A Phase Ib/IIa Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Immunogenicity of Different Doses, Regimens and Combinations of Tau Targeted Vaccines in Subjects With Early Alzheimer's Disease
Phase: PHASE1
Conditions: Alzheimer's Disease, Cognitive Impairment, Tauopathies, Mild Cognitive Impairment, Dementia, Brain Diseases, Central Nervous System Diseases
Sponsor: AC Immune SA

 
 
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ACI-35-1802 
Protocol v7.0, Final – 22 October 2021 
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CLINICAL STUDY PROTOCOL 
 
 
A Phase Ib/IIa Multicenter, Double-Blind, 
Randomized, Placebo-Controlled Study to 
Evaluate the Safety, Tolerability and 
Immunogenicity of Different Doses, Regimens 
and Combinations of Tau Targeted Vaccines in 
Subjects with Early Alzheimer’s Disease 
 
Study No ACI-35-1802 
 
Protocol version 7.0, 22 October 2021 
 
EudraCT Number 2018-004573-27 
 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to AC 
Immune SA. Any unauthorized copying or use of this document is prohibited. 
 
 

 
 
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SIGNATURE PAGE 
Sponsor 
 
 
 
AC Immune SA 
EPFL Innovation Park - Building G 
CH-1015 Lausanne, Switzerland 
Tel: 
 
Fax: 
 
email: 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
AC Immune SA 
EPFL Innovation Park - Building G 
CH-1015 Lausanne, Switzerland 
Tel : 
 
Fax : 
 
     email: 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 

 
 
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ACI-35-1802 
Protocol v7.0, Final – 22 October 2021 
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International Coordinating Investigator 
 
 
 
 
Amsterdam UMC 
Alzheimer Center 
de Boelelaan 1118  
1081 HZ Amsterdam 
The Netherlands  
Tel: 
 
Mob: 
 
email: 
 
 
 
 
 
Signature 
 
Date 
 
 
 

 
 
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ACI-35-1802 
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STUDY SYNOPSIS 
Study Title 
A Phase Ib/IIa multicenter, double blind, randomized, placebo-controlled study to evaluate the safety, 
tolerability and immunogenicity of different doses, regimens and combinations of Tau targeted 
vaccines in subjects with early Alzheimer’s Disease 
Study number 
ACI-35-1802 
EudraCT number 
2018-004573-27 
Investigators/study 
Centers  
This study will be conducted in approximately 15 study centers located in Europe. 
 
Objectives 
Primary Objectives 
To assess the safety and tolerability of study vaccines 
To assess the immunogenicity of study vaccines (induction of IgG titers against phosphorylated Tau 
(pTau) in serum) 
Secondary Objectives 
To further assess the immunogenicity of study vaccines (induction of IgG titers against Tau and IgM 
titers against pTau and Tau in serum) 
To assess the avidity of antibodies elicited by immunization 
Exploratory Objectives 
To explore the effect of study vaccines on putative biomarkers of the progression of Alzheimer’s 
Disease (AD), i.e. blood and/or CSF concentrations of total Tau and pTau proteins, Tau fragments 
and other related biomarkers 
To explore the effect of study vaccines on the activation of T-cells in blood 
To explore the activity of study vaccines on blood inflammatory cytokines (e.g. IL-1B, IL-2, IL-6, IL-8, 
IL-10, IFN- γ, and TNF- α)  
To further explore the effect of study vaccines on the immune response (e.g. antibodies against 
vaccine components, functional capacity of vaccine-induced antibodies) 
To explore the effect of study vaccines on behavior, cognitive (including, in the Netherlands, the 
maintenance of the decisional capacity) and functional performance 
Study Endpoints 
Primary Endpoints 
Safety and tolerability: Adverse events, immediate and delayed reactogenicity (e.g. anaphylaxis, 
local and systemic reactogenicity, including immune-complex disease); suicidal ideation (C-SSRS); 
behavior (NPI); cognitive and functional assessments (RBANS, CDR-SB) to assess safety; vital signs; 
MRI imaging; electrocardiogram; routine hematology and biochemistry evaluation in blood and urine; 
evaluation of autoimmune antibodies including anti-dsDNA antibodies in blood; inflammatory markers 
in blood and CSF  
Immune response (i.e. immunogenicity): Anti-pTau IgG titers in serum (geometric mean, change 
from baseline, responder rate, peak and area under the curve) 
Secondary Endpoints 
Immune response (i.e. immunogenicity): Anti-Tau IgG, anti-pTau and anti-Tau IgM titers in serum 
(geometric mean, change from baseline, responder rate, peak and area under the curve), 
determination of the IgG response profile by avidity testing 
Exploratory Endpoints 
Change from baseline of putative AD biomarker titers in blood and/or CSF (e.g. total Tau, pTau, Tau 
fragments and other related biomarkers), change from baseline in T-cell activation levels as measured 
in  blood, change from baseline of inflammatory cytokine titers in blood, change from baseline in 
antibody titers in blood, change from baseline in behavior (NPI), cognitive (including the proportion of 
subjects maintaining their decisional capacity during the study using the MacCAT-CR interview in the 
Netherlands) and functional performance (RBANS, CDR-SB) scores  

 
 
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Design 
This protocol is a master protocol aimed at investigating two different Tau targeted study vaccines. 
This study is a multicenter prospective placebo-controlled, double-blind and randomized study to 
assess the safety, tolerability and immunogenicity of different doses, and combinations of Tau targeted 
vaccines versus placebo over 50 weeks (i.e. 12 months). Immunizations will be performed at months 
0 (Week 0), 2 (Week 8), 6 (Week 24)* and 12 (Week 48).   
*Due to the Covid-19 pandemic, local travel restrictions in Finland effective as of 18 March 
2020, and the need to preserve the safety of study participants, modifications are made to the 
schedule of immunizations of sub-cohort 1.1 subjects not having received the 3rd injection at 
month 6 already: immunizations at month 6 (week 24) will not be performed in 7 of 8 sub-cohort 1.1 
subjects for whom the planned Visit 5 does not allow all assessments to be done according to the 
protocol. In addition, Visits 5 (week 24), 6 (week 26) and 7 (week 36) are replaced by remote visits in 
case these fall during the at-risk period (refer to sections 3.5.2. 10, 3.5.2.11, 3.5.2.12 and 3.5.2.14).  
Due to the resurgence of the Covid-19 pandemic in multiple participating countries since September 
2020, additional adjustments related to the mode of administration of study assessments including 
study vaccine administration may apply in Finland and other participating countries after the above 
measures were implemented in Finland.  
 
Cohort 1 with ACI-35.030: 
Up to 3 dose levels of ACI-35.030 administered by the intramuscular route will be tested.  The rationale 
for dose escalation is to obtain a dose response curve of both safety and immunogenicity in order to 
select the optimal dose and combination for future studies.   
 
Sub-cohort 1.1 (8 subjects): 
ACI-35.030 at 300 μg/dose will be administered to 6 subjects and the placebo will be administered 
to 2 subjects. The safety and tolerability data after all subjects have received the second injection 
in sub-cohort 1.1 will permit dose escalation after review by the Data Safety Monitoring Board 
(DSMB).  
 
Sub-cohort 1.2 (8 subjects): 
ACI-35.030 at 900 μg/dose will be administered to 6 subjects and the placebo will be administered 
to 2 subjects. The safety and tolerability data after all subjects have received the second injection 
in sub-cohort 1.2 will permit dose escalation after review by the DSMB.  
 
Sub-cohort 1.3 (8 subjects): 
ACI-35.030 at 1800 μg/dose will be administered to 6 subjects and the placebo will be 
administered to 2 subjects.  
 
Cohort 2 with JACI-35.054: 
The administration schedule, route of administration, duration of treatment and follow-up are identical 
to cohort 1. Up to 3 dose levels of JACI-35.054 administered by the intramuscular route will be tested 
in up to 3 sub-cohorts.  
 
Sub-cohort 2.1 (8 subjects): 
JACI-35.054 at 15 μg/dose will be administered to 6 subjects and the placebo will be administered 
to 2 subjects. The safety and tolerability data after all subjects have received the second injection 
in sub-cohort 2.1 will permit dose escalation after review by DSMB. 
 

 
 
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Sub-cohort 2.2 (8 subjects) - Optional:  
JACI-35.054 at up to 60 μg/dose will be administered to 6 subjects and the placebo will be 
administered to 2 subjects. This sub-cohort will be optional and may be conducted based on good 
safety and tolerability observed in sub-cohort 2.1 and in case the antibody response in this 
previous sub-cohort is anticipated to be optimized at the dosage of up to 60 μg. 
 
Sub-cohort 2.3 (8 subjects) - Optional 
JACI-35.054 at up to 150 μg/dose will be administered in 6 subjects and the placebo will be 
administered in 2 subjects. This sub-cohort will be optional and may be conducted based on good 
safety and tolerability observed in sub-cohort 2.2 and in case the antibody response in this 
previous sub-cohort is anticipated to be further optimized at a higher dosage. 
 
Cohort 3 with ACI-35.030 and JACI-35.054 in sequential administration  
The administration schedule, route of administration, duration of treatment and follow-up are identical 
to cohorts 1 and 2 but both vaccines ACI-35.030 and JACI-35.054 will be administered in a sequence 
based on non-human primate immunogenicity data and on data reviewed during the previous sub-
cohort interim analyses. In any of the sub-cohorts listed below, the selected dosages of the 2 study 
vaccines will have been evaluated in cohorts 1 and 2 and safety monitored for at least 10 weeks and 
safety data of the selected dosages of the 2 study vaccines reviewed by the DSMB. 
Sub-cohort 3.1 (8 subjects) 
ACI-35.030 and JACI-35.054 at dosages previously evaluated in cohorts 1 and 2 respectively and 
found to be safe after a study treatment period of at least 10 weeks will be administered 
sequentially to 6 subjects and placebo will be administered at each dosing occasion to 2 subjects. 
Immunizations with ACI-35.030 will be performed at months 0 (Week 0) and 2 (Week 8), and with 
JACI-35.054 at month 6 (Week 24) and 12 (Week 48). 
 
Sub-cohort 3.2 (8 subjects) - Optional 
This optional sub-cohort may include a different sequence of administration than in sub-cohort 3.1 
and/or different dosages of ACI-35.030 and/or JACI-35.054 based on available safety, tolerability 
and immunogenicity data from previous sub-cohort interim analyses. Dosages of ACI-35.030 and 
of JACI-35.054 will have been previously evaluated in cohorts 1, 2 and/or 3 without significant 
safety or tolerability concerns. 
 
Sub-cohort 3.3 (8 subjects) - Optional 
This optional sub-cohort may include a different sequence of administration than in sub-cohorts 
3.1 and 3.2 and/or different dosages of ACI-35.030 and/or JACI-35.054 based on available safety, 
tolerability and immunogenicity data from previous sub-cohort interim analyses. Dosages of ACI-
35.030 and of JACI-35.054 will have been previously evaluated in cohorts 1, 2 and/or 3 without 
significant safety or tolerability concerns. 
 
Sub-cohort expansion: 
Optional sub-cohort expansion of up to 16 additional subjects (i.e. up to 12 on active treatment and 
up to 4 on placebo per sub-cohort) may be considered in sub-cohort(s) with a favorable safety and 
immunogenicity profile with the objective to confirm the initial sub-cohort(s) immunogenicity results. 
The number of additional subjects to be enrolled will be determined based on the observed 
immunogenicity response rate in the sub-cohort(s) and on the potential gain in precision of the 
response rate estimate in the expanded sub-cohort(s), and will not exceed 16 (i.e., up to 24 subjects 
overall per sub-cohort). In addition, all other immunogenicity endpoints available at the interim 

 
 
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timepoint may be considered. The dose-level, sequence of administration and administration regimen 
of study vaccine(s) will be identical to the initial part of the sub-cohort. 
 
Safety follow-up: 
All subjects will be kept under clinical observation for 24 hours after the first administration of study 
vaccine and for 4 hours after subsequent administrations of study vaccine. During that period, the vital 
signs will be monitored and the injection site will be observed on a regular basis. A physical 
examination will be performed prior to discharge. The clinical observation may be prolonged in case 
of safety concerns according to the clinical judgement of the investigator. A subsequent safety 
assessment will also be performed 48 to 72 hours after each immunization by telephone call for all 
study subjects. For adverse events considered possibly or probably related to the study vaccine of 
greater than mild severity according to investigator assessment, subjects will be required to return to 
the clinic for additional safety assessment. In each sub-cohort, the first dosing of the first 4 subjects 
should be performed once the safety assessment at 48 to 72 hours of the previous subject has been 
performed. This will allow the site principal investigator to assess whether there is any clinically 
relevant safety issue related to study vaccine prior to dosing the subsequent subject. Safety laboratory 
samples will be collected at baseline, prior to each injection and 2-4 weeks after each injection. 
Laboratory results will be reviewed by the Medical Monitor on a periodic basis including all out of range 
values. 
All treated subjects will have a safety follow-up period of 24 weeks (6 months) after the end of the 
treatment period. During this period, subjects will be asked to attend a first follow-up visit 19 weeks 
after the last administration and a last visit at the end of the follow-up period (26 weeks after the last 
administration). Participants’ safety will be monitored throughout the study with regular review of safety 
data by the DSMB. 
 
Post-injection period extension (optional): 
Based on immunogenicity data, subjects from sub-cohort(s) may be invited to attend two additional 
visits (at Week 86 and Week 98) taking place after the end of the safety follow-up period (week 74) in 
order to evaluate the durability of the immune response and collect additional biomarker data. All 
subjects participating in this post-injection period extension will have to reconsent. During this 
additional 24-week (6 month) period, blood will be collected for immunogenicity and biomarker testing. 
The aim of this optional study extension is to help inform the dosing regimen in subsequent clinical 
trials of the vaccine(s). AEs/SAEs and concomitant medications (new and/or changes from the 
previous visit) will also be collected during these 2 additional visits. Upon investigator’s medical 
judgement, other assessments can be performed during this period (e.g., MRI, ECG, etc.) if clinically 
indicated. 
In the Netherlands, the subjects’ decisional capacity will be re-assessed before consenting for this 
optional post-injection extension. 
 
Interim analyses (IAs) 
Interim analyses of safety, tolerability and immunogenicity data may be conducted in each sub-cohort, 
including expanded sub-cohorts, as follows: 
- 
all available subjects in the sub-cohort have completed Visit 4 (Week 10), i.e. 2 to 4 weeks 
after the second injection 
- 
all available subjects in the sub-cohort have completed Visit 6 (Week 26), i.e. 2 to 4 weeks 
after the third injection 
- 
all available subjects in the sub-cohort have completed Visit 9 (Week 50), i.e. 2 to 4 weeks 
after the last injection at Week 48 
- 
all available subjects in the sub-cohort have completed Visit 11 (Week 74), i.e. end of the 
safety follow-up period 

 
 
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If the post-injection period is extended in any sub-cohort, IA of immunogenicity data may also be 
conducted at Visit 13 (Week 98), and optionally at Visit 12 (Week 86).  
Available biomarker data may also be reviewed during any of these IAs. The IAs described above may 
also be performed for any expanded sub-cohort. 
Additional IAs to review the sustainability of immune response data may be conducted between weeks 
26 and 50 and between weeks 50 and 74. 
Independently of the above-mentioned interim analyses, the DSMB will perform regular reviews of the 
safety and tolerability data throughout the study.  
 
Rationale and scope of IAs: 
The objectives of the above mentioned IAs in the sub-cohorts (whether expanded or not) is to ensure 
a regular review of safety, tolerability and immunogenicity with the support of optional biomarker data. 
A decision to escalate to the next dose in one given sub-cohort may be taken once IA data of the 
previous dose are available from Visit 4 (Week 10) onwards and pending prior DSMB approval. A 
decision to expand a sub-cohort may be taken based on satisfactory review of safety data by the 
DSMB and analysis of immunogenicity IA data of this sub-cohort dose from Visit 4 (Week 10) onwards. 
The IA at the end of the optional extended post-injection period is intended to monitor the durability of 
the immune response and any biomarker changes in blood. 
No of subjects 
The number of subjects to be enrolled will be dependent upon the overall number of sub-cohorts as 
described below, and the number of sub-cohorts in which expansion occurs. 
 
A minimum of 40 subjects will be enrolled in the three cohorts (8 subjects in each sub-cohort 1.1, 1.2 
and 1.3 in Cohort 1, and sub-cohorts 2.1 and 3.1 respectively in Cohorts 2 and 3). The total number 
of subjects per cohort would be 72 if all 3 sub-cohorts in each cohort are expanded up to 24 subjects. 
Potential expansion is anticipated only in a limited number of sub-cohorts. However, if all sub-cohorts 
were to be expanded, this would lead to a total of 216 subjects. The number of subjects in each of the 
cohorts and potential sub-cohorts is further described below.  
   
Cohort 1 (ACI-35.030): Up to 72 subjects depending on dose escalation and a decision to expand 
one or more sub-cohort(s): 
• 
8 subjects in sub-cohort 1.1 with 6 subjects on ACI-35.030 at 300 μg and 2 on placebo;  
• 
8 subjects in sub-cohort 1.2 with 6 subjects on ACI-35.030 at 900 μg and 2 on placebo;  
• 
8 subjects in sub-cohort 1.3 with 6 subjects on ACI-35.030 at 1800 μg and 2 on placebo;  
• 
In case of sub-cohort expansion, up to 16 additional subjects in sub-cohort 1.1, 1.2 and/or 1.3 
with the same randomization ratio.  
 
Cohort 2 (JACI-35.054): Up to 72 subjects depending on dose escalation and a decision to expand 
one or more sub-cohort(s): 
• 
8 subjects in sub-cohort 2.1 with 6 subjects on JACI-35.054 at 15 μg and 2 on placebo;  
• 
Optional sub-cohorts:  
o 
8 subjects in sub-cohort 2.2 with 6 subjects on JACI-35.054 up to 60 μg and 2 on 
placebo;  
o 
8 subjects in sub-cohort 2.3 with 6 subjects on JACI-35.054 up to 150 μg and 2 on 
placebo; 
• 
In case of sub-cohort expansion, up to 16 additional subjects in sub-cohort 2.1, 2.2 and/or 2.3 
with the same randomization ratio. 
 

 
 
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Cohort 3 (ACI-35.030 and JACI-35.054 in sequential administration): Up to 72 subjects depending 
on the decision to conduct several sub-cohorts and/or to expand one or more sub-cohort(s): 
• 
8 subjects in sub-cohort 3.1 with 6 subjects on ACI-35.030 and JACI-35.054 at dosages 
previously evaluated in cohorts 1 and 2 respectively and found to be safe after a study treatment 
period of at least 10 weeks in sequential administration and 2 on placebo. 
• 
Optional sub-cohorts:  
o 
8 subjects in sub-cohort 3.2 with 6 subjects on active treatment and 2 on placebo.  
o 
8 subjects in sub-cohort 3.3 with 6 subjects on active treatment and 2 on placebo.  
• 
In case of sub-cohort expansion, up to 16 additional subjects in sub-cohorts 3.1, 3.2 and/or 3.3 
with the same randomization ratio. 
 
Any randomized subject withdrawing before the 2nd injection for reasons other than safety may be 
replaced. 
Study Population 
50-75 years of age (male and female) with a diagnosis of mild AD or MCI due to AD according to 
National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria and a Clinical Dementia Rating 
Scale (CDR) global score of 0.5 or 1 
Inclusion/Exclusion 
Criteria 
Inclusion criteria 
1. 
Male or female with age from 50 and up to 75 years old inclusive.  
2. 
Mild Cognitive Impairment (MCI) due to AD or Mild AD according to NIA-AA criteria and a Clinical 
Dementia Rating scale (CDR) global score of 0.5 or 1 respectively. 
3. 
Mini Mental State Examination (MMSE) score of 22 or above. 
4. 
Abnormal level of CSF Abeta amyloid 42 (Aß42) consistent with AD pathology at screening.  
• 
In borderline cases for CSF Aß42 levels, other results may be considered to help 
determine amyloid positivity e.g. the Aß42/Aß40 ratio and, on a case by case basis, a 
history of positive amyloid PET scan or positive CSF Aß42 level. 
• 
Results from CSF sampling performed within 6 months prior to screening are 
acceptable on a case by case basis provided that they are consistent with the presence 
of amyloid pathology and that the corresponding CSF sample can be used in the study 
for testing. 
5. 
Subjects either not taking any marketed treatment for AD or receiving a stable dose of an 
acetylcholinesterase inhibitor and/or memantine for at least 3 months prior to baseline. 
6. 
Subjects cared for by a reliable informant or caregiver to assure compliance, assist with clinical 
assessments and report safety issues. 
7. 
Women must be post-menopausal for at least one year and/or surgically sterilized. Women of 
childbearing potential or not post-menopausal must have a negative blood pregnancy test at 
screening (blood draw between day -14 and day -3 prior to baseline) and be willing to use highly 
effective methods of contraception from the screening visit until the end of their participation. 
Urine pregnancy testing will be performed throughout the treatment period to determine if the 
subject can continue receiving the study vaccine. Male participants in the trial with female 
partners of child bearing potential are required to use barrier methods of contraception (condoms 
with spermicide) in addition to contraceptive measures used by female partners during the whole 
study duration. 
8. 
Subjects who in the opinion of the investigator are able to understand and provide written 
informed consent. In the Netherlands, the subjects’ decisional capacity will be also assessed and 
must be consistent with the ability to provide informed consent using the MacArthur Competency 
Tool for Clinical Research in order to evaluate their abilities in the areas of understanding, 
reasoning, appreciation and choice. 
9. 
Both subject and informant or caregiver must be fluent in one of the languages of the study and 
able to comply with all study procedures, including lumbar punctures. 

 
 
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Exclusion criteria 
1. 
Participation in previous clinical trials for AD and/or for neurological disorders using active 
immunization unless there is documented evidence that the subject was treated with placebo 
only and the placebo vaccine is not expected to induce any specific immune response. 
2. 
Participation in previous clinical trials for AD and/or for neurological disorders using any passive 
immunization within the past 6 months (or 5 half-lives of the investigational antibody, whichever 
is longer) prior to screening unless there is documented evidence that the subject was treated 
with placebo only and the placebo is not expected to induce any specific immune response. 
3. 
Participation in previous clinical trials for AD and/or for neurological disorders using any small 
molecule drug including BACE-1 inhibitors within the past 3 months prior to screening. 
4. 
Concomitant participation in any other clinical trial using experimental or approved medications 
or therapies. 
5. 
Presence of positive Anti-nuclear Antibody (ANA) titers at a dilution of at least 1:160 in subjects 
without clinical symptoms of auto-immune disease. 
6. 
Current or past history of auto-immune disease, or clinical symptoms consistent with the 
presence of auto-immune disease. 
7. 
Immune suppression including but not limited to the use of immunosuppressive drugs or 
systemic steroids unless they have been prescribed transiently more than 3 months prior to 
screening. 
8. 
History of severe allergic reaction (e.g., anaphylaxis) including but not limited to severe allergic 
reaction to previous vaccines and/or medications. 
9. 
Prior history of clinically significant hypoglycaemic episodes.  
10. Drug or alcohol abuse or dependence currently met or within the past five years according to 
Diagnostic and Statistical Manual of Mental Disorders-V (DSM-V) criteria. 
11. Any clinically significant medical condition likely to interfere with the evaluation of safety and 
tolerability of the study treatment and/or the adherence to the full study visit schedule. 
12. Any clinically significant medical condition likely to impact the immune system (e.g, any history 
of acquired or innate immune system disorder). 
13. Use of hydralazine, procainamide, quinidine, isoniazide, TNF-inhibitors, minocycline within the 
last 12 months prior to screening. 
14. Use of diltiazem unless on a stable dose for at least 3 months prior to screening. 
15. Significant risk of suicide defined, using the Columbia-Suicide Severity Rating Scale, as the 
subject answering: “yes” to suicidal ideation questions 4 or 5 or answering: “yes” to suicidal 
behavior within the past 12 months. 
16. Concomitant psychiatric or neurologic disorder other than those considered to be related to AD 
(e.g. head injury with loss of consciousness, symptomatic stroke, Parkinson’s disease, severe 
carotid occlusive disease, TIAs). 
17. History or presence of uncontrolled seizures. If history of seizures, they must be well controlled 
with no occurrence of seizures within 2 years prior to screening. The use of anti-epileptic 
medications is permitted if at stable dose for at least 3 months prior to screening. 
18. History of meningoencephalitis within the past 10 years prior to screening. 
19. Subjects with a history of hemorrhagic and/or non-hemorrhagic stroke. 
20. Presence or history of peripheral neuropathy. 
21. History of inflammatory neurological disorders with potential for CNS involvement. 
22. Screening MRI scan showing structural evidence of alternative pathology not consistent with AD 
which could cause the subject's symptoms. Evidence of space occupying lesions other than 
benign meningioma of less than 1 cm diameter, more than two lacunar infarcts or one single 
infarct larger than 1 cm in diameter or any single area of superficial siderosis or evidence of a 
prior macro-hemorrhage ≥10 mm. Microbleeds on T2* MRI are allowed up to a maximum of 10, 
regardless of the location. 

