Visit 2, Day 29/Month 1 (+2/-4 days):  
 
This visit should preferably be conducted as in-person visit. If an in-person visit cannot be done 
or is inacceptable due to COVID-19, e.g. travel restrictions, local recommendations, 
circumstances at the study site’s location that prohibit an in-person visit, or if the PI believes 
that the subject’s safety and well-being might be jeopardized with an in-person visit at the study 
site due to COVID-19, the visit should be conducted remotely (e.g., phone/ video call).  
 
For in-person visits:  
 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Perform symptom-driven physical examination. 
• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4).  
• 
Inspect vaccination site for (ongoing) Adverse Events. 
• 
Review eDiary: including verification of entries with the subject. Clinician to re-assess 
severity of reported solicited local and systemic AEs. In addition, re-assess causality 
for any reported medically attended or severe solicited local and systemic AEs.  
• 
Perform scripted safety assessment.  
• 
Record any unsolicited AEs, any AESI or SAE since last study visit. Instruct subject/ 
legal representative(s) to continue using the eDiary for documenting AEs. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 

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For remote visits:  
• 
Laboratory tests:  
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Review eDiary: verify entries with subject. Instruct subject/ legal representative(s) to 
continue using the eDiary for documenting AEs.  
• 
Perform scripted safety assessment. 
• 
Record any unsolicited AEs, any AESI or SAE since last study visit. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
 
Visit 3, Day 57/Month 2 (+/-4 days):  
 
This visit is performed as an in-person visit at the study site. 
 
• 
Check vaccination delay criteria. 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Perform symptom-driven physical examination, measure vital signs (systolic and 
diastolic blood pressure, pulse rate) in seated position and at rest, measure oral 
body temperature (vaccination should be postponed in case of an acute febrile 
illness). 
• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). Pregnancy test result must be obtained 
prior to vaccination. 
• 
Perform scripted safety assessment. 
• 
Record any unsolicited AEs, any AESI or SAE since last study visit. 
• 
Designated unblinded staff member only (Section 4.2.12): Prepare vaccination 
according to assigned treatment group. As this study is performed observer-blind, 
subjects and study staff involved in general study conduct and safety assessments 
must not be informed about the treatment group allocation. 
• 
Administration of vaccination according to assigned treatment group can be 
performed by blinded OR unblinded staff.  Vaccine is to be administrated into 
deltoid of the non-dominant arm. 
− 
Blinded staff member: Observe subject for at least 30 minutes after 
vaccination for immediate treatment of possible AEs. Record any AEs and 
local and systemic tolerability following vaccination, if applicable. 

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− 
If the subject has any complaints after vaccination, perform a symptom-
driven physical examination and record vital signs prior to discharge. Only 
discharge subject if in the opinion of the investigator no further concerns 
exist. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
• 
Supply subjects with additional urine pregnancy test kits to ensure that subjects can 
test for pregnancy at home in case the COVID-19 pandemic prohibits in-person visits 
at subsequent scheduled visits.  
 
Visit 4, Day 85/Month 3: Visit 3 + 28 days (+/- 4 days):  
 
This visit should preferably be conducted as in-person visit. If an in-person visit cannot be done 
or is inacceptable due to COVID-19, e.g., travel restrictions, local recommendations, 
circumstances at the study site’s location that prohibit an in-person visit, or if the PI believes 
that the subject’s safety and well-being might be jeopardized with an in-person visit at the study 
site due to COVID-19, the visit should be conducted remotely (e.g., phone/ video call).  
 
For in-person visits:  
 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Perform symptom-driven physical examination. 
• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). 
• 
Collect immunogenicity and assay development sample: Assay development sera 
will be collected from subjects in age group 18 to 65 years only. 
• 
Inspect vaccination site for (ongoing) Adverse Events. 
• 
Review eDiary: including verification of entries with the subject. Clinician to re-
assess severity of reported solicited local and systemic AEs. In addition, re-assess 
causality for any reported medically attended or severe solicited local and systemic 
AEs.  
• 
Perform scripted safety assessment. 
• 
Record any unsolicited AEs, any AESI or SAE since last study visit. Instruct subject/ 
legal representative(s) to continue using the eDiary for documenting AEs. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
For remote visits:  

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• 
Laboratory tests:  
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Review eDiary: verify entries with subject. Instruct subject/ legal representative(s) to 
continue using the eDiary for documenting AEs.  
• 
Perform scripted safety assessment. 
• 
 Record any unsolicited AEs, any AESI or SAE since last study visit. 
• 
The immunogenicity sample will be taken by a mobile nurse professional at the 
subject’s home within the specified time window.  
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
 
Visit 5, Day 180/Month 6 (+4/-28 days):  
 
This visit is performed as an in-person visit at the study site. 
 
• 
Check vaccination delay criteria. 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Perform symptom-driven physical examination, measure vital signs (systolic and 
diastolic blood pressure, pulse rate) in seated position and at rest, measure oral 
body temperature (vaccination should be postponed in case of an acute febrile 
illness). 
• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). Pregnancy test result must be obtained 
prior to vaccination. 
• 
Collect immunogenicity sample before vaccination.  
• 
Perform scripted safety assessment. 
• 
Record any unsolicited AEs, any AESI or SAE since last study visit. 
• 
Designated unblinded staff member only (Section 4.2.12): Prepare vaccination 
according to assigned treatment group. As this study is performed observer-blind, 
subjects and study staff involved in general study conduct and safety assessments 
must not be informed about the treatment group allocation. 
• 
Administration of vaccination according to assigned treatment group can be 
performed by blinded OR unblinded staff. Vaccine is to be administrated into 
deltoid of the non-dominant arm. 

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− 
Blinded staff member: Observe subject for at least 30 minutes after 
vaccination for immediate treatment of possible AEs. Record any AEs and 
local and systemic tolerability following vaccination, if applicable. 
− 
If the subject has any complaints after vaccination, perform a symptom-
driven physical examination and record vital signs prior to discharge. Only 
discharge subject if in the opinion of the investigator no further concerns 
exist. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
• 
Supply subjects with additional urine pregnancy test kits to ensure that subjects can 
test for pregnancy at home in case the COVID-19 pandemic prohibits in-person visits 
at subsequent scheduled visits.  
 
Visit 5A, Day 194/Month 6.5: Visit 5 + 14 days (+/-2 days):  
Visit 5A will be performed in a subset of approximately 150 adult subjects. Subjects will be 
asked prior to study start, if they agree to perform this additional visit. This visit should 
preferably be conducted as in-person visit. If an in-person visit cannot be done or is 
inacceptable due to COVID-19, e.g., travel restrictions, local recommendations, circumstances 
at the study site’s location that prohibit an in-person visit, or if the PI believes that the subject’s 
safety and well-being might be jeopardized with an in-person visit at the study site due to 
COVID-19, the visit should be conducted remotely (e.g., phone/ video call).  
For in-person visits: 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Perform symptom-driven physical examination. 
• 
Collect immunogenicity sample.  
• 
Inspect vaccination site for (ongoing) Adverse Events. 
• 
Review eDiary: including verification of entries with the subject. Clinician to re-
assess severity of reported solicited local and systemic AEs. In addition, re-assess 
causality for any reported medically attended or severe solicited local and systemic 
AEs.  
• 
Perform scripted safety assessment. 
• 
Record any unsolicited AEs, any AESI or SAE since last study visit. Instruct subject/ 
legal representative(s) to continue using the eDiary for documenting AEs. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
For remote visits: 

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• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Review eDiary: verify entries with subject. Instruct subject/ legal representative(s) to 
continue using the eDiary for documenting AEs.  
• 
Perform scripted safety assessment. 
• 
Record any unsolicited AEs, any AESI and any SAE since the last study visit. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
• 
The immunogenicity sample will be taken by a mobile nurse professional at the 
subject’s home within the specified time window. 
 
Visit 6, Day 208/Month 7/ Visit 5 + 28 days (+2/- 4 days):  
 
This visit should preferably be conducted as in-person visit. If an in-person visit cannot be done 
or is inacceptable due to COVID-19, e.g., travel restrictions, local recommendations, 
circumstances at the study site’s location that prohibit an in-person visit, or if the PI believes 
that the subject’s safety and well-being might be jeopardized with an in-person visit at the study 
site due to COVID-19, the visit should be conducted remotely (e.g., phone/ video call).  
 
 
For in-person visits:  
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Perform symptom-driven physical examination. 
• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4).  
• 
Collect immunogenicity and assay development sample. Assay development sera 
will be collected from subjects in age group 18 to 65 years only. 
• 
Inspect vaccination site for (ongoing) Adverse Events. 
• 
Review eDiary: including verification of entries with the subject. Clinician to re-
assess severity of reported solicited local and systemic AEs. In addition, re-assess 
causality for any reported medically attended or severe solicited local and systemic 
AEs.  
• 
Perform scripted safety assessment. 
• 
Record any unsolicited AEs, any AESI or SAE since last study visit. Instruct subject/ 
legal representative(s) to continue using the eDiary for documenting AEs. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 

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For remote visits:  
• 
Laboratory tests:  
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Review eDiary: verify entries with subject. Instruct subject/ legal representative(s) to 
continue using the eDiary for documenting AEs.  
• 
Perform scripted safety assessment.  
• 
Record any unsolicited AEs, any AESI and any SAE since the last study visit. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
• 
The immunogenicity sample will be taken by a mobile nurse professional at the 
subject’s home within the specified time window. 
 
Visit 7, Day 365/Month 12 (+/- 14 days):  
 
This visit should preferably be conducted as in-person visit. If an in-person visit cannot be done 
or is inacceptable due to COVID-19, e.g., travel restrictions, local recommendations, 
circumstances at the study site’s location that prohibit an in-person visit, or if the PI believes 
that the subject’s safety and well-being might be jeopardized with an in-person visit at the study 
site due to COVID-19, the visit should be conducted remotely (e.g., phone/ video call).  
 
For in-person visits:  
 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Perform symptom-driven physical examination. 
• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4).  
• 
Collect immunogenicity sample;  
• 
Perform scripted safety assessment. 
• 
Record any AESI or SAE since last study visit. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 

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For remote visits:  
• 
Laboratory tests:  
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Review eDiary: verify entries with subject. Instruct subject/ legal representative(s) to 
continue using the eDiary for documenting SAEs 
• 
Perform scripted safety assessment.  
• 
Record any unsolicited AEs, any AESI and any SAE since the last study visit. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
• 
The immunogenicity sample will be taken by a mobile nurse professional at the 
subject’s home within the specified time window. 
 
Visit 8, Day 545/Month 18 (+/- 14 days):  
 
This visit should preferably be conducted as in-person visit. If an in-person visit cannot be done 
or is inacceptable due to COVID-19, e.g., travel restrictions, local recommendations, 
circumstances at the study site’s location that prohibit an in-person visit, or if the PI believes 
that the subject’s safety and well-being might be jeopardized with an in-person visit at the study 
site due to COVID-19, the visit should be conducted remotely (e.g., phone/ video call).  
 
For in-person visits:  
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Perform symptom-driven physical examination. 
• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). In case Visit 8 and Visit 8B are performed 
as a combined visit, the pregnancy test result must be obtained prior to 
vaccination. 
− 
B.b. s.l. screening test: For serological screening on previous infection with 
Lyme borreliosis, a commercially available Lyme borreliosis screening test will 
be performed. Serum samples that are tested positive will have to be verified by 
a confirmatory immunoblot.  
• 
Collect immunogenicity sample: In case Visit 8 and Visit 8B are performed as a 
combined visit, the immunogenicity sample has to be drawn prior to vaccination.  
• 
Perform scripted safety assessment. 
• 
Record, any AESI and any SAE since the last study visit.  

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• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
For remote visits:  
• 
Laboratory tests:  
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Review eDiary: verify entries with subject. For subjects who continue study, instruct 
subject/ legal representative(s) to continue using the eDiary for documenting AEs 
• 
Perform scripted safety assessment.  
• 
Record any unsolicited AEs, any AESI and any SAE since the last study visit. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
• 
The immunogenicity and B.b. s.l. screening sample will be taken by a mobile nurse 
professional at the subject’s home within the specified time window. 
 
ET Visit, Early Termination Visit before V8:  
 
Subjects who terminate participation or who are withdrawn from the study prematurely undergo 
the following investigations during an Early Termination Visit, if possible: 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Perform symptom-driven physical examination. 
• 
If ET visit is prior to Visit 6, inspect vaccination site for (ongoing) Adverse Events. 
• 
Review eDiary: including verification of entries with the subject. Clinician to re-
assess severity of reported solicited local and systemic AEs. In addition, re-assess 
causality for any reported medically attended or severe solicited local and systemic 
AEs. 
• 
Record any unsolicited AEs, any AESI or SAE since last study visit.  
• 
Laboratory tests: 
- Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4).  
- B.b. s.l. screening test: For serological screening on previous infection with 
Lyme borreliosis, a commercially available Lyme borreliosis screening test will 
be performed. Serum samples that are tested positive will have to be verified by 
a confirmatory immunoblot. 

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The reason for early termination should be clarified in as much detail as possible. If an AE is 
the reason for early study termination details on that specific AE(s) should be captured. If the 
subject is unwilling to perform an ET Visit or an in-person ET visit is not possible due to 
circumstances of the ongoing COVID-19 situation, a remote visit (e.g., phone/video call) should 
be made as soon as possible after termination to follow-up on concomitant medication 
including vaccination(s) and AEs ongoing (including persisting injection site reactions, if 
applicable) and any new AEs since the previous study visit should be documented. The reason 
for early termination should be clarified in as much detail as possible. If an AE is the reason 
for early study termination details on that specific AE(s) should be captured. See also Section 
10.3 of the study protocol. 
Note: If subject presents at a regular study visit within the acceptable time window and inform 
that he/she discontinues the study after this visit, the study visit is not performed as an ET visit 
but is performed and documented as a regular study visit including all events that are described 
for respective study visit. In this case a Lyme borreliosis screening test is performed in addition 
for serological screening on infection with Lyme borreliosis. 
 
In the Booster Phase (Part B), the following procedures are performed for all subjects: 
 
Visit 8B, Month 18 (Visit 8 + 14 days):  
 
This visit is performed as an in-person visit at the study site. Visit 8 and Visit 8B should be 
combined in one visit if possible. The time window between Visit 8 and Visit 8B should be kept 
as short as possible (max. 14 days apart). If both visits are scheduled on the same day, all 
procedures from Visit 8 have to be performed prior to performing any procedures from Visit 
8B.  
• 
Reconfirm consent/assent 
• 
Check booster inclusion and exclusion criteria. 
• 
Check vaccination delay criteria. 
• 
Document any changes to medical history and concomitant medication/treatments 
including vaccination(s) since the previous study visit.  
• 
Perform physical examination (general appearance including assessment of body 
weight and height, skin, head/ eyes /ears/ nose/ throat, chest, lungs, heart, abdomen, 
extremities and joints, lymph nodes, and neurological system), measure vital signs 
(systolic and diastolic blood pressure, pulse rate) in seated position and at rest, 
measure oral body temperature (vaccination should be postponed in case of an acute 
febrile illness).  
 
• 
Laboratory tests:  
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). Pregnancy test result must be obtained 
prior to vaccination. 
• 
Perform scripted safety assessment. 
• 
Record any AESI or SAE since last study visit 
• 
Designated unblinded staff member only (Section 4.2.12): Prepare vaccination 
according to assigned treatment group. As this study is performed observer-blind, 
subjects and study staff involved in general study conduct and safety assessments 
must not be informed about the treatment group allocation. 