 
 
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23. MRI examination cannot be done for any reason, including but not limited to metal implants 
contraindicated for MRI studies and/or severe claustrophobia. 
24. Significant hearing or visual impairment or other issues judged relevant by the investigator 
preventing to comply with the protocol and to perform the outcome measures. 
25. Clinically significant infections or major surgical operation within 3 months prior to screening. 
Planned surgery anticipated to occur during participation in the study must be reviewed and 
approved by the medical monitor at screening. 
26. Any vaccine received within the past 2 weeks before screening, including influenza vaccine. 
27. Clinically significant arrhythmias or other clinically significant abnormalities on ECG at screening. 
28. Myocardial infarction within one year prior to baseline, unstable angina pectoris, or significant 
coronary artery disease.  
29. History of cancer within the past 5 years other than treated squamous cell carcinoma, basal cell 
carcinoma and melanoma in situ, or in-situ prostate cancer or in-situ breast cancer which have 
been fully removed and are considered cured. 
30. Clinically significant deviations from normal values for hematologic parameters, liver function 
tests, and other biochemical measures, that are judged to be clinically significant in the opinion 
of the investigator. 
31. Pregnancy confirmed by blood test at screening, or subject planning to be pregnant or lactating. 
32. Receipt of any anticoagulant drug or antiplatelet drug, except aspirin at doses of 100 mg daily or 
lower (in order to avoid risk of bleeding during scheduled or unscheduled lumbar puncture). 
33. Receipt of any antipsychotic drugs unless on stable low doses for the treatment of insomnia. 
34. Donation of blood or blood products within 30 days prior to screening or plans to donate blood 
while participating in the study. 
35. Positive Venereal Disease Research Laboratory (VDRL) consistent with active syphilis at 
screening. 
36. Positive HIV test at screening. 
37. Laboratory or clinical evidence of active hepatitis B and/or C at screening.  
38. Serum creatinine greater than 1.5x upper limit of normal, abnormal thyroid function tests or 
clinically significant reduction in serum B12 or folate levels (note: all oral doses of thyroid 
replacement agents, B12 or folate have to be stable for at least 3 months prior to screening). 
Study Vaccines 
ACI-35.030 vaccine 
JACI-35.054 vaccine 
Placebo: Phosphate-buffered saline (PBS) solution 
Dosage, duration of 
treatment 
In Cohort 1, ACI-35.030 and placebo will be administered by the intramuscular route. The dosage of 
ACI-35.030 will be 300 µg, 900 µg and 1800 µg in sub-cohorts 1.1, 1.2 and 1.3, respectively.  
In Cohort 2, JACI-35.054 and placebo will be administered by the intramuscular route. The dosage of 
JACI-35.054 will be 15 µg in sub-cohort 2.1, up to 60 µg in optional sub-cohort 2.2 and up to 150 µg 
in optional sub-cohort 2.3. 
In Cohort 3, ACI-35.030 and JACI-35.054 or placebo will be administered by the intramuscular route 
with the same administration schedule as in cohorts 1 and 2. In each sub-cohort, ACI-35.030 and 
JACI-35.054 will be administered sequentially to 6 subjects and placebo will be administered at each 
dosing occasion to 2 subjects. 
In sub-cohort 3.1, ACI-35.030 and JACI-35.054 at dosages previously evaluated in cohorts 1 and 2 
respectively and found to be safe after a study treatment period of at least 10 weeks will be 
administered. Immunizations with ACI-35.030 will be performed at months 0 (Week 0) and 2 (Week 
8), and with JACI-35.054 at month 6 (Week 24) and 12 (Week 48).  
In optional sub-cohorts 3.2 and 3.3, the dosages of ACI-35.030 and/or of JACI-35.054 and/or the 
sequence of administration may differ from sub-cohorts 3.1 and 3.2 and will be based on available 
safety, tolerability and immunogenicity data from previous study interim analyses. The selected 

 
 
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dosages will have already been evaluated and found safe and well tolerated in the previously available 
IAs. 
 
In all cohorts, the vaccine or placebo will be administered 4 times at 8, 16* and 24 week intervals 
between each dose. *Due to the Covid-19 pandemic, local travel restrictions in Finland effective 
as of 18 March 2020, and the need to preserve the safety of study participants, modifications 
are made to the schedule of immunizations of sub-cohort 1.1 subjects having not received the 
3rd injection at month 6 already: immunizations at month 6 (week 24) will not be performed in 7 of 8 
sub-cohort 1.1 subjects for whom the planned Visit 5 does not allow all assessments to be done 
according to the protocol.  
Due to the resurgence of the Covid-19 pandemic in multiple participating countries since September 
2020, additional adjustments related to the mode of administration of study assessments including 
study vaccine administration may apply in Finland and other participating countries after the above 
measures were implemented in Finland.  
In all cohorts, the treatment duration is anticipated to be 50 weeks (12 months) and followed by a 24-
week (6 months) safety follow-up period. The overall subject participation will be up to around 80 
weeks from first screening assessment to last safety follow-up visit. If the follow-up period is extended 
in a given sub-cohort by another 24 weeks (6 months), the overall duration will be up to around 104 
weeks. 
 
 

 
 
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TABLE OF CONTENTS 
 
Signature Page ................................................................................................................................................. 2 
Study Synopsis ................................................................................................................................................. 5 
Table of Contents........................................................................................................................................... 14 
List of Abbreviations and Definition of Terms ................................................................................................ 17 
Study Contacts ............................................................................................................................................... 19 
1. 
Introduction ........................................................................................................................................... 20 
1.1 
Background ........................................................................................................................................... 20 
1.1.1 
Alzheimer’s Disease ...................................................................................................................... 20 
1.1.2 
Introduction to ACI-35.030 ........................................................................................................... 21 
1.1.3 
Introduction to JACI-35.054 .......................................................................................................... 22 
1.1.4 
Heterologous immunization; priming with ACI-35.030 vaccine and boosting with JACI-35.054 
vaccine 23 
1.1.5 
Conclusion..................................................................................................................................... 24 
1.2 
Study Rationale ..................................................................................................................................... 24 
1.3 
Dose Rationale ...................................................................................................................................... 25 
1.4 
Study Endpoint Rationale ...................................................................................................................... 26 
1.5 
Risks and Benefits for Subjects .............................................................................................................. 26 
1.5.1 
Risk of Study Intervention ............................................................................................................. 26 
1.5.2 
Risks of Participation during Covid-19 Pandemic ......................................................................... 27 
2. 
Study Objectives and Endpoints ............................................................................................................. 29 
2.1 
Study Objectives .................................................................................................................................... 29 
2.1.1 
Primary Objectives ........................................................................................................................ 29 
2.1.2 
Secondary Objectives .................................................................................................................... 29 
2.1.3 
Exploratory Objectives .................................................................................................................. 29 
2.2 
Study Endpoints .................................................................................................................................... 29 
2.2.1 
Primary Endpoints ........................................................................................................................ 29 
2.2.2 
Secondary Endpoints .................................................................................................................... 30 
2.2.3 
Exploratory Endpoints .................................................................................................................. 30 
3. 
Investigational Plan ................................................................................................................................ 30 
3.1 
Overall Study Design and Plan .............................................................................................................. 30 
3.1.1 
Cohort 1 with ACI-35.030 ............................................................................................................. 30 
3.1.2 
Cohort 2 with JACI-35.054 ............................................................................................................ 31 
3.1.3 
Cohort 3 with ACI-35.030 and JACI-035.054 in Sequential Administration .................................. 31 
3.1.4 
Sub-cohort expansion ................................................................................................................... 32 
3.1.5 
Safety follow-up ............................................................................................................................ 32 
3.1.6 
Post-injection period extension (optional) ................................................................................... 33 

 
 
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3.1.7 
Interim analyses (IA) ..................................................................................................................... 33 
3.1.8 
Schematic overview of cohorts design ......................................................................................... 35 
3.2 
Study Duration ...................................................................................................................................... 36 
3.2.1 
Screening Period ........................................................................................................................... 36 
3.2.2 
Treatment Period .......................................................................................................................... 36 
3.2.3 
Follow-up Period ........................................................................................................................... 36 
3.2.4 
Post-Injection Period Extension (optional) ................................................................................... 36 
3.2.5 
Overall Study Duration ................................................................................................................. 36 
3.2.6 
End of Study Definition ................................................................................................................. 36 
3.3 
Selection of Study Population ............................................................................................................... 37 
3.3.1 
Inclusion Criteria ........................................................................................................................... 37 
3.3.2 
Exclusion Criteria .......................................................................................................................... 37 
3.3.3 
Removal of Subjects from Therapy or Assessment ...................................................................... 39 
3.4 
Treatments ............................................................................................................................................ 40 
3.4.1 
Details of Study Treatments ......................................................................................................... 40 
3.4.2 
Dosage Schedule ........................................................................................................................... 42 
3.4.3 
Treatment Assignment ................................................................................................................. 43 
3.4.4 
Drug Packaging and Blinding......................................................................................................... 43 
3.4.5 
Drug Inventory and Accountability ............................................................................................... 44 
3.4.6 
Treatment Compliance ................................................................................................................. 44 
3.4.7 
Prior and Concomitant Illness and Treatments ............................................................................ 44 
3.5 
Assessments .......................................................................................................................................... 45 
3.5.1 
Schedule of Assessments .............................................................................................................. 45 
3.5.2 
Study Procedures .......................................................................................................................... 51 
3.5.3 
Assessments for Premature Termination ..................................................................................... 60 
3.5.4 
Safety/Tolerability Assessments ................................................................................................... 60 
3.5.5 
Primary and Secondary Immune Response Assessments ............................................................. 64 
3.5.6 
Exploratory assessments .............................................................................................................. 64 
4. 
Safety Procedures .................................................................................................................................. 66 
4.1 
Definitions and Criteria ......................................................................................................................... 66 
4.1.1 
Adverse Events.............................................................................................................................. 66 
4.1.2 
Serious Adverse Event .................................................................................................................. 66 
4.1.3 
Unexpected Adverse Drug Reactions ........................................................................................... 67 
4.1.4 
Abnormal Laboratory Values ........................................................................................................ 67 
4.1.5 
Assessing Intensity and Relationship ............................................................................................ 67 
4.1.6 
Monitoring and Management of Adverse Events Including Specific Risks ................................... 68 
4.2 
Reporting Procedures and Requirements ............................................................................................. 68 
4.2.1 
Adverse Events.............................................................................................................................. 68 
4.2.2 
Serious Adverse Events ................................................................................................................. 69 
4.2.3 
Contraceptive measures and procedures for documenting pregnancy during the study ............ 70 
4.2.4 
Stopping Rules .............................................................................................................................. 71 
5. 
Data Management and Statistical Analysis ............................................................................................ 72 
5.1 
Data Management Considerations ....................................................................................................... 72 
5.2 
Electronic CRFs ...................................................................................................................................... 72 

 
 
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5.3 
Statistical Considerations ...................................................................................................................... 73 
5.3.1 
Sample Size Justification ............................................................................................................... 73 
5.3.2 
Analysis Population ....................................................................................................................... 73 
5.3.3 
Protocol Deviations ....................................................................................................................... 74 
5.3.4 
Demographic and Baseline Characteristics ................................................................................... 74 
5.3.5 
Safety Analyses ............................................................................................................................. 74 
5.3.6 
Immune Response Analyses ......................................................................................................... 76 
5.3.7 
Exploratory Analyses..................................................................................................................... 76 
5.3.8 
Interim Analysis ............................................................................................................................ 78 
6. 
Study Management ................................................................................................................................ 81 
6.1 
Ethics and Consent ................................................................................................................................ 81 
6.1.1 
Regulations and Guidelines .......................................................................................................... 81 
6.1.2 
Institutional Review Board/Independent Ethics Committees and regulatory authorities ........... 81 
6.1.3 
Informed Consent ......................................................................................................................... 81 
6.1.4 
Confidentiality and privacy ........................................................................................................... 82 
6.1.5 
Future Use of Stored Samples ...................................................................................................... 82 
6.2 
Indemnification ..................................................................................................................................... 82 
6.3 
Discontinuation of the Study by the Sponsor ........................................................................................ 83 
6.4 
Study Monitoring and Auditing ............................................................................................................. 83 
6.5 
Retention of Records ............................................................................................................................. 84 
6.6 
Use of Study Findings ............................................................................................................................ 84 
6.7 
Publications ........................................................................................................................................... 84 
7. 
References ............................................................................................................................................. 85 
8. 
Appendices ............................................................................................................................................ 87 
Appendix 1  
NIA/AA Criteria for probable AD Dementia (McKhann et al., 2011) ......................................... 87 
 

 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Aβ 
Amyloid Beta 
AD 
Alzheimer’s Disease 
AE 
Adverse Event 
ANA 
Anti-nuclear Antibodies 
Anti-dsDNA 
Anti-double stranded DNA Antibodies 
ApoE 
Apolipoprotein E 
aPTT 
activated Partial Thromboplastin Time 
CDR-SB 
Clinical Dementia Rating scale Sum of Boxes 
CHMP 
Committee for Medicinal Products for Human Use 
cm (unit) 
Centimeter 
CNS 
Central Nervous System  
Covid-19 
Coronavirus disease of 2019 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CSF 
Cerebrospinal Fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSMB 
Data and Safety Monitoring Board 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-Linked Immunosorbent Assay 
ELISPOT 
Enzyme-Linked Immunospot 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IFN-γ 
Interferon-gamma 
IgG 
Immunoglobulin G 
IL-4 
Interleukin-4 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intention To Treat 

 
 
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IUD 
Intrauterine Device 
kg (unit) 
Kilogram 
LSLV 
Last Subject Last Visit 
µg (unit) 
Microgram 
MacCAT-CR 
MacArthur Competence Assessment Tool for Clinical Research 
MCI 
Mild Cognitive Impairment 
MMSE 
Mini Mental State Examination 
MPLA 
Monophosphoryl Lipid A 
MRI 
Magnetic Resonance Imaging 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 
NPI 
Neuropsychiatric Inventory Scale 
PBMC 
Peripheral Blood Mononuclear Cell 
PBS 
Phosphate Buffered Saline 
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PP 
Per Protocol 
 
 
pTau 
Phospho-Tau 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T3 
Triiodothyronine 
T4 
Thyroxine 
TEAE 
Treatment Emergent Adverse Event 
TNF-α 
Tumor Necrosis Factor alpha 
TSH 
Thyroid-Stimulating Hormone 
VDRL 
Venereal Disease Research Laboratory 
WOCBP 
Woman Of Child Bearing Potential 
 

 
 
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1. INTRODUCTION 
1.1 Background 
1.1.1 
Alzheimer’s Disease 
Alzheimer’s Disease (AD) is a progressive degenerative disorder of insidious onset characterized 
by loss of memory and other cognitive function, loss of ability to perform daily living activities and 
behavioral disturbances. In 2018, an estimated 5.7 million Americans of all ages have been living 
with Alzheimer's dementia. Worldwide, the number was believed to be close to 50 million people 
in 2017 (Alzheimer’s Disease International). 
Currently available treatments are primarily symptomatic in their effects. Hence, there is a need 
for new therapeutic approaches targeting the pathology of the disease and thereby slowing its 
progression. 
The key pathological hallmarks of the disease are: 
• 
Senile plaques, consisting of abnormal aggregates of the beta-amyloid (Aβ) peptides 
outside of neurons, 
• 
Neurofibrillary tangles, consisting of abnormally intraneuronal aggregated forms of Tau 
protein.  
Tau protein is a normal component of neurons, and is known as a microtubule-associated protein 
(MAP) as it interacts with tubulin to stabilize and promote assembly of microtubules in neuronal 
axons. In AD, Tau protein becomes hyperphosphorylated due to an imbalance in the activity of 
kinase and phosphatase enzymes. Abnormal phosphorylated Tau aggregates readily into 
insoluble oligomers which are neurotoxic and contribute to neurodegeneration (Goedert et al, 
1991). The oligomers progress to tangles of so-called paired helical filaments (Alonso et al., 
2001). The degree of neurofibrillary tangle pathology has been consistently shown to be 
correlated to the degree of dementia in AD subjects (Bierer et al, 1995; Braak and Braak, 1991; 
Delacourte, 2001). 
Understanding of the biology of Tau in normal brain and in AD is evolving rapidly. There is new 
evidence that Tau is released from neurons under normal conditions and taken up by adjacent 
cells, suggesting that it might have a role in cell signaling (Pooler et al, 2013). Furthermore there 
is evidence that hyperphosphorylated Tau can be released from neurons and taken up by 
adjacent neurons where it seeds further aggregation and spreading of Tau pathology (Iba et al, 
2013). The presence of abnormal Tau outside of cells suggests that cell penetration may not be 
a prerequisite for therapeutic intervention to interfere with the propagation of Tau pathology. 
Recent data from Positron Emission Tomography (PET) studies suggest that the interaction 
between beta-amyloid and Tau may be particularly important in the progression of the disease, 
with Tau spreading occurring more rapidly when amyloid and Tau pathologies coexist in temporal 
brain areas (Iaccarino et al, 2017). 
To date, few studies have been conducted with agents specifically targeting Tau pathology. 
Whereas the formation of senile plaques appears to occur very early in AD, tangle formation, 
while also present early in the condition, continues to progress as the disease evolves. This 
suggests that a therapy addressing Tau pathology might be effective both early and later in the 
disease. Indeed, Axon Neurosciences is developing the active vaccine, AADvac1, directed 
against pathological Tau proteins, as it has shown to reduce the amount of Tau pathology in the 
brains of animal models in Alzheimer’s disease, almost completely eliminating a range of AD Tau 
phospho-species. A phase 1 (Novak et al, 2017) and phase 2 (Novak et al, 2021) trials evaluating 
safety and immunogenicity of AADvac1 in subjects with mild to moderate AD were completed. 

 
 
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Development of therapies aiming at modifying Tau pathology is therefore a rational approach in 
the continuing search for effective treatments for this condition. 
1.1.2 
Introduction to ACI-35.030  
ACI-35 is a liposomal vaccine consisting of a tetra-palmitoylated pTau T3 peptide (393-408 amino 
acid (aa) of the longest human Tau isoform (441aa) with phosphorylation on S396 and S404) 
and monophosphoryl lipid A (MPLA) as adjuvant. Both components are embedded into the 
bilayer of liposomes. This first generation vaccine has been investigated in a phase 1 clinical trial 
(ACI-35-1201 study). 
ACI-35.030 is a modified version of the ACI-35 vaccine and therefore, referred to as a “second 
generation vaccine”. A clinical trial assessing ACI-35 demonstrated a favourable safety and 
tolerability profile when using the antigen (T3 peptide) and the liposomal vehicle composition yet 
a limited induction of an anti-pTau IgG response at all doses tested. In addition, a boosting effect 
was not observed with the subsequent injections. Thus, ACI-35.030 is modified to maintain the 
original antigen (i.e. T3 peptide) and liposomal vehicle composition as ACI-35, while 
incorporating two additional adjuvants (i.e. 3D-6A-MPLA and CpG7909-cholesterol) and one 
universal T-cell epitope (i.e. T50 peptide) into the vaccine to potentially improve the anti-pTau 
IgG response.   
1.1.2.1 
Pharmacology Studies 
One pharmacology study in mice and three studies in Rhesus monkeys showed that the 
immunization with ACI-35.030 induced: 
• 
a strong and consistent anti-pTau peptide IgG response in C57BL/6 wild type mice 
• 
a strong and consistent anti-pTau peptide IgG response in Rhesus monkeys 
• 
a strong and consistent anti-PHF (paired helical filaments from human Alzheimer’s disease 
subject) IgG response in Rhesus monkeys 
Further details are available in the investigator’s brochure (IB).  
1.1.2.2 
Toxicology and Safety Studies 
One repeated dose GLP toxicology study has been conducted with ACI-35.030 in Rhesus 
monkey. This study determined that: 
• 
ACI-35.030 immunization was locally well-tolerated and was not associated with organ 
toxicity.  
Additional non-clinical information can be found in the latest version of the IB. 
1.1.2.3 
Clinical Data 
ACI-35.030 
At the time of the version of this protocol, 26 subjects have been exposed to ACI-35.030, i.e. the 
second generation vaccine, or placebo in the current study, in sub-cohorts 1.1, 1.2 and 1.3. 
 
ACI-35 
Although ACI-35 differs from the currently tested vaccine, ACI-35.030, in its composition and 
adjuvants, the safety data generated in the Phase Ib study are included below for information.  