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• 
Administration of vaccination according to assigned treatment group can be 
performed by blinded OR unblinded staff. Vaccine is to be administrated into 
deltoid of the non-dominant arm. 
− 
Blinded staff member: Observe subject after vaccination for immediate 
treatment of possible AEs. Record any AEs and local and systemic 
tolerability following vaccination, if applicable. 
− 
If the subject has any complaints after vaccination, perform a symptom-
driven physical examination and record vital signs prior to discharge. Only 
discharge subject if in the opinion of the investigator no further concerns 
exist. 
• 
Explain eDiary: Instruct subject/ legal representative(s) how and when to complete 
the eDiary. Distribute thermometer and measuring tape. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
 
Visit 9, Month 19/V8B + 28 days (+/-4 days):  
This visit is performed as an in-person visit at the study site. 
• 
Document any changes to medical history and concomitant medication/treatments 
including vaccination(s) since the previous study visit.  
• 
Perform symptom-driven physical examination. 
• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4).  
• 
Collect immunogenicity and assay development sample. Assay development sera 
will be collected from subjects in age group 18 to 65 years only.  
• 
Inspect vaccination site for (ongoing) Adverse Events. 
• 
Review eDiary: including verification of entries with the subject. Clinician to re-assess 
severity of reported solicited local and systemic AEs. In addition, re-assess causality 
for any reported medically attended or severe solicited local and systemic AEs. 
• 
Perform scripted safety assessment. 
• 
Record any unsolicited AEs, any AESI or SAE since last study visit. Instruct subject/ 
legal representative(s) to continue using the eDiary for documenting AEs. 
 
Visit 10, Month 23 (+/-14 days):  
This visit is performed as an in-person visit at the study site. 
• 
Document any changes to medical history and concomitant medication/treatments 
including vaccination(s) since the previous study visit.  
• 
Perform symptom-driven physical examination. 

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• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4).  
• 
Collect immunogenicity sample.  
• 
Perform scripted safety assessment. 
• 
Record any AESI or SAE since last study visit. Instruct subject/ legal 
representative(s) to continue using the eDiary for documenting AEs. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
 
Visit 11, Month 26 (+28/-14 days):  
 
This visit is performed as an in-person visit at the study site. 
• 
Reconfirm consent/ assent.  
• 
Document any changes to medical history and concomitant medication/treatments 
including vaccination(s) since the previous study visit.  
• 
Perform symptom-driven physical examination. 
• 
Collect immunogenicity sample.  
• 
Perform scripted safety assessment. 
• 
Record any AESI or SAE since last study visit. Instruct subject/ legal 
representative(s) to continue using the eDiary for documenting AEs. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
 
Visit 12, Month 30 (+/-28 days):  
 
This visit is performed as an in-person visit at the study site. 
• 
Reconfirm consent/assent. 
• 
Check Inclusion/Exclusion criteria.  
• 
Check vaccination delay criteria. 
• 
Document any changes to medical history and concomitant medication/treatments 
including vaccination(s) since the previous study visit.  
• 
Perform physical examination (general appearance including assessment of body 
weight and height, skin, head/ eyes /ears/ nose/ throat, chest, lungs, heart, abdomen, 
extremities and joints, lymph nodes, and neurological system), measure vital signs 
(systolic and diastolic blood pressure, pulse rate) in seated position and at rest, 

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measure oral body temperature (vaccination should be postponed in case of an acute 
febrile illness).  
• 
Perform scripted safety assessment. 
• 
Record any AESI or SAE since last study visit. 
• 
Laboratory tests:  
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). Pregnancy test result must be obtained 
prior to vaccination. 
− 
B.b. s.l. screening test: For serological screening on previous infection with 
Lyme borreliosis, a commercially available Lyme borreliosis screening test 
will be performed. Serum samples that are tested positive will have to be 
verified by a confirmatory immunoblot. 
• 
Collect immunogenicity sample before vaccination.  
• 
Designated unblinded staff member only (Section 4.2.12): Prepare vaccination 
according to assigned treatment group. As this study is performed observer-blind, 
subjects and study staff involved in general study conduct and safety assessments 
must not be informed about the treatment group allocation. 
• 
Administration of vaccination according to assigned treatment group can be 
performed by blinded OR unblinded staff. Vaccine is to be administrated into 
deltoid of the non-dominant arm. 
− 
Blinded staff member: Observe subject after vaccination for immediate 
treatment of possible AEs. Record any AEs and local and systemic 
tolerability following vaccination, if applicable. 
− 
If the subject has any complaints after vaccination, perform a symptom-
driven physical examination and record vital signs prior to discharge. Only 
discharge subject if in the opinion of the investigator no further concerns 
exist. 
• 
Explain eDiary: Instruct subject/ legal representative(s) how and when to complete 
the eDiary. Distribute thermometer and measuring tape in case subject lost these 
items. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
 
Visit 13, Month 31/ V12 + 28 days (+/- 4 days):  
This visit is performed as an in-person visit at the study site. 
• 
Document any changes to medical history and concomitant medication/treatments 
including vaccination(s) since the previous study visit.  
• 
Perform symptom-driven physical examination. 
• 
Laboratory tests: 

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− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4).  
• 
Collect immunogenicity and assay development sample. Assay development sera 
will be collected from subjects in age group 18 to 65 years only. 
• 
Inspect vaccination site for (ongoing) Adverse Events. 
• 
Review eDiary: including verification of entries with the subject. Clinician to re-assess 
severity of reported solicited local and systemic AEs. In addition, re-assess causality 
for any reported medically attended or severe solicited local and systemic AEs. 
• 
Perform scripted safety assessment. 
• 
Record any unsolicited AEs, any AESI or SAE since last study visit. Instruct subject/ 
legal representative(s) to continue using the eDiary for documenting AEs. 
 
Visit 14, Month 39 (+/-14 days):  
This visit is performed as an in-person visit at the study site. 
• 
Document any changes to medical history and concomitant medication/treatments 
including vaccination(s) since the previous study visit.  
• 
Perform symptom-driven physical examination. 
• 
Collect immunogenicity sample.  
• 
Perform scripted safety assessment. 
• 
Record any AESI or SAE since last study visit. Instruct subject/ legal 
representative(s) to continue using the eDiary for documenting AEs. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
 
Visit 15, Month 42 (+/-28 days):  
This visit is performed as an in-person visit at the study site. 
• 
Reconfirm consent/assent. 
• 
Check Inclusion/Exclusion criteria.  
• 
Check vaccination delay criteria. 
• 
Document any changes to medical history and concomitant medication/treatments 
including vaccination(s) since the previous study visit.  
• 
Perform physical examination (general appearance including assessment of body 
weight and height, skin, head/ eyes /ears/ nose/ throat, chest, lungs, heart, abdomen, 
extremities and joints, lymph nodes, and neurological system), measure vital signs 
(systolic and diastolic blood pressure, pulse rate) in seated position and at rest, 
measure oral body temperature (vaccination should be postponed in case of an acute 
febrile illness).  
• 
Perform scripted safety assessment. 

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• 
Record any AESI or SAE since last study visit. 
• 
Laboratory tests:  
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4). Pregnancy test result must be obtained 
prior to vaccination. 
− 
B.b. s.l. screening test: For serological screening on previous infection with 
Lyme borreliosis, a commercially available Lyme borreliosis screening test 
will be performed. Serum samples that are tested positive will have to be 
verified by a confirmatory immunoblot. 
• 
Collect immunogenicity sample before vaccination.  
• 
Designated unblinded staff member only (Section 4.2.12): Prepare vaccination 
according to assigned treatment group. As this study is performed observer-blind, 
subjects and study staff involved in general study conduct and safety assessments 
must not be informed about the treatment group allocation. 
• 
Administration of vaccination according to assigned treatment group can be 
performed by blinded OR unblinded staff. Vaccine is to be administrated into 
deltoid of the non-dominant arm. 
− 
Blinded staff member: Observe subject after vaccination for immediate 
treatment of possible AEs. Record any AEs and local and systemic 
tolerability following vaccination, if applicable. 
− 
If the subject has any complaints after vaccination, perform a symptom-
driven physical examination and record vital signs prior to discharge. Only 
discharge subject if in the opinion of the investigator no further concerns 
exist. 
• 
Explain eDiary: Instruct subject/ legal representative(s) how and when to complete 
the eDiary. Distribute thermometer and measuring tape in case subject lost these 
items. 
• 
Remind subject/ legal representative(s) to immediately inform the site in case 
subject experiences one of the following:  
− 
any severe adverse event 
− 
any symptoms suspicious for Lyme borreliosis or diagnosis of LB, e.g., red or 
bluish-red patch (≥5 cm, indicate location), or joint swelling (indicate which joint). 
 
Visit 16, Month 43 (V15 + 28 days (+/- 4 days)): 
This visit is performed as an in-person visit at the study site. 
• 
Document any changes to medical history and concomitant medication/treatments 
including vaccination(s) since the previous study visit.  
• 
Perform symptom-driven physical examination. 
• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥12 years and women of 
childbearing potential (Section 6.4).  
• 
Collect immunogenicity and assay development sample. Assay development sera 
will be collected from subjects in age group 18 to 65 years only. 

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• 
Inspect vaccination site for (ongoing) Adverse Events. 
• 
Review eDiary: including verification of entries with the subject. Clinician to re-assess 
severity of reported solicited local and systemic AEs. In addition, re-assess causality 
for any reported medically attended or severe solicited local and systemic AEs. 
• 
Perform scripted safety assessment. 
• 
Record any unsolicited AEs, any AESI or SAE since last study visit. Instruct subject/ 
legal representative(s) to continue using the eDiary for documenting AEs. 
 
Visit 17, Month 48 (+/-14 days):  
This visit is performed as an in-person visit at the study site. 
• 
Document any changes to medical history and concomitant medication/treatments 
including vaccination(s) since the previous study visit.  
• 
Perform symptom-driven physical examination. 
• 
Laboratory tests: 
− 
Urine pregnancy test: In female subjects aged ≥ 12 years and women of 
childbearing potential (Section 6.4).  
− 
B.b. s.l. screening test: For serological screening on previous infection with 
Lyme borreliosis, a commercially available Lyme borreliosis screening test will 
be performed. Serum samples that are tested positive will have to be verified 
by a confirmatory immunoblot. 
• 
Collect immunogenicity sample.  
• 
Perform scripted safety assessment. 
• 
Record any AESI or SAE since last study visit.  
 
 
ET Visit, Early Termination Visit before V17:  
 
Subjects who terminate participation or who are withdrawn from the study prematurely undergo 
the following investigations during an Early Termination Visit, if possible: 
• 
Document 
any 
changes 
to 
concomitant 
medication/treatments 
including 
vaccination(s) since the previous study visit. 
• 
Perform symptom-driven physical examination. 
• 
Inspect vaccination site for (ongoing) Adverse Events. 
• 
Perform scripted safety assessment. 
• 
Review eDiary: including verification of entries with the subject. Clinician to re-
assess severity of reported solicited local and systemic AEs. In addition, re-assess 
causality for any reported medically attended or severe solicited local and systemic 
AEs. Record any unsolicited AEs, any AESI or SAE since last study visit.   
• 
Laboratory tests: 
- Urine pregnancy test: In female subjects aged ≥12 years and women of 
childbearing potential (Section 6.4). 

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- B.b. s.l. screening test: For serological screening on previous infection with 
Lyme borreliosis, a commercially available Lyme borreliosis screening test will 
be performed. Serum samples that are tested positive will have to be verified by 
a confirmatory immunoblot. 
The reason for early termination should be clarified in as much detail as possible. If an AE is 
the reason for early study termination details on that specific AE(s) should be captured. 
If the subject is unwilling to perform an ET Visit or an in-person ET visit is not possible due to 
circumstances of the ongoing COVID-19 situation, a remote visit (e.g., phone/ video call) 
should be made as soon as possible after termination to follow-up on concomitant medication 
including vaccination(s) and AEs ongoing (including persisting injection site reactions, if 
applicable) and any new AEs since the previous study visit should be documented. The reason 
for early termination should be clarified in as much detail as possible. If an AE is the reason 
for early study termination details on that specific AE(s) should be captured. See also Section 
10.3 of the study protocol. 
Note: If subject presents at a regular study visit within the acceptable time window and inform 
that he/she discontinues the study after this visit, the study visit is not performed as an ET visit 
but is performed and documented as a regular study visit including all events that are described 
for respective study visit. Additionally, a Lyme borreliosis screening test is performed as 
required for the ET visit. 
 
Unscheduled Visits: 
An unscheduled visit can be held at any time during the study if deemed necessary by the 
Investigator (e.g., follow-up on unexpected AEs, SAEs or AESIs) or requested by the DMC. 
Unscheduled visits and any assessments performed during the visit (e.g., physical 
examination, laboratory test) should be documented in the source data and the eCRF. 
4.2.5 Number of subjects and study centres 
A total of 715 subjects were screened and 625 healthy subjects aged 5 to 65 years were 
enrolled in this study: 320 subjects aged 18-65 years, 150 subjects aged 12-17 years and 155 
subjects aged 5-11 years. Subjects were recruited at in total 14 active study centers. Study 
sites are located in Lyme borreliosis endemic areas in the U.S.  
4.2.6 Timely conduct of the study 
Study start for the Main Study Phase (Part A) was March 2021. Booster Phase (Part B) started 
in September 2022.  
4.2.7 Study duration 
Study duration per subject will be a maximum of 50 months per subject. Overall study duration 
(i.e., First-Subject-In to Last-Subject-Out) is estimated to be 4 years and 5 months. The end of 
the study is defined as the date of the last visit performed by the last subject. 
4.2.8 Assignment of subjects to study groups 
In the Main Study Phase (Part A) 625 subjects were randomized 1:1:1 to receive VLA15 
vaccinations at Month 0-2-6 (Group 1) or Month 0-6 (plus a placebo injection at Month 2, Group 
2) or placebo injections at Month 0-2-6 (Group 3) according to the procedure described in 
Section 4.2.11. During the Booster Phase (Part B) Group 1 and Group 2 subjects will receive 
a VLA15 booster dose at Month 18, 30 and 42. Group 3 will receive additional placebo 
injections at Month 18, 30 and 42.  
4.2.9 Subject Identification 
At Visit 0 a 10-digit subject number was assigned to each subject. The first five digits are the 
study identifier (15221 for this study). The sixth and seventh digit is the site identification 

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number (e.g., 01). The last three digits are assigned in ascending order as the subjects are 
screened. 
4.2.10 Re-screening 
Re-screening of subjects was allowed once. Assessments, which have been performed during 
the first screening visit, remained valid for 14 days. In case re-screening occurs outside this 
time frame, already performed measures have to be repeated.  
4.2.11 Randomization 
Subjects were allocated to study groups via the randomization module of the EDC system. 
Subjects were randomized 1:1:1 to the three study groups, randomization was stratified by age 
in a 2:1:1 (adults: 18-65 years; adolescents: 12-17; children: 5-11 years) ratio. Date and time 
of enrollment will be defined as the time point at which the subject was randomized.  
4.2.12 Blinding 
The study is an observer-blinded study, which is conducted in a blinded manner for the study 
investigators, the sponsor including laboratory personnel, and the subjects. At the study site, 
only designated study staff who randomize subjects into study groups and perform preparation 
of the vaccine are unblinded.  
 
Administration of the vaccine can be performed by staff from either the blinded or unblinded 
study site team. An overview of persons who will be unblinded and blinded is provided below: 
 
Unblinded: 
• 
Designated study site staff who randomize subjects to study groups and are concerned 
with IMP handling (i.e., perform preparation and maintain drug dispensing log). These 
unblinded study staff members will not conduct any other study procedures; 
• 
CRAs responsible for monitoring of IMP handling and related data for verifying drug 
accountability during the study and performing overall drug accountability; 
• 
Dedicated statistical team at the CRO performing statistical analyses for generation of 
safety data tables for the DMC and IRC; 
• 
DMC members; 
• 
IRC members. 
 