 
 
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The safety, tolerability and immunogenicity of ACI-35 vaccine was evaluated in a clinical phase 
Ib study conducted in subjects with mild to moderate AD in UK and Finland (ACI-35-1201: A 
Phase Ib Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of the Safety, 
Tolerability and Immunogenicity of ACI-35 in Subjects with Mild to Moderate Alzheimer’s 
Disease). The clinical trial was completed on 15 June 2017. 
Five cohorts were studied. Each cohort consisted of a different dose (300 µg, 900 µg or 1800 µg) 
and/or dosing regimen spread over 24 weeks of varying intervals (2, 3 or 5 dose administrations), 
followed by a final injection that occurred at Week 48 (cohorts 2-5) or between Week 48 and 
Week 76 (cohort 1).  
Twenty-four subjects were randomized and received at least 1 dose of study vaccine. Twenty-
two completed the study. Two subjects discontinued the study due to a significant unrelated 
medical condition which seriously hampered or made the completion of the study impossible.  
Overall, ACI-35 was well tolerated in the participating population at all doses tested. Injection site 
erythema and injection site reactions and fatigue were the most common study vaccine-related 
Treatment Emergent Adverse Events (TEAE). There was no evidence clinically or from laboratory 
or radiology findings to suggest the development of CNS inflammation. In general, no pattern of 
AEs emerged, except injection site reactions on active treatment, which occurred in all subjects 
at the highest doses tested but were generally mild and self-limiting and did not lead to subject 
withdrawal. 
Treatment with ACI-35 induced IgG and IgM antibodies recognizing both pTau and Tau in most 
subjects after the first injection. The antibody response in serum was higher for pTau than for 
Tau confirming the selectivity for an anti-pTau response observed in animal studies. Most 
subjects receiving the vaccine exhibited a measurable IgM response after the primary and 
subsequent immunizations. Many subjects also showed a measurable IgG response to the pTau 
peptide incorporated in the vaccine, but this was variable between individuals and generally did 
not increase with repeated administrations.   
Biomarker analysis in serum or plasma showed inconsistent changes over the course of the 
study. Furthermore, the ability to draw any conclusion from the biomarker analyses in the 
samples from the CSF was hampered by the limited number of data obtained. Toll-Like Receptor 
4 (TLR4) expression levels in the blood remained stable over the course of the study.  
Clinical and cognitive endpoints showed the expected variability over time without evidence for 
a detrimental effect of the vaccine. Larger studies will be needed to explore effects of the vaccine 
on these endpoints. 
1.1.3 
Introduction to JACI-35.054 
JACI-35.054 is a vaccine consisting of a conjugate called CRM197-pTau with Aluminum 
Hydroxide and CpG7909 as adjuvants. CRM197-pTau is a conjugate of a carrier protein called 
CRM197 and peptide JNJ-66649687. JNJ-6649687 is a chemically synthesized peptide that 
shares its core 16 amino acid sequence with the T3 peptide described in the ACI-35/ACI-35.030 
study vaccines. CRM197 is a well-defined recombinant protein that is a commercially available 
version of a non-toxic mutant of diphtheria toxin (DT) A chain and that has proven to be a safe 
carrier protein in commercial prophylactic vaccines and clinical trials for a plethora of different 
vaccine candidates.  
JACI-35.054 is referred to as a “second generation vaccine” because it maintains the original 
antigen (i.e. T3 peptide) of the ACI-35 vaccine. Pharmacology studies in Rhesus monkeys have 
indicated that this vaccine induces a slightly different epitope profile of pTau-specific antibodies 
in the same antigenic sequence as compared to ACI-35.030. This makes JACI-35.054 a good 
candidate to potentially be used together with ACI-35.030 in order to be able to increase the 

 
 
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quality of immune response. Thus, this second generation vaccine will be tested alone in cohort 
2 and in a selected sequence of injection with ACI-35.030 in cohort 3. The goal will be to identify 
the optimal dosages and regimens for subsequent clinical development.  
1.1.3.1 
Pharmacology Studies 
Two pharmacology studies in Rhesus monkeys showed that the immunization with JACI-35.054 
alone or in combination with ACI-35.030 induced: 
• 
a strong and consistent anti-pTau peptide IgG response 
• 
a strong and consistent anti-PHF (paired helical filaments from human Alzheimer’s disease 
subjects) IgG response  
 
Two pharmacology studies in wild type mice showed that the immunization with JACI-35.054 
alone induced: 
• 
a strong and consistent anti-pTau peptide IgG response 
• 
optimal anti-pTau peptide IgG response when JACI-35.054 is administered with both 
Aluminum Hydroxide and CpG7909 adjuvants 
Further details are available in the investigator’s brochure (IB). 
1.1.3.2 
Toxicology and Safety Studies 
GLP toxicology studies have been conducted with JACI-35.054 in mice and in Rhesus monkey. 
These studies determined that: 
• 
JACI-35.054 immunization was locally well-tolerated and was not associated with systemic 
toxicity.  
Additional non-clinical information can be found in the latest version of the IB. 
1.1.3.3 
Clinical Data 
At the time of the version of this protocol, 16 subjects have been exposed to JACI-35.054 or 
placebo in the current study, in sub-cohorts 2.1 and 2.2. 
1.1.4 
Heterologous immunization; priming with ACI-35.030 vaccine and boosting with 
JACI-35.054 vaccine 
It has been shown over the past decades in non-clinical and clinical studies that a heterologous 
prime-boost vaccination approach (delivering the same antigen with different vaccine backbones) 
can be advantageous over a homologous prime-boost regimen (immunizing several times with 
the same vaccine) (Lu et al, 2009; Jalah et al, 2014; Khurana et al, 2014; Shukarev et al, 2017). 
Heterologous prime-boost vaccination will avoid the re-exposure of the immune system with the 
“vaccine backbone” and is therefore meant to focus the immune response against the desired 
antigen(s). This can have two main consequences: (I) avoid a more rapid elimination of the 
vaccine during a booster vaccination due to pre-existing immunity and memory against several 
components of the vaccine; (II) induce a more directed immune response against the common 
antigen (in this specific case the pTau peptide) as only this antigen will be recognized by already 
primed immune cells. Thus, a heterologous prime-boost approach using the ACI-35.030 
liposomal formulation in combination with the JACI-35.054 conjugate vaccine which could 
improve the immune response elicited towards the pTau peptide will be evaluated in Cohort 3 as 
described below.   

 
 
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1.1.4.1 
Pharmacology Studies 
Pharmacology studies in Rhesus monkeys showed that priming with ACI-35.030 and boosting 
with JACI-35.054 induced: 
• 
a strong and consistent anti-pTau peptide IgG response 
• 
a strong and consistent anti-PHF (paired helical filaments from human Alzheimer’s disease 
subjects) IgG response 
• 
Antibodies that bind to the N-terminal and C-terminal regions of the pTau peptide, thus 
increasing the epitope coverage of the pTau peptide as compared to the ACI-35.030 or 
JACI-35.054 alone. 
• 
Decreased anti-T50 or anti-CRM197 IgG antibody titers as compared to the homologous 
immunization regimen.  
1.1.4.2 
Toxicology and Safety Studies 
A heterologous combination repeated dose toxicology GLP study was carried out with ACI-
35.030 and JACI-35.054 in Rhesus monkey. Rhesus monkeys were treated first with a single 
dose of ACI-35.030 and subsequently with two doses of JACI-35.054. The study demonstrated: 
• 
ACI-35.030 and JACI-35.054 were both locally and systemically well-tolerated and were not 
associated with organ toxicity 
Additional non-clinical information can be found in the latest version of the IB. 
1.1.5 
Conclusion 
The preceding clinical study ACI-35-1201 demonstrated that ACI-35, i.e. the first generation 
vaccine, was safe and well tolerated at all doses and treatment regimens tested. However, the 
IgG response induced in individuals after the first injection did not result in a boosting effect upon 
subsequent injections and thus, considered of an insufficient magnitude to confer a sustainable 
clinical benefit. To address this situation, second generation vaccines were developed. ACI-
35.030 utilizes properties of ACI-35 (i.e. the liposome and antigen composition). JACI-35.054 
incorporates the same pTau peptide antigen, but presents the pTau to the immune system in a 
different way. In JACI-35.054 the pTau peptide is attached to a large carrier protein (CRM197) 
instead of being inserted in a liposome. The carrier protein should help the immune system to 
respond more efficiently to the pTau peptide. At the time of the version of this protocol, ACI-
35.030 and JACI-35.054 have been well tolerated in humans in this ongoing clinical study. A total 
of four serious adverse events in four different subjects have been reported to date (at the time 
of the version of this protocol) in cohort 1, all considered unlikely related to the study medication. 
The strong rationale for testing compounds which have the potential to modify Tau pathology in 
AD, in conjunction with favorable preclinical safety and efficacy profile, make ACI-35.030 and 
JACI-35.054 suitable candidates for testing in AD subjects. 
1.2 Study Rationale 
The preceding clinical trial ACI-35-1201 showed that the original vaccine ACI-35 was safe and 
well tolerated at all doses and treatment regimens tested. However, the antibody response 
observed after the first injection in most subjects was not boosted with the subsequent injections 
thus making it unlikely to confer a potential clinical benefit. To overcome this problem, new 
“second generation” vaccines were developed, ACI-35.030 and JACI-35.054. 
Each second generation vaccine will be tested alone with potential dose escalation and together 
in a selected sequence of injections (heterologous prime-boost vaccination).  

 
 
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It has been shown that a heterologous prime-boost vaccination strategy can confer superior 
protection as compared to a homologous prime-boost regimen. However, it has also become 
clear that the order of administration is crucial to obtain optimal immune responses. This has 
been extensively observed in the context of infectious diseases, where a DNA vaccine prime 
followed by a protein vaccine boost was shown to induce higher antibody titers and enhance T 
cell responses as compared to a protein vaccine prime followed by a DNA vaccine boost (Sin et 
al, 1999; Lu et al, 2009). In order to choose the best possible combination between the liposomal 
formulation ACI-35.030 and the conjugate vaccine JACI-35.054, different heterologous prime-
boost regimens have been tested in rhesus monkeys. The resulting data show that a sequence 
in which priming twice with ACI-35.030 followed by boosting twice with JACI-035.054 induces 
higher antibody titers against the pTau peptide at the end of the treatment as compared to when 
priming twice with JACI-35.054 and boosting twice with ACI-35.030. Moreover, a superior 
capacity to boost the anti-pTau peptide IgG response after each consecutive immunization was 
observed with the first regimen. In addition, a similar trend was also observed for the antibody 
response directed against PHF (paired helical filaments isolated from the brain of an AD patient), 
with higher anti-PHF IgG titers at the end of the treatment when priming with ACI-35.030 and 
boosting with JACI-35.054. 
Based on the above non-clinical data, the selected immunization schedule for the current study 
in patients is one in which subjects are primed twice with ACI-35.030 followed by two booster 
immunizations with JACI-35.054. 
The results obtained from the use of single second generation vaccines or from heterologous 
prime-boost vaccination will be compared to select the best strategy for further clinical 
development. 
1.3 Dose Rationale 
ACI-35.030 will be tested in up to 3 dose levels in cohort 1, i.e. 300 µg/dose, 900 µg/dose and 
1800 µg/dose. The initial dose of 300 µg has been used to evaluate the safety of ACI-35.030 
before higher doses are administered to subjects. Both higher doses were determined based on 
the results of the preceding clinical study and/or on results of pre-clinical studies.  
The best performing dose cohort and administration pattern in terms of immunogenicity, safety 
and tolerability will optionally be expanded to confirm the safety, tolerability and immunogenicity 
of ACI-35.030.  
JACI-35.054 will be tested in cohort 2 at 15 µg/dose and optionally in 2 subsequent cohorts with 
dosages up to 60 and up to 150 µg/dose (at the time of the version of this protocol, one sub-
cohort with a dosage of 60 µg/dose has been initiated following the dose escalation after the 15 
µg/dose sub-cohort). The initial dosage of 15 µg will be used to evaluate the safety and 
immunogenicity of JACI-35.054 before a potential higher dose is administered to subjects. The 
upper limit of 150 µg/dose is based on non-clinical toxicology data. 
ACI-35.030 and JACI-35.054 will be tested in a selected heterologous vaccination regimen in 
cohort 3. In sub-cohort 3.1, ACI-35.030 and JACI-35.054 will be tested at dosages previously 
evaluated in cohorts 1 and 2 respectively and found to be safe after a study treatment period of 
at least 10 weeks. The two optional subsequent sub-cohorts of cohort 3 may include a different 
sequence of administration than in the previous sub-cohort(s) of cohort 3 and/or different 
dosages of ACI-35.030 and/or JACI-35.054 based on available safety, tolerability and 
immunogenicity data from previous sub-cohort interim analyses.  
In this study, the administration route will be intramuscular (instead of subcutaneous, as was 
done in the previous ACI-35-1201 study) in order to improve potentially both local safety at the 
injection site and immunogenicity. Indeed, better local tolerability and doubling of the area under 

 
 
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the curve for antibody responses to the Aβ vaccine CAD 106 has been reported when switching 
from the subcutaneous to the intramuscular route of administration (Farlow et al, 2015). For 
vaccines against infectious diseases, intramuscular administration has also been associated with 
higher immune responses – notably in the case of Hepatitis B vaccine (Wahl et al, 1987). The 
incidence of injection related reactions is often reduced by using this route of administration 
despite similar or enhanced immune responses to vaccination (Cook, 2008, Diez-Domingo et al, 
2015).  
1.4 Study Endpoint Rationale 
The study endpoints were determined from the results of the previous Phase Ib trial and 
knowledge associated with Alzheimer’s Disease. 
Primary endpoints will evaluate: 
- 
The safety and tolerability of the study vaccines 
- 
The immunogenicity of the study vaccines (induction of anti-pTau IgG in serum) 
These endpoints will form the basis for selection of the vaccine with the optimal profile in terms 
of safety and immune response. 
The secondary endpoints will further evaluate the immune response including: 
- 
The induction of anti-Tau IgG and anti-pTau and anti-Tau IgM in serum as a quantitative 
response to vaccination. 
- 
The avidity of antibodies elicited by immunization in order to confirm that elicited 
antibodies have the right profile (qualitative immune response and not only quantitative). 
These endpoints will provide further support in selection of the optimal vaccine for further 
development. 
The exploratory endpoints will explore:  
- 
The effect of the vaccines on markers of unwanted inflammation (Induction of tau-specific 
cytotoxic T cells, inflammatory cytokines) 
- 
The ability of the vaccines to induce antibodies against (p)Tau and against other 
components of the vaccine (e.g. T50, CRM197, adjuvants) 
- 
The functional capacity of vaccine-induced antibodies as measured by e.g., in vitro Tau 
uptake assays  
- 
The effect of the vaccines on putative AD biomarker levels in blood and/or CSF (total 
Tau and pTau) as preliminary evidence of epitope engagement 
- 
The effect of the vaccines on cognitive and clinical endpoints, to assess any unwanted 
negative effects on these endpoints and obtain preliminary information concerning any 
positive effects on such endpoints, taking into account that the study is not powered to 
detect efficacy on such measures. 
1.5 Risks and Benefits for Subjects 
1.5.1 
Risk of Study Intervention 
ACI-35.030 and JACI-35.054 include small peptides as antigen encapsulated in liposomes or 
attached to a recombinant protein, respectively. ACI-35.030 and JACI-35.054 have not shown 
any systemic adverse reactions in animals. Allergic or autoimmune reactions could, however, 
theoretically occur. Likewise, a risk of anaphylactic reaction cannot be excluded. Injection site 
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As for other vaccines aimed to act on pathology in the central nervous system, there is a 
theoretical risk of inducing central nervous system inflammation/meningoencephalitis. Based on 
the available non-clinical data, the risk of such occurrences is considered to be low. 
Nevertheless, the possibility of T cell activation leading to such unwanted CNS inflammation 
cannot be completely excluded.  
In addition, although antibodies produced after immunization show specificity for phospho-tau 
over normal tau, some effect on normal tau might occur. There is no evidence from non-clinical 
safety studies that the vaccines are associated with abnormalities of neuronal function. 
Nevertheless, investigators must remain vigilant by carefully evaluating any adverse events 
reported by the subjects and caregivers. Investigators should also carefully monitor any clinical 
abnormalities during physical and neurological examinations, especially any possible symptoms 
or signs of CNS inflammation or neuronal dysfunction and strictly follow and evaluate the safety 
assessments including MRI scans as per the study protocol. The management of suspected 
meningoencephalitis cases is described in section 4.1.6. 
In the preceding Phase Ib study, the first generation vaccine ACI-35 was well tolerated at all 
doses tested. Injection site erythema and injection site reactions and fatigue were the most 
common study vaccine-related AEs. There was no evidence clinically or from laboratory or 
radiology findings to suggest the development of CNS inflammation. The dose-dependent 
injection site reactions observed on active treatment were generally mild and self-limiting and did 
not lead to subject withdrawal.  
ACI-35.030 and JACI-35.054 differ from ACI-35. There is thus no guarantee that the good safety 
profile of the first generation vaccine will be similar for the second generation vaccines. It is also 
not possible to predict that both second generation vaccines will have the same safety profile 
based on pre-clinical and clinical results obtained to date. Investigators must therefore remain 
vigilant and carefully monitor safety according to the study protocol in order to detect early any 
adverse events.  
New safety information arising from the current study which may modify the benefit-risk balance 
will be provided on an ongoing basis to principal investigators (PIs), ECs and regulatory 
authorities in the form of SUSAR reports, Development Safety Update Report (DSUR) and/or 
separate communications or updates to the Investigator’s Brochure.  
More generally, it is not possible to guarantee that the participating subjects will benefit from 
being in this study.  
Two out of 8 participants will be receiving placebo administrations in each study sub-cohort.  
1.5.2 
Risks of Participation during Covid-19 Pandemic 
Risks of acquiring infection with Covid-19 must be mitigated as much as possible during the 
ongoing pandemic. Safety of travelling to and attending the site must be evaluated taking into 
account any local travel restrictions and regulations. Subjects are to be advised to use all possible 
measures to reduce the risk of infection including social distancing, use of private transportation 
to the study site, frequent hand washing and use of face masks as appropriate.  
Due to the Covid-19 pandemic, health authorities, PIs or the sponsor may consider it is not 
appropriate for subjects to attend on-site visits. The situation will be monitored on an ongoing 
basis and the following decisions may be made, before each subject visit, depending on the 
situation at the local level: 
- 
If the planned screening assessments cannot be completed in safe conditions, all screening 
assessments will be postponed. 

 
 
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- 
If a subject is deemed eligible after completing the screening assessments but it is 
anticipated that randomization (V1) and/or any subsequent visit cannot be completed for logistical 
or safety reasons, the randomization visit and the related first administration of study vaccine will 
be postponed.  
- 
Randomization and the related first administration of study vaccine also may be postponed 
per PI judgment or/and local measures against Covid-19 infection. 
- 
If a subject is already randomized and has already received one dose of study vaccine, it 
will be assessed whether the subsequent visits can take place safely on site: 
• 
If yes, the visit and associated on site assessments will take place as planned. 
• 
If no, on site visits will be replaced by either phone visits or visits at a subject’s home 
including the administration of the study vaccine if permitted according to local 
regulations (see section 3.5.1.1). 
Should home visits be performed, subjects and site staff will be advised to use all possible 
measures to reduce the risk of infection as per local regulations. 
 
 

 
 
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2.  STUDY OBJECTIVES AND ENDPOINTS 
The overall study objective is to assess the safety, tolerability and immunogenicity of two study 
vaccines and the best performing administration pattern in subjects with early Alzheimer’s 
Disease (AD), i.e. Mild AD or MCI as diagnosed by the criteria of the National Institute on Aging 
– Alzheimer’s Association (NIA-AA) with a score at initial screening of 22 or above on the Mini-
Mental State Examination scale (MMSE). 
2.1 Study Objectives 
2.1.1 
Primary Objectives 
- 
To assess the safety and tolerability of study vaccines.  
- 
To assess the immunogenicity of study vaccines (induction of IgG titers against pTau in 
serum). 
2.1.2 
Secondary Objectives 
- 
To further assess the immunogenicity of study vaccines (induction of IgG titers against 
Tau and of IgM titers against pTau and Tau in serum) 
- 
To assess the avidity of antibodies elicited by immunization  
2.1.3 
Exploratory Objectives 
- 
To explore the effect of study vaccines on putative biomarkers of the progression of AD, 
i.e. blood and/or CSF concentrations of total Tau and pTau proteins, Tau fragments and 
other related biomarkers 
- 
To explore the effect of study vaccines on the activation of T-cells in blood 
- 
To explore the activity of study vaccines on blood inflammatory cytokines (e.g., IL-1B, 
IL-2, IL-6, IL-8, IL-10, IFN- γ, and TNF- α) 
- 
To further explore the effect of study vaccines on the immune response (e.g. antibodies 
against vaccine components, functional capacity of vaccine-induced antibodies) 
- 
To explore the effect of study vaccines on behavior, cognitive (including, in the 
Netherlands, the maintenance of the decisional capacity) and functional performance 
2.2 Study Endpoints  
2.2.1 
Primary Endpoints 
Safety and tolerability: Adverse events, immediate and delayed reactogenicity (e.g. 
anaphylaxis, local and systemic reactogenicity, including immune-complex disease); suicidal 
ideation (C-SSRS); behavior (NPI); cognitive and functional assessments (RBANS, CDR-SB) to 
assess safety; vital signs; MRI imaging; electrocardiogram; routine hematology and biochemistry 
evaluation in blood and urine; evaluation of autoimmune antibodies including anti-dsDNA 
antibodies in blood; inflammatory markers in blood and CSF. 
Immune response (i.e. immunogenicity): Anti-pTau IgG titers in serum (e.g. geometric mean, 
change from baseline, responder rate, peak and area under the curve). 
 
 

 
 
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2.2.2 
Secondary Endpoints 
Immune response (i.e. immunogenicity): Anti-Tau IgG, anti-pTau and anti-Tau IgM titers in 
serum (e.g. geometric mean, change from baseline, responder rate, peak and area under the 
curve), determination of the IgG response profile by avidity testing. 
2.2.3 
Exploratory Endpoints 
Change from baseline of putative AD biomarker titers in blood and/or CSF (e.g. total Tau, pTau, 
Tau fragments and other related biomarkers), change from baseline in T-cell activation levels as 
measured in  blood, change from baseline of inflammatory cytokine titers in blood, change from 
baseline in antibody titers in blood, change from baseline in behavior (NPI), cognitive (including 
the proportion of subjects maintaining their decisional capacity during the study using the 
MacCAT-CR interview in the Netherlands) and functional performance (RBANS, CDR-SB) 
scores.  
3. INVESTIGATIONAL PLAN  
3.1 Overall Study Design and Plan 
This protocol is a master protocol aimed at investigating two different Tau targeted vaccines.  
This study is a multicenter prospective placebo-controlled, double-blind and randomized study to 
assess treatment with Tau targeted vaccines versus placebo over 50 weeks (i.e. 12 months) in 
up to 216 subjects with early Alzheimer’s Disease. Immunizations will be performed at months 0 
(Week 0), 2 (Week 8), 6 (Week 24)* and 12 (Week 48). Based on the safety and immunogenicity 
results the protocol may be amended to test additional regimens. The subjects will be enrolled in 
up to 3 Cohorts, each with up to 72 subjects, the actual number depending on the number of 
sub-cohorts studied and the number of sub-cohorts in which expansion is performed. The 
Cohorts and their respective sub-cohorts are described in detail below.   
*Due to the Covid-19 pandemic, local travel restrictions in Finland effective as of 18 March 
2020, and the need to preserve the safety of study participants, modifications are made to 
the schedule of immunizations of sub-cohort 1.1 subjects having not received the 3rd 
injection at month 6 already: immunizations at month 6 (week 24) will not be performed in 7 of 
8 sub-cohort 1.1 subjects for whom the planned Visit 5 does not allow all assessments to be 
done according to the protocol. In addition, Visits 5 (week 24), 6 (week 26) and 7 (week 36) are 
replaced by remote visits in case these fall during the at-risk period (refer to sections 3.5.2.10, 
3.5.2.11, 3.5.2.12 and 3.5.2.14).  
Due to the resurgence of the Covid-19 pandemic in multiple participating countries since 
September 2020, additional adjustments related to the mode of administration of study 
assessments including study vaccine administration may apply in Finland and other participating 
countries after the above measures were implemented in Finland. 
3.1.1 
Cohort 1 with ACI-35.030 
For all cohort 1 subjects, the treatment period will last 50 weeks with the treatment/placebo being 
administered 4 times at respectively 8, 16 and 24-week intervals between each dose. The 
treatment period will be followed by a 24-week safety follow-up period starting 2 weeks after the 
last administration until week 74. Subjects who for any reasons have received less than 4 
administrations will be followed at least for the same duration after their last administration. 
Up to 3 dose levels of ACI-35.030 administered by the intramuscular route will be tested in 3 sub-
cohorts.  

 
 
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Sub-cohort 1.1 (8 subjects): 
ACI-35.030 at 300 μg/dose will be administered to 6 subjects and the placebo will be 
administered to 2 subjects. The safety and tolerability data after all subjects have received the 
second injection in sub-cohort 1.1 will permit dose escalation after review by the DSMB. 
 