Blinded: 
• 
Study participants and legal representative(s); 
• 
Investigators and other study staff involved in general study conduct and safety 
assessments; 
• 
All other CRAs (responsible for monitoring study data apart from IMP handling/drug 
accountability); 
• 
All other sponsor/ collaboration partner and CRO staff including laboratory personnel 
at the sponsor’s labs for immunogenicity assessments. 
 
Blinding process: 
To ensure that study participants cannot tell the group they have been allocated to from the 
physical appearance of the syringe, preparation of IMP must be done by unblinded staff 
members only in a separate room, unobserved by blinded staff members and the subject and 
its legal representative(s). Details on blinding will be provided in the study specific IMP manual.  
 
Unblinding during the study: 
The blind must not be broken for anyone involved in the study conduct. Unblinding of individual 
subjects can be performed by the investigator in case of emergency and if knowledge of the 
treatment assignment is mandatory for emergency treatment. Designated personnel at 

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/Pfizer Safety and a sponsor representative otherwise not involved in the study conduct 
may be unblinded for individual cases of SAEs that are both unexpected and suspected to 
have a causal relationship to the study vaccines (SUSARs), to fulfil safety reporting 
requirements. Procedures are described in a safety management plan. 
The study sponsor/ collaboration partner and study statisticians were unblinded at the time of 
the primary endpoint analysis, i.e., Day 208 analysis, in each age cohort (i.e., Analysis 1.1, 
Analysis 1.2 and Analysis 1.3) after the respective database snapshot had been performed. 
All other study personnel including the investigators and other study staff involved in general 
study conduct and safety assessments as well as laboratory personnel who are performing 
analytical assays will remain blinded until study end.  
5 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Valneva’s VLA15 Lyme borreliosis vaccine candidate is composed of three ~35 kDa fusion 
proteins, each containing the C-terminal part of two OspA serotypes, fused together by a 21 
residues long linker and stabilized each by one disulfide bond. The proteins, designated as 
Lip-D1B2B (ST1 and ST2), Lip-D4Bva3B (ST4 and ST3) and Lip-D5B6B (ST5 and ST6), are 
attached to a lipid moiety on their N-Terminus. The putative T-cell epitope in OspA ST1 
presenting homology to human leukocyte function-associated antigen-1 (hLFA-1), that has 
previously been claimed to induce antibiotic-refractory Lyme arthritis in a subset of naturally 
infected patients, has been replaced with corresponding sequence from OspA ST2.  
VLA15 is formulated with aluminum hydroxide (alum) as adjuvant. PBS is used as placebo. 
 
Description of IMP  
In this study, a new VLA15 presentation is used. Compared to the previous Phase 2 studies 
(VLA15-201 and VLA15-202), this presentation contains the same amounts of VLA15 (i.e., 180 
µg) and alum (i.e. 0.5 mg) in a more concentrated form (i.e., formulated in 0.5 mL instead of 
1.0 mL of buffer). Subjects are vaccinated with 180 µg VLA15/dose. The injection volume is 
0.5 mL. For the primary vaccination series (i.e., Month 0-(2)-6) and first booster vaccinations 
(i.e., at Month 18) material filled in vials (see Section 5.1.1, 5.1.2 and 5.1.7) is used, whereas 
for second and third booster shots (i.e., at Month 30 and 42) material filled in pre-filled syringes 
(PFS) is used (see Section 5.1.4 and 5.1.4).  
5.1.1 VLA15 Presentation for primary vaccination series and first booster  
The VLA15 presentation contains the three proteins Lip-D1B2B, Lip-D4Bva3B and Lip-D5B6B, 
which are formulated in a 1:1:1 ratio in buffer (10 mM L-Methionine, 10 mM NaH2PO4 
dihydrate, 150 mM NaCl, 5% (w/v) Sucrose, 0.05% (v/v) Tween®20 at pH 6.7).  
The 180 µg dose contains 360 µg/ mL total protein (i.e., 120 µg/mL for each protein). 
 
After sterilizing filtration of the VLA15 solution, sterile aluminum hydroxide is added aseptically 
to a target concentration of 1.0 mg/mL aluminum. The VLA15 presentation for is filled into 2R 
Type I Plus® glass vials (0.65 mL filling volume per vial, resulting in 0.50 mL extractable 
volume) closed with 13 mm injection Flurotec® stoppers secured by crimp caps. The new 
presentation is available in 2 mL glass vials in form of a white to off-white suspension with a 
protein content of 360 µg/mL (180 µg/ 0.5 mL). 
The VLA15 presentation should be stored at +2 to +8°C and a retest date of 24 months from 
date of production will be assigned. This retest date will be extended to 36 months with data 
from ongoing stability program provided no significant trends in product quality are observed. 

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Table 9 Overview of components of 180 µg VLA15 presentation 
Component 
Amount 
Lip-D1B2B 
120 µg/mL 
Lip-D4Bva3B 
120 µg/mL 
Lip-D5B6B 
120 µg/mL 
L-Methionine 
10 mM 
NaH2PO4 dihydrate 
10 mM 
NaCl 
150 mM 
Sucrose 
5% (w/v) 
Tween®20 
0.05% (v/v) 
Aluminum hydroxide, 0.30% 
1.0 mg/mL 
5.1.2 VLA Placebo for primary vaccination series and first booster 
The VLA Placebo is a PBS buffer based on Dulbecco’s PBS media presentation without 
Calcium and Magnesium. Subjects receive placebo injections with a volume of 0.5 mL. VLA 
Placebo is filtered and filled in sterile 2R glass vials under constant stirring. The vials are 2R 
Type I Plus® glass vials closed with 13 mm injection Flurotec® secured by aluminum crimp 
caps. 
 
The total filling volume of 0.6 mL will ensure an extractable volume of 0.5 mL. Only excipients 
of non-human and/or non-animal origin are used for VLA Placebo presentation. Storage of 
VLA Placebo should be done at +2-8°C. 
The Placebo should be stored at +2 to +8°C and a retest date of 24 months from date of 
production will be assigned. This retest date will be extended to 36 months with data from 
ongoing stability program provided no significant trends in product quality are observed. 
5.1.3 Condition of storage of IMP for primary vaccination series and first booster 
VLA15 and Placebo will be stored in a refrigerator at +2°C to +8°C (+35° to +46°F) in a room 
not accessible to unauthorized persons. Temperature monitoring systems will be used. 
DO NOT FREEZE THE VACCINE!  
 
More details on packaging and labelling as well as storage of IMP will be provided in the study 
specific IMP manual.  
5.1.4 VLA15 presentation for subsequent booster vaccinations  
Intervention Name 
PF-07307405 (VLA15)  
Type 
Vaccine 
Dose Presentation 
120 µg/mL Lip-D1B2B, 120 µg/mL Lip‑D4Bva3B, 120 
µg/mL Lip-D5B6B, 10 mM sodium phosphate (pH 6.7), 
150 mM sodium chloride, 10 mM L‑methionine, 5% 
sucrose, 0.05% polysorbate 20, 1.0 mg/mL aluminum (as 
aluminum hydroxide) 
Unit Dose Strength(s) 
0.5 mL 

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Route of Administration 
Intramuscular injection 
Use 
Experimental 
IMP or NIMP 
IMP 
Sourcing 
Provided centrally by the sponsor 
Packaging and Labeling 
Study intervention will be provided in PFSs. Each PFS 
will be labeled as required per country requirement 
5.1.5 Placebo for subsequent booster vaccinations 
Intervention Name 
Normal Saline (Placebo) 
Type 
Placebo 
Dose Formulation 
 
Normal saline (0.9% sodium chloride solution for 
injection) 
Unit Dose Strength(s) 
0.5 mL 
Route of Administration 
Intramuscular injection 
Use 
Placebo 
IMP or NIMP 
IMP 
Sourcing 
Provided centrally by the sponsor 
Packaging and Labeling 
Placebo will be provided in PFSs. Each PFS will be 
labeled as required per country requirement 
 
5.1.6 Condition of storage of IMP for subsequent booster vaccinations  
PFS must be stored in the refrigerator at 2 to 8 °C (36 °F to 46 °F) and allowed to reach room 
temperature for approximately 15 minutes prior to use. Unused syringes can be returned 
once to 2 to 8°C (36 to 46 °F) within the 4-hour storage at room temperature. Unused 
syringes of IP products should be discarded after 4 hours of storage at room temperature 
(not to exceed 30 ºC or 86 ºF). 
5.1.7 Packaging & labelling of IMP  
Packaging and labeling of VLA15 and placebo are performed by a qualified CMO. Labels will 
be written in accordance with local law.  

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6 
TREATMENT OF SUBJECTS 
 
Investigational Treatment 
6.1.1 Dose and dosing schedule 
Within the VLA15-221 study different vaccination schedules are applied.  
 
 

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Table 1 summarizes the treatment and vaccination schedule for each study group.  
Table 1 Study Groups and Vaccinations 
 
Study Group 
Subjects 
Age Cohort  
(Age in years at 
Screening) 
Treatment 
Vaccination 
Schedule  
Part A: Main Study Phase 
Group 1 
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg 
Month 0-2-6 
Group 2 
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg  
Placebo 
Month 0-6 
Month 2* 
Group 3 
Total: 200 
100 
50 
50 
 
 
18-65 
12-17 
5-11 
 
Placebo 
Month 0-2-6 
Part B: Booster Phase  
Group 1  
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg 
Month 18, 
30 and 42 
Group 2 
Total: 200 
100 
50  
50 
 
 
18-65 
12-17 
5-11 
 
VLA15 180 µg 
Month 18, 
30 and 42 
Group 3 
 
Total: 200 
100 
50  
50 
 
18-65 
12-17 
5-11 
Placebo 
Month 18, 
30 and 42 
*In order to keep the blind, subjects assigned to Group 2 will receive a sham injection of placebo at Month 2.  
6.1.2 Preparation and method of administration for primary vaccination series and 
first booster vaccination 
All IMPs are filled in glass vials with a minimum extractable volume of 0.5 mL. 
Remove the vial from the refrigerator. Invert vial at least three times before drawing the 
respective injection volume into the syringe. DO NOT SHAKE! 
 
Preparation of IMP needs to be done by designated unblinded staff members only in a separate 
room unobserved by the subject/legal representative(s) and blinded study staff. A second 
unblinded staff performs a check on volume and IMP/ Placebo (4 eye-principle). After drawing 
the respective injection volume into a syringe and visual check, the syringe will be masked by 

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covering it with a non-see-through adhesive label so that subject and blinded study staff cannot 
detect content of the syringe. Identification of the syringe is guaranteed by placing a tear-off 
label containing Kit number and Subject number onto the label. 
Administration should take place shortly after the preparation of the syringe after a maximum 
time period of one hour for removal of the vial from the fridge to administration. Just prior to 
administration invert the syringe at least three times again to ensure a homogenous 
suspension (be aware that Alum will settle down within short time). 
Subjects will receive injections of VLA15 or Placebo I.M. in the deltoid region of the non-
dominant arm. Vaccinations should be administered in the contra-lateral arm e.g., in case 
subject has a history of skin cancer at the deltoid region of the non-dominant arm or if subject 
has a tattoo or scar that could prohibit evaluation of adverse reactions at the injection site. 
A study specific IMP manual with further details on IMP handling will be provided.  
6.1.3 Preparation and method of administration for subsequent booster vaccinations 
IMP for subsequent booster vaccination is provided in PFS. VLA15 or Placebo should be 
administered intramuscularly by injecting 0.5 mL into the deltoid muscle, preferably of the 
nondominant arm. Shake product vigorously immediately before administration. 
Standard vaccination practices must be observed and vaccine must not be injected into blood 
vessels. Appropriate medication and other supportive measures for management of an acute 
hypersensitivity reaction should be available in accordance with local guidelines for standard 
immunization practices. 
Administration of study interventions should be performed by an appropriately qualified, GCP-
trained, and vaccine-experienced member of the study staff (e.g., physician, nurse, physician’s 
assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by local, state, and 
institutional guidance.  
Study intervention administration details will be recorded in the eCRF. 
6.1.4 Treatment duration 
In the Main Study Phase (Part A) subjects will be vaccinated within a period of approximately 
6 months (vaccinations at Months 0, 2 and 6). In the Booster Phase (Part B) all subjects will 
receive booster vaccinations at Month 18, 30 and 42.   
 
Prior and Concomitant Therapy 
6.2.1 Permitted prior and concomitant therapy 
Any vaccination within the last three years prior to Visit 0, and any medication being taken at 
Visit 0 have to be documented in the respective section of the eCRF.  
Any medication taken or vaccination received during the study has to be documented in the 
eCRF. 
6.2.2 Forbidden concomitant therapy 
The following concomitant therapy is not allowed: 
• 
Administration of anticoagulants within three weeks prior to each study vaccination 
contraindicating I.M. vaccination as judged by the investigator.  
• 
Administration of any active or passive immunization 4 weeks before or after any study 
vaccination; except for influenza or pandemic vaccines which may be administered 
outside a 7-days interval before or after any study vaccination. 

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• 
Administration of any other registered or non-registered medicinal product in another 
clinical study throughout Month 43 in Part B.  
• 
Administration of chronic (longer than 14 consecutive days) prednisone or equivalent 
0.05 mg/kg/day. Topical and inhaled steroids are allowed. 
• 
Donation of blood or blood-derived products (e.g., plasma) within 4 weeks prior to each 
study vaccination or administration of any blood or blood-derived products (e.g., 
plasma or immunoglobulins) within 3 months prior to each study vaccination and within 
4 weeks after each study vaccination. 
Subjects are to be asked about concomitant medication and vaccinations at each visit; any 
concomitant medication or vaccination has to be documented. 
 
All forbidden concomitant medications are reflected in exclusion criteria.  
 
Treatment Compliance 
6.3.1 Drug dispensing and accountability 
A drug shipment log is kept current by the site, detailing the date and quantity of IMP received 
from and returned to the sponsor. Moreover, a current drug dispensing log has to be 
maintained by unblinded staff. This documentation is available to the unblinded CRA to verify 
drug accountability during the study and to perform overall drug accountability. 
Any unused IMP and used vials are accounted for and returned to the sponsor. 
 
Pregnancy testing and birth control 
Females of childbearing potential with a negative pregnancy test and the use of adequate birth 
control before (as defined below) and during conduct of the study are eligible for inclusion into 
the study. A woman is considered of childbearing potential if fertile and until becoming post-
menopausal unless permanently sterile. Females aged ≥ 12 years and women of childbearing 
potential must have a negative serum pregnancy test at Visit 0 (Screening Visit of Part A), a 
negative urine pregnancy test before each vaccination and should be practicing an acceptable 
method of birth control throughout the entire Main Study Phase (Part A). During Part A, urine 
pregnancy tests will be conducted in females aged ≥ 12 years and women of childbearing 
potential at defined study visits (see Table 2) and at the ET Visit (if applicable). To ensure that 
subjects can perform pregnancy testing at home in case visits are performed remotely instead 
of in-person due to the ongoing COVID-19 pandemic, subjects will be supplied with urine 
pregnancy test kits at on-site vaccination visits (Visit 1, 3 and 5).  
 
During the Booster Phase (Part B) women of childbearing potential must have a negative urine 
pregnancy test before administration of any booster vaccination at the respective booster 
vaccination visits. An acceptable method of birth control should be applied until 5 months after 
each booster vaccination (i.e., Month 18 to Month 23, Month 30 to Month 35 and Month 42 to 
Month 47). During the Booster Phase urine pregnancy tests will be conducted at study visits 
8B, 9, 10, 12, 13, 15, 16 and 17 (see Table 3) and at the ET Visit (if applicable). 
 
An acceptable method of birth control is defined as those, which result in a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly. Such methods include combined 
(estrogen and progesterone containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal or transdermal), progesterone-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device 
(IUD), intrauterine hormone-releasing system (IUS), vasectomized partner, sexual abstinence 
or same sex relationships. Hormonal contraception associated with inhibition of ovulation need 
to be in place at least for 1 month prior to Visit 1. 

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Females without childbearing potential do not need to perform any birth control. A female is 
considered of non-childbearing potential, if she is surgically sterilized for at least 3 months prior 
to Visit 1 (permanent sterilization methods include hysterectomy, bilateral salpingectomy or 
bilateral oophorectomy25, transcervical sterilization (Essure and Adiana procedures), tubal 
ligation, or being postmenopausal for at least one year prior to the study start as confirmed by 
a gynecologist. For reporting of pregnancies refer to Section 8.4.4 
7 
ASSESSMENT OF IMMUNOGENICITY 
 
Immunogenicity Measurements  
Immunogenicity assessments measuring OspA serotype specific IgG by an IgG binding assay 
will be performed on samples collected at Visit 0 and Visit 4 to 8 of the Main Study Phase (Part 
A) and at Visit 9 to 17 during the Booster Phase (Part B).  
 
 
  
Assays will be performed at Valneva Austria GmbH Vienna, Department of Clinical Serology 
and at Pfizer, Pearl River, New York according to Standard Operating Procedures (SOPs). 
Work will be performed in an environment that is certified to Biological Safety Level 2 (BSL2), 
internally audited, and conform to GCLP requirements. Raw data will be stored on a separate, 
secure server in a defined Information Technology environment complying with regulatory 
standards. Operators conducting the assays will be blinded to the samples.  
Details on the analysis of immunogenicity assessments described below will be provided in 
the Statistical Analysis Plan (SAP). 
7.1.1 OspA serotype specific IgG binding assay  
For the evaluation of immunogenicity, human sera will be analyzed for IgG against each OspA 
serotype (ST1 to ST6) separately by a quantitative ELISA. Dilution series of sera will be added 
to microtiter plates coated with full length OspA ST1, ST2, ST3, ST4, ST5 or ST6. Presence 
of binding IgGs will be detected with an anti-human IgG enzyme conjugate followed by addition 
of the substrate. The optical density of the colored end product is proportional to the amount 
of protein specific IgG present in the serum that can be quantified on the basis of the Reference 
Substance curve by four-parameter logistic fit and parallel line analysis. The ELISA method 
was limited validated for analysis of Phase 2 clinical samples.  
 
Anti-OspA IgG against the six serotypes included in the VLA15 vaccine may also be assessed 
by a direct Luminex immunoassay (dLIA). This assay will be based on Luminex MagPlex® 
microspheres read off the xMAP® family of instruments. MagPlex® microspheres are 
superparamagnetic carboxylated xMAP microspheres that allow for potential assay 
multiplexing and automation. For this, microspheres will be coated with different OspAs and 
will be distinguished by their internal impregnated dyes. Bound anti-OspA IgG will be detected 
with a secondary antibody conjugated to a fluorophore and read by fluorescence excitation on 
a Luminex reader. Signals will be expressed as median fluorescent intensities and read against 
an arbitrarily assigned reference standard. The magnitude of the fluorescent signal is 
proportional to the amount of antigen-specific IgG present in the sample.  
 
 
 
 
 
 

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7.1.3 Additional Testing Procedures  
Serum samples obtained in this study may, in addition to its use for assessment of OspA 
specific IgG antibodies 
, also be used for further development 
of the vaccine, including other serological assays and for the development of proficiency 
panels and reference standards for the purpose of vaccine development. 
8 
ASSESSMENT OF SAFETY 
For the exact time points of the safety assessment, please refer to Table 2 for the Main Study 
Phase and Table 3 for the Booster Phase.  
 
AE occurrence frequencies will be used to evaluate the study objectives on safety. Solicited 
AEs will be recorded as detailed in Section 8.3. Unsolicited AEs, SAEs and AESIs will be 
recorded and reported as detailed in Section 8.4. 
The following safety measures will be taken: 
 
Physical Examination 
At Visit 0, 8B, 12 and 15, all subjects undergo a physical examination on the following body 
systems: general appearance (including assessment of body weight and height), skin, head/ 
eyes /ears/ nose/ throat, chest, lungs, heart, abdomen, extremities and joints, lymph nodes, 
and neurological system. 
A symptom-driven physical examination will be performed at all in-person study visits except 
the Visit 0, 8B, 12 and 15, i.e., only in case a symptom is reported by the subject, a system-
based assessment will be performed for a detailed check of the affected body system(s). A 
symptom-driven examination should also be performed in case the subject has complaints 
within the observation time after vaccination. 
Any symptom reported, including worsening of existing conditions, will be recorded as an AE 
unless it occurred prior to vaccination at Visit 1. Symptoms noted during the symptom-driven 
physical examination at Visit 1 (prior to vaccination) are not considered AEs but are recorded 
as medical history. 
 
Vital Signs, ECG and Oral Body Temperature 
Vital signs (i.e., systolic and diastolic blood pressure, pulse rate) and oral body temperature 
will be measured at screening and before each vaccination, i.e., in the Main Study Phase at 
Visit 0, 1, 3 and 5 and in the Booster Phase at Visit 8B, 12 and 15. Vital signs will be recorded 

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in a seated position and at rest. At least 15 min should have passed before measurement of 
oral body temperature after consumption of hot or cold beverages or smoking, if applicable. 
An ECG will be done at Visit 0 of Part A. 
 
Solicited AEs and Subject Diary 
Subjects will record AEs for the first seven days after each vaccination (starting on the day of 
vaccination) in electronic Subject Diaries (eDiaries). Solicited AEs (predefined) are listed in the 
eDiaries and comprise reactions at the injection site or systemic reactions typical for 
vaccinations. Solicited AEs are per definition regarded as related to IMP. 
Solicited local AEs are the following injection site reactions: pain, tenderness, induration/ 
hardening, swelling and erythema/ redness. 
Solicited systemic AEs are: headache, myalgia (muscle pain), arthralgia (joint pain), fever (oral 
body temperature), nausea, vomiting and fatigue. 
In case of an emergency, the study participants will be given a 24 h telephone number they 
can call to receive instruction and information from study staff. In case of severe local and 
systemic reactions, study physician and study participant should liaise immediately, 
independent of any scheduled study visit.   
8.3.1 Collection, assessment and documentation of solicited AEs 
Subjects/ legal representative(s) will be instructed to report solicited AEs via eDiaries. At 
vaccination visits V1 in the Main Study Phase (Part A), at Visit V8B and for subsequent 
vaccination visits in the Booster Phase (Part B), the use of eDiaries will be explained to the 
subjects. Subjects/ legal representative(s) will be trained to assess presence of solicited AEs 
and impact on daily activities; to measure the size of the affected area with a measuring tape 
(for symptoms induration/ hardening, swelling and erythema/ redness), and instructed to take 
oral temperature once every day. 
Assessments will start on the day of vaccination and take place once daily for a total of seven 
consecutive days. Assessments of oral temperature should occur preferably in the late 
afternoon. If fever (oral body temperature ≥ 38.0 °C/100.4 °F) occurs, body temperature should 
be measured at least every 8 hours until it returns to normal (< 38.0 °C/100.4 °F). All body 
temperature measurements including the date and time should be recorded in the eDiary. In 
case of fever, the subject/ legal representative(s) should record all fever measurements in the 
subject eDiary including the first value that shows a return to normal body temperature. For 
other symptoms the maximum severity observed on a given day should be recorded. The 
subject/ legal representative(s) will note down information about the symptom by selecting the 
appropriate description. Additionally, the following information will be collected: symptoms 
present after Day 6 (yes/ no), last day of symptoms (date).  
Subjects/ legal representative(s) and site staff should liaise immediately in case of symptoms 
suggesting possible Lyme borreliosis, severe solicited AEs or other severe symptoms as 
instructed in the eDiary. 
The eDiary entries will be reviewed by a clinician together with the subject/ legal 
representative(s) at the subject’s next visit to the study site. The investigator should enquire 
whether any solicited AE required medical attention (i.e., subject was seeking medical care at 
a doctor’s office, emergency service, or hospital, but not use of self-medication) or if an event 
was an SAE. The investigator should not suggest answers when performing the eDiary 
verification with the subject/ legal representative(s) but can question and call the subject’s 
attention to obviously wrong and misleading entries. If the subject comes to the conclusion that 
an eDiary question had been misunderstood or that an entry was made by mistake, the 
investigator will take this information into account when performing the severity assessment.   
After eDiary verification, the clinician will perform a severity assessment on the basis of the 
information provided by the subject in the eDiary. If an AE existed over a period of days, only 

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the maximum severity will be documented in the eCRF. The severity assessment will be based 
on the grading scale in Table 10 below. Severity categories in this table are NOT identical to 
the categories provided in the eDiary.  
For solicited AEs, which are serious and/ or medically attended or solicited systemic Grade 3/4 
reactions, the investigator will carry out more detailed assessments as performed for 
unsolicited AEs (causality, outcome, action taken) and will document them in the eCRF. 
For solicited local and systemic AEs persisting beyond Day 6 after vaccination, stop date will 
also be documented in the eCRF. 
Any unsolicited AE documented in the eDiary should be documented and assessed as outlined 
in Section 8.4.  
8.3.2 Severity of solicited AEs 
Severity grading of solicited AEs by the investigator will be performed according to Table 10 
below. Criteria are based on the FDA Guidance for Industry (Toxicity Grading Scale for Healthy 
Adult and Adolescent Subjects Enrolled in Preventive Vaccine Clinical Trials; 2007) and on 
Division of AIDS (Table for Grading the Severity of Adult and Pediatric Adverse Events; July 
2017).  
 
 

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Table 10 Grading of Solicited Adverse Events 
Vaccine 
specific 
Criteria 
Age 
Grade 1  
mild 
Grade 2  
moderate 
Grade 3 
 severe 
Grade 4  
potentially 
life-
threatening 
Injection Site 
Pain  
5-65 
years (A) 
Does not 
interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency 
room (ER) 
visit or 
hospitalization 
Tenderness  
5-65 
years (A) 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant discomfort 
at rest 
ER visit or 
hospitalization 
Injection Site 
Induration/ 
Hardening (1)  
5-11 
years (B) 
1.0 - ≤  2.5 cm 
(0.39-0,98 inch) 
in diameter 
> 2.5 - 5.0 cm (2) in 
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
> 5 cm (2)  OR ≥ 50% 
surface area of the 
extremity segment 
involved (e.g., upper 
arm or thigh) OR 
Ulceration OR 
Secondary infection 
OR Phlebitis  
Potentially 
life-
threatening 
consequences 
(e.g., Skin 
necrosis) 
12-65 
years (A) 
2.5–5 cm             
(0.98–1.96 inch) 
and does not 
interfere with 
activity  
5.1–10 cm (1.97 – 
3.94 inch) or 
interfere with 
activity 
>10 cm (>3.94 inch) or 
prevents daily activity 
Necrosis 
Injection Site 
Swelling 1 
5-11  
years (B) 
1.0 - ≤  2.5 cm 
(0.39-0,98 inch) 
in diameter 
> 2.5 - 5.0 cm (2)  
in diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
> 5 cm (2)  OR ≥ 50% 
surface area of the 
extremity segment 
involved (e.g., upper 
arm or thigh) OR 
Ulceration OR 
Secondary infection 
OR Phlebitis  
Potentially 
life-
threatening 
consequences 
(e.g., Skin 
necrosis) 
12-65 
years (A) 
2.5–5 cm          
(0.98–1.96 inch) 
and does not 
interfere with 
activity  
5.1–10 cm (1.97 – 
3.94 inch) or 
interfere with 
activity 
>10 cm (>3.94 inch) or 
prevents daily activity 
Necrosis 
Injection Site 
Erythema or 
Redness1  
5-11  
years (B) 
1.0 - ≤  2.5 cm 
(0.39-0,98 inch) 
in diameter 
> 2.5 - 5.0 cm (2) in 
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
> 5 cm (2)  OR ≥ 50% 
surface area of the 
extremity segment 
involved (e.g., upper 
arm or thigh) OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage 
Potentially 
life-
threatening 
consequences 
(e.g., Skin 
necrosis) 
12-65 
years (A) 
2.5–5 cm 
(0.98–1.96 inch) 
5.1–10 cm   
1.97–3.94 inch 
>10 cm 
>3.94 inch 
Necrosis or 
exfoliate 
dermatitis 
 
 
 

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Vaccine 
specific 
Criteria 
Age 
Grade 1  
mild 
Grade 2  
moderate 
Grade 3 
 severe 
Grade 4  
potentially 
life-
threatening 
Headache  
5-65  
years (A)  
No interference with 
activity  
Repeated use of 
non-  
narcotic pain  
reliever >24 
hours or some 
interference  
with activity  
Significant; any  
use of narcotic  
pain reliever or  
prevents daily  
activity  
ER visit or  
hospitalization  
Myalgia  
5-65  
years (A) 
No interference with 
activity  
Some 
interference  
with activity  
Significant;  
prevents daily  
activity  
ER visit or  
hospitalization  
Arthralgia(3)  
5-65  
years (A) 
No interference with 
activity  
Some 
interference  
with activity  
Significant;  
prevents daily  
activity  
ER visit or  
hospitalization  
Fever(4)  
(°C)/(°F) 
5-65  
years (A) 
38.0–38.4/  
100.4–101.1  
38.5–38.9/  
101.2–102.0  
39.0–40/  
102.1–104  
>40/  
>104  
Nausea 
5-65 
years (A) 
No interference  
with activity or 1–2 
episodes/24 hours 
Some 
interference  
with activity or >2  
episodes/24 
hours 
Prevents daily  
activity, requires  
outpatient IV  
hydration 
ER visit or  
hospitalization 
for  
hypotensive 
shock 
Vomiting 
5-65  
years (A) 
No interference  
with activity or 1–2 
episodes/24 hours 
Some 
interference  
with activity or >2  
episodes/24 
hours 
Prevents daily  
activity, requires  
outpatient IV  
hydration 
ER visit or  
hospitalization 
for  
hypotensive 
shock 
Fatigue 
5-65 
years (A) 
No interference with 
activity  
Some 
interference  
with activity  
Significant;  
prevents daily  
activity  
ER visit or  
hospitalization  
(A) Grading based on FDA Guidance on Toxicity Grading Scales Adults/ Adolescents26 
(B) Grading based on Division of AIDS, Table for Grading the Severity of Adult and Pediatric Adverse Events27 
(1) Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or                        
     measured surface area 
(2) Modified grading based on Division of AIDS; 5.0 cm cut-off will be included as moderate instead of severe 
(3) Symptom not described in the FDA or Division of AIDS guidelines.  
(4) Oral temperature; no recent hot or cold beverages or smoking.  
 
Unsolicited AEs 
An AE is any untoward medical occurrence in a subject administered an investigational 
product, whether or not related to this treatment. All new abnormalities or exacerbations in 
intensity or frequency (worsening) of a pre-existing condition during or after the first vaccination 
represent AEs.  
Study participants/ legal representative(s) will be given a 24 h telephone number they can call 
to receive instruction and information from study staff in case of emergency.  
In the event of severe local and systemic reactions, the study physician should be contacted 
immediately, outside from scheduled study visits. 
Unsolicited AEs are defined as follows:  
• 
Any solicited local or systemic AE if it has an onset date more than 6 days after 
vaccination. 
• 
Any other symptom or untoward medical event. 