Sub-cohort 1.2 (8 subjects): 
ACI-35.030 at 900 μg/dose will be administered to 6 subjects and the placebo will be 
administered to 2 subjects. The safety and tolerability data after all subjects have received the 
second injection in sub-cohort 1.2 will permit dose escalation after review by the DSMB. 
Sub-cohort 1.3 (8 subjects): 
ACI-35.030 at 1800 μg/dose will be administered to 6 subjects and the placebo will be 
administered to 2 subjects. 
For further information on the current study status/progress and relevant safety information, 
please refer to the IB. 
3.1.2 
Cohort 2 with JACI-35.054 
The administration schedule, route of administration, duration of treatment and follow-up are 
identical to cohort 1.  
Up to 3 dose levels of JACI-35.054 administered by the intramuscular route will be tested in up 
to 3 sub-cohorts.  
Sub-cohort 2.1 (8 subjects): 
JACI-35.054 at 15 μg/dose will be administered to 6 subjects and the placebo will be 
administered to 2 subjects. The safety and tolerability data after all subjects have received the 
second injection in sub-cohort 2.1 will permit dose escalation after review by the DSMB. 
Sub-cohort 2.2 (8 subjects) - Optional: 
JACI-35.054 at up to 60 μg/dose will be administered to 6 subjects and the placebo will be 
administered to 2 subjects. This sub-cohort will be optional and may be conducted based on 
good safety and tolerability observed in sub-cohort 2.1 and in case the antibody response in this 
previous sub-cohort is anticipated to be optimized at the dosage of 60 μg. At the time of the 
version of this protocol, this sub-cohort with a dosage of 60 µg/dose has been initiated following 
the dose escalation after the 15 µg/dose sub-cohort. 
Sub-cohort 2.3 (8 subjects) - Optional: 
JACI-35.054 at up to 150 μg/dose will be administered to 6 subjects and the placebo will be 
administered to 2 subjects. This sub-cohort will be optional and may be conducted based on 
good safety and tolerability observed in sub-cohort 2.2 and in case the antibody response in this 
previous sub-cohort is anticipated to be optimized at a higher dosage. 
For further information on the current study status/progress and relevant safety information, 
please refer to the IB. 
3.1.3 
Cohort 3 with ACI-35.030 and JACI-035.054 in Sequential Administration 
The administration schedule, route of administration, duration of treatment and follow-up are 
identical to cohorts 1 and 2 but both vaccines ACI-35.030 and JACI-35.054 will be administered 
in a sequence based on non-human primate immunogenicity data and on data reviewed during 
the previous sub-cohort interim analyses. In any of the sub-cohorts listed below, the selected 

 
 
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dosages of the 2 study vaccines will have been evaluated in cohorts 1 and 2 and safety 
monitored for at least 10 weeks, and safety data of the 2 study vaccines reviewed by the DSMB.  
 
Sub-cohort 3.1 (8 subjects) 
ACI-35.030 and JACI-35.054 at dosages previously evaluated in cohorts 1 and 2 respectively 
and found to be safe after a study treatment period of at least 10 weeks will be administered 
sequentially to 6 subjects and placebo will be administered at each dosing occasion to 2 
subjects. Immunizations with ACI-35.030 will be performed at months 0 (Week 0) and 2 (Week 
8), and with JACI-35.054 at month 6 (Week 24) and 12 (Week 48). 
 
Sub-cohort 3.2 (8 subjects) - Optional 
This optional sub-cohort may include a different sequence of administration than in sub-cohort 
3.1 and/or different dosages of ACI-35.030 and/or JACI-35.054 based on available safety, 
tolerability and immunogenicity data from previous sub-cohort interim analyses. Dosages of 
ACI-35.030 and of JACI-35.054 will have been previously evaluated in cohorts 1, 2 and/or 3 
without significant safety or tolerability concerns. 
 
Sub-cohort 3.3 (8 subjects) - Optional 
This optional sub-cohort may include a different sequence of administration than in sub-cohorts 
3.1 and 3.2 and/or different dosages of ACI-35.030 and/or JACI-35.054 based on available 
safety, tolerability and immunogenicity data from previous sub-cohort interim analyses. Dosages 
of ACI-35.030 and of JACI-35.054 will have been previously evaluated in cohorts 1, 2 and/or 3 
without significant safety or tolerability concerns. 
 
3.1.4 
Sub-cohort expansion 
Optional sub-cohort expansion of up to 16 additional subjects (i.e. up to 12 on active treatment 
and up to 4 on placebo per sub-cohort) may be considered in sub-cohort(s) with a favorable 
safety and immunogenicity profile with the objective to confirm the initial sub-cohort(s) 
immunogenicity results. The number of additional subjects to be enrolled will be determined 
based on the observed immunogenicity response rate in the sub-cohort(s) and on the potential 
gain in precision of the response rate estimate in the expanded sub-cohort(s), and will not 
exceed 16 (i.e., up to 24 subjects overall per sub-cohort). In addition, all other immunogenicity 
endpoints available at the interim timepoint may be considered. The dose-level, sequence of 
administration and administration regimen of study vaccine(s) will be identical to the initial part 
of the sub-cohort. 
3.1.5 
Safety follow-up 
All subjects will be kept under clinical observation for 24 hours after the first administration of 
study vaccine and for 4 hours after subsequent administrations of study vaccine. During that 
period, the vital signs will be monitored and the injection site will be observed on a regular basis. 
A physical examination will be performed prior to discharge. The clinical observation may be 
prolonged in case of safety concerns according to the clinical judgement of the investigator. A 
subsequent safety assessment will also be performed 48 to 72 hours after each immunization by 
telephone call for all study subjects. For adverse events considered possibly or probably related 
to the study vaccine of greater than mild severity according to investigator assessment, subjects 
will be required to return to the clinic for additional safety assessment.  In each sub-cohort, the 
first dosing of the first 4 subjects should be performed once the safety assessment at 48 to 72 
hours of the previous subject has been performed. This will allow the site principal investigator 
to assess whether there is any clinically relevant safety issue related to study vaccine prior to 

 
 
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dosing the subsequent subject. Safety laboratory samples will be collected at baseline, prior to 
each injection and 2-4 weeks after each injection. Laboratory results will be reviewed by the 
Medical Monitor on a periodic basis including all out of range values. 
All treated subjects will have a safety follow-up period of 24 weeks (6 months) after the end of 
the treatment period. During this period, subjects will be asked to attend a first follow-up visit 19 
weeks after the last administration and a last visit at the end of the follow-up period (26 weeks 
after the last administration).  
Additionally to the monitoring and recording of the AEs throughout the course of the study and 
the reporting of SAEs, participant safety will be monitored throughout the study with regular 
review of safety data by a Data and Safety Monitoring Board (DSMB). The DSMB will consist of 
specific experts in the field, who will meet on a regular basis to review the safety data of the 
participants. The outcome of the DSMB meeting will be registered in minutes and will include a 
recommendation as to whether to continue the study as planned or to modify or stop the study. 
The DSMB’s responsibilities and activities will be described in a charter. 
3.1.6 
Post-injection period extension (optional) 
Based on immunogenicity data, subjects from sub-cohort(s) may be invited to attend two 
additional visits (at Week 86 and Week 98) taking place after the end of the safety follow-up 
period (week 74) in order to evaluate the durability of the immune response and collect additional 
biomarker data. All subjects participating in this post-injection period extension will have to 
reconsent. During this additional 24-week (6-month) period, blood will be collected for 
immunogenicity and biomarker testing. The aim of this optional study extension is to help inform 
the dosing regimen in subsequent clinical trials of the vaccine(s). AEs/SAEs and concomitant 
medications (new and/or changes from the previous visit) will also be collected during these 2 
additional visits. Upon investigator’s medical judgement, other assessments can be performed 
during this period (e.g., MRI, ECG, etc.) if clinically indicated. 
In the Netherlands, the subjects’ decisional capacity will be re-assessed before consenting for 
this optional post-injection extension. 
3.1.7 
Interim analyses (IA) 
Interim analyses of safety, tolerability and immunogenicity data may be conducted in each sub-
cohort, including expanded sub-cohorts, as follows: 
• 
all available subjects in the sub-cohort have completed Visit 4 (Week 10), i.e. 2 to 4 
weeks after the second injection 
• 
all available subjects in the sub-cohort have completed Visit 6 (Week 26), i.e. 2 to 4 
weeks after the third injection 
• 
all available subjects in the sub-cohort have completed Visit 9 (Week 50), i.e. 2 to 4 
weeks after the last injection at Week 48 
• 
all available subjects in the sub-cohort have completed Visit 11 (Week 74), i.e. end of 
the safety follow-up period 
 
If the post-injection period is extended in any sub-cohort, IA of immunogenicity data may also be 
conducted at Visit 13 (Week 98), and optionally at Visit 12 (Week 86).  
 
Available biomarker data may also be reviewed during any of these IAs. The IAs described above 
may also be performed for any expanded sub-cohort. 
 

 
 
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Additional IAs to review the sustainability of immune response data may be conducted between 
weeks 26 and 50 and between weeks 50 and 74. 
 
Independently of the above-mentioned interim analyses, the DSMB will perform regular reviews of 
the safety and tolerability data throughout the study.  
 
Rationale and Scope of IAs: 
The objectives of the above mentioned IAs in the sub-cohorts (whether expanded or not) is to ensure 
a regular review of safety, tolerability and immunogenicity with the support of optional biomarker 
data. A decision to escalate to the next dose in one given sub-cohort may be taken once IA data of 
the previous dose are available from Visit 4 (Week 10) onwards and pending prior DSMB approval. 
A decision to expand a sub-cohort may be taken based on satisfactory review of safety data by the 
DSMB and analysis of immunogenicity IA data of this sub-cohort dose from Visit 4 (Week 10) 
onwards. The IA at the end of the optional extended post-injection period is intended to monitor the 
durability of the immune response and any biomarker changes in blood. 
 

 
 
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3.1.8 
Schematic overview of cohorts design 
 
 
NB: The start of subject screening and treatment in cohort 2 is not linked to any IA performed in 
cohort 1. It is anticipated that screening in sub-cohort 2.1 will be done in parallel with screening 
for sub-cohort 1.2. Potential lags in the start of the screening may occur depending on e.g. subject 
recruitment rate or regulatory approval timelines.  
The start of subject screening and treatment in cohort 3 will be based on IA data generated in 
sub-cohorts 1.1, 1.2, 1.3 and 2.1, and if needed in sub-cohort 2.2, from at least week 10 onwards. 
As specified previously, several IAs will be performed in the study to allow for dose escalation, 
decision on expansion or potential comparison of cohorts.  
All IAs planned for cohort 1, 2 and 3 are described also in Section 5.3.8.  

 
 
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Based on immunogenicity data, subjects from sub-cohort(s) may be invited to attend two 
additional visits (at Week 86 and Week 98) taking place after the end of the safety follow-up 
period (week 74). In such a case, an IA of immunogenicity data as well as available biomarker 
data may also be conducted at Visit 13 (Week 98), and optionally at Visit 12 (Week 86), to monitor 
the durability of the immune response and any biomarker changes in blood. 
 
*Due to the Covid-19 pandemic, local travel restrictions in Finland effective as of 18 March 
2020, and the need to preserve the safety of study participants, modifications are made to 
the schedule of immunizations of sub-cohort 1.1 subjects having not received the 3rd 
injection at month 6 already: immunizations at month 6 (week 24) will not be performed in 7 of 
8 sub-cohort 1.1 subjects for whom the planned Visit 5 does not allow all assessments to be 
done according to the protocol.  
3.2 Study Duration  
3.2.1 
Screening Period 
The screening period for each subject will be up to 42 days. Screening assessments will be done 
sequentially over multiple visits as described in the Schedule of Assessment (see section 3.5.1).  
3.2.2 
Treatment Period 
In all cohorts, the treatment duration is anticipated to be 50 weeks (12 months). 
3.2.3 
Follow-up Period 
Subjects participating in the study will be followed up for 24 weeks starting 2 weeks after the last 
study vaccine administration (treatment completion or early termination). The follow-up period 
will consist of on-site visits 19 weeks and 26 weeks (6 months) after the last administration. 
3.2.4 
Post-Injection Period Extension (optional) 
If the post-injection period is extended in one or more sub-cohorts as described in section 3.1.6, 
subjects of the selected sub-cohort(s) will be asked to attend two additional visits over 24 weeks 
(6 months) after the end of the safety follow-up period and up to week 98. 
3.2.5 
Overall Study Duration 
The duration of participation in the study for subjects completing the study is up to 80 weeks 
(around 1.5 year) from first screening assessment to the last safety follow-up visit, and up to 
around 104 weeks (around 2 years) in case the post-injection period is extended by 24 weeks (6 
months) at the end of the safety follow-up period (optional). 
3.2.6 
End of Study Definition 
A subject is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of 
Assessments, Section 3.5, including the optional post-injection extension period, if applicable. 
The end of the study is defined as completion of the last visit of the last participating subject, 
including the optional post-injection extension period, if applicable. 

 
 
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3.3 Selection of Study Population 
Subjects will be 50-75 years old with a clinical diagnosis of mild AD or MCI as assessed by NIA-
AA core clinical criteria (McKhann et al, 2011, see Appendix 1) and a Clinical Dementia Rating 
Scale (CDR) global score of 0.5 or 1.  
3.3.1 
Inclusion Criteria 
Subjects meeting all of the following inclusion criteria at screening should be considered as 
eligible to participate to the study: 
1. Male or female with age from 50 and up to 75 years old inclusive.  
2. Mild Cognitive Impairment (MCI) due to AD or Mild AD according to NIA-AA criteria and a 
Clinical Dementia Rating Scale (CDR) global score of 0.5 or 1 respectively. 
3. MMSE score of 22 or above. 
4. Abnormal level of CSF Abeta amyloid 42 (Aß42) consistent with AD pathology at screening.  
o 
In borderline cases for CSF Aß42 levels, other results may be considered to help 
determine amyloid positivity, e.g., the Aß42/Aß40 ratio and, on a case by case 
basis, a history of positive amyloid PET scan or positive CSF Aß42 level.  
o 
Results from CSF sampling performed within 6 months prior to screening are 
acceptable on a case by case basis provided that they are consistent with the 
presence of amyloid pathology and that the corresponding CSF sample can be used 
in the study for testing.  
5. Subjects either not taking any marketed treatment for AD or receiving a stable dose of an 
acetylcholinesterase inhibitor and/or memantine for at least 3 months prior to baseline. 
6. Subjects cared for by a reliable informant or caregiver to assure compliance, assist with 
clinical assessments and report safety issues. 
7. Women must be post-menopausal for at least one year and/or surgically sterilized. Women 
of childbearing potential or not post-menopausal must have a negative blood pregnancy test 
at screening (blood draw between day -14 and day -3 prior to baseline) and be willing to use 
highly effective methods of contraception from the screening visit until the end of their 
participation. Urine pregnancy testing will be performed throughout the treatment period to 
determine if the subject can continue receiving the study vaccine. Male participants in the 
trial with female partners of child bearing potential are required to use barrier methods of 
contraception (condoms with spermicide) in addition to contraceptive measures used by 
female partners during the whole study duration. 
8. Subjects who in the opinion of the investigator are able to understand and provide written 
informed consent. In the Netherlands, the subjects’ decisional capacity will be also assessed 
and must be consistent with the ability to provide informed consent using the MacArthur 
Competency Tool for Clinical Research in order to evaluate their abilities in the areas of 
understanding, reasoning, appreciation and choice. 
9. Both subject and informant or caregiver must be fluent in one of the languages of the study 
and able to comply with all study procedures, including lumbar punctures. 
3.3.2 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria at screening should not be considered 
as eligible to participate to the study: 
1. Participation in previous clinical trials for AD and/or for neurological disorders using active 
immunization unless there is documented evidence that the subject was treated with 
placebo only and the placebo vaccine is not expected to induce any specific immune 
response. 

 
 
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2. Participation in previous clinical trials for AD and/or for neurological disorders using any 
passive immunization within the past 6 months (or 5 half-lives of the investigational antibody, 
whichever is longer) prior to screening unless there is documented evidence that the subject 
was treated with placebo only and the placebo is not expected to induce any specific 
immune response. 
3. Participation in previous clinical trials for AD and/or for neurological disorders using any 
small molecule drug including BACE-1 inhibitors within the past 3 months prior to screening. 
4. Concomitant participation in any other clinical trial using experimental or approved 
medications or therapies. 
5. Presence of positive ANA titers at a dilution of at least 1:160 in subjects without clinical 
symptoms of auto-immune disease. 
6. Current or past history of auto-immune disease, or clinical symptoms consistent with the 
presence of auto-immune disease. 
7. Immune suppression including but not limited to the use of immunosuppressive drugs or 
systemic steroids unless they have been prescribed transiently more than 3 months prior to 
screening. 
8. History of severe allergic reaction (e.g., anaphylaxis) including but not limited to severe 
allergic reaction to previous vaccines and/or medications. 
9. Prior history of clinically significant hypoglycaemic episodes.  
10. Drug or alcohol abuse or dependence currently met or within the past five years according 
to DSM-V criteria. 
11. Any clinically significant medical condition likely to interfere with the evaluation of safety and 
tolerability of the study treatment and/or the adherence to the full study visit schedule. 
12. Any clinically significant medical condition likely to impact the immune system (e.g, any 
history of acquired or innate immune system disorder). 
13. Use of hydralazine, procainamide, quinidine, isoniazide, TNF-inhibitors, minocycline within 
the last 12 months prior to screening. 
14. Use of diltiazem unless on a stable dose for at least 3 months prior to screening. 
15. Significant risk of suicide defined, using the Columbia-Suicide Severity Rating Scale, as the 
subject answering: “yes” to suicidal ideation questions 4 or 5 or answering: “yes” to suicidal 
behavior within the past 12 months. 
16. Concomitant psychiatric or neurologic disorder other than those considered to be related to 
AD (e.g. head injury with loss of consciousness, symptomatic stroke, Parkinson’s disease, 
severe carotid occlusive disease, TIAs). 
17. History or presence of uncontrolled seizures. If history of seizures, they must be well 
controlled with no occurrence of seizures within 2 years prior to screening. The use of anti-
epileptic medications is permitted if at stable dose for at least 3 months prior to screening. 
18. History of meningoencephalitis within the past 10 years prior to screening. 
19. Subjects with a history of hemorrhagic and/or non-hemorrhagic stroke. 
20. Presence or history of peripheral neuropathy. 
21. History of inflammatory neurological disorders with potential for CNS involvement. 
22. Screening MRI scan showing structural evidence of alternative pathology not consistent with 
AD which could cause the subject's symptoms. Evidence of space occupying lesions other 
than benign meningioma of less than 1 cm diameter, more than two lacunar infarcts or one 
single infarct larger than 1 cm in diameter or any single area of superficial siderosis or 
evidence of a prior macro-hemorrhage ≥10 mm. Microbleeds on T2* MRI are allowed up to 
a maximum of 10, regardless of the location. 
23. MRI examination cannot be done for any reason, including but not limited to metal implants 
contraindicated for MRI studies and/or severe claustrophobia. 
24. Significant hearing or visual impairment or other issues judged relevant by the investigator 
preventing to comply with the protocol and to perform the outcome measures. 

 
 
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25. Clinically significant infections or major surgical operation within 3 months prior to screening. 
Planned surgery anticipated to occur during participation in the study must be reviewed and 
approved by the medical monitor at screening. 
26. Any vaccine received within the past 2 weeks before screening, including influenza vaccine. 
27. Clinically significant arrhythmias or other clinically significant abnormalities on ECG at 
screening. 
28. Myocardial infarction within one year prior to baseline, unstable angina pectoris, or 
significant coronary artery disease.  
29. History of cancer within the past 5 years other than treated squamous cell carcinoma, basal 
cell carcinoma and melanoma in situ, or in-situ prostate cancer or in-situ breast cancer which 
have been fully removed and are considered cured. 
30. Clinically significant deviations from normal values for hematologic parameters, liver 
function tests, and other biochemical measures, that are judged to be clinically significant in 
the opinion of the investigator. 
31. Pregnancy confirmed by blood test at screening, or subject planning to be pregnant or 
lactating. 
32. Receipt of any anticoagulant drug or antiplatelet drug, except aspirin at doses of 100 mg 
daily or lower (in order to avoid risk of bleeding during scheduled or unscheduled lumbar 
puncture). 
33. Receipt of any antipsychotic drugs unless on stable low doses for the treatment of insomnia. 
34. Donation of blood or blood products within 30 days prior to screening or plans to donate 
blood while participating in the study. 
35. Positive VDRL consistent with active syphilis at screening. 
36. Positive HIV test at screening. 
37. Laboratory or clinical evidence of active hepatitis B and/or C at screening.  
38. Serum creatinine greater than 1.5x upper limit of normal, abnormal thyroid function tests or 
clinically significant reduction in serum B12 or folate levels (note: all oral doses of thyroid 
replacement agents, B12 or folate have to be stable for at least 3 months prior to screening). 
3.3.3 
Removal of Subjects from Therapy or Assessment 
A subject will be considered to have completed the study when he or she completes the Visit 11 
at Week 74 (or the Visit 13 at Week 98 in case of optional post-injection period extension). If a 
subject is discontinued at any time after randomization into the study, the investigator will make 
every effort to follow the subject and complete the premature discontinuation assessments as 
shown in Section 3.5.3. 
Additional participants may be recruited to replace withdrawn subjects unless the subject 
withdrew for safety reasons. 
 
A termination electronic case report form (eCRF) page should be completed for every subject 
who received investigational product, whether or not the subject completes the study. The reason 
for any early discontinuation should be indicated on this form.  
 
The primary reason for a subject discontinuing early should be selected from the following 
standard categories of early termination: 
• 
Adverse Event (Adverse Reaction): Clinical or laboratory events occurred that, in the 
medical judgement of the investigator for the best interest of the subject, are grounds for 
discontinuation. This includes serious and non-serious adverse events (AEs) regardless of 
relation to the investigational product. 
• 
Death: The subject died. 
• 
Withdrawal of Consent:  

 
 
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o 
The subject or caregiver desired to withdraw from further participation in the study 
in the absence of an investigator-determined medical need to withdraw. If the 
subject gave a reason for withdrawing, it should be recorded in the eCRF. In case 
of caregiver withdrawal, the subject can continue in the study if a new caregiver 
consents to act in this role.  
o 
In the Netherlands, subjects who become unable to maintain their decisional 
capacity during the course of the study as assessed with the MacCAT-CR interview 
(refer to section 3.5.6  and 6.1.3). 
• 
Protocol Violation: The subject’s findings or conduct failed to meet the protocol entry criteria 
or failed to adhere to the protocol requirements (e.g., drug noncompliance, use of prohibited 
concomitant treatment (section 3.4.7.2), failure to return for a defined number of visits). The 
violation is important enough to justify early discontinuation since it would hamper the 
evaluation of the primary endpoints of the study. 
• 
Lost to Follow-up: The subject stopped coming for subsequent study visits and study 
personnel were unable to contact the subject. 
• 
Other: The subject was discontinued for a reason other than those listed above, such as 
termination of study by sponsor.  
3.4 Treatments 
3.4.1 
Details of Study Treatments 
Name and Description 
Study Active Treatment in cohort 1: ACI-35.030 is a sterile suspension supplied in vials.  
Study Active Treatment in cohort 2: JACI-35.054 is a reconstituted solution of the conjugate 
CRM197-pTau with 2 adjuvants, i.e. Aluminum Hydroxide and CpG7909. Each product is a sterile 
suspension supplied in vials.  
Study Active Treatments in cohort 3: ACI-35.030 and JACI-035.054. 
The placebo of the study consists of a PBS solution in vials.  
Manufacturing 
ACI-35.030 is manufactured by 
, a contract manufacturing organization 
located in 
.  
The conjugate and adjuvants of JACI-35.054 are manufactured by the following contract 
manufacturing organizations: 
• 
CRM197-pTau: 
 
• 
Aluminum Hydroxide: 
 
• 
CpG7909: 
 
The Placebo is manufactured by 
.  
Treatment Administration and Preparation 
Because the appearance of the liquid in the vial differs between placebo and active treatments 
(ACI-35.030 or JACI-35.054), the dose preparation will be performed by an unblinded pharmacist 
or duly trained delegate, independent from the study medical team. An unblinded study nurse 
will then obtain the study product from the pharmacy and administer the study medication (study 
vaccine or placebo). JACI-35.054 must be reconstituted before administration. Contact between 
the unblinded site staff and the blinded site staff or subject must not disclose treatment 
assignment. Study site staff other than the unblinded pharmacist and the unblinded study nurse 
must not be allowed to know the study product assigned to any study subject. To maintain the 

 
 
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blinding to subject during study medication administration, the syringes used for injection will be 
masked.  
Treatment administration for subjects in cohorts 1, 2 and 3: To administer doses of study active 
treatment or corresponding placebo, the following dose preparation should be followed.  
Cohort 1   
Sub-cohort 1.1: 
300 µg antigen 
or placebo 
administration 
To administer 300 µg of antigen or corresponding placebo, 1 vial of study 
medication/placebo should be used. 
 
Sub-cohort 1.2: 
900 µg antigen 
or placebo 
administration 
To administer 900 µg of antigen or corresponding placebo, 1 vial of study 
medication/placebo should be used. 
 
 
 
Sub-cohort 1.3: 
1800 µg antigen 
or placebo 
administration 
To administer 1800 µg of antigen or corresponding placebo, 2 vials of 
study medication/placebo should be used. 
 
 
 
 
Cohort 2 
Sub-cohort 2.1: 
15 µg JACI-
35.054 or 
placebo 
administration 
To administer 15 µg of JACI-35.054 or corresponding placebo, 1 vial of 
study medication (obtained after reconstitution)/placebo should be used. 
 
 
Optional Sub-
cohorts 2.2 and 
2.3: 
Up to 60 µg and 
up to 150 µg 
JACI-35.054 or 
placebo 
administration  
To administer the required dose of CRM197-pTau or corresponding 
placebo, 1 vial of study medication (obtained after reconstitution)/placebo 
should be used. 
 
 
 
Cohort 3 
Sub-cohort 3.1: 
ACI-35.030 and 
JACI-035.054 
(dosages to be 
determined) or 
placebo 
administration 
The same instructions for dose preparation provided for cohort 1 and 2 
should be followed depending on the selected dosage and on the study 
vaccine administered. 

 
 
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Optional Sub-
cohort 3.2 and 
3.3: 
ACI-35.030 and 
JACI-035.054 
(respective 
dosages to be 
determined) or 
placebo 
administration 
The same instructions for dose preparation provided for cohort 1 and 2 
should be followed depending on the selected dosages and on the study 
vaccine administered. 
A complete product handling instruction manual will be provided to the study site staff responsible 
for drug handling, reconstitution and administration. 
Subjects will be kept under clinical observation for 24 hours after the first administration of study 
vaccine and for 4 hours after subsequent administrations of study vaccine (second, third and 
fourth administrations). 
In each sub-cohort, the first dosing of the first 4 subjects should be performed once the safety 
assessment at 48 to 72 hours of the previous subject has been performed. This will allow the site 
principal investigator to assess there is no clinically relevant safety issue related to study vaccine 
prior to dosing the subsequent subject.  
Treatment administration for the subsequent cohorts: information on the treatment administration 
will be provided at a later stage in a dedicated substantial protocol amendment. 
Distribution and Storage 
The vials will be supplied by the appointed Drug Distribution Company to the study sites after the 
study has been approved by the Ethics Committee and applicable regulatory authorities.  
All vials will be supplied to the pharmacist. The person appointed to administer the product will 
collect the appropriate vials and will proceed to the study vaccine injection. The empty and half-
empty vials will be returned to the pharmacist for accountability. 
Vials of ACI-35.030 and JACI-35.054 adjuvants (Aluminum hydroxide, CpG7909) should be 
stored refrigerated at 2-8 °C. Vials of JACI-35.054 conjugate (CRM197-pTau) should be stored 
frozen at -85 to -65°C. The pharmacist agrees not to distribute the test articles to anyone, except 
to the appointed person who is responsible for administering the product. This person agrees not 
to administer the products to anyone else, except to the subjects having given written informed 
consent to take part in this study. 
Unused product remaining at completion of the study should be returned to the Drug Distribution 
Company or destroyed on site upon approval from Sponsor. 
3.4.2 
Dosage Schedule 
For cohorts 1 2 and 3, immunizations will be performed at months 0 (Week 0), 2 (Week 8), 6 
(Week 24)* and 12 (Week 48). Refer to the Schedule of Assessment specified in section 3.5.  
*Due to the Covid-19 pandemic, local travel restrictions in Finland effective as of 18 March 
2020, and the need to preserve the safety of study participants, modifications are made to 
the schedule of immunizations of sub-cohort 1.1 subjects having not received the 3rd 
injection at month 6 already: immunizations at month 6 (week 24) will not be performed in 7 of 
8 sub-cohort 1.1 subjects for whom the planned Visit 5 does not allow all assessments to be 
done according to the protocol.  

 
 
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3.4.3 
Treatment Assignment 
A randomization list based on a sequence of numbers, and individual medication codes will be 
computer generated. Study medication will be labelled with the corresponding medication 
number. Investigators will use a secure web-based system to randomize eligible subjects to study 
medication. An Interactive Response Technology (IRT) system will be used for randomization in 
the study. At screening, participating subjects will be given a subject number that will also 
correspond to the subject’s identification in the study. Assigned numbers will be unique identifiers 
with 4 digits for the site and 2 last digits for the sequential order of enrolment at a given site.  
3.4.4 
Drug Packaging and Blinding 
Packaging and Labelling  
The out-packaging and the labeling of all active treatment and placebo vials are performed by 
 according to the EU GMP and local regulations. Information on the subject 
identity and visit number will have to be added to the boxes and vials assigned to subjects by the 
site.  
Blinding 
Study participants, site personnel, CRO, study vendors, sponsor will be blinded to treatment 
assignment until all subjects in a given sub-cohort have reached the end of the safety follow-up 
visit (Visit 11, Week 74). 
If the follow-up of a specific sub-cohort is extended to allow for the assessment of the durability 
of the immune response, the study participants and site investigator/personnel will remain blinded 
to the treatment assignment until the end of the extended period (Visit 13, Week 98).  During this 
extended follow-up period (weeks 74-98), designated sponsor representatives may be unblinded 
to the treatment assignment to allow for data review in preparation for subsequent trials. Fully 
unblinded designated sponsor representatives will have no access to the study database and will 
not be authorized to share any unblinding information with any blinded study staff. 
The study is unblinded to the pharmacist and any duly trained and delegated staff responsible 
for the IMP receipt, accountability and preparation of the syringes, as well as to the study nurse 
responsible for treatment administration who should not be otherwise involved in the study. In 
addition, an unblinded monitor from the CRO will control study medication (drug accountability) 
on site. The Principal Investigator will be provided with the site specific unblinded list after data 
lock. Database lock will be performed after all subjects have completed the study. It is the 
Principal investigators’ responsibility to decide whether this information should or should not be 
shared with the subjects. 
In order to remain blinded, raters performing the cognitive tests should not have access to any 
clinical assessment data (e.g. clinical rating scales, adverse events). 
Individual immunogenicity or biomarker results will not be shared with any site personnel until 
after database lock. 
Unblinding of individual subjects is restricted to emergency situations and should only be used 
under circumstances where knowledge of the treatment is considered necessary for the proper 
management of subject safety. If the treatment code is unblinded, the reason and the date should 
be documented by the Investigator and the Sponsor should be informed in a promptly manner. 
In emergency circumstances where the investigator identifies an urgent clinical need to know 
whether the subject is receiving active medication or placebo, the IRT allows the immediate 
unblinding of the subject by the investigator directly. In such cases the rationale must be 
documented on the subject source data, with immediate notification of the monitor and medical 
monitor.  

 
 
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The code break will also be reported in the subject specific CRF and events leading to the 
emergency breaking will be recorded in the serious adverse event (SAE) report form. 
Subjects will be given a specific study card containing the information that they are participating 
in the study and the contact details of the investigator. 
3.4.5 
Drug Inventory and Accountability 
The investigator must keep an accurate accounting of the number of investigational product units 
delivered to the site, dispensed to subjects, and returned to the sponsor or other disposition 
during and at the completion of the study. The investigational product must be dispensed to 
subjects only by an appropriately qualified person. The investigational product is to be used in 
accordance with the protocol and should be administered to subjects by qualified and pre-
identified study site personnel who are under the responsibility of the site principal investigator. 
Investigators or dedicated study personnel should maintain records that document adequately 
that the subjects were provided the doses specified by the protocol and reconcile all 
investigational products received at the site before final disposition. At the end of the study, or as 
directed, all study vaccines, including unused, partially used, and empty containers, will be 
returned to the Drug Distribution company or destroyed on site upon approval from Sponsor. 
Product accountability and product reconstitution forms will be used by the pharmacist of the 
study site/the assigned person responsible for the injection. Used vials will be kept for 
accountability. All study vials (investigational product and placebo) received and dispensed 
throughout the study period will be inventoried and accounted for the trial period by the 
pharmacy/site team on the corresponding “product accountability form”. 
3.4.6 
Treatment Compliance 
Administration of the investigational products will be performed by pre-identified and qualified 
study personnel. Any noncompliance to study treatment (e.g. incorrect dose injected, treatment 
interruption) will be recorded. 
3.4.7 
Prior and Concomitant Illness and Treatments 
3.4.7.1 
Prior and Concomitant Illnesses 
Investigators should document any prior relevant illnesses (i.e. with an end date before the 
informed consent is given) in the medical history of the subject. Additional illnesses present at 
the time informed consent is given are to be regarded as concomitant illnesses. Illnesses first 
occurring or detected during the study and/or worsening of a concomitant illness during the study 
are to be documented as AEs on the eCRF. 
3.4.7.2 
Prior and Concomitant Treatments 
Prior treatments, defined as those ongoing or started within 3 months before screening and 
stopped before the first dosing, should be recorded in the eCRF as prior medications. 
Concomitant treatments, defined as treatments ongoing at the time of the first dosing or started 
after the first dosing should be recorded in the eCRF as concomitant medications. 
After randomization, subjects may receive the prescribed concomitant medications and 
treatments as indicated by their clinical condition. Concomitant medication and treatments should 
be kept unchanged as much as possible during the course of the study. Any change in the nature 
and/or the dose of the concomitant medication and treatments should be recorded in the 
appropriate section of the eCRF. 

 
 
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All medications and treatments must be documented in the concomitant medication section of 
the case report forms. 
Subjects receiving acetylcholinesterase inhibitor and/or memantine should have been on a stable 
dosage for at least 3 months prior to baseline.  
The following treatments are not permitted throughout the study:  
o 
Anticoagulants or antiplatelet drugs, except aspirin at doses of 100 mg daily or lower. 
o 
Standard of care immunizations during the period ranging from 2 weeks before or after any 
administration of study vaccine to avoid potential interference. 
o 
Hydralazine, procainamide, quinidine, isoniazide, TNF-inhibitors, minocycline.  
o 
Diltiazem unless subject is on stable dose 3 months prior to screening. 
o 
Any investigational or non-investigational drugs given as part of another clinical trial.  
Wherever possible any change in current medication or introduction of new standard of care 
medications must be discussed first with the Study Investigator, and if appropriate, the Medical 
Monitor and Sponsor.  
3.5 Assessments 
3.5.1 
Schedule of Assessments 
The study plan proposed is for cohort 1 (ACI-35.030 or placebo), cohort 2 (JACI-35.054 or 
placebo) and cohort 3 (ACI-35.030 and JACI-35.054, or placebo). 
 

 
 
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details in sections 3.5.2.10, 3.5.2.11, 3.5.2.12 and 3.5.2.14. ∂ Only applicable for sub-cohorts in which the subject has not yet reached the visit timepoint. If feasible, agreed with subject and locally permitted, these visits may also be performed 
at subject’s home. π Optional extended study period, only applicable if a decision is made by the sponsor. Concerned subjects will consent and in the Netherlands, the subjects’ decisional capacity will be assessed before consenting.

 
 
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3.5.1.1 
Alternative Mode of Administration of Assessments to Reduce Safety Risks due to 
Participation during Covid-19 pandemic 
The below table applies to subjects who are already randomized (i.e., completed Vs and V1) in the 
event that the study procedures cannot be performed on-site (O) at the study facility due to the 
Covid-19 situation but is feasible and locally permitted to be conducted by phone (P) and/or at 
subject’s home (H). This approach will be implemented on a case-by-case basis after an evaluation 
of the risk for the participant to attend on-site visits (refer to section 1.5.2 Risks of Participation during 
Covid-19 Pandemic) or when travel restrictions/site’s policy prevent the on-site visit from being 
performed. Documentation regarding the mode of administration of study assessments will be 
maintained on-site in the source documents and/or the investigator site file. 
Alternative modes of administration of cognitive tests will be used following specific training of raters 
and supporting study staff if applicable.   
A physician (investigator or delegate) will always be responsible for the 4-hour safety observation 
post-dosing to ensure that any acute reactions can be addressed. Staff conducting home visits will 
be informed of pre-identified local acute care facility/system by the site PI. 

 
 
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5. At V6, the lumbar puncture will be performed either at the study facility or if locally feasible at an alternate (external) facility according to the visit window. If facilities are unavailable, the procedure will be postponed until 
the earliest possible timeslot. Should the lumbar puncture be delayed at V6, the timing of the last lumbar puncture at V9 will be adjusted or cancelled on a case-by-case basis to avoid repeated procedures within a short 
interval of time.    
6. At V4, V6, V9 and V11, MRI scans will be performed either at the qualified imaging facility or if locally feasible at an alternate (non-qualified) facility according to the visit window. If facilities are unavailable, the procedure 
will be postponed until the earliest possible timeslot. Should a MRI scan be delayed, the timing of the subsequent scan will be adjusted or cancelled on a case-by-case basis to avoid repeated procedures within a short 
interval of time. 
7. Only applicable for sub-cohorts in which the subject of the sub-cohort has not yet reached the visit timepoint. 
8. Only in the Netherlands. 
9. Optional extended study period, only applicable if a decision is made by the sponsor. Concerned subject will consent and in the Netherlands, the subjects’ decisional capacity will be assessed before consenting. 
 
 
 

 
 
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3.5.2 
Study Procedures 
During their participation in the study, subjects will have to undergo a certain number of 
procedures as summarized in the Schedule of Assessment (section 3.5.1). A list of the different 
procedures, samplings and type of data collected at each visit is available below for cohorts 1, 2 
and 3. A more detailed description of the procedures the subject will undergo is available in 
sections 3.5.4 to 3.5.6.  
Due to the resurgence of the Covid-19 pandemic in multiple participating countries since 
September 2020, an alternative mode of administration of study assessments will apply to 
randomized subjects who have previously received the first immunization if the study procedure 
cannot be performed on-site at the study facility and if the procedure is feasible and locally 
permitted to be administered by phone and/or at subject’s home (see section 3.5.1.1 Alternative 
Mode of Administration of Assessments to Reduce Safety Risks due to Participation during 
Covid-19 pandemic).  
3.5.2.1 
Vs-Screening [day -42 to -3] 
The procedures listed below will be performed sequentially over a period of 42 to 3 days prior to 
the baseline visit (Week 0). The sequence is specified in the Schedule of Assessments (section 
3.5.1).  
− 
Subject’s decisional capacity to consent: MacCAT-CR interview (in the Netherlands). To 
be performed prior to the informed consent signature. 
− 
Subject information and consent discussion 
− 
Written informed consent from the subject 
− 
Written informed consent from the caregiver 
− 
Year of birth 
− 
Gender 
− 
Ethnic origin 
− 
Women of child bearing potential: discussion on reliable contraceptive measures (refer 
to section 4.2.3) 
− 
Report former brain MRI assessment (<1 year) 
− 
Year of onset of disease 
− 
Familial history for AD 
− 
Previous medications for AD (describe) 
− 
Relevant medical and surgical history for other diseases 
− 
Prior medications  
− 
AEs 
− 
Review NIA-AA diagnostic criteria 
− 
Cognition: MMSE, RBANS (form C) 
− 
Clinical status: C-SSRS, CDR 
− 
Physical and neurological examination 
− 
Vital signs 
− 
Blood sample collected for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers 
Inflammatory cytokines 
coagulation indices assessment 
screening tests: B12, folate, thyroid function tests, HIV, Hepatitis B and C and VDRL 
(syphilis serology), ApoE genotyping, serum pregnancy testing 
ANA and anti-dsDNA testing 

 
 
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− 
Routine urine evaluation 
− 
ECG  
− 
Brain MRI  
− 
Lumbar puncture for cerebrospinal fluid sample (12 mL) for cell count, inflammatory 
markers, exploratory biomarker testing and for confirming amyloid and Tau positivity 
according to inclusion criteria (note: blood for serum albumin should be taken and 
measured concomitantly).  
− 
Review inclusion and exclusion criteria 
3.5.2.1.1 
Re-screening: 
If a subject has entered a screening period and is considered eligible for the study but cannot 
be randomized in one sub-cohort for logistical reasons (e.g., due to completion of 
randomization in current sub-cohort(s)), the subject may be re-screened at a later time for 
potential randomization in subsequent sub-cohorts in the study.  
In such cases, the following screening assessments should be re-done over a period of 42 
to 3 days prior to the baseline visit (Week 0) to re-confirm eligibility, i.e.:  
− 
Subject’s decisional capacity to consent: MacCAT-CR interview (in the Netherlands). To 
be performed prior to the informed consent signature. 
− 
Subject information and consent discussion 
− 
Written informed consent from the subject 
− 
Written informed consent from the caregiver 
− 
Women of child bearing potential: discussion on reliable contraceptive measures (refer 
to section 4.2.3) 
− 
Report former brain MRI assessment (<1 year) 
− 
Previous medications for AD (describe) 
− 
Relevant medical and surgical history for other diseases 
− 
Prior medications  
− 
AEs 
− 
Review NIA-AA diagnostic criteria 
− 
Cognition: MMSE, RBANS (form C) 
− 
Clinical status: C-SSRS, CDR 
− 
Physical and neurological examination 
− 
Vital signs 
− 
Blood sample collected for all lab tests applicable to Screening visit except ApoE 
genotyping 
− 
Routine urine evaluation 
− 
ECG  
− 
Brain MRI should be repeated if clinically indicated (e.g. abnormality on neurological 
exam) or if the MRI scan from the preceding screening period is more than 6 months 
prior to re-screening 
− 
Lumbar puncture for cerebrospinal fluid sample (12 mL) should be repeated if the 
procedure from the preceding screening period is more than 6 months before re-
screening  
− 
Review inclusion and exclusion criteria 
3.5.2.2 
Visit 1/ Baseline [Week 0] 
− 
Check that inclusion/exclusion criteria are still applicable 
− 
Subject and caregiver training to report any AE and SAE 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 

 
 
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− 
Physical and neurological examination 
− 
Vital signs before the administration of study medication 
− 
Cognition: RBANS (form A) 
− 
Clinical status: CDR (only applicable to sub-cohort 1.1), NPI, C-SSRS 
− 
Blood sample collected prior to administration of study medication for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
Inflammatory cytokines 
AD biomarker assessment 
T-Cell profile assessment 
ANA and anti-dsDNA testing 
− 
Routine urine evaluation and urinary pregnancy test 
− 
Administration of study medication 
− 
24-hour clinical observation: 
o 
Vital signs and observation of injection site 1, 2, 4, 8, 12 and 24 hours after the 
administration of study medication  
o 
Physical examination before discharge 
3.5.2.3 
Phone call 1 [Week 0] 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
In case of safety concerns, as per investigator assessment, an additional visit will be 
scheduled in order to further assess the event(s). 
3.5.2.4 
Visit 2 [Week 2] 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
Physical and neurological examination 
− 
Vital signs 
− 
Blood sample collected for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
Inflammatory cytokines 
AD biomarker assessment 
ANA and anti-dsDNA testing 
− 
Routine urine evaluation 
3.5.2.5 
Visit 3 [Week 8] 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
Physical and neurological examination 
− 
Vital signs before the administration of study medication 
− 
Blood sample collected prior to administration of study medication for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers 
Inflammatory cytokines 

 
 
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AD biomarker assessment 
ANA and anti-dsDNA testing 
− 
Routine urine evaluation and urinary pregnancy test 
− 
Administration of study medication 
− 
4-hour clinical observation: 
o 
Vital signs and observation of the injection site 1, 2 and 4 hours after the 
administration of study medication  
o 
Physical examination before discharge 
3.5.2.6 
Phone call 2 [week 8] 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
In case of safety concerns, as per investigator assessment, an additional visit will be 
scheduled in order to further assess the event(s). 
3.5.2.7 
Visit 4 [Week 10] 
This visit can take place within a period of up to 2 days. 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
Physical and neurological examination 
− 
Vital signs 
− 
Blood sample collected for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
Inflammatory cytokines 
AD biomarker assessment 
ANA and anti-dsDNA testing 
− 
Routine urine evaluation  
− 
Brain MRI 
3.5.2.8 
Visit 4.1 [Week 15] 
This visit is only applicable in future sub-cohorts or in ongoing sub-cohorts, in subjects not 
having yet reached this visit timepoint. If feasible, agreed with subject and locally permitted, 
these visits may also be performed at subject’s home. 
- 
AEs 
- 
Concomitant medications (describe new and/or changes from the previous visit) 
- 
Blood samples collected for: 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
AD biomarker assessment 
3.5.2.9 
Visit 4.2 [Week 20] 
This visit is only applicable in future sub-cohorts or in ongoing sub-cohorts, in subjects not 
having yet reached this visit timepoint. If feasible, agreed with subject and locally permitted, 
these visits may also be performed at subject’s home. 
- 
AEs 
- 
Concomitant medications (describe new and/or changes from the previous visit) 
- 
Blood samples collected for: 

 
 
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antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
AD biomarker assessment 
3.5.2.10 
Visit 5 [Week 24] 
− 
Assessment of the subject’s decisional capacity: MacCAT-CR interview (in the 
Netherlands) 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
Physical and neurological examination 
− 
Vital signs before the administration of study medication 
− 
Blood sample collected prior to administration of study medication for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
coagulation indices assessment 
Inflammatory cytokines 
AD biomarker assessment 
ANA and anti-dsDNA testing 
− 
Routine urine evaluation and urinary pregnancy test 
− 
Administration of study medication 
− 
4-hour clinical observation: 
o 
Vital signs and observation of the injection site 1, 2 and 4 hours after the 
administration of study medication  
o 
Physical examination before discharge 
 
Due to the Covid-19 pandemic, local travel restrictions in Finland effective as of 18 March 
2020, and the need to preserve the safety of study participants, changes are made to the 
schedule of visits and procedures of sub-cohort 1.1 subjects:  
• 
Given that the situation is not anticipated to be resolved to allow all procedures to be 
performed according to the protocol, Visit 5 will not be performed for any sub-cohort 1.1 
subjects for whom the planned Visit 5 falls during the at-risk period. 
• 
Instead, a remote visit will be performed in which the subject and caregiver are interviewed 
by telephone concerning any adverse events or changes in concomitant medications. 
Where possible, the NPI and C-SSRS scales will be administered during this interview. The 
remote visit will be performed at the initially planned Visit 5 date and according to the time-
window defined in the Schedule of Assessments, i.e. at week 24 ± 7 days.  
• 
This change is not applicable to the subject who had Visit 5 (week 24) procedures according 
to the protocol on 18 February 2020. 
3.5.2.11 
Phone call 3 [Week 24] 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
In case of safety concerns, as per investigator assessment, an additional visit will be 
scheduled in order to further assess the event(s). 
Due to the Covid-19 pandemic, local travel restrictions in Finland effective as of 18 March 
2020, and the need to preserve the safety of study participants, changes are made to the 
schedule of visits and procedures of sub-cohort 1.1 subjects: Phone call 3 is not applicable in 
case Visit 5 and the associated immunization have not been performed. 
 