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8.4.1 Collection, follow-up and documentation of unsolicited AEs 
Unsolicited AEs will be reported in the eCRF up to 28 days after each vaccination and will be 
documented in the eCRF within this respective timeframe. Thereafter, only SAEs and AESIs 
will be documented in the eCRF.    
Investigators are not obligated to actively seek information on AEs or SAEs after the subject 
has concluded study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a subject has completed the study, and he/she considers the event to 
be reasonably related to the study intervention, the investigator must promptly report the SAE 
to Pfizer Safety using the Vaccine SAE Report Form. 
Collection:  
• 
The eDiary is explained at V1 of the Main Study Phase, at V8B and at subsequent 
vaccination visits of the Booster Phase. The eDiary will contain sections for the 
assessment of unsolicited AEs. Unsolicited AEs will be captured in the eCRF up to 28 
days after each vaccination. The subjects will be asked to complete the eDiary 
throughout the study. The eDiary entries will be verified by the study physician together 
with the subject/ legal representative(s) at the subject’s next visit to the study site. 
Subjects will be encouraged to note down any either ongoing or new AEs plus the dates 
of onset/ resolution, whether medication was taken in response and whether medical 
care was sought. 
• 
Subjects/ legal representative(s) will be instructed to immediately inform the site in case 
of an SAE or AESI.  
• 
Additionally, the investigator should enquire about unsolicited AEs and should perform 
the scripted safety assessment during each study visit. 
• 
Symptoms noted during the symptom-driven physical exams (unless already covered 
by respective solicited AE) constitute unsolicited AEs too.  
Follow-up: 
The investigator will follow-up each AE until it is resolved or until the medical condition of the 
subject is stable. All relevant follow-up information will be reported until the end of the study 
for the subject. SAEs ongoing at the time of last regular study visit for a subject (or ET Visit) 
will be followed until resolution or achievement of stable clinical conditions, latest until the 
global end of the study. 
Documentation: 
All unsolicited AEs with an onset date up to 28 days after each vaccination need to be 
documented in the respective AE section of the eCRF, regardless of their source (e.g. open 
question to subject, symptom-driven physical examination, unsolicited AEs noted in the 
eDiary). Thereafter, only SAEs and AESIs have to be documented in the eCRF. 
Any symptom is regarded as separate AE. However, if the investigator considers several 
symptoms to be in the context of one underlying diagnosis, (s)he may merge them into one 
single appropriate AE. The AE term entered into the electronic case report form (eCRF) should 
contain all symptoms summarized to one event (e.g. “Influenza with flu-like-symptoms, fever 
and headache”).  
 
The following information will be evaluated and documented for each unsolicited AE: Causality 
(see Section 8.4.2.7), Severity (see Section 8.4.2.6), Outcome (see Section 8.4.2.8), 
Seriousness (see Section 8.4.2.2), Medically-attended (see Section 8.4.2.1), Action Taken to 
Treat AE and on IMP (see Section 8.4.2.9), Start and Stop Dates. 
 
 
 

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8.4.2 Evaluation of unsolicited AEs 
8.4.2.1 Definition of medically attended AEs 
All adverse events where subjects are seeking medical care (i.e., doctor’s office, emergency 
service, hospital, but not use of self-medication). 
8.4.2.2 Definition of Serious Adverse Events (SAEs) 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life-threatening. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is another medically important condition. 
 
This definition also applies to progression of disease leading to a serious outcome. 
Neither the condition, leading to a hospitalization or prolonged hospitalization, nor the medical 
procedure itself need to be reported as a serious adverse event in the following circumstance: 
Hospitalization or prolonged hospitalization for diagnostic or elective medical procedures 
planned prior to first vaccination to treat a pre-existing condition, which did not change in 
severity. 
In this case, the underlying diagnosis or condition should be reported in the medical history 
section of the eCRF. The corresponding medical procedure should be documented as a 
comment to the underlying diagnosis or condition in the medical history section of the eCRF. 
The sponsor will classify the SAEs as either expected or unexpected. 
Expected:  An AE that is listed in the current Investigator's Brochure. 
Unexpected:  An AE that is not listed in the current Investigator's Brochure, or it differs 
because of greater severity or greater specificity. 
 
8.4.2.3 SAE reporting procedure 
Correct SAE reporting will have to cite a diagnosis or a symptom. Any diagnosis and any 
symptom is regarded as separate SAE. However, if the investigator considers several 
symptoms to be in the context of one underlying diagnosis, he or she may specify the diagnosis 
as the reportable SAE and describe the attendant symptoms in one single appropriate SAE 
report. 
Medical or diagnostic procedures due to an underlying disease or symptom are not considered 
an AE but a consequent measure following an AE. A correct SAE report will therefore have to 
specify the disease or symptom as the reportable AE and the medical or diagnostic procedure 
as action taken. 
The investigator must report immediately after discovery all SAEs that are: 
• 
Fatal 
• 
Life-threatening 
• 
Suspected to be related to study treatment 
Regardless of the description above, any SAE should be reported by fax within 24 hours after 
the investigator has become aware of it to Pfizer Safety.  
 
 
 

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Pfizer Safety 
SAE Fax Number: 
 
 
In addition, expedited and periodic reporting to Competent Authorities and IRBs will be 
performed in accordance with local requirements. Further reporting details can be found in the 
study-specific SAE procedure which is in accordance with respective US/ EU requirements, 
International Conference on harmonization (ICH) GCP, national laws and site-specific 
requirements. SAEs that are considered as probably or possibly related and additionally are 
unexpected need to be reported according to the requirements for suspected unexpected 
serious adverse reactions (SUSARs). 
SAE reports will be reviewed by a study site’s physician and Pfizer Safety and will be provided 
to the Medical Monitor, Valneva Austria GmbH and the independent DMC. 
8.4.2.4 Definition of Adverse Events of Special Interest (AESIs) 
An Adverse Event of Special Interest (serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might 
warrant further investigation in order to characterize and understand it.28  
8.4.2.5 Collection and evaluation of Adverse Events of Special Interest (AESIs) 
Subjects will be carefully monitored for development of AESIs. Since a previous LB vaccine 
was accused of inducing auto-immune symptoms similar to those caused by disseminated LB 
infection, e.g., autoimmune arthritis, such events will constitute AESIs. In addition, the onset 
of any potentially autoimmune or neuro-inflammatory disorders will constitute AESIs. A subunit 
vaccine like VLA15 is not considered capable of inducing LB as such. Nevertheless, any 
potential LB cases are of relevance to development of the vaccine and will therefore receive 
particular attention and be captured as AESIs as well. Therefore, symptoms suggesting a LB-
associated event and/ or onset of potentially autoimmune or neuro-inflammatory disorders will 
receive special attention. Identification of such events from a pre-defined list of AESIs and 
symptoms suggesting a Borrelia infection will be assessed in a guided approach as described 
below.  
 
The following symptoms will receive particular consideration: 
• 
Erythema migrans: an expanding red or bluish-red patch (≥5 cm in diameter) with or 
without central clearing; 
• 
Symptoms suggesting an arthritis (e.g., recurrent attacks or persisting objective joint 
swelling (synovitis) in one or a few large joints); 
• 
Neurological symptoms (e.g., meningo-radiculitis, meningitis, encephalitis, myelitis, 
cerebral vasculitis, facial palsy); 
• 
Cardiac 
symptoms 
(e.g., 
atrio-ventricular 
conduction 
disturbances, 
rhythm 
disturbances, myocarditis); 
• 
Immune-mediated disorders as proposed by competent authorities for previous clinical 
programs (please refer to APPENDIX 1). 
 
For avoidance of doubt, solicited AEs do not qualify as AESI and should not be 
reported as such. 
 
As part of unsolicited AE assessments, at each study visit starting from Visit 1A, the 
investigator will be guided through a scripted safety assessment (i.e., questionnaire) to enquire 

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about symptoms that are consistent with Lyme borreliosis, allowing the investigator to assess 
whether there is a clinical suspicion for infection with Borrelia or a LB-associated event. In 
addition, presence of or symptoms suggesting one of the other AESIs from the pre-defined list 
will be determined by the investigator.  
 
In case there is clinical suspicion for Lyme borreliosis or a LB-associated event, investigators 
are asked to perform a clinical workup as described in APPENDIX 2, including specialist 
referral as needed. Subjects with suspected other AESIs (i.e., immune-mediated disorders) 
should also be referred to a respective clinical expert for full diagnostic work-up as needed. 
The investigator will request the medical records from the clinical expert, if applicable. In case 
an AESI is identified (by the investigator or a clinical specialist upon referral or without referral) 
the investigator will fill out the AESI Report Form with all available information, including 
information provided by the clinical expert, if applicable, and will provide the AESI Report Form 
together with the medical records to the DMC through the 
 Safety Desk. For cases of 
Lyme borreliosis or LB-associated events, the DMC will confirm the diagnosis. In case an AESI 
(LB or immune-mediated disorders as depicted in the pre-defined list) has already been 
diagnosed by a healthcare specialist prior to identification of a potential AESI by the 
investigator at the study visit, the investigator will also provide the AESI Report Form together 
with available medical records to the DMC through the 
Safety Desk. In addition, the 
DMC will regularly review accruing AEs and can recommend specialist work-up to the 
investigator for any case they consider potential AESIs or cases of LB. The DMC will do a final 
adjudication of all AESIs and will assess whether cases were new in onset and whether there 
is any relationship to application of the study vaccine. Narratives with detailed case 
descriptions will be provided for all AESIs. 
 
If an AESI meets the definition of an SAE the event must be submitted through the SAE 
reporting instructions in Section 8.4.2.3 using the Pfizer Vaccine SAE Report Form. In addition, 
an AESI report has to be completed and send to
 Safety Desk.  
 
The AESI Report Form (for serious and non-serious AESIs) should be reported by the 
investigator by email to 
 Safety Desk: 
 
 
Safety Desk 
E-mail: 
 
 
8.4.2.6 Severity of unsolicited AEs 
In general, for AEs mild (Grade 1), moderate (Grade 2), severe (Grade 3) and potentially life 
threatening (Grade 4) are defined as follows: 
 
Mild: 
Awareness of signs or symptoms, but easily tolerated, does 
not interfere with daily activities. 
 
Moderate: 
Discomfort enough to interfere with usual activity but not 
requiring medical intervention. 
 
Severe: 
Incapable of work/ usual activity and requiring medical 
intervention. 
 
Potentially life threatening: Occurrence places the patient or subject at immediate risk 
of death. 
 

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For a standardized approach, the NCI-CTCAE v 5.0, 2017 using Grade 1 = mild, Grade 2 = 
moderate, Grade 3 = severe and Grade 4 = potentially life threatening will be used for AEs, 
which do not readily fall into the mild/ moderate/ severe/ potentially life threatening categories 
described above.  
8.4.2.7 Causality assessment 
Probable: 
 A reaction that follows a reasonable temporal sequence from 
administration of the investigational medicinal product; or that 
follows a known or expected response pattern to the suspected 
treatment; or that is confirmed by stopping or reducing the dosage 
of the treatment; and that could not reasonably be explained by 
known characteristics of the subject’s clinical state. 
 
Possible:  
A reaction that follows a reasonable temporal sequence from 
administration of the investigational medicinal product; that follows 
a known or expected response pattern to the suspected treatment; 
but that could readily have been produced by a number of other 
factors. 
 
Unlikely:  
Reports not following a reasonable temporal sequence from 
administration of the investigational medicinal product; an event, 
which may have been produced by the subject’s clinical state or by 
other environmental factors. 
 
Not related (unrelated): Events for which sufficient information exists to conclude that the 
etiology is unrelated to the investigational medicinal product. 
 
AEs with a causality reported as probable or possible will be considered related to study 
vaccine. AEs with missing causality assessment will be regarded as related unless further 
specified. All other AEs will be considered as not related to study vaccine. 
 
8.4.2.8 Outcome 
▪ 
recovered/ resolved 
▪ 
recovered/ resolved with sequelae 
▪ 
not recovered/ not resolved 
▪ 
fatal 
▪ 
unknown 
NOTE: A subject's death per se is not an event, but an outcome. The event which resulted in 
the subject's death must be fully documented and reported, regardless of being considered 
treatment related or not. 
 
8.4.2.9 Actions taken 
AEs requiring therapy must be treated with recognized standards of medical care to protect 
the health and well-being of the subject. Appropriate resuscitation equipment and medicines 
must be available to ensure the best possible treatment of an emergency situation. 
The investigator must be adequately trained in the treatment of allergic reactions including the 
proper use of rescue medication. The facility has to be equipped with an emergency set that 
is readily available. 
The treatment of severe allergic reactions involves prompt treatment with oxygen, 
antihistamines, prednisolone, epinephrine and theophylline as required. An appropriately sized 
intravenous line has to be available to ensure fast infusion of colloid volume substitution. 

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In the case of a severe anaphylactic reaction subjects will promptly be transferred to the 
intensive care unit of a nearby hospital. 
The action taken by the investigator must be documented: 
a) in general 
b) on the investigational product 
None 
Not applicable 
Drug therapy started 
None  
Diagnostic test performed (e.g., laboratory) Delay of further vaccination  
Medical procedure started (e.g., surgery) 
Second dose not administered  
Unknown 
Third dose not administered 
Withdrawn from study 
 
8.4.3 Timeframe for reporting of unsolicited AEs 
Unsolicited AEs will be captured in the eCRF until 28 days after each study vaccination. AESIs 
and SAEs will be captured throughout the entire study period.  
8.4.4 Environmental Exposure, Exposure During Pregnancy or Breastfeeding and 
Occupational Exposure reporting procedures 
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure. 
Any such exposure to the study intervention under study are reportable to Pfizer Safety within 
24 hours of investigator awareness. 
 
Females must not become pregnant during the entire Main Study Phase and within five months 
after each booster vaccination. Urine pregnancy tests are performed before any vaccination 
and at study end. If a subject becomes pregnant during the study, she or the legal 
representative(s) must immediately inform the investigator. No further study vaccinations must 
be administered but the subject should attend all remaining visits as planned. 
 
The investigator should report pregnancies to Pfizer Safety using the Pfizer Vaccine SAE 
Report Form and Exposure During Pregnancy (EDP) Supplemental Form. Reporting 
procedures are similar to SAE reporting procedures (contacts and processing), although a 
pregnancy per se is not considered an SAE. 
 
If a seriousness criterion applies in addition to the pregnancy (e.g., hospitalization, congenital 
anomaly/birth defect) the pregnancy qualifies as an SAE. In such case an Exposure During 
Pregnancy (EDP) supplemental form and a Pfizer Vaccine CT SAE Report Form have to be 
filled out.  
8.4.4.1 Exposure During Pregnancy (EDP)  
 
An EDP occurs if:  
• 
A female participant is found to be pregnant while receiving or after discontinuing study 
intervention.  