 
 
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3.5.2.12 
Visit 6 [Week 26] 
This visit can take place within a period of up to 2 days. 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
Physical and neurological examination 
− 
Vital signs 
− 
Cognition: RBANS (form B) 
− 
Clinical status: CDR, NPI, C-SSRS 
− 
Blood sample collected for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
Inflammatory cytokines 
AD biomarker assessment 
T-Cell profile assessment 
ANA and anti-dsDNA testing 
− 
Lumbar puncture for cerebrospinal fluid sample (12 mL) for cell count, inflammatory 
markers and exploratory biomarker testing (note: blood for serum albumin should be 
taken and measured concomitantly)  
− 
Routine urine evaluation 
− 
Brain MRI  
− 
ECG 
 
Due to the Covid-19 pandemic, local travel restrictions in Finland effective as of 18 March 
2020, and the need to preserve the safety of study participants, changes are made to the 
schedule of visits and procedures of sub-cohort 1.1 subjects:  
• 
Given that the situation is not anticipated to be resolved to allow all procedures to be 
performed according to the protocol, Visit 6 will not be performed for any sub-cohort 1.1 
subjects for whom the planned Visit 6 falls during the at-risk period. 
• 
Instead, a remote visit will be performed in which the subject and caregiver are interviewed 
by telephone concerning any adverse events or changes in concomitant medications. 
Where possible, the CDR, NPI and C-SSRS scales will be administered during this 
interview. The remote visit will be performed at the initially planned Visit 6 date and 
according to the time-window defined in the Schedule of Assessments, i.e. at week 26 ± 2 
days. 
• 
This change is not applicable to the subject who had Visit 5 (week 24) procedures according 
to the protocol on 18 February 2020. 
3.5.2.13 
Visit 6.1 [Week 31] 
This visit is only applicable in future sub-cohorts or in ongoing sub-cohorts, in subjects not 
having yet reached this visit timepoint. If feasible, agreed with subject and locally permitted, 
these visits may also be performed at subject’s home. 
- 
AEs 
- 
Concomitant medications (describe new and/or changes from the previous visit) 
- 
Blood samples collected for: 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
AD biomarker assessment 
 
 

 
 
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3.5.2.14 
Visit 7 [Week 36] 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
Physical and neurological examination 
− 
Vital signs 
− 
Blood sample collected for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers 
Inflammatory cytokines 
AD biomarker assessment 
ANA and anti-dsDNA testing 
− 
Routine urine evaluation 
 
Due to the Covid-19 pandemic, local travel restrictions in Finland effective as of 18 March 
2020, and the need to preserve the safety of study participants, changes are made to the 
schedule of visits and procedures of sub-cohort 1.1 subjects:  
• 
In case the situation is anticipated to not be resolved to allow all procedures to be performed 
according to the protocol, Visit 7 will not be performed. The decision will be taken on a case-
by-case basis depending whether the visit for a particular subject is falling during the at-risk 
period. 
• 
Instead, a remote visit will be performed in which the subject and caregiver are interviewed 
by telephone concerning any adverse events or changes in concomitant medications. 
Where possible, the NPI and C-SSRS scales will be administered during this interview. The 
remote visit will be performed at the initially planned Visit 7 date and according to the time-
window defined in the Schedule of Assessments, i.e. at week 36 ± 3 days.  
3.5.2.15 
Visit 7.1 [Week 42] 
This visit is only applicable in future sub-cohorts or in ongoing sub-cohorts, in subjects not 
having yet reached this visit timepoint. If feasible, agreed with subject and locally permitted, 
these visits may also be performed at subject’s home. 
- 
AEs 
- 
Concomitant medications (describe new and/or changes from the previous visit) 
- 
Blood samples collected for: 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
AD biomarker assessment 
3.5.2.16 
Visit 8 [Week 48] 
− 
Assessment of the subject’s decisional capacity: MacCAT-CR interview (in the 
Netherlands) 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
Physical and neurological examination 
− 
Vital signs before the administration of study medication 
− 
Blood sample collected prior to administration of study medication for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
coagulation indices assessment 

 
 
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Inflammatory cytokines 
AD biomarker assessment 
ANA and anti-dsDNA testing 
− 
Routine urine evaluation and urinary pregnancy test 
− 
Administration of study medication 
− 
4-hour clinical observation: 
o 
Vital signs and observation of the injection site 1, 2 and 4 hours after the 
administration of study medication  
o 
Physical examination before discharge 
3.5.2.17 
Phone call 4 [Week 48] 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
In case of safety concerns, as per investigator assessment, an additional visit will be 
scheduled in order to further assess the event(s). 
3.5.2.18 
Visit 9 [Week 50] 
This visit can take place within a period of up to 2 days. 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
Physical and neurological examination 
− 
Vital signs 
− 
Cognition: RBANS (form A) 
− 
Clinical status: CDR, NPI, C-SSRS 
− 
Blood sample collected for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers 
Inflammatory cytokines 
AD biomarker assessment 
T-Cell profile assessment 
ANA and anti-dsDNA testing 
− 
Lumbar puncture for cerebrospinal fluid sample (12 mL) for cell count, inflammatory 
markers and exploratory biomarker testing (note: blood for serum albumin should be 
taken and measured concomitantly) 
− 
Routine urine evaluation  
− 
ECG 
− 
Brain MRI 
3.5.2.19 
Visit 10 [Week 67] 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
Physical and neurological examination 
− 
Vital signs 
− 
Blood sample collected for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers 
Inflammatory cytokines 

 
 
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AD biomarker assessment 
ANA and anti-dsDNA testing 
3.5.2.20 
Visit 11 [Week 74] 
This visit can take place within a period of up to 2 days. 
− 
AEs 
− 
Concomitant medications (describe new and/or changes from the previous visit) 
− 
Physical and neurological examination 
− 
Vital signs 
− 
Cognition: RBANS (form B) 
− 
Clinical status: CDR, NPI, C-SSRS 
− 
Blood sample collected for: 
routine hematology and biochemistry evaluation, including CRP 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers 
Inflammatory cytokines 
AD biomarker assessment 
ANA and anti-dsDNA testing  
− 
ECG 
− 
Brain MRI 
3.5.2.21 
Visit 12 [Week 86] (Optional) 
This visit would be applicable for future or ongoing sub-cohorts where the sponsor is 
interested in extending the post-injection follow-up period and where subjects have not yet 
passed study visit 12 (week 86). Prior to any assessment described below, written consent 
of subjects will be obtained, and in the Netherlands, the subjects’ decisional capacity will 
be re-assessed before consenting. 
If feasible, after subject consent and if locally permitted, this visit may also be performed at 
subject’s home. 
- 
AEs 
- 
Concomitant medications (describe new and/or changes from the previous visit) 
- 
Blood samples collected for: 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
AD biomarker assessments 
3.5.2.22 
Visit 13 [Week 98] (Optional) 
This visit would be applicable for sub-cohorts where the post-injection follow-up period has 
been extended. Prior to any assessment described below, written consent of subjects will 
have been obtained, and in the Netherlands, the subjects’ decisional capacity will have 
been re-assessed before consenting. 
If feasible, after subject consent and if locally permitted, these visits may also be performed 
at subject’s home. 
- 
AEs 
- 
Concomitant medications (describe new and/or changes from the previous visit) 
- 
Blood samples collected for: 
antibody response components including for example anti-pTau and anti-Tau IgG 
and IgM titers  
AD biomarker assessments 
 

 
 
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3.5.2.23 
Unscheduled Visit (UV) 
At any time during the study, subjects might be invited to the site for additional visits (e.g. further 
evaluation needed following a phone call with the subject). In case of safety concerns, as per 
investigator assessment during a scheduled “Phone call” or a visit of the post-injection period 
extension (if applicable) with the subject, an additional visit will be scheduled in order to further 
assess the event(s). Any subjects attending an unscheduled visit should at a minimum complete 
the following safety related assessments: 
- 
Provide information on new AEs/SAEs since last visit. 
- 
Provide information on new concomitant medication since last visit. 
- 
Be examined for the Vital signs 
- 
Go through physical and neurological examination 
- 
Have blood withdrawn for standard safety evaluation 
Upon investigator’s medical judgement, other assessments considered as needed can be 
performed during those visits (MRI, ECG, etc.). 
 
Due to the resurgence of the pandemic in multiple participating countries since September 2020 
and in case the subject and caregiver cannot travel to the site due to Covid-19 restriction, the 
Unscheduled Visit and related assessments will be performed at subject’s home if feasible and 
locally permitted (see details under 3.5.1.1 Alternative Mode of Administration of Assessments 
to Reduce Safety Risks due to Participation during Covid-19 pandemic).  
3.5.3 
Assessments for Premature Termination 
Any subject, who withdraws from the study prior to completion (see standard categories of early 
termination under section 3.3.3), will be encouraged to at least complete the safety assessment 
evaluation (see detail under 3.5.2.21 Unscheduled Visit) by attending a last visit.  
If this is not possible, subject will be asked to at a minimum, provide the reason for withdrawal 
and provide information on any adverse events that might have arisen since the last visit and the 
outcome of any previously recorded AEs.  
3.5.4 
Safety/Tolerability Assessments 
Safety monitoring after administration of study medication 
All subjects will be kept under clinical observation for 24 hours after the first administration of 
study vaccine and for 4 hours after subsequent administrations of study vaccine (second, third 
and fourth administrations). During that period, the vital signs will be monitored and the injection 
site will be observed on regular basis. A physical examination will be performed prior to 
discharge. The clinical observation may be prolonged in case of safety concerns according to 
the clinical judgement of the investigator.  
A subsequent safety assessment will also be performed 48 to 72 hours after each immunization 
by telephone call for all study subjects. An unscheduled visit should be proposed in case of 
moderate or severe suspected adverse reactions reported by telephone assessment, according 
to clinical judgement. 
Physical and Neurological Examination 
Physical examination will include assessment of general appearance, the head, eyes, ears, nose, 
throat, heart, chest, lungs, abdomen, lymph nodes, extremities, peripheral pulses, skin and any 
other physical conditions of note. Weight will be recorded in kg and height (first attempt) in cm. 
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extremities for muscle strength, reflexes, sensation and cerebellar function. Examinations will be 
performed at each visit at the center. 
Vital Signs 
Vital signs will be measured at each visit. During dosing visits, vital signs (blood pressure, heart 
rate, respiratory rate and temperature) will be measured before and after the administration of 
study vaccine. At V1 (baseline), measurements will be made just before the first injection (time 
0) and at the following time after the injection at 1, 2, 4, 8, 12, and 24 hours. On subsequent 
dosing visits (V3, V5*, V8), measurements will be done at time 0, 1, 2, and 4 hours. *The vital 
signs assessment does not apply in case V5 is performed remotely in sub-cohort 1.1 subjects 
(refer to section 3.5.2.10). 
Blood pressure and heart rate will be measured in the sitting and standing positions at the 
screening visit and at time 0 of V1 (baseline). The sitting blood pressure should be measured 
first and should be measured after the subject has been sitting down for at least 5 minutes. The 
subject should then be asked to stand and the standing blood pressure should be measured after 
the subject has been standing for 2 minutes. At all other time points for V1 or for all other visits, 
blood pressure and heart rate will be measured in the sitting position only. 
Blood pressures will be measured with a standardized mercury manometer; alternative validated 
methods of measurement may also be used. The point of disappearance of Korotkoff sounds 
(phase V) will be recorded as the diastolic blood pressure where a sphygmomanometer is used. 
Heart rate will be determined over 60 seconds following the recording of blood pressure in the 
corresponding position. 
Body temperature will be measured and recorded.  
Pregnancy Testing 
In women of child bearing potential, blood pregnancy tests will be performed at the screening 
visit (blood draw between day -14 and day -3 prior to baseline). Subsequently, pregnancy tests 
from urine will be performed prior to the dosing. The test strips will be provided by the Central 
Laboratory. 
Electrocardiogram (ECG) 
12-lead ECG recording machines will be provided by the central reading company. Printouts of 
each ECG must be kept at the site for archiving. The central reading company will manage ECG 
data through their Web-based platform. The system allows the acquisition, storage and display 
of ECG recordings from the ECG machines so that cardiologists can review them. A manual 
describing all methods for collecting ECG data will be provided to the Investigator.  
Magnetic Resonance Imaging (MRI) 
Brain MRI scans will be conducted according to the schedule of assessments and examined for 
evidence of encephalitis and other brain pathology. Scans will be systematically analyzed e.g. 
for the presence of micro hemorrhages or vasogenic edema by the Central reading company. A 
manual describing all methods for collecting MRI data will be provided to the site. 
Safety Blood and Urine Analysis 
Tests for safety blood and urine analysis will be performed at the central laboratory. Details 
regarding handling, storage and shipment of the safety blood and urine samples will be provided 
to the study centers in writing (see Laboratory Investigator Manual). 
 
 

 
 
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Hematology 
Safety hematological analysis will be performed at all visits. Analyses will include: red blood 
cell count, hemoglobin, hematocrit, red cell indices, white blood cell count (including 
differential), platelet count.  
Coagulation indices (PT (INR)/aPTT) will be measured at the Screening Visit and at visits 
preceding the visits where the lumbar punctures take place. 
Biochemistry 
Safety biochemistry will be performed at all visits. Analyses will include: 
Sodium, potassium, chloride, urea, creatinine, calcium, inorganic phosphate, glucose, total 
bilirubin, total protein, albumin, aspartate aminotransferase, alanine aminotransferase, 
alkaline phosphatase, Gamma GT, creatine kinase, cholesterol, triglycerides and uric acid 
and CRP. 
Diagnosis of auto-immune diseases 
Anti-Nuclear Antibody (ANA) and anti-double stranded DNA (anti-dsDNA) antibody titers will 
be tested at all visits. At dosing visits, the blood sample will be collected prior to injection of 
the study vaccine. A detailed assessment for lupus or other rheumatologic disease will be 
performed if the anti-ds DNA antibody test is positive. Subjects who have a positive anti-
dsDNA antibody result and associated clinical symptoms will be discontinued from further 
immunizations but will be followed for safety. A DSMB review will be held to determine 
further immunizations on the study. 
Safety Urine Analysis 
Safety urine analysis will be performed at visits indicated in the schedule of assessments 
(section 3.5.1). Analyses will include: pH, protein, glucose, ketones and blood. 
Inflammatory Markers in CSF 
CSF samples will be obtained (as per the schedule of assessments of section 3.5.1) using 
standard lumbar puncture procedures performed by a physician experienced in the 
procedure who will ensure that the subject receives appropriate medical care after the 
procedure has been performed. Materials for and details regarding collecting and 
processing CSF samples will be provided to the investigator. CSF samples will be sent to 
Central Laboratory according to provided instructions.  
The lumbar puncture which is conducted at screening should be performed at least 3 days 
prior to the administration of the study medication. This is to reduce the chance that any 
post-lumbar puncture headache might interfere with the assessment of adverse events 
occurring after administration of the study medication. The CSF samples will be examined 
for evidence of inflammation including: 
− 
Protein 
− 
CSF/serum albumin ratio  
− 
IgG + IgM index 
− 
Oligoclonal bands 
− 
Glucose  
− 
Cell Count and differential count when applicable (to be performed at the local site 
laboratory) 
 
 
 

 
 
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Screening Tests  
The following tests will be performed on serum at screening visit only as part of work-up to rule 
out other causes of cognitive impairment: VDRL (Syphilis serology), Vitamin B12 and folate, 
Thyroid function tests (T4, T3, TSH), HIV. In addition Hepatitis B and C testing will be conducted.  
Adverse Events 
All AEs occurring after the subject signs the ICF and up to the last safety follow-up visit (V11 
Week 74) or up to Visit 13 (Week 98) in case the post-injection period is extended, will be 
recorded. 
See Section 4 for additional information. 
Cognitive tests 
The cognitive tests are used either to verify eligibility criteria or as part of the safety assessments 
to verify there is no impairment of subject cognitive status that could be related to the study 
vaccine. The tests have been selected as suitable for the degree of cognitive impairment in 
eligible subjects.  Tests should be performed by a trained rater, who except for the cognitive 
rating activities is not involved in any other study-related activities. The rater should be a 
psychologist or other site personnel, experienced on psychometric tests, who should neither 
perform nor have access to any other subject clinical assessments during the course of the study. 
An experienced and adequately trained back-up rater should exist. Training on cognitive tests 
will be provided by 
. 
Whenever possible the cognitive tests should be performed at the same time of day throughout 
the study for each individual subject, i.e. ideally within a ± 2 hours-time window. 
MMSE 
The Mini Mental State Examination (MMSE) (Folstein 1975) is a widely used test of overall 
cognitive function, assessing memory, orientation and praxis in a short series of tests. The 
score is from 0 to 30 with 30 being the best possible and 0 being the worst possible score. 
The test will only be performed at the screening visit to confirm subject’s eligibility to 
participate.  
RBANS 
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
(Randolph, 1998) is a test designed to measure cognitive decline or improvement in a short 
series of 12 subtests that measure attention, language, visuospatial/constructional abilities, 
and immediate and delayed memory. The test yields 5 Index scores and a Total Scale score. 
Normative information from the test manual is used to calculate the Index and Total scores. 
Three versions of the scale are used during the study: form A (at V1 and V9), form B (at V6 
and V11) and form C (at Screening). 
Clinical rating scales 
The clinical rating tests are used as part of the safety assessments to verify there is no 
impairment of subject clinical status that could be related to the study vaccine. The clinical rating 
scales should be performed by a trained clinical rater (experienced site personnel). The clinical 
rater should not perform the cognitive tests. Training on clinical tests will be provided by 
. 
C-SSRS 
Recent guidance from the FDA has indicated the importance of collecting data on potential 
induction of suicidal behavior with all new agents acting on the central nervous system. 
Although no such effects are anticipated with the study vaccines investigated, this will be 
directly evaluated with the Columbia-Suicide Severity Rating Scale (C-SSRS) at several 

 
 
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time points during the study. Questions related to suicidal behavior or ideation are directly 
asked by the rater to the subject. Two versions of the questionnaire are used during the 
study: Baseline/Screening version (at Screening) and Since Last Visit Version (at V1). 
CDR 
The Clinical Dementia Rating Scale (Hughes et al. 1982) is a global rating of the function of 
AD subjects assessed in six categories: memory, orientation, judgement and problem 
solving, community affairs, home and hobbies and personal care. It is based on a semi-
structured interview conducted with the subject and caregiver, by a rater without access to 
the results of the cognitive tests described above. Each category has scores from 0 (no 
symptoms) to 3 (severe) and the sum of these items (sum of boxes) may therefore range 
from 0 to 18 points. The CDR global score is derived from scores of each individual category 
and will be used as part of the selection criteria (score of 0.5 or 1 at Screening).   
NPI 
The Neuropsychiatric Inventory (NPI) is a 12-item scale which assesses behavioral 
disturbances commonly occurring in dementia subjects. Twelve behavioral areas are 
included in the NPI: delusions, hallucinations, agitation/aggression, depression/dysphoria, 
anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, aberrant motor 
behavior, night-time behaviors, and appetite/eating changes. Through a structured interview 
with the caregiver, each of these 12 domains will be assessed. Both the frequency (0-4) and 
severity (0-3) of each domain will be determined and multiplied together and summed across 
domains for a total score of 0-144; a higher score indicates more severe psychopathology. 
3.5.5 
Primary and Secondary Immune Response Assessments 
At all visits (including visits in the extension of the post-injection period, if applicable), blood will 
be collected for determination of the immune response in serum, i.e. anti-pTau and anti-Tau IgG 
and IgM titers. 
Serum samples after conduct of the per-protocol performed analyses will be stored appropriately 
for up to 10 years after the end of the study and if necessary used for additional analyses with 
other immunogenicity assays. 
3.5.6 
Exploratory assessments 
T cell activation 
Samples of baseline V1, V6 and V9 will be assessed by ELISPOT analysis. 
Remaining unused aliquots of PBMC samples after conduct of the per-protocol performed 
analyses will be stored appropriately for up to 10 years after the end of the study and if necessary 
used for additional analyses with other immunogenicity assays. 
Inflammatory cytokines 
At all visits, blood will be collected for assessment of the inflammatory cytokines (e.g. IL-1β, IL-
2, IL-6; IL-8, IL-10, IFN-γ and TNF-α). 
Biomarkers in CSF and Plasma 
The following putative AD biomarkers will be assessed in CSF and/or in plasma: 
− 
Total tau, pTau, Tau fragments 
− 
Other biomarkers of relevance 
Blood samples for AD biomarker testing will be collected at all visits except screening (including 
visits in the extension of the post-injection period, if applicable).  

 
 
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CSF samples will be collected at Screening, V6 and V9.   
CSF and plasma samples after conduct of the per-protocol performed analyses will be stored 
appropriately for up to 10 years after the end of the study and if necessary used for additional 
analyses with other related biomarker assays.  
Immune response 
At all visits (including visits in the extension of the post-injection period, if applicable), blood will 
be collected for further exploring the immune response in serum. e.g. antibodies against vaccine 
components, functional capacity of vaccine-induced antibodies). 
Serum samples after conduct of the per-protocol performed analyses will be stored appropriately 
for up to 10 years after the end of the study and if necessary used for additional analyses with 
other immunogenicity assays. 
Clinical rating scales and cognitive tests 
The cognitive and clinical assessments described in section 3.5.4 as safety parameters will also 
be examined for any preliminary evidence of efficacy, taking into account that the study is not 
powered for statistical comparisons. 
Subject capacity to consent: MacCAT-CR 
In the Netherlands, the subject’s decisional capacity will be assessed by using the MacArthur 
Competence Assessment Tool for Clinical Research (MacCAT-CR). The MacCAT-CR assesses 
the subject capacities to consent to research participation (Appelbaum and Grisso, 2001). It is a 
21-item structured interview with four subscales assessing the following four main dimensions of 
decision making: understanding, appreciation, reasoning, and expressing a choice. Questions 
are tailored to the research context defined in this protocol. The determination that the subject is 
able to give informed consent and is able to maintain his/her decisional capabilities during the 
study will be based on the subject’s responses to the questions in conjunction with the 
Investigator’s clinical judgement. The rater must be an investigator or delegate adequately 
trained. 
The MacCAT-CR interview will be performed at study start prior to signing the informed consent 
form and subsequently at V5 and V8, and before consenting to the extension of the post-injection 
period. In case it is determined that the subject is no longer able to maintain his/her decisional 
capacity, participation should be discontinued.  
 