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• 
A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.  
• 
A female is found to be pregnant while being exposed or having been exposed to study 
intervention due to environmental exposure. Below are examples of environmental 
EDP:   
o A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by inhalation or skin contact. 
o A male family member or healthcare provider who has been exposed to the study 
intervention by inhalation of skin contact then exposes his female partner prior to 
or around the time of conception.  
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to termination 
of pregnancy).  
• 
If EDP occurs in a participant, the investigator must report this information to Pfizer 
Safety on the Pfizer Vaccine SAE Report Form and an EDP Supplemental Form, 
regardless of whether an SAE has occurred. Details of the pregnancy will be collected 
after the start of study intervention and until the participant’s last visit in the study.  
• 
If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the Pfizer Vaccine SAE Report Form and EDP 
Supplemental Form. Since the exposure information does not pertain to the participant 
enrolled in the study, the information is not recorded on a eCRF; however, a copy of 
the completed Pfizer Vaccine SAE Report Form is maintained in the investigator site 
file. 
Follow up is conducted to obtain general information on the pregnancy and its outcome for all 
EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow- -up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural integrity 
of the terminated fetus should be assessed by gross visual inspection (unless preprocedure 
test findings are conclusive for a congenital anomaly and the findings are reported). 
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, 
neonatal death, or congenital anomaly the investigator should follow the procedures for 
reporting SAEs. Additional information about pregnancy outcomes that are reported to Pfizer 
Safety as SAEs follows:  
• 
Spontaneous abortion including miscarriage and missed abortion; 
• 
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention.  
• 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case by case basis (eg, follow-up on 

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preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents 
that the subject was given the Pregnant Partner Release of Information Form to provide 
to his partner. 
8.4.4.2 Exposure During Breastfeeding 
An exposure during breastfeeding occurs if:  
• 
A female participant is found to be breastfeeding while receiving or after discontinuing 
study intervention. 
• 
A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact.    
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours of 
the investigator’s awareness, irrespective of whether an SAE has occurred. The information 
must be reported using the Pfizer Vaccine SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on an 
eCRF. However, a copy of the completed Pfizer Vaccine SAE Report Form is maintained in the 
investigator site file. 
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (e.g., vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding. 
8.4.4.3 Occupational Exposure 
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the Pfizer Vaccine SAE Report Form, regardless 
of whether there is an associated SAE. Since the information about the occupational exposure 
does not pertain to a participant enrolled in the study, the information is not recorded on an 
eCRF; however, a copy of the completed Pfizer Vaccine SAE Report Form must be maintained 
in the investigator site file. 
8.4.5 Medication Errors 
Medication errors may result from the administration or consumption of the study intervention 
by the wrong participant, or at the wrong time, or at the wrong dosage strength.  
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors. 
Safety Event 
Recorded on the eCRF 
Reported on the CT SAE Report Form 
to Pfizer Safety Within 24 Hours of 
Awareness 
Medication errors  All (regardless of whether 
associated with an AE) 
Only if associated with an SAE 
 

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Medication errors include: 
• 
Medication errors involving participant exposure to the study intervention; 
• 
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant. 
Other examples include, but are not limited to: 
• 
The administration of expired study intervention; 
• 
The administration of an incorrect study intervention; 
• 
The administration of an incorrect dosage; 
• 
The administration of study intervention that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use. 
Such medication errors occurring to a study participant are to be reported as Protocol Deviation 
and captured on the medication error page of the eCRF, which is a specific version of the AE 
page. 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured as Protocol Deviation and recorded on the 
medication error page of the eCRF and, if applicable, any associated AE(s), serious and non-
serious, are recorded on the AE page of the eCRF.   
Medication errors should be reported to Pfizer Safety within 24 hours on a Pfizer Vaccine SAE 
Report Form only when associated with an SAE. 
8.4.6 Lack of Efficacy 
 
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to Pfizer 
Safety only if associated with an SAE.   
 
Laboratory Parameters 
The following laboratory parameters will be assessed at time points specified below. 
Parameters will be analyzed on site or by local laboratories according to the applicable 
laboratory SOP: 
 
▪ 
HIV test: for subjects aged ≥12 years, a positive HIV test obtained by ELISA will have to 
be confirmed by a second method [e.g., Western blotting or PCR]. Performed at following 
visits: Part A at Visit V0. [3.0 mL blood] 
▪ 
Serum pregnancy test: for female subjects aged ≥12 years and women of childbearing 
potential. Refer to Section 6.4 for consideration of females as being of childbearing 
potential. Performed at following visits: Part A at Visit V0. [2.0 mL blood] 

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▪ 
Urine pregnancy test: for female subjects aged ≥ 12 years and women of childbearing 
potential. Refer to Section 6.4 for consideration of females as being of childbearing 
potential). Performed at following visits: Part A at Visit 1 and 2-5 and 6-8 and ET, if 
applicable; Part B at Visits 8B, 9, 10, 12, 13, 15, 16, 17 and ET, if applicable.  
The following laboratory parameter will be assessed at time points specified below and will be 
analyzed by a central laboratory specified by the sponsor:  
▪ 
Borrelia burgdorferi s.l. screening by commercially available Lyme borreliosis screening 
test, verified by a confirmatory immunoblot for samples with positive result. Performed 
at following Visits: Part A at Visit 0, 8 and ET, if applicable; Part B at Visit 12, 15 and 
17 and ET, if applicable. [5.0 mL blood] 
▪ 
All laboratory assessments will be documented in the eCRF.  
In case lab tests performed during the study as part of medical care reveal abnormal laboratory 
parameters that are clinically relevant in the opinion of the investigator, these need to be 
documented as unsolicited AEs. They should be assessed further as done for unsolicited AEs 
described in Section 8.4.2.  
 
Safety Monitoring 
8.6.1 Internal Review Committee (IRC)  
As VLA15-221 is the first study with VLA15 enrolling a pediatric study population, rigorous 
safety monitoring precautions were implemented to ensure well-being of all subjects. An 
independent Internal Review Committee (IRC) was installed at the sponsor’s collaboration 
partner Pfizer in order to review safety data of sentinel subjects in each age cohort prior to 
advancing the study into the next younger age cohort and prior to enrolling remaining subjects 
within each of the pediatric age cohorts (i.e., Cohort 2 and Cohort 3). The IRC was composed 
of qualified personnel from Pfizer, and included at least one pediatrician, statistician, vaccine 
safety expert and a senior member of the Pfizer Vaccine Research and Development 
organization. All IRC members were independent from the VLA15-221 study team. During the 
staggered subject enrollment phase, the IRC reviewed unblinded safety data and gave 
recommendation on whether enrollment of the next younger age cohorts as well as enrollment 
of remaining subjects of the current age cohort could be initiated as described in Section 4.2.1 
(“Subject enrollment”). A written IRC charter was provided prior to the study start, including a 
detailed description of IRC set-up and processes.  
8.6.2 Data Monitoring Committee (DMC) 
An external independent Data Monitoring Committee (DMC) comprising an experienced 
vaccinologist/pediatrician, a family practitioner/pediatrician, a rheumatologist and a 
neurologist, who are all experts in the field of Lyme borreliosis, is installed. The DMC reviews 
accruing safety data in an unblinded manner at regular intervals throughout the study and 
might recommend adjusting, pausing or discontinuing the study at any time. 
The DMC confirms diagnosis of potential LB cases based on medical records received from 
the investigator after clinical workup according to a standardized procedure. The DMC 
adjudicates AESIs and assesses whether cases were new in onset and whether there is any 
relationship to the study vaccine.  
 
During vaccination periods (i.e., Day 1 to Day 180 in Part A; Months 18, 30 and 42 in Part B), 
the DMC periodically reviews tables and listings of SAEs, Deaths, AESIs, medically attended 
AEs, solicited AEs, unsolicited AEs and AEs leading to withdrawal from further vaccination on 
a regular basis in scheduled meetings and via remote safety data reviews. SAE reports will be 
provided to the DMC up to one year after first booster administration at Month 18. Thereafter, 
SAEs will be reviewed on an ad-hoc basis by Pfizer up to the end of the study. AESIs will be 

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reviewed by the DMC on an ad-hoc basis until study end. A written DMC charter is provided 
including a detailed description of DMC set-up and processes.  
• 
Part A: During the vaccination period (i.e., Day 1 to Day 180), the DMC periodically 
reviewed tables and listings of SAEs, Deaths, AESIs, medically attended AEs, solicited 
AEs, unsolicited AEs and AEs leading to withdrawal from further vaccination e.g., on a 
bi-weekly basis in alternating DMC meetings and remote reviews.  
• 
Part B: During the vaccination period (i.e., ongoing Visits 8B/Month 18, Visit 12/Month 
30 and Visit 15/Month 42), the DMC will remotely review tables and listings of SAEs, 
Deaths, AESIs, medically attended AEs, solicited AEs, unsolicited AEs and AEs 
leading to withdrawal from further vaccination e.g., on a monthly basis. Schedules may 
be adjusted as described in the DMC charter. 
• 
Any case reports of SAEs will be provided to the DMC up to one year after first booster 
dose administration at Month 18.   
• 
Any case reports of AESIs will be reviewed by the DMC on an ad-hoc basis until study 
end. The DMC will verify diagnosis of potential LB cases (based on medical records), 
adjudicate all AESIs and assess whether cases are new in onset and causally linked 
to application of the study vaccine. 
• 
Ad-hoc DMC reviews will be initiated if at any time during study conduct enrollment is 
interrupted by a principal investigator, the sponsor or the medical monitor for any safety 
reasons, or if a pre-specified study stopping rule applies, as described in Section 14.2.  
8.6.3 Sponsor  
Until the last subject reached Day 180 of Part A or Months 18, 30 and 42 in Part B, available 
safety data will be reviewed by the sponsor on a regular basis to identify any potential safety 
concerns and applicability of study stopping rule as described in Section 14.2. SAEs and AESIs 
will be reviewed during the entire study period on an ad-hoc basis. 
9 
STATISTICAL METHODS AND SAMPLE SIZE 
 
General Aspects 
The data is analyzed by 
. An SAP is 
available describing in more detail, how the study results are evaluated. 
Data is summarized by study group and, where appropriate, by visit and age group. Descriptive 
statistics (number of observations, mean, standard deviation, minimum, median, and 
maximum) is provided for continuous variables (e.g., age and weight). Frequency counts and 
percentages are presented for categorical variables (e.g., gender). 
All data exclusions, including premature terminations, will be detailed and tabulated. Data 
listings will include enrolled subjects.  
Baseline characteristics including demographic variables, medical and vaccination history and 
concomitant medications are subject to descriptive analyses. 
AEs and medical history are coded using the MedDRA coding dictionary. Concomitant 
medications (including vaccinations) are coded using the WHO Drug Dictionary.  
More detailed criteria to identify subjects in each analysis population, other research questions 
of interest not covered in this protocol, the definition of endpoints and details of their 
calculation, as well as how to deal with missing, unused and spurious data are covered in the 
SAP. Generally, missing values of immunogenicity variables will not be imputed, and the 
analysis will be limited to observed values. For missing data in AE evaluation (e.g., severity 
information) a worst case approach will be applied. If a change of the planned analyses is 

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considered necessary after protocol finalization, this will be described and justified in the SAP. 
If a change is made after the final statistical analysis has been performed, this will be described 
and justified in the CSR. 
 
Analysis Sets 
Safety Analysis Set (SAS) 
The Safety Analysis Set (SAS) includes all subjects who entered into the study and received 
at least one vaccination. The SAS will be used for all baseline, safety and tolerability analyses 
including demographic data, local/systemic tolerability, laboratory data, (S)AEs and AESIs. All 
analyses based on the SAS will be carried out using the actual treatment received. 
 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) is defined to include all subjects enrolled who received at least 
one vaccination. Subjects will be analyzed according to the study group they had been 
allocated to, rather than by the actual treatment they received. 
 
Per-Protocol Analysis Set (PPAS) 
The Per-Protocol Analysis Set (PPAS) will consist of the FAS population excluding subjects 
that meet one of the following criteria, which possibly have an impact on the immunogenicity 
read-out:   
• 
Subjects with less than three primary vaccinations (Day 1, 57 and 180). 
• 
Subjects who received the wrong study medication.  
• 
Subjects who fulfilled exclusion criteria 2, 8, 9, 13. 
 
These criteria for potential protocol violations are identified at the time of study planning. 
However, during the course of the study unforeseen events may occur or new scientific 
knowledge may become available, therefore final decisions on all protocol violations will be 
made on a case by case decision in a blind data review meeting. 
 
Booster Safety Analysis Set (BSAS) 
All safety analyses of Part B will be based on the Booster Safety Analysis Set (BSAS), which 
is defined as all subjects enrolled in Part B who received the respective booster vaccination. 
The BSAS will be used for all baseline, safety and tolerability analyses including demographic 
data, local/systemic tolerability, laboratory data and (S)AEs and AESIs. All analyses based on 
the BSAS will be carried out using the actual treatment received. 
 
Booster Full Analysis Set (BFAS) 
The Booster Full Analysis Set (BFAS) is defined as all subjects who received the respective 
booster vaccination. Subjects will be analyzed according to the study group they had been 
allocated to, rather than by the actual treatment they received. 
 
Booster Per-Protocol Analysis Set (BPPAS) 
The Booster Per-Protocol Analysis Set (BPPAS) will consist of the BFAS excluding subjects 
that meet one of the following criteria, which possibly have an impact on the immunogenicity 
read-out:  
 
• 
Subjects enrolled despite exclusion from the PPAS of the Main Study Phase 
• 
Subjects who received the wrong booster medication   
• 
Subjects who fulfilled the Booster Phase exclusion criteria 5 and 8 

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Booster Analysis Sets will be defined for each analysis separately. Further criteria may be 
defined in the SAP. 
 
Immunogenicity Analysis 
Immunogenicity analyses include the analysis of OspA serotype (ST1 to ST6) specific IgG 
levels by an IgG binding assay 
 
  
Main Study Phase (Part A): 
The primary immunogenicity analysis compared the Geometric Mean Titers (GMTs) of 
serotype specific IgG against each OspA ST1 to ST6 between study groups in the PPAS on 
Day 208. GMTs and GMT ratios will be estimated by applying an analysis of variance (ANOVA) 
including the factor study group and age cohort. This will be done using log10 transformed 
data and taking the anti-log of the resulting point estimates for the least squares means, least 
squares means differences and the corresponding 95% CIs. Tukey’s HSD test will be applied 
for pair-wise comparisons. In addition, sensitivity analyses (ANOVAs with factors study site, 
study group, age cohort, study group*age cohort, and B.b. s.l. serostatus at baseline) will be 
performed. 
As secondary analysis, GMTs and GMT ratios will be analyzed as outlined above at baseline 
(screening visit) and Day 85, 180, 194*, 208, 365 and Month 18 for the Main Study Phase; 
 
 
   
Further secondary immunogenicity analyses will compare the following at time points outlined 
in the study endpoints: 
• 
The Geometric Mean of the fold rise as compared to baseline (GMFR) for IgG against 
each OspA ST 1-6 as determined by an IgG binding assay, e.g., ELISA (ANOVA). 
• 
Seroconversion Rates against each OspA serotype. Seroconversion rates will be 
compared using Fisher-Freeman-Halton tests, a significant overall test will be 
amended by pair-wise tests (Fisher’s exact test). 
 
o For ELISA:  
- 
For subjects that are seronegative at Visit 0 (baseline) the SCR is defined 
as a change from seronegative at Visit 0 to seropositive (i.e., antibody 
titer of ≥40 U/mL) at a certain time point. 
- 
For subjects that are seropositive at Visit 0 (baseline) the SCR is defined 
as a ≥ 4-fold rise in IgG antibody titer from Visit 0.  
o 
 
 
 
 
 
 
 
 
    
• 
GMTs for IgG against each OspA serotype (ST1 to ST6), at specified time points, 
stratified by age group. 
• 
Reverse cumulative distribution analyses of IgG responses will be provided for Day 0, 
85, 180, 194†, 208, 365 and Month 18. 
 
* Visit 5A will be performed by a subset of approximately 150 adult subjects only.  
† Visit 5A will be performed by a subset of approximately 150 adult subjects only.  

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All immunogenicity analyses will be performed for the PPAS. It will be described in the SAP 
which analyses will be repeated for the FAS and which analyses will also be repeated by 
baseline B.b. s.l. serostatus and by age group.  
 
Booster Phase (Part B) 
Immunogenicity analyses include the analysis of OspA serotype (ST1 to ST6) specific IgG 
levels by an IgG binding assay 
 
  
The primary immunogenicity analysis will provide 95% Confidence Intervals for Geometric 
Mean Titers (GMTs) of serotype specific IgG against each OspA ST1 to ST6 in the BPPAS 
population at Visit 9 (Month 19).  
As secondary analysis, GMTs and 95% CI will be provided at Month 18, 23, 26, 30, 31, 39, 42, 
43 and 48 in the Booster Phase. 
 
Further secondary immunogenicity analyses will provide the following: 
 
• 
The Geometric Mean of the fold rise (GMFR) at Month 19, 31 and 43 as compared to 
Visit 0 (baseline), Day 208, Month 18, Month 30 and Month 42 for IgG against each 
OspA ST 1-6 as determined by an IgG binding assay (ANOVA) 
, if applicable.  
• 
Seroconversion Rates against each OspA serotype separately at all study visits. 
• 
GMTs for IgG against each OspA serotype (ST1 to ST6), determined by an IgG binding 
assay, at specified time points, by age group. 
• 
Reverse cumulative distribution analyses of IgG responses will be provided for Day 0, 
85, 180, 194*, 208, 365 and Month 18, 19, 23, 26, 30, 31, 39, 42, 43 and 48. 
All immunogenicity analyses of the Booster Phase will be performed for the BPPAS. It will be 
described in the SAP whether any analyses will be repeated for the BFAS.   
 
Safety Analysis 
Main Study Phase (Part A):  
All subjects entered into the study who received at least one vaccination (SAS) will be included 
in the safety analysis. Safety tabulations will generally be provided separately for solicited AEs 
and unsolicited AEs, and for both types of AEs combined. 95% CI according to Altman will 
generally be provided for all AE rates. Further details in addition to the outline below will be 
provided in the SAP. 
The number and percentage of subjects with any AE, any unsolicited AE, any related 
unsolicited AE, any SAEs, any AESI, any related SAEs, any related AESIs, any medically 
attended AE and any AE leading to withdrawal from further treatment will be presented for 
each study group, overall and by system organ class/preferred term up to Day 208. The 
number and percentage of subjects with any SAE, any AESI, any related SAEs and any related 
AESIs will also be presented up to Month 18. Differences between study groups will be 
assessed for significance using Fisher’s exact (Fisher-Freeman-Halton) test, whereby a 
significant overall test will be amended by pair-wise tests.  
The number and percentage of subjects with solicited local and systemic AEs within 7 days 
after each vaccination and within 7 days after any vaccination will be tabulated. Differences 
between the study groups will be assessed for significance using Fisher’s exact test, a 
significant overall test will be amended by pair-wise tests. 
It will be defined in the SAP which safety analyses will also be repeated by baseline B.b. s.l. 
serostatus and age group. 
 

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Booster Phase (Part B):  
All subjects included in the Booster Phase who received the Month 18 booster vaccination will 
be included in the booster safety analysis (BSAS). The number and percentage of subjects 
with solicited local and systemic AEs up to 7 days after any booster vaccination, with any 
solicited or unsolicited AE, with any unsolicited AE, with any AESI, and with any SAE up to 
Visit 9 (Month 19) and with any AESI or SAE up to Visit 17 (Month 48) will be presented for 
each study group overall and by body system/preferred term. The safety analysis will be done 
in accordance to procedures used in Part A as outlined in Section 9.4. 
 
General considerations for the determination of the optimal schedule 
The following considerations for identification of the optimal primary vaccination schedule for 
further development are anticipated. However, these considerations may change with 
availability of new knowledge (e.g., new information from ongoing studies) or upon review of 
actual results. In general, exclusion or ranking of primary vaccination schedules will be based 
on the combined results for all age groups.  
 
1. If both primary vaccination schedules (Month 0-6 or Month 0-2-6) are similarly 
immunogenic, in general the schedule with the lowest number of vaccinations will be 
selected; 
2. In general, immunogenicity data generated to date indicate a consistent pattern with 
regards to immune responses to VLA15 in the six serotypes, i.e., groups that induced 
a high immune response against one serotype induced high immune response against 
all six serotypes and vice versa. Therefore, as a conservative approach, the immune 
response for serotype 1, which was the serotype against which VLA15 induced lowest 
immune responses in clinical data so far and which is the serotype that circulates 
almost exclusively in the U.S., will be compared with highest priority for determination 
of the optimal schedule. In case no significant difference between schedules is 
observed for serotype 1, immune responses for serotype 2, the most prevalent 
serotype in Europe, will be considered. Therefore, immunogenicity parameters in 
general will be interpreted with the following order of priority: 
• 
GMTs for IgG against OspA serotype 1, determined by an IgG binding assay, 
has first priority. Significantly higher GMTs favor one schedule over the other. 
• 
GMTs for IgG against OspA serotype 2, determined by an IgG binding assay, 
has second priority. Significantly higher GMTs favor one dose over the other. 
 
Determination of Sample Size 
The sample size has been chosen to allow detection of common AEs. A total of 400 subjects 
in the VLA15 groups (Group 1 and Group 2) will provide 95% confidence that an AE not seen 
in the study would have a true incidence of not more than 0.75%. In addition, the overall group 
size for the two VLA15 study groups has been selected to provide a sufficient safety database 
and for determining the optimal vaccination schedule before advancing the vaccine candidate 
into Phase 3. Upon completion of the study, the total number of subjects exposed to the final 
dose as used for upcoming Phase 3 studies would be a minimum of approximately N=710. 
The database would, thus, allow 95% confidence that a given reaction would not be observed 
at a higher rate than 1:(710/3) rate, i.e., 0.4%, if it is not observed in the studies preceding 
Phase 3. 
 
With respect to the primary endpoint, GMTs for ST1-6 specific IgGs on Day 208: In the absence 
of an established protective titer, sample size calculation is based on somewhat arbitrary 
differences in GMTs between VLA15 study groups, in order to demonstrate which titer levels 
could be distinguished with the proposed sample size.  

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Titers observed in the primary endpoint immunogenicity analysis (i.e., Day 208; one month 
after third vaccination) of 86 subjects receiving 180 µg of VLA15 in an ongoing Phase 2 study 
with VLA15 (VLA15-202) were used as basis: In the 180 µg group (i.e. the dose chosen for 
further development of VLA15), a GMT of 274.7 was observed for ST1 (i.e. the serotype with 
lowest titers) with a Standard Deviation (LOG10) of 0.53. A total of 180 subjects per group 
(assuming 10% of the 200 subjects per study group are excluded from the primary PP analysis) 
will provide 80% power at a two-sided alpha level of 5% to distinguish a GMT of 274.7 in one 
study group from a putative higher GMT of 394.3 in the other study group.   
 
The overall sample size of 200 subjects in the placebo group has been selected to allow for 
the internal validation of both safety and immunogenicity results. 
 
 
Data Analyses  
Analysis 1 included all safety and immunogenicity data from selected time points from Part A 
up to Day 208/ Month 7. This analysis was done in four parts. Every age cohort was analyzed 
separately as soon as data from each cohort was available (Analysis 1.1 (Cohort 1, aged 18-
65 years), Analysis 1.2 (Cohort 2, aged 12-17 years), Analysis 1.3 (Cohort 3, aged 5-11 
years)). Pooled data from all three cohorts concluded Analysis 1.   
 
Analysis 2 included all safety and immunogenicity data from selected time points from Part A 
up to Month 12 (i.e., 6 months after the third immunization).   
 
Analysis 3 included all safety data and immunogenicity data from selected time points from 
Part A up to Month 18 and safety and immunogenicity data from Part B up to Month 19.  
 
Analysis 4 will include safety and immunogenicity data of Part B up to Month 31. 
Analysis 5 will include safety and immunogenicity data of Part B up to Month 43. 
Analysis 6 will include safety and immunogenicity data of Part B up to Month 48. 
 
In case analyses fall close in timing, they may be merged.  
10 DEVIATIONS FROM THE PROTOCOL 
 Relevant Protocol Deviations 
All protocol deviations will be tracked, actions defined, as feasible, and reviewed and 
assessed. Furthermore, Protocol Deviations will be assessed in a blinded Data Review 
Meeting before data analyses for their impact on the immunogenicity analysis.  
 Premature Subject Withdrawal from Study or Treatment 
Subjects have the right to withdraw from the study at any time for any reason, without the need 
to justify. The investigator also has the right to prematurely terminate a subject’s further 
participation in the study, e.g., in the case of non-compliance.  
The investigations described for Early Termination, see Table of Events (Main Study Phase 
Table 2 and Booster Phase Table 3), should be carried out and recorded at the time of the 
subject’s withdrawal, including obtaining an explanation of why the subject is withdrawing, if 
possible. Subjects will not be replaced. 
Additionally, a subject will be withdrawn from further vaccination if any of the following criteria 
are met: 

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10.2.1 Individual stopping criteria 
The following criteria will lead to a subject withdrawal from further vaccinations: 
1. 
If subject becomes pregnant (please refer to Section 8.4.4 for pregnancy reporting 
procedures). 
2. 
If a subject reports symptoms which are considered unacceptable by the subject or the 
investigator, he or she will be withdrawn from further treatment. 
3. 
If a subject experiences an SAE with no likely alternative cause than the study vaccine 
(i.e., possibly or probably related).  
4. 
Solicited local AE: Grade 3 or 4 injection site reaction that lasts longer than 3 days. 
5. 
Solicited systemic AE: Grade 3 or 4 solicited systemic reaction that lasts longer than 3 
days. However, the subject may receive further vaccinations if there is a more plausible 
alternative cause for the reaction. 
6. 
Any acute systemic allergic reaction after administration of the vaccine within 14 days 
following study vaccine administration, with no likely alternative cause than the study 
vaccine. 
7. 
If subject develops a malignancy during vaccination phase and receives radiation- or 
chemotherapy. 
8. 
If subject develops or is found to violate one of the following in- or exclusion criteria of 
Main Study Phase after enrollment: inclusion criterion 3, exclusion criteria 1, 4-6, 10, 
13-15. 
If subject develops LB during course of the study and receives treatment for LB within 3 months 
prior to planned next vaccination, respective vaccination will not be performed. 
 
Subjects withdrawn from further vaccination should perform their remaining regular study visits 
as scheduled if there are no other reasons for premature withdrawal from the study. 
 Documentation of Premature Withdrawal 
The reasons for premature withdrawal of a study subject from treatment should be documented 
in the eCRF as follows: 
• 
Withdrawal due to meeting individual stopping criteria (identify the respective criteria 
and AE, if applicable) 
• 
Consent/assent withdrawal due to adverse event (identify the respective AE) 
• 
Consent/assent withdrawal not due to an adverse event 
• 
Investigator/ sponsor recommended withdrawal (include reasons, e.g., AE, 
incompliance, exclusion criterion met/ developed) 
The reasons for premature withdrawal of a study subject from the study should be documented 
in the eCRF as follows: 
• 
Consent/assent withdrawal due to adverse event (identify the respective AE) 
• 
Consent/assent withdrawal not due to an adverse event 
• 
Investigator/ sponsor recommended withdrawal (include reasons, e.g., AE, 
incompliance, exclusion criterion met/ developed) 
• 
Moved from study area 
• 
Lost to follow up 

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• 
Death 
 Subsequent Therapy 
Not applicable. 
11 ETHICAL AND REGULATORY ASPECTS 
 Ethical/ Regulatory Framework 
The study will be conducted in accordance with the protocol, the current Declaration of 
Helsinki, current ICH/GCP guidelines, and with the applicable regulatory requirements.  
 Institutional Review Board 
Prior to study initiation, the investigator, sponsor or CRO submitted the protocol, ICF/ assent 
form and further requested information to the appropriate IRBs in accordance with local 
requirements. The site did not enroll subjects before approval had been obtained. 
 Subject Information and Informed Consent/Assent 
It is the investigator’s responsibility to obtain freely given written informed consent/assent from 
the subject or the subject’s legal representative(s), as required by local regulations, and the 
subject’s written assent, depending on the subject’s age and capability, after adequate 
explanation of the aims, methods, potential benefits and hazards of the study. Written informed 
consent/assent has to be obtained before the subject is exposed to any study-related 
procedures, including screening tests for eligibility. 
For children below 7 years of age or according to local requirements, the investigator has to 
orally explain the aims of the study, its procedures, benefits and risks in an appropriate level.  
For children aged 7 years and older or according to local requirements, assent has to be 
sought.  
The investigator will explain that the subjects are completely free to refuse to enter the study 
or to withdraw from it at any time, without any prejudice and need for justification. The subjects 
will be informed that representatives of the sponsor and health authority inspector may review 
their source records, and that these persons are bound by confidentiality obligations. 
The subject’s legal representative(s) and the subject, as applicable, will be given a copy of the 
signed informed consent/assent documentation. The original of the signed and dated informed 
consent/assent must be retained in the site’s records, and is subject to inspection by 
representatives of the sponsor, or representatives from CAs. 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
 Source Data and Records 
Source data are defined as all information related to clinical findings, observations or other 
activities in the study, written down in original records or certified copies of original records. 
The investigator will permit study-related monitoring, audits, IRB review and regulatory 
inspections, by providing direct access to source data/records. Source records should be 
preserved for the maximum period of time required by local regulations. 
Source data entries must be made in accordance with local requirements. Signed and dated 
copies of the laboratory result reports have to be kept within the subject’s source data file. 

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The following data may directly be recorded in the eCRF at study visits and the eCRF is 
regarded as source document: 
- 
Ethnic Group 
- 
Systolic and diastolic blood pressure, pulse rate, oral body temperature 
- 
Result of urine pregnancy test 
 
eCRFs will not be used as source data for any other variable. 
 Periodic Monitoring 
A designated CRA will check electronic system data and source data at regular intervals 
throughout the study to verify completeness, accuracy and consistency of the data, protocol 
adherence, and adherence to GCP guidelines. The monitor will work according to the 
Monitoring Plan; a risk-based monitoring approach is planned for this study. The investigator 
will cooperate with the monitor to ensure that any discrepancies identified are resolved. 
 Audit and Inspection 
Upon request, the investigator will make all study-related source data and records available to 
a qualified quality assurance auditor mandated by the sponsor or to regulatory inspectors. The 
main purposes of an audit or inspection are to confirm that the rights and welfare of the subjects 
have been adequately protected, and that all data relevant for the assessment of safety and 
efficiency of the investigational product have appropriately been reported to the sponsor. 
 Confidentiality of Subject’s Data 
The investigator will exercise all reasonable precautions within the constraints of the applicable 
regulatory requirements to maintain the confidentiality of subjects’ identities. On exported 
electronic source data or any other documents submitted to the sponsor, subjects will only be 
identified by subject number. Documents not for submission to the sponsor, e.g., subject 
identification log and original ICF/ assent form, will be maintained by the investigator in strict 
confidence. 
13 DATA HANDLING AND RECORD KEEPING 
 Information for Investigators 
An Investigator’s Brochure (IB) containing all important data relating to the safe use of the 
investigational product was supplied to the investigator prior to study start. 
The investigator will be kept informed on new relevant safety data as the study proceeds. 
 Electronic Case Report Forms (eCRFs) 
13.2.1 eCRF entries 
eCRF entries and corrections will only be performed by study site staff authorized by the 
investigator. Each user is informed of the clinical study’s web-site internet address and is 
allocated to a user account with personal password to access the confidential web site. The 
personal password must be kept confidential and must only be used by the person to whom it 
was assigned. For additional authorized users at the site, a new user account needs to be 
requested to ensure that each entry/ change can be allocated to the person who performed 
the entry/ change. 
All visit data need to be recorded in the eCRF database as soon as possible after each study 
visit.   