 

 
 
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4. SAFETY PROCEDURES 
Throughout the course of the study, all AEs will be monitored and recorded on an AE eCRF, 
including the AE’s description, start and end date, seriousness, severity, action taken, and 
relationship to the investigational product. If AEs occur, the first concern will be the safety of the 
study subjects. All AEs will be followed until resolved or stable and the outcome documented on 
the eCRFs. While not considered an AE per se, pregnancies will also be reported in an expedited 
manner like AEs.  
For the purpose of safety reporting, the trial period is defined as the interval between the 
signature of the informed consent by the subject and the end of the designated follow-up period, 
or the end of the post-injection period extension, if applicable (or last visit/assessment in case of 
early termination). 
4.1 Definitions and Criteria 
4.1.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. 
Pre-existing conditions which worsen during the study, exacerbation of a pre-existing illness or 
increase in frequency or intensity of a pre-existing episodic event or condition are to be reported 
as AEs. A condition detected or diagnosed after the informed consent signature even though it 
may have been present prior to the start of the study should also be reported as an AE. 
4.1.2 
Serious Adverse Event 
A Serious Adverse Event (SAE) is any AE occurring at any dose that results in any of the following 
outcomes: 
o 
Death (Note: Death is an outcome, not an event) 
o 
Life-threatening (Note: life-threatening refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which could hypothetically have 
caused death had it been more severe) 
o 
Inpatient hospitalization or prolongation of an existing hospitalization (Note: “inpatient 
hospitalization” refers to an unplanned, overnight hospitalization) 
o 
Persistent or significant disability / incapacity 
o 
Congenital anomaly / birth defect 
o 
Important medical event (an event not meeting the above criteria but deemed by the 
investigator) to be one that may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above (e.g. intensive treatment in an emergency room or 
at home for allergic bronchospasm or blood dyscrasias or convulsions that do not result in 
hospitalization). 
4.1.2.1 
Clarifications 
Hospitalization for elective treatment of a pre-existing condition that did not worsen during the 
study is not considered an SAE. 

 
 
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Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization, or meets any of the other SAE criteria, then the event is an SAE. 
4.1.3 
Unexpected Adverse Drug Reactions 
An unexpected adverse drug reaction (ADR) is a reaction for which the nature or severity is not 
consistent with the applicable reference safety information (e.g. Investigator’s Brochure). 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. The phrase "responses to a medicinal product" means that 
a causal relationship between a medicinal product and an AE is at least a reasonable probability, 
i.e. the relationship or probability cannot be ruled out. 
4.1.4 
Abnormal Laboratory Values 
Abnormal laboratory findings and other abnormal assessments that are judged by the 
investigator as clinically significant must be recorded as AEs or SAEs if they meet the definition 
of an AE, as defined in section 4.1.1, or an SAE, as defined in section 4.1.2. Clinically significant 
abnormal laboratory findings or other abnormal assessments that are detected after study drug 
administration or that are present at baseline and worsen following the start of the study are 
included as AEs or SAEs. The investigator should exercise medical and scientific judgement in 
deciding whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
4.1.5 
Assessing Intensity and Relationship 
Intensity 
All AEs must be rated on a 3-point scale of increasing severity using the following definitions: 
MILD 
An adverse event that is easily tolerated by the subject causes minimal discomfort and 
does not interfere with everyday activities. 
MODERATE 
An adverse event that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed. Event is not hazardous to the subject’s health. 
SEVERE 
An adverse event that prevents normal everyday activities; treatment or other 
intervention usually needed. Event is a definite hazard to the subject’s health. 
 
Relationship 
The investigator should make an assessment of whether the AE is likely to be related to the IMP 
according to the following definitions 
UNRELATED 
A relationship to the study vaccine can be definitely ruled out (reasonable explanation 
must be given, e.g. involved in traffic accident while in back seat of car). 
UNLIKELY RELATED 
A relationship to the study vaccine is considered unlikely: the time relationship to the 
administration of study vaccine does not suggest a causal relationship and/or the 
underlying disease, other concomitant illnesses or medications appear more likely 
explanations according to present knowledge. 
POSSIBLY RELATED 
There is a reasonable possibility that the adverse event may have been caused by 
the study vaccine: there is a reasonable time relationship to the administration of study 
vaccine but the nature of the event, the underlying disease, and/or concomitant 
medication or concomitant illnesses suggest that other explanations are a significant 
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PROBABLY RELATED 
The study vaccine is considered to be the most likely cause of the adverse event: 
there is a reasonable time relationship to the administration of the study vaccine and 
the event is considered unlikely to be attributed to concurrent disease or concomitant 
medications. 
 
All AEs assessed as having a reasonable suspected causal relationship to the study medication 
(i.e., possibly, probably) will be considered as related to the study medication for regulatory 
reporting purposes. 
4.1.6 
Monitoring and Management of Adverse Events Including Specific Risks 
Adverse events should be managed using adequate measures and symptomatic treatment as 
needed as there is no specific antidote to ACI-35.030 and JACI-35.054.  
Skin reactions at the injection site should be managed symptomatically. In case of local reaction, 
it is recommended to use the alternate arm for the subsequent injection. 
Allergic and anaphylactic reactions should be treated according to standard medical practice.  
Signs and symptoms of neurological adverse events (e.g. headache, confusion, motor and/or 
sensitive deficits) must be assessed in every clinical visit. As per the study protocol, MRI scans 
should be reviewed carefully for abnormalities. Subjects should be regularly reminded to contact 
the site without delay if they experience significant adverse events. An unscheduled visit should 
be proposed in case of moderate or severe suspected adverse reactions reported by telephone 
assessment, according to clinical judgement. 
In suspected cases of meningoencephalitis, patients should be investigated as deemed clinically 
appropriate, e.g. by neurological/psychiatric examination as well as CSF sampling, MRI scanning 
and electroencephalography (EEG). In confirmed cases related to the study vaccine, further 
injections of study vaccine should be withheld, and appropriate treatment such as intravenous 
corticosteroids should be administered according to clinical judgement. If appropriate, 
consideration may be given to the use of plasmapheresis which was reported to be effective in 
one of 2 subjects with meningoencephalitis secondary to the anti-amyloid vaccine AN1792 not 
responding to steroids (Orgogozo et al, 2003). Complications such as convulsions should be 
managed according to standard medical practice. 
4.2 Reporting Procedures and Requirements 
4.2.1 
Adverse Events 
If several signs, symptoms or diagnostic abnormalities are clearly related to a medically defined 
diagnosis or syndrome, the diagnosis should be reported on the AE pages in the eCRF. All clearly 
related signs, symptoms and abnormal diagnostic procedures should be grouped together as a 
single diagnosis. Grouping into a medical diagnosis should only be done if every component sign 
and symptom is a medically and clearly acknowledged component of the diagnosis by standard 
textbooks of medicine. If any aspect of the signs or symptoms does not fit into a classic pattern 
of the diagnosis or syndrome, a separate AE should be reported for each such sign or symptom. 
A diary will be given to subjects as a memory aid for recording adverse events and concomitant 
medication changes occurring during the study conduct. It will be kept with the help of the 
caregiver. Subject diaries should be reviewed by site personnel at each study visit.  
All AEs during the trial will be recorded in the eCRF. For each sign, symptom or diagnosis, the 
Investigator will provide the following information: Type of event, date initiated/observed, severity, 

 
 
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action taken, seriousness, date stopped, outcome and relation to investigational medicinal 
product.  
4.2.2 
Serious Adverse Events 
The Sponsor delegates to 
 the reporting of pharmacovigilance information and data entry 
into the EudraVigilance database. The investigators report to the CRO’s Safety Officer who will 
keep the Sponsor informed. This reporting routine will be described in a written procedure prior 
to start of screening. 
The SAE must be reported immediately by the investigator, within one calendar day (24 hours) 
from time of awareness by telephone or fax to the Safety Officer. Any follow-up data will be 
detailed in a subsequent SAE form, which also must be reported to the Safety Officer within one 
calendar day (24 hours) from time of awareness. Study medication errors, including overdoses 
must be reported in an expedited manner like SAEs, even in the absence of associated clinical 
symptoms.  
All safety related information will be collected and processed promptly, to comply with regulatory 
requirements. 
All AEs that meet the criteria for SAEs, study medication errors, including overdoses require a 
completion of a SAE Report Form. All SAEs must also be recorded on the AE pages in the 
eCRF. AEs (including SAEs) will be collected and recorded from the time the subject signs the 
Informed Consent Form until the last follow-up visit.  
Follow-up: 
a) The investigator should take all appropriate measures to ensure the safety of the 
subjects, notably he/she should follow up the outcome of any SAEs (clinical signs, 
laboratory values or other etc.) until the return to normal or until consolidation of the 
subject’s condition. 
b) In case of any SAE, the subject must be followed up until clinical recovery is complete 
and laboratory results have returned to normal, or until progression has stabilized. This 
may imply that follow-up will continue after the subject has left the trial and that additional 
investigations may be requested by the Sponsor. 
c) In case of any SAE brought to the attention of the investigator at any time after cessation 
of investigational medicinal product and considered by him/her caused by the trial 
treatment with a reasonable possibility, this should be reported to the Sponsor. 
d) The treatment code must be broken only in exceptional circumstances when knowledge 
of the investigational medicinal product is essential for treating the subject. 
e) The Safety Officer identified below will report SAEs to the Competent Authorities and 
Ethical Committees on behalf of the Sponsor according to the applicable regulatory 
requirements. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be notified by the Safety 
Officer to the Competent Authorities and Ethics Committee (EC) in an expedited manner as 
follows: fatal or life- threatening SUSARs – as soon as possible but no later than 7 calendar 
days after receipt of the minimum criteria for expedited reporting; non-fatal and non-life-
threatening SUSARs - as soon as possible but no later than 15 calendar days after receipt of 
the minimum criteria for expedited reporting. Relevant follow- up information for fatal or life-
threatening SUSARs will be provided to the Competent Authorities and EC(s) within an 
additional 8 calendar days. The IB will be used as the reference safety information for the 
determination of the expectedness of the SAE. 

 
 
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testing before the dosing to exclude the possibility of pregnancy. Women who could become 
pregnant must use an effective contraceptive during the course of this study.  
Any woman who finds that she has become pregnant while taking part in the study including 
during the SAE follow-up period should immediately contact the Investigator who should notify 
the Safety Officer without delay. Women who become pregnant during the study will be 
withdrawn from the study and no further immunizations given. While not a SAE, pregnancy must 
be reported as an SAE for monitoring and follow-up. Pregnancy should be followed up until 
delivery, and the Safety Officer informed of the outcome. 
Male participants in the trial with female partner of child bearing potential will be informed about 
the potential risk of the treatment on the partner’s pregnancy and are required to use barrier 
methods of contraception (condoms with spermicide) in addition to contraceptive measures used 
by female partners during the whole study duration. In case a female partner becomes pregnant 
during the subject’s participation in the study, pregnancy will be reported and followed up until 
delivery, and the Safety Officer informed of the outcome. 
4.2.4 
 Stopping Rules 
4.2.4.1 
Stopping at the Individual Subject Level 
Dosing will be suspended at the individual level if a SAE considered related to study medication 
is observed. Dosing will also be suspended at the individual level in the case of adverse reactions 
of moderate intensity persisting for more than 2 weeks or of severe intensity until further 
evaluation by the DSMB. Dosing may also be suspended in the case of adverse reactions of 
shorter duration or lower intensity if the investigator considers this clinically indicated.  
Dosing may also be suspended in the case safety assessments cannot be performed during the 
Covid-19 pandemic and/or are exposing subjects to an increased risk of infection with Covid-19  
(refer to section 1.5.2. Risks of Participation during Covid-19 Pandemic). 
4.2.4.2 
Stopping or Suspension of Dosing  
Dosing will be suspended in all subjects if meningoencephalitis is observed in any subject, until 
further evaluation by the DSMB. The Competent Authority in each participating country will be 
informed of such a temporary halt to dosing following a case of meningoencephalitis. Dosing will 
not recommence until a protocol substantial amendment is submitted to the Competent 
Authorities requesting trial restart. 
All SAEs will be reported to the DSMB who will evaluate them and give recommendations 
whether dosing in the cohort as a whole can continue. Where two or more clinically relevant non-
serious adverse reactions of moderate intensity persisting for more than 2 weeks or severe 
intensity are observed, this will be drawn to the attention of the DSMB who will evaluate the cases 
and determine whether dosing can continue in the cohort as a whole. 
 
 

 
 
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5. DATA MANAGEMENT AND STATISTICAL ANALYSIS 
5.1 Data Management Considerations 
The database is set up and managed by 
 and hosted in a secure web environment by 
software vendor Perceptive Informatics. The database system used is DataLabs which is a 
software designed by Perceptive Informatics and programmed by 
 to provide applications 
for data management, data collection, data validation and storage of clinical trial data. The 
system is in compliance with industry regulations, including FDA 21 Code of Federal Regulations 
(CFR) Part 11. 
The study is run as an EDC-study (Electronic Data Capture), i.e. all relevant data are entered by 
the sites directly into the clinical database under the supervision of the site investigator.  
The subjects enrolled into the trial will be identified in the database by a unique subject number.  
Subject data should be entered into the eCRF by authorized site staff in a timely manner. After 
data entry systematic data validation will be performed and any data discrepancies will be 
presented electronically to the site staff through the DataLabs.  
Queries for discrepant data may be generated automatically by the software upon entry or 
generated manually by the monitor or the trial data manager. All queries, whether generated by 
the system or by trial staff, will be in electronic format.  
The systematic data validation will provide a clean and consistent database prior to the statistical 
analysis. Data will be processed in accordance with the general terms and conditions of the EU’s 
General Data Protection Regulation and any applicable national legislation. 
Handling of data entered into the eCRF and other external data such as laboratory data will be 
specified in the Data Management Plan.  
Data Management will be performed according to current 
 standard operating procedures. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. All source documents should be completed in a neat, legible manner to 
ensure accurate interpretation of data. Data recorded in the electronic case report form (eCRF) 
derived from source documents should be consistent with the data recorded on the source 
documents. 
5.2 Electronic CRFs 
DataLabs will be used for data collection. Following training, trial site staff will be given access to 
the software. Access to the software is restricted to trial staff participating in the trial and the 
extent of access will depend on the staff members’ user role in the trial. 
Data recorded in the eCRFs will be accessible to trial staff through a secure internet connection 
immediately after entry.  
The investigator or staff authorized by the investigator will enter subject data into electronic 
eCRFs. The eCRFs must be maintained in an up-to-date condition at all times by the investigator 
or designee. The investigator, or co-investigator(s) authorized by the investigator, will sign 
electronically all sections of eCRFs used. This signature information (including date of signature) 
will be kept in the audit trail and is unalterable. Only medically qualified (co)investigators can sign 
data on clinical assessments/safety.  
Any correction(s) made by the investigator, or authorized site staff, to the eCRF after original 
entry will be documented in the audit trail. Changes to data already approved require the re-

 
 
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signature of investigator or authorized staff. The audit trail will identify the person making the 
change and the date, time and reason for the change.  
The trial monitor will check the eCRFs for accuracy and completion and perform source data 
verification (SDV). The trial monitor will document electronically SDV of all sections of eCRFs 
used. 
For archiving purposes, each investigator will be supplied with a copy of the eCRFs, for all 
subjects enrolled at the site, via an electronic medium at completion of the trial. Audit trail 
information will be included.  
The eCRFs will be available for inspection by authorized representatives from Sponsor and from 
Regulatory Authorities and/or EC. 
5.3 Statistical Considerations 
Statistical analysis will be performed by 
 and by 
. The presentation and analysis of 
data will be detailed in a Statistical Analysis Plan (SAP) that will be approved by AC Immune. 
5.3.1 
Sample Size Justification 
Antibody titer assessment: The preliminary assessment of the antibody response and of the 
safety/tolerability (comparison between sub-cohorts) will be performed based on the data of all 
randomized subjects (6 on ACI-35.030/JACI-35.054 and 2 on placebo per sub-cohort) based on 
the timepoints related to the different IAs that will be conducted during the study. The initial 
number of subjects in each sub-cohort is consistent with the customary sample size employed in 
this type of studies. It is expected to allow clinical judgement of safety and tolerability, and to get 
preliminary evidence of an acceptable immune response. This sample size is also anticipated to 
provide sufficient evidence to support the possible enrollment of up to 16 additional subjects in 
the sub-cohort(s) showing the most favorable antibody response profile(s) with the objective to 
confirm the initial results. The number of additional subjects to be enrolled will be determined 
based on the preliminary observed immunogenicity response rate in the sub-cohort(s) and on 
the potential gain in precision of the response rate estimate in the expanded sub-cohort(s), and 
will not exceed 16 (12 on ACI-35.030/JACI-35.054 and 4 on placebo per sub-cohort). In addition, 
all other immunogenicity endpoints available at the interim timepoint may be considered in the 
sample size re-estimation. This may include but is not limited to the observed variability of titers 
such as the Anti-pTau IgG and the Anti-e-PHF IgG.  
 
In total, up to 24 subjects can be randomized to cohort 1, cohort 2 and cohort 3, respectively (not 
taking into account sub-cohort(s) expansion). Any randomized subject withdrawing before the 
2nd injection for reasons other than safety may be replaced in the cohort.  
For safety, if an AE occurs at the rate of 1% or 10%, then the chance of observing such an AE 
among 6 subjects receiving that dose of active treatment will be 6% or 47%, respectively. If no 
AE of a given type is observed in any of the 6 subjects at a given dose of active treatment, then 
with 80% (90%) confidence the true incidence of that type of AE at that dose is at most 24% 
(32%). An optional recruitment expansion of up to 16 additional subjects may be considered in 
any sub-cohort to allow further assessment of safety at that dose.  
5.3.2 
Analysis Population 
The intention-to-treat (ITT) analysis set is defined as all randomized subjects who received at 
least one dose of the drug during the study.  

 
 
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The ITT analysis set will be used for presentation of primary, secondary and exploratory 
endpoints and for description of baseline characteristics.  
The per-protocol analysis set (PP) is defined as all subjects from the ITT set who do not have 
any major protocol deviations.  
Major protocol deviations will be defined prior to database lock. In any case, withdrawals from 
the study prior to completion either during the treatment period or during the safety follow-up 
period are considered major protocol deviations.  
The PP analysis set will be used as a supportive analysis of the primary endpoints.  
The definition of the safety analysis set, which will be used for analysis of safety data, is identical 
to the ITT analysis set. 
5.3.3 
Protocol Deviations 
Protocol deviations should be collected by site and grouped into different categories, such as: 
o 
Subjects who enter the study even though they did not satisfy the entry criteria 
o 
Those who developed withdrawal criteria during the study but were not withdrawn 
o 
Those who received the wrong treatment or incorrect dose 
o 
Those who received any excluded concomitant treatment 
Major protocol violations will lead to exclusion from the PP analysis set. 
5.3.4 
Demographic and Baseline Characteristics 
Dose groups will be compared with respect to subject demographics and baseline characteristics 
will be summarized using descriptive statistics. No formal statistical analysis tests will be 
performed.  
Placebo subjects can be pooled over different (sub-)cohorts for presentation, where appropriate. 
5.3.5 
Safety Analyses 
The primary safety endpoints are type, frequency and intensity of AEs evaluated until the end of 
treatment and change from baseline in the parameters of physical and neurological examination, 
vital signs, MRI imaging, ECG, routine hematology and biochemistry evaluation in blood and 
urine, evaluation of autoimmune antibodies in blood and inflammatory markers in blood and CSF. 
Other cognitive and clinical variables related to safety are described below. 
5.3.5.1 
Cognitive/Clinical variables 
The following variables will be included in the analyses: 
1) Global function (change from baseline in CDR-SB (Clinical Dementia Rating Scale-Sum of 
Boxes) 
2) Other cognitive tests (change from baseline in RBANS) 
3) Behavior (change from baseline in NPI) 
4) Columbia-Suicide Severity Rating Scale (C-SSRS) scores 
Data will be presented per measurement time and dose group. 
For endpoint 1), the baseline value is the score obtained at Screening except for subjects of sub-
cohort 1.1 for which the baseline value is the score obtained at V1 [Week 0]. For other endpoints, 
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Screening] at Visit 6 [Week 10], Visit 9 [Week 50] and Visit 11 [Week 74] will be summarized per 
dose group.  
For endpoint 4), individual narratives will be presented for all subjects who report serious suicidal 
intent or any suicidal acts during the study. 
 
Where data on RBANS, CDR-SB and NPI have been collected remotely by telephone interview, 
at subjects’ homes or by videoconference, specific sub-analyses will be conducted in order to 
explore the potential impact of the remote mode of administration on the related results.  
5.3.5.2 
Adverse Events 
All adverse events (AEs) will be coded using the most up-to-date version of the Medical 
Dictionary for Regulatory Affairs (MedDRA). As AEs are collected starting from the moment of 
the ICF signature, AEs and treatment-emergent adverse events (TEAEs) will be discriminated. 
A TEAE is defined as any AE that has an onset date/time on or after the first dose of 
investigational product, or any pre-existing condition that has worsened on or after the first dose 
of investigational product.  
Overview of AEs will be given in terms of number and percentage of subjects per dose group 
experiencing: 
o 
AEs 
o 
SAEs 
o 
Severe adverse events 
o 
Adverse drug reactions 
o 
AEs leading to withdrawal 
o 
Deaths 
AEs will also be summarized by System Organ Class and Preferred Term, according to severity 
(mild, moderate, severe) and according to relationship to drug. 
Most frequent AEs will be presented per dose group in bar charts and time to first SAE will be 
presented graphically. 
5.3.5.3 
Other Variables Related to Safety 
The following variables will be included in the analyses: 
1) Routine hematology and biochemistry evaluations in blood 
2) Routine biochemistry evaluations in urine 
3) Inflammatory markers in blood and CSF 
4) Autoimmune antibodies in blood 
5) Physical examination results 
6) Neurological examination results 
7) Vital signs 
8) Brain imaging (MRI) results 
9) Electrocardiograms 
 
Endpoints 1-4: 
All laboratory parameters will be summarized per dose group and measurement time point. 
Change from baseline will be presented per dose group at Visit 11 [Week 74]. Shift tables will 
present shift from baseline [Week 0] to Visit 9 [Week 50]. 
A box plot will present laboratory values per measurement time and dose group. 

 
 
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Endpoints 5-6: 
Data will be summarized per measurement time and dose group. 
Endpoint 7: 
Vital signs will be presented as described for laboratory parameters. 
Endpoints 8-9: 
Data will be summarized per measurement time and dose group. 
5.3.6 
Immune Response Analyses 
5.3.6.1 
Primary Endpoint 
Anti-pTau IgG titers in serum (geometric mean, change from baseline, responder rate, peak and 
area under the curve). 
5.3.6.2 
Analysis of Primary Endpoint 
Geometric mean and change from baseline at Visit 9 [Week 50] in Anti-pTau IgG titer will be 
calculated. The response will be defined using the parameters given in the SAP. Time-dependent 
development of the titers will be displayed graphically per dose group and per subject. 
The number and proportion of subjects with a positive response will be summarized per visit and 
per dose group. The determination of negative/positive response will be done using a threshold 
defined during assay validation. Response rates will be displayed graphically in a response rate 
vs. dose plot to investigate whether there is any dose response relationship. 
In addition, the peak and area under the curve of antibody response will be described. The results 
will be summarized per dose group.  
No statistical testing has been planned for antibody responses. 
During interim reviews, similar analyses will be performed up to the relevant visit as specified in 
section 5.3.8. 
5.3.6.3 
Secondary Endpoint 
Anti-Tau IgG, anti-pTau and anti-Tau IgM titers in serum (geometric mean, change from baseline, 
responder rate, peak and area under the curve), determination of the IgG response profile by 
avidity testing. 
5.3.6.4 
Analysis of Secondary Endpoint 
The analyses specified under 5.3.5.1 will be done to evaluate the induction of anti-Tau IgG, anti-
pTau IgM and anti-Tau IgM titers in serum.  
The response profile by avidity testing will also be described. 
5.3.7 
Exploratory Analyses 
5.3.7.1 
Exploratory Endpoints 
1) AD biomarkers in blood and CSF 
a. antibody response components including for example total Tau, pTau and Tau 
fragments 

 
 
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b. other putative AD biomarkers as relevant 
2) T-cell activation (ELISPOT) 
3) Inflammatory cytokines in blood (e.g. IL-1B, IL-2, IL-6, IL-8, IL-10, IFN- γ, and TNF- α) 
4) Immune response e.g. antibodies against vaccine components, functional capacity of 
vaccine-induced antibodies 
5) Behavior (NPI), cognitive (including the assessment of the decisional capacity using the 
MacCAT-CR interview in the Netherlands) and functional performance (RBANS, CDR-SB) 
scores 
5.3.7.2 
Analysis of Exploratory Endpoints 
Endpoint 1: 
Data will be summarized per measurement time and dose group. Change from baseline [Week 
0] at Visit 4 [Week 10] (blood biomarkers only), Visit 6 [Week 26] and Visit 9 [Week 50] will also 
be analyzed. 
Data will be presented graphically in a time series plot, presenting mean values per dose group, 
and in a box plot per measurement time and dose group. 
Endpoint 2: 
T-cell activation will be summarized by cohort, dose group and measurement time point. Change 
from baseline [week 0] at Visit 6 [Week 26] and Visit 9 [Week 50] will be presented per dose 
group. 
Endpoint 3: 
Data will be summarized per measurement time and dose group. Change from baseline [week 
0] at Visit 4 [Week 10], Visit 6 [Week 26] and Visit 9 [Week 50].  
Data will be presented graphically in a time series plot, presenting mean values per dose group, 
and in a box plot per measurement time and dose group.  
Endpoint 4: 
Geometric mean and change from baseline at Visit 9 [Week 50] in antibody titers will be 
calculated. The response will be defined using the parameters included in the SAP. Time-
dependent development of the titers will be displayed graphically per dose group and per subject. 
Endpoint 5: 
Data will be presented per measurement time and dose group. 
For the CDR-SB score, the baseline value is the score obtained at Screening except for subjects 
of sub-cohort 1.1 for which the baseline value is the score obtained at V1 [Week 0]. For the NPI 
and RBANS scores, the baseline value is the score obtained at V1 [Week 0]. Change from 
baseline [week 0 or Screening] at Visit 6 [Week 26], Visit 9 [Week 50] and Visit 11 [Week 74] will 
be summarized per dose group. For the MacCAT-CR assessment, the baseline value is the score 
obtained at Screening. The proportion of subjects in the Netherlands who are maintaining their 
decision-making capacity at Visit 5 [Week 24] and Visit 8 [Week 48] using the MacCAT-CR 
assessment will also be presented per dose group. 
Where data on RBANS, CDR-SB and NPI have been collected remotely by telephone interview, 
at subjects’ homes or by videoconference, specific sub-analyses will be conducted in order to 
explore the potential impact of the remote mode of administration on the related results. 
 

 
 
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5.3.8 
Interim Analysis 
The following interim analyses may be conducted in this study (also refer to Figure 1 for 
schematic overview under section 3.1.7).  
Cohort 1 
Timepoint 
Sub-cohorts 
Scope/objective 
Visit 4 [Week 10], 
i.e. 2 to 4 weeks 
after the second 
injection 
Sub-cohort 1.1, 1.2 and 1.3 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of 300 µg, 900 µg and 1800 µg 
ACI-35.030 to dose escalate the sub-cohorts 1.2 
and 1.3 and/or potentially expand the recruitment 
in the sub-cohort 1.1, 1.2 and/or 1.3. Biomarker 
results may also be reviewed  
Visit 6 [Week 26], 
i.e. 2 to 4 weeks 
after 
the 
third 
injection 
Sub-cohort 1.1, 1.2 and 1.3 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of 300 µg, 900 µg and 1800 µg 
ACI-35.030 at this timepoint and potentially 
expand the recruitment in the sub-cohort 1.1, 1.2 
and/or 1.3. Biomarker results may also be 
reviewed. 
Visit 9 [Week 50], 
i.e. 2 to 4 weeks 
after 
the 
last 
injection at Week 
48 
Sub-cohort 1.1, 1.2 and 1.3 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of 300 µg, 900 µg and 1800 µg 
ACI-35.030 at this timepoint, and potentially 
expand the recruitment in the sub-cohort 1.1, 1.2 
and/or 1.3. Biomarker results may also be 
reviewed. 
Visit 11 [Week 
74] 
Sub-cohort 1.1, 1.2 and 1.3 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of 300 µg, 900 µg and 1800 µg 
ACI-35.030 at this timepoint and potentially 
expand the recruitment in the sub-cohort 1.1, 1.2 
and/or 1.3. Biomarker results may also be 
reviewed.  
 
Cohort 2 
Timepoint 
Sub-cohorts 
Scope/objective 
Visit 4 [Week 10], 
i.e. 2 to 4 weeks 
after the second 
injection 
Sub-cohort 2.1, 2.2 
(optional) and 2.3 (optional) 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of 15 µg, 60 µg and 150 µg JACI-
35.054 to dose escalate the sub-cohorts 2.2 and 
2.3 and/or potentially expand the recruitment in 
the sub-cohort 2.1 and/or 2.2 and/or 2.3. 
Biomarker results may also be reviewed. 
Visit 6 [Week 26], 
i.e. 2 to 4 weeks 
after 
the 
third 
injection 
Sub-cohort 2.1, 2.2 
(optional) and 2.3 (optional) 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of 15 µg, 60 µg and 150 µg JACI-
35.054 at this timepoint and potentially expand the 
recruitment in the sub-cohort 2.1, 2.2 and/or 2.3. 
Biomarker results may also be reviewed. 
Visit 9 [Week 50], 
i.e. 2 to 4 weeks 
after 
the 
last 
injection at Week 
48 
Sub-cohort 2.1, 2.2 
(optional) and 2.3 (optional) 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of 15 µg, 60 µg and 150 µg JACI-
35.054 at this timepoint, and potentially expand 
the recruitment in the sub-cohort 2.1, 2.2 and/or 
2.3. Biomarker results may also be reviewed. 

 
 
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Visit 11 [Week 
74] 
Sub-cohort 2.1, 2.2 
(optional) and 2.3 (optional) 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of 15 µg, 60 µg and 150 µg JACI-
35.054 at this timepoint and potentially expand the 
recruitment in the sub-cohort 2.1, 2.2 and/or 2.3. 
Biomarker results may also be reviewed.  
 
Cohort 3 with both vaccines in sequential administration 
Timepoint 
Sub-cohorts 
Scope/objective 
Visit 4 [Week 10], 
i.e. 2 to 4 weeks 
after the second 
injection 
Sub-cohort 3.1, 3.2 (optional) 
and 3.3 (optional) 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of ACI-35.030 and JACI-35.054 
(dosages to be determined) to dose escalate the 
sub-cohorts 3.2 and 3.3 and/or potentially expand 
the recruitment in the sub-cohort 3.1, 3.2 and/or 
3.3. Biomarker results may also be reviewed. 
Visit 6 [Week 26], 
i.e. 2 to 4 weeks 
after 
the 
third 
injection 
Sub-cohort 3.1, 3.2 (optional) 
and 3.3 (optional) 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of ACI-35.030 and JACI-35.054 
(dosages to be determined) at this timepoint and 
potentially expand the recruitment in the sub-
cohort 3.1, 3.2 and/or 3.3. Biomarker results may 
also be reviewed. 
Visit 9 [Week 50], 
i.e. 2 to 4 weeks 
after 
the 
last 
injection at Week 
48 
Sub-cohort 3.1, 3.2 (optional) 
and 3.3 (optional) 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of ACI-35.030 and JACI-35.054 
(dosages to be determined) at this timepoint, and 
potentially expand the recruitment in the sub-
cohort 3.1, 3.2 and/or 3.3. Biomarker results may 
also be reviewed. 
Visit 11 [Week 
74] 
Sub-cohort 3.1, 3.2 (optional) 
and 3.3 (optional) 
Evaluate 
the 
safety, 
tolerability 
and 
immunogenicity of ACI-35.030 and JACI-35.054 
(dosages to be determined) at this timepoint and 
potentially expand the recruitment in the sub-
cohort 3.1, 3.2 and/or 3.3. Biomarker results may 
also be reviewed.  
 
The administration schedule of ACI-35.030 and JACI-35.054 may be subject to modification in 
case the magnitude of immunogenicity response observed during planned interim analysis will 
not be considered satisfactory by the Sponsor. If deemed necessary, such modification will be 
implemented in a protocol amendment. 
 
The IAs described above for the 3 cohorts may also be performed in case of any sub-cohort 
expansion. Additional IAs to review the sustainability of immune response data may be 
conducted between weeks 26 and 50 and between weeks 50 and 74. If the post-injection period 
is extended in any sub-cohort, IA of immunogenicity data may also be conducted at Visit 13 
(Week 98), and optionally at Visit 12 (Week 86).  
 
In case data cut points occur within a short interval of time, interim analysis may be combined as 
deemed appropriate.  
 
 
 

 
 
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Safety assessment by the DSMB 
Additionally to the above interim analyses, the safety data will be reviewed on a quarterly basis 
by the DSMB as described in a DSMB statistical analysis plan. DSMB members will receive 
unblinded packages containing all the safety/tolerability data prior to the meeting. Scope and 
frequency of the meetings are detailed in the DSMB charter. 
Blinding 
For all data analyses, the study treatment assignment will remain blinded for study participants, 
site personnel, CRO, study vendors and sponsor until all subjects in a given sub-cohort have 
reached the end of the safety follow-up visit (Visit 11, Week 74). The DSMB members may be 
unblinded to individual subjects. Designated sponsor representatives who have no access to the 
study database may be semi-unblinded to individual data, i.e. only after systematic re-coding of 
the subject number in order to prevent the identification of the associated treatment assignment.  
If the follow-up of a specific sub-cohort is extended to allow for the assessment of the durability 
of the immune response, the study participants and site investigator/personnel will remain blinded 
to the treatment assignment until the end of the extended period (Visit 13, Week 98). During this 
extended follow-up period (weeks 74-98), designated sponsor representatives may be unblinded 
to the treatment assignment to allow for data review in preparation for later stage trials. Fully 
unblinded designated sponsor representatives will have no access to the study database and will 
not be authorized to share any unblinding information with any blinded study staff. 
Unblinding at an individual level can be performed by site PIs or delegated site staff only for 
emergency reasons. Further information about the blinding of treatment assignment at the site 
level can be found in section 3.4.4. 
Blind management will be outlined in a blinding/unblinding study plan. 
 
 
 

 
 
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6. STUDY MANAGEMENT 
6.1 Ethics and Consent 
6.1.1 
Regulations and Guidelines 
The trial will be conducted according to the principles and rules laid down in the Declaration of 
Helsinki and its subsequent amendments and will be conducted following the principles of ICH 
(International Conference on Harmonization) guideline for Good Clinical Practice and adherence 
with the applicable regulatory or legal requirements. 
6.1.2 
Institutional Review Board/Independent Ethics Committees and regulatory 
authorities  
The study protocol will be submitted for examination to Institutional Review Board (IRB) / Ethics 
Committee (EC) and all applicable regulatory authorities. Commencement of the clinical trial is 
not permitted without written approval of the ethics committee and all applicable regulatory 
authorities. 
The IRB/EC(s) must be notified of and approve all subsequent additions or changes in the study 
protocol. The regulatory authorities must be notified of and approve any substantial protocol 
amendments according to the requirements of applicable regulations. 
6.1.3 
Informed Consent 
The written informed consent procedure should comply with any applicable regulatory 
requirement(s) and should adhere to GCP/ICH guidelines and to the ethical principles that have 
origin in the Declaration of Helsinki, as defined below but not limited to:  
• 
The written informed consent must be obtained before any study specific procedures have 
been undertaken. 
− 
The investigator (or a study site staff designated by the investigator), must obtain 
a written informed consent signed and personally dated by the subject.  
− 
In addition, the Investigator (or a study site staff designated by the investigator) 
must obtain the consent from the subject’s caregiver to conduct his or her study 
related tasks, including supervision of concomitant medications, and contribution 
to assessment of global function, activities of daily living and behavior. 
• 
One original of the informed consent form should be kept in the Investigator’s file and one 
original (or a copy if accepted according to local regulation) provided to the 
subject/caregiver.  
Subjects and/or caregivers may withdraw consent throughout the study, whenever they consider 
appropriate to do so. Country-specific regulatory requirements regarding written informed 
consent procedures will be observed, in addition to the general principles outlined above.  
In the Netherlands, the decisional capacity of subjects will be assessed at study start prior to 
signing the Informed Consent Form to evaluate their capacity to consent and the decisional 
capacity will be also assessed subsequently at V5 and V8, and before consenting for the optional 
post-injection extension. 
Details on this assessment are available under section 3.5.6. 
 

 
 
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6.1.4 
Confidentiality and privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the Sponsor and their contracted vendors. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the Sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the ECs, 
regulatory agencies or pharmaceutical company supplying the IMP may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the ECs, regulatory agencies, or Sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at 
. This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by clinical sites and by 
 research staff will be secured and password protected. At the 
end of the study, all de-identified study databases will be archived at the Sponsor.  
6.1.5 
Future Use of Stored Samples  
Available biological samples (serum, cells and CSF) will be stored for potential exploratory 
assessments, e.g. potential biomarkers (CSF neurogranin, CSF VILIP-1, plasma NFL, Aβ1-42 
and Aβ1-40), antibodies against vaccine components, functional capacity of vaccine-induced 
antibodies, binding of vaccine-induced antibodies to human paired filament tau, anti Tau B cell 
response, T cell activation in CSF, B cell activation in blood. Future use will be limited to research 
related to the study vaccines and/or Alzheimer’s disease.  
With the participant’s approval and as approved by ECs, de-identified leftover blood and CSF 
samples will be stored at a Biosample Repository for up to 10 years after the end of the study 
(i.e. last subject completing the last follow-up visit). Genetic analyses will not be conducted with 
the leftover samples. Permission to transmit and store biological samples to long-term biosample 
repository will be included in the informed consent.  
An individual participant can choose to withdraw consent to have biological specimens stored for 
future research anytime during the storage period.  
6.2 Indemnification 
The sponsor’s indemnification of the investigator and institution during the conduct of this study 
is addressed in a letter of indemnification provided as a separate document. Other 
indemnification or insurance will be provided as necessary under EU and local regulations. 
 
 

 
 
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6.3 Discontinuation of the Study by the Sponsor 
Should it prove necessary to discontinue the study permanently prior to completion (e.g. for 
compromised safety), subjects will be examined as per the final visit and appropriate early study 
completion CRFs completed.  
In case it is decided to terminate the study prematurely, the sponsor will immediately notify 
investigators, relevant authorities and additional contacts. Investigators will promptly notify their 
relevant Ethics Committees and the study participants. The study products and materials will be 
returned.   
In the Netherlands, based on Article 3 of the Revised CCMO Directive on the Assessment of 
Clinical Trial Agreements dated 1 November 2011, premature termination is only possible: 
a. if the judgement of the competent medical research ethics committee that has assessed 
the study is irrevocably revoked; 
b. if a reasonable case can be made for terminating the study in the interests of the health 
of the research subjects; 
c. if it transpires that continuation of the study cannot serve any scientific purpose, and this 
is confirmed by the medical research ethics committee that has issued a positive decision 
on the study; 
d. if one of the parties or the funder has been declared insolvent or a bankruptcy/winding-
up petition has been filed in respect of one of the parties or the financier, or one of the 
parties or the financier is dissolved as a legal entity; 
e. if the principal investigator is no longer capable of performing the tasks of the principal 
investigator, and no replacement agreeable to both parties can be found; 
f. 
if one of the two parties fails to comply with the obligations arising from the agreement 
and, provided compliance is not permanently impossible, this compliance has not taken 
place within thirty days of the defaulting party receiving a written request to comply, 
unless failure to comply is not in reasonable proportion to the premature termination of 
the study; 
g. if circumstances beyond the control of the sponsor, investigator or funder make it 
unreasonable to require the study's continuation. 
6.4 Study Monitoring and Auditing 
This study will be monitored for quality assurance at all stages of its development and conduct 
by the clinical research personnel employed by the sponsor or its representative. Monitoring will 
include personal visits and telephone communication to assure that the investigation is 
conducted according to the protocol, standard operating procedures, Guidelines of Good Clinical 
Practice, and applicable regulatory requirements. Quality control procedures will be applied to 
each stage of data handling to ensure that all data are reliable and have been processed 
correctly. On-site review of eCRFs will include a review of forms for completeness and clarity, 
and consistency with source documents available for each subject. A variety of original 
documents, data and records will be considered as source documents in this trial. The eCRF 
itself is not to be used as a source document under any circumstances. 
Medical advisors and CRAs or assistants may request to witness subject evaluations occurring 
as part of this protocol. The investigator and appropriate personnel will be periodically requested 
to attend meetings organized by the sponsor to assure acceptable protocol execution. The study 
may be subject to audit by the sponsor or by regulatory authorities. If such an audit occurs, the 
investigator must agree to allow access to required subject records. By signing this protocol, the 
investigator grants permission to personnel from the sponsor, its representatives, and 
appropriate regulatory authorities, for on-site monitoring of all appropriate study documentation, 

 
 
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as well as on-site review of the procedures employed in eCRF generation, where clinically 
appropriate. 
6.5 Retention of Records 
The investigational sites will maintain all trial documentation and take measures to prevent 
accidental or premature destruction of these documents. 
The investigator agrees to keep records, including the identity of all participating subjects, all 
original signed Informed Consent Forms, a copy of all eCRFs, and detailed records of drug 
disposition. These should be kept in an Investigator’s File that should be set-up by the Sponsor 
and kept regularly updated by the Investigator during the study. 
To comply with international regulations, the records should be retained by the Investigator 
following the duration of the most stringent authority. The investigational sites must notify the 
sponsor before destroying any data or records. 
6.6 Use of Study Findings 
By signing the study protocol, the investigator agrees to the use of results of the study for the 
purposes of national and international registration. If necessary, the authorities will be notified of 
the investigator’s name, address, qualification, and extent of involvement. Reports covering 
clinical and biometric aspects of the study will be prepared by the sponsor or its representative. 
6.7 Publications 
As a multicenter trial, the sponsor intends to publish clinical data from all centers participating in 
the investigation. A publication committee selected by the sponsor will submit draft manuscripts 
to all participating investigators for their comments. In conformity with the Uniform Requirements 
for Manuscripts Submitted to Biomedical Journals published by the International Committee of 
Medical Journal Editors, investigators whose contribution consists solely in the collection of data 
will not be named individually as authors. Rather, those investigators will receive a collective 
authorship and will be identified in a note. 
Individual investigators and/or their associates subsequently may publish additional finding of the 
study in scientific journals or present them at scientific meetings, provided that the sponsor is 
given ample opportunity to review any proposed abstract, manuscript, or slide presentation 
before its submission. This review is required to ensure that the sponsor is aware of all written 
and oral presentations of the data and does not imply any editorial review or restriction of the 
contents of the presentation or use. 

 
 
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7. REFERENCES 
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Appelbaum PS, Grisso T (2001). MacArthur competence assessment tool for clinical research 
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Bierer LM, Hof PR, et al. (1995) Neocortical neurofibrillary tangles correlate with dementia 
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Farlow MR, et al. (2015) Long-term treatment with active Aβ immunotherapy with CAD106 in mild 
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the cognitive state of patients for the clinician. J Psychiatr Res 12:189-198 
Goedert M, Spillantini MG, Crowther RA (1991) Tau proteins and neurofibrillary degeneration. 
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566-572 
Iaccarino L,et at. (2018) Local and distant relationships between amyloid, tau and 
neurodegeneration in Alzheimer's Disease. NeuroImage: Clinical 17 (2018) 452–464 
Iba M, et al. (2013) Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a 
transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci 33: 1024-1037 
Jalah R, et al. (2014) DNA and Protein Co-Immunization Improves the Magnitude and Longevity 
of Humoral Immune Responses in Macaques. PLoS ONE 9(3): e91550 
Khurana S, et al. (2014) Heterologous Prime-Boost Vaccination with MF59-Adjuvanted H5 
Vaccines Promotes Antibody Affinity Maturation towards the Hemagglutinin HA1 Domain and 
Broad H5N1 Cross-Clade Neutralization. PLoS ONE 9(4): e95496 
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346–351 
McKhann GM, et al. (2011) The diagnosis of dementia due to Alzheimer's disease: 
Recommendations from the National Institute on Aging – Alzheimer's Association workgroups on 
diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia: The Journal of the 
Alzheimer's Association 7(3): 263-269 
Novak P, et al. (2017) Safety and immunogenicity of the tau vaccine AADvac1 in subjects with 
Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neuro 
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Novak P, et al. (2021) ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, 
an active immunotherapy against pathological tau in Alzheimer’s disease. Nature Aging volume 
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Randolph C, et al. (1998) The Repeatable Battery for the Assessment of Neuropsychological 
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and Th1-Type Cellular Immune Responses in a Murine Herpes Simplex Virus-2 gD Vaccine 
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Shukarev G, et al. (2017) A two-dose heterologous prime-boost vaccine regimen eliciting 
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hepatitis B vaccine: side effects and antibody response. Scand J Infect Dis 19(6): 617-21 

 
 
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8. APPENDICES 
Appendix 1  
NIA/AA Criteria for probable AD Dementia (McKhann et al., 
2011) 
I. 
Core Clinical criteria 
Dementia is diagnosed when there are cognitive or behavioral (neuropsychiatric) 
symptoms that: 
o 
Interfere with the ability to function at work or at usual activities; and 
o 
Represent a decline from previous levels of functioning and performing; and 
o 
Are not explained by delirium or major psychiatric disorder; 
o 
Cognitive impairment is detected and diagnosed through a combination of (1) 
history-taking from the patients and knowledgeable information and (2) an objective 
cognitive assessment, either a “bedside” mental status examination or 
neuropsychological testing. 
o 
The cognitive or behavioral impairment involves a minimum of two of the following 
domains: 
 
Impaired ability to acquire and remember new information 
 
Impaired reasoning and handling of complex tasks, poor judgement 
 
Impaired visuospatial abilities 
 
Impaired language functions 
 
Changes in personality, behavior, or comportment 
 
II. 
Criteria for the clinical diagnosis of PROBABLE Alzheimer’s disease 
Probable AD dementia is diagnosed when the patient: 
o 
Meets criteria for dementia as described above and has the following characteristics: 
 
Insidious onset; 
 
Clear-cut history of worsening of cognition by report or observation; and 
 
The initial and most prominent cognitive deficits are evident on history and 
examination in one of the following category. 
 
Amnestic presentation 
 
Nonamnestic presentations 
 
III. 
Other parameters increasing the certainty of AD dementia diagnosis 
o 
Evidence of causative mutation 
o 
Presence of AD biomarkers 
 Low CSF Aβ42 
 Positive PET amyloid imaging 
 Elevated CSF tau (total tau and phosphorylated tau) 
 Decreased fluorodeoxyglucose uptake on PET in temporo-parietal cortex 
 Disproportionate atrophy on structural magnetic resonance imaging in 
medial, basal and lateral temporal lobe and medial parietal cortex.