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13.2.2 Changes to eCRF data 
Corrections may be requested as follows: 
▪ 
Investigators’ responses are checked as they are entered and are rejected if they do not 
fulfill quality criteria. A message will specify the type of error or syntax error and assist in 
its correction. 
▪ 
If required, the CRA can ask for information to be corrected during monitoring.  
▪ 
Computerized data-check programs and manual checks will identify clinical data 
discrepancies for resolution. Corresponding queries will be created within the data 
capturing system and the site will be informed about new issues to be resolved on-line. 
All discrepancies will be solved on-line directly by the investigator or by authorized staff. 
Corrections of eCRF data may be performed by authorized staff only. The person performing 
the changes in the eCRF is required to electronically confirm the changes made.  
13.2.3 eCRF entry validation 
The principal investigator or the authorized delegate will thoroughly review the data on the 
eCRF, and will finally certify the contents of the eCRF by electronic signature after completion 
of each patient. If a correction is made to the eCRF data after the investigator’s final approval, 
the certification must be repeated after the changes have been performed. 
13.2.4 Data collection 
All visits and assessments are entered into an interactive form. All eCRFs will be source 
document verified as detailed in the Monitoring Plan. Maintenance of the study database will 
be performed. Details to eCRF handling are provided in a study specific eCRF manual. 
 Coding of Adverse Events, Drugs and Diseases 
After data entry AEs and Medical History will be coded according to MedDRA, latest version. 
Previous and Concomitant Medication and Vaccines will be coded according to WHO Drug 
Reference List and Anatomical Therapeutic Chemical (ATC) Classification System, latest 
version.  
 Investigator File 
13.4.1 Maintenance 
The investigator will be provided with an initial investigator file during the initiation visit. The 
investigator is responsible for maintaining all records up to date to enable the conduct of the 
study to be fully documented. The records should include the protocol, study approval letters, 
all original ICFs, drug dispensing and accountability logs and all relevant correspondence 
pertaining to the study. 
13.4.2 Archiving and destruction 
All study related documents should be kept by the investigator for the maximum period of time 
required by local regulations. No study document should be destroyed without prior written 
agreement between the investigator and the sponsor. Should the investigator elect to assign 
the study documents to another party, or move them to another location, the sponsor must be 
notified. 

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 Provision of Additional Information 
On request, the investigator will supply the sponsor with additional data relating to the study or 
copies of relevant source records, duly anonymized. In case of particular issues or 
governmental queries, it is also necessary to have access to the complete study records, 
provided that the subject's confidentiality is protected in accordance with applicable 
regulations. 
14 CHANGES IN THE CONDUCT OF THE STUDY 
 Protocol Amendments 
Proposed amendments must be submitted to the appropriate CA and IRB in line with regulatory 
requirements. Amendments may be implemented only after CA and IRB approval has been 
obtained, if applicable. Amendments that are intended to eliminate an apparent immediate 
hazard to subjects may be implemented prior to receiving CA and IRB approval. However, in 
this case, approval must be obtained as soon as possible after implementation. 
 Study Termination – Study Stopping Rules 
The sponsor and an independent DMC will monitor safety data at regular intervals to identify 
applicability of study stopping rule or identify any potential safety concern. 
The occurrence of the following criterion will lead to suspension of any further enrollment and 
suspension of any subsequent vaccination of subjects already enrolled, until available safety 
data has been reviewed by the DMC and their recommendation is available whether or not to 
proceed with enrollment and vaccinations: 
• Two or more related SAEs with the same suspected underlying pathological mechanism, 
where relationship to VLA15 cannot be ruled out (i.e., judged as probably or possibly related 
to vaccination). 
The DMC can issue a recommendation to stop the study or to discontinue a study group during 
planned or ad-hoc DMC meetings, e.g., in response to an excess rate of AEs or AESIs with 
the same suspected underlying pathological mechanism. 
If a study stopping rule is met or the DMC recommends halting the study for other reasons, the 
sponsor will notify the FDA, IRBs and Principal Investigators within 48 hours by phone or fax. 
Vaccination of subjects already enrolled in the study and restart of recruitment may only 
proceed after positive DMC recommendation and Competent Authorities will be informed. 
If the sponsor or the investigator decides to terminate the study before it is completed, they will 
notify each other in writing, stating the reasons for early termination. In terminating the study, 
the sponsor and the investigator will ensure that adequate consideration is given to the 
protection of the subjects’ interests. The investigator, sponsor or CRO will notify the relevant 
CA or IRB/ EC in writing in accordance with local requirements. Documentation will be 
submitted for filing in the Central and Investigator File and the Trial Master File. 
 Study Changes in Response to the COVID-19 Pandemic Situation 
The study sponsor will continuously monitor and evaluate the development of the COVID-19 
pandemic in the area of study sites to determine if any measures need to be implemented to 
mitigate undue risks to the subjects or in response to local governmental recommendations. 
Such measures may include, temporarily halting further recruitment, switching in-person visits 
to phone/video calls, or employing mobile teams to collect serum samples. Any measure would 
be communicated to the relevant CA and IRB.   

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15 REPORTING AND PUBLICATION 
 Clinical Study Report 
In total 5 study reports with following content will be compiled:  
 
Clinical study report 1 compiles the data from Analysis 1:  
• 
All safety and immunogenicity data from selected time points from Part A up to Day 
208/ Month 7 
Clinical study report 2 compiles the data from Analysis 2 and 3: 
• 
All safety and immunogenicity data from selected time points from Part A up to Month 
12 (i.e., 6 months after the third immunization) 
• 
All safety data and immunogenicity data from selected time points from Part A up to 
Month 18 and safety and immunogenicity data from Part B up to Month 19. 
Clinical study report 3 will include the data compiled in Analysis 4:  
• 
Safety and immunogenicity data of Part B up to Month 31 
Clinical study report 4 will include the data compiled in Analysis 5: 
• 
Safety and immunogenicity data of Part B up to Month 43 
Clinical study report 5 will include the data compiled in Analysis 6:  
• 
Safety and immunogenicity data of Part B up to Month 48 
 Publication Policy 
All results generated in this study will be considered to be strictly confidential. The investigator 
may not submit the results for publication or presentation without prior written permission of 
the sponsor. Authorship for any publication will be determined in mutual agreement. Within the 
scope of publication, co-authorship may be offered, at the sole discretion of the sponsor, on a 
case by case basis taking scientific contribution into consideration. This is according to uniform 
requirements for manuscripts submitted to biomedical journals proposed by the International 
Committee of Medical Journal Editors. 
16 LIABILITIES AND INSURANCE 
The sponsor will contract a clinical trial insurance.  
The name, address and the insurance policy number will be given to the investigator. 
Moreover, a copy of the insurance conditions will be filed on site. 
The investigator is responsible for dispensing the investigational product according to this 
protocol, and for its secure storage and safe handling throughout the study. 
 
 
 
 

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17 APPENDIX 1 
Immune-mediated and neuroinflammatory disorders as proposed by FDA for previous clinical 
programs29: 
Gastrointestinal disorders  
• 
Celiac disease  
• 
Crohn’s disease  
• 
Ulcerative colitis  
• 
Ulcerative proctitis  
 
Liver disorders  
• 
Autoimmune cholangitis  
• 
Autoimmune hepatitis  
• 
Primary biliary cirrhosis  
• 
Primary sclerosing cholangitis  
 
Metabolic diseases  
• 
Addison’s disease  
• 
Autoimmune thyroiditis (including Hashimoto 
thyroiditis)  
• 
Diabetes mellitus type 1  
• 
Grave’s or Basedow’s disease  
 
Musculoskeletal disorders  
• 
Antisynthetase syndrome  
• 
Dermatomyositis  
• 
Juvenile chronic arthritis (including Still’s 
disease)  
• 
Mixed connective tissue disorder  
• 
Polymyalgia rheumatic  
• 
Polymyositis  
• 
Psoriatic arthropathy  
• 
Relapsing polychondritis  
• 
Rheumatoid arthritis  
• 
Scleroderma, including diffuse systemic form 
and CREST syndrome  
• 
Spondyloarthritis, including ankylosing 
spondylitis, reactive arthritis (Reiter’s 
Syndrome) and undifferentiated 
spondyloarthritis  
• 
Systemic lupus erythematosus  
• 
Systemic sclerosis 
 
Neuroinflammatory disorders  
• 
Acute disseminated encephalomyelitis, 
including site specific variants: eg, 
noninfectious encephalitis, encephalomyelitis, 
myelitis, myeloradiculomyelitis  
• 
Cranial nerve disorders, including 
paralyses/paresis (eg, Bell’s palsy)  
• 
Guillain-Barré syndrome, including Miller 
Fisher syndrome and other variants  
• 
Immune-mediated peripheral neuropathies and 
plexopathies (including chronic inflammatory 
demyelinating polyneuropathy, multifocal 
motor neuropathy and polyneuropathies 
associated with monoclonal gammopathy)  
• 
Multiple sclerosis  
• 
Narcolepsy  
• 
Optic neuritis  
• 
Transverse Myelitis 
 
Skin disorders  
• 
Alopecia areata  
• 
Autoimmune bullous skin diseases (including 
pemphigus, pemphigoid and dermatitis 
herpetiformis)  
• 
Cutaneous lupus erythematosus  
• 
Erythema nodosum  
• 
Morphoea  
• 
Lichen planus  
• 
Psoriasis  
• 
Sweet’s syndrome  
• 
Vitiligo  
 
Vasculitides 
• 
Large vessels vasculitis including: giant cell 
arteritis such as Takayasu’s arteritis and 
temporal arteritis 
• 
Medium sized and/or small vessels vasculitis 
including: polyarteritis nodosa, Kawasaki’s 
disease, microscopie polynagiitis, Wegener’s 
granulomatosis, Churg-Strauss syndrome 
(allergic granulomatous angiitis), Buerger’s 
disease (thromboangiitis obliterans), 
necrotizing vasculitis and anti-neutrophil 
cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch-
Schonlein purpura, Behcet’s syndrome, 
leukocytoclastic vasculitis 
 
Others  
• 
Antiphospholipid syndrome  
• 
Autoimmune hemolytic anemia  
• 
Autoimmune glomerulonephritis (including IgA 
nephropathy, glomerulonephritis rapidly 
progressive, membranous glomerulonephritis, 
membranoprofilerative glomerulonephritis, and 
masangioproliferative glomerulonephritis  
• 
Autoimmune myocarditis/cardiomyopathy  
• 
Autoimmune thrombocytopenia  
• 
Goodpasture syndrome  
• 
Idiopathic pulmonary fibrosis  
• 
Pernicious anemia  
• 
Raynaud’s phenomenon  
• 
Sarcoidosis  
• 
Sjögren’s syndrome  
• 
Stevens- Johnson syndrome  
• 
Uveitis  
 
 
 
 
 
 
 
 

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18 APPENDIX 2 
In case there is clinical suspicion for Lyme borreliosis or a LB-associated event according to 
the scripted safety assessment, investigators are advised to perform the following clinical 
workup: 
 
A. Travel history and physical examination, medical history 
1. Assess subjects‘ travel and exposure history 
If subject observed a tick bite, time/date of tick attachment and time/date of tick removal 
should be requested. 
2. Perform physical exam: general appearance (including assessment of body weight and 
height), skin, head/ eyes /ears/ nose/ throat, chest, lungs, heart, abdomen, extremities 
and joints, lymph nodes, and neurological system, assess body temperature and vital 
signs. Especially assess for symptoms of fever, fatigue, headache, mild stiff neck, 
arthralgia, myalgia and thoroughly check skin for rash, including under (body) hair. 
3. Assess medical history  
 
B. Subject presents with an Erythema Migrans (EM) rash - early localized disease 
(<30 days after tick bite): 
1. Document localization of rash 
2. Perform a photograph of the EM rash for documentation. Only the affected area should 
be visible in the picture. Avoid full-face views or other personal identification in 
photographs to ensure the subject’s anonymity. 
Characteristics of an EM rash10 
• 
Erythema migrans usually occurs 7 to 14 days (range 3 to 30 days) after tick 
detachment or tick removal.  
• 
Starts from a macule or papule and expands over time to form red or bluish-red patch 
• 
EM should be at least 5 cm in largest diameter and usually increases in size over time, 
reaching up to 30 cm.  
• 
EM can be homogeneously erythematous or can have prominent central clearing: See 
examples of Erythema migrans rashes on 
https://www.cdc.gov/lyme/signs_symptoms/index.html 
The clinical diagnosis of Lyme borreliosis through presentation of a distinctive Erythema 
migrans is done by visual inspection of the skin lesion without laboratory confirmation. 
Treatment of patients should be initiated according to standard of care.10,30   
In case there is diagnostic uncertainty and symptoms persist, acute-phase and convalescent-
phase (i.e., 2 weeks after the acute phase) serum samples should be tested using 2-tier testing 
algorithm as recommended by the CDC.31  
 
C. Subject presents with signs / symptoms suggesting early disseminated disease 
(< 3 months) or Late disseminated disease (≥3 months) 
 
• 
In case of clinical suspicion of early disseminated or late disseminated Lyme borreliosis 
serologic testing via a two-tier approach using a sensitive enzyme-linked 

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immunosorbent assay (ELISA) and confirmation of positive or equivocal results by a 
standardized Western blot/ Immuno blot assay as recommended by the CDC31 should 
be ordered. Additional work-up as depicted in Table 11should be initiated. 
• 
In case of clinical suspicion of early disseminated or late disseminated Lyme 
borreliosis, consider initiating treatment according to standard of care10,30 and send 
patient for consultation with a specialist as appropriate.  
Table 11 Early disseminated or late disseminated Lyme borreliosis 
 
Symptom 
Additional work up at 
study site 
Disseminated 
skin 
manifestations 
Multiple EM skin lesions 
• 
might be <5 cm in diameter and may 
expand 
Borrelial Lymphocytom (rare) 
• 
solitary 
bluish-red 
swelling 
with 
diameter up to few cm 
• 
most commonly presents at ear lobe, 
ear helix, breast (on or near the nipple), 
or scrotum 
Acrodermatitis Chronica Atrophicans 
• 
develops several years after infection, 
mainly observed in Europe 
• 
lesions are characterized by a slight 
bluish-red discoloration and doughy 
swelling 
• 
lesions enlarge slowly over months to 
years, in association with resolution of 
the edema and development of skin 
atrophy 
Perform 
photograph 
and 
document localization of EM 
rashes 
and/or 
borrelial 
lymphocytom. 
Only 
the 
affected area should be 
visible in the picture. Avoid 
full-face 
views 
or 
other 
personal 
identification 
in 
photographs to ensure the 
subject’s anonymity.  
 
Send patient for consultation 
with infectious disease/ LB 
specialist as appropriate for 
further clinical work-up 
Neurological 
symptoms 
• 
episodes of dizziness or shortness of 
breath 
• 
nerve pain  
suggesting suspicion of: 
• 
inflammation of the brain and spinal 
cord 
• 
cranial nerve palsy 
• 
meningo-radiculitis 
• 
meningitis  
• 
radiculopathy 
• 
encephalitis 
• 
myelitis 
• 
cerebral vasculitis 
• 
facial palsy 
Send patient for consultation 
with 
infectious 
disease 
specialist/ 
neurologist 
as 
appropriate 
for 
further 
clinical work-up 
Arthritis 
e.g. 
Send patient for consultation 
with 
infectious 
disease 

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Symptom 
Additional work up at 
study site 
• 
recurrent attacks or persisting objective 
joint swelling (synovitis) in one or a few 
large joints 
• 
intermittent pain in tendons, muscles, 
joints and bones 
specialist 
/rheumatologist  
as appropriate for further 
clinical work-up 
Cardiac 
symptoms (rare) 
• 
heart palpitations or an irregular heart 
beat  
e.g. suspicion of 
• 
atrio-ventricular 
conduction 
disturbances 
• 
rhythm disturbances 
• 
myocarditis 
Perform ECG;  
Send patient for consultation 
with 
infectious 
disease 
specialist/ cardiologist as 
appropriate 
for 
further 
clinical work-up 
Ocular 
manifestations 
(rare) 
e.g. 
• 
conjunctivitis 
• 
uveitis 
• 
papillitis 
• 
episcleritis 
• 
keratitis 
Send patient for consultation 
with 
infectious 
disease 
specialist/ 
ophthalmologist 
as appropriate for further 
clinical work-up 
 
 
 

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2. 
MEETING REPORT: Expert Consultation on Tick-Borne Diseases with Emphasis on 
Lyme 
Borreliosis 
and 
Tick-Borne 
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Rizzoli A, Hauffe HC, Carpi G, Vourc’h GI, Neteler M, Rosà R. Lyme borreliosis in 
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Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lyme Disease with 
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