Research

JAMA Neurology | Original Investigation

Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine

in Adults With Down Syndrome
A Phase 1b Randomized Clinical Trial
Michael S. Rafii, MD, PhD; Olivier Sol, MD; William C. Mobley, MD, PhD; Saskia Delpretti, PhD; Brian G. Skotko, MD, MPP; Anna D. Burke, MD;
Marwan N. Sabbagh, MD; Shauna H. Yuan, MD; Robert A. Rissman, PhD; Margaret Pulsifer, PhD; Casey Evans, PhD; A. Carol Evans, BA;
Gregory Beth, BS; Nicolas Fournier, PhD; Julian A. Gray, MD; Antonio Melo dos Santos, MD; Valerie Hliva, PhD; Marija Vukicevic, PhD;
Marie Kosco-Vilbois, PhD; Johannes Streffer, MD; Andrea Pfeifer, PhD; Howard H. Feldman, MD

Supplemental content
IMPORTANCE Individuals with Down syndrome (DS) are at high risk of developing
Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP,
which leads to increased levels of full-length APP and its products, including amyloid-β (Aβ).
The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders
caused by misfolded Aβ pathological protein. However, the safety, tolerability, and
immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined.

OBJECTIVE To assess the safety and tolerability of the ACI-24 vaccine among adults with DS
as well as its ability to induce immunogenicity measured by anti-Aβ immunoglobulin G titers.

DESIGN, SETTING, AND PARTICIPANTS This multicenter double-blind placebo-controlled

dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical
centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020.
A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate.
Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of
either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27,
2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts
(8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving
placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an
additional 48 weeks of safety follow-up.

INTERVENTIONS Participants were randomized to receive 7 subcutaneous injections of

ACI-24, 300 μg or 1000 μg, or placebo.

MAIN OUTCOMES AND MEASURES Primary outcomes were measures of safety and tolerability
as well as antibody titers.

RESULTS Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years;
9 participants were women, and 7 were men. All participants were White, and 1 participant
had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of
meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a
result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events
[83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events
[85.6%]). No amyloid-related imaging abnormalities with edema or cerebral
microhemorrhage and no evidence of central nervous system inflammation were observed
on magnetic resonance imaging scans. Increases in anti-Aβ immunoglobulin G titers were
observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 μg and 2 receiving
1000 μg) compared with 0 participants receiving placebo. In addition, a greater increase was
observed in plasma Aβ1-40 and Aβ1-42 levels among individuals receiving ACI-24.

CONCLUSIONS AND RELEVANCE In this study, the ACI-24 vaccine was safe and well tolerated
Author Affiliations: Author
in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target affiliations are listed at the end of this
engagement were observed, and anti-Aβ antibody titers were not associated with any article.
adverse findings. These results support progression to clinical trials using an optimized Corresponding Author: Michael S.
formulation of the ACI-24 vaccine among individuals with DS. Rafii, MD, PhD, Alzheimer’s
Therapeutic Research Institute,
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02738450 Keck School of Medicine, University
of Southern California, San Diego,
JAMA Neurol. 2022;79(6):565-574. doi:10.1001/jamaneurol.2022.0983 9860 Mesa Rim Rd, San Diego, CA
Published online May 9, 2022. 92121 (mrafii@usc.edu).

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 Research Original Investigation Safety, Tolerability, and Immunogenicity of ACI-24 Vaccine in Adults With Down Syndrome
D
own syndrome (DS) is most often caused by trisomy
21, which results from an extra copy of chromosome
21 that encodes no fewer than 350 genes,1 including
APP (OMIM 104760); this gene encodes the amyloid precur-
sor protein, APP, whose cleavage products include the amy-
loid-β (Aβ) peptide. This process results in generation of ex-
cess full-length APP and Aβ. In individuals with DS, diffuse Aβ
deposits are visible in the cerebral cortex as early as age 12
years.2 Fibrillar amyloid plaques are observed in almost all
individuals with DS after age 40 years.3-5 The lifetime risk of
AD among individuals with DS is approximately 90%6; as a
result, AD is the leading cause of death among adults with DS
older than 35 years.7
Genetic support for the role of APP in the pathogenesis of
AD among adults with DS is compelling. Individuals with DS
who have trisomy 21 but are disomic for APP develop no amy-
loid plaques or neurofibrillary tangles and have no symp-
toms of dementia.8 In the general population, a mutation in
the APP gene that prevents its cleavage from producing Aβ is
protective against the development of amyloid plaques and
neurofibrillary tangles as well as dementia.9 Amyloid-β there-
fore remains a prime target for therapies intended to treat AD
among individuals with DS. When examined, the neuropa-
thology of AD in persons with DS closely resembles that of AD
in persons without DS.10-14
It is currently estimated that 200 000 persons in the US15
and 417 000 persons in Europe have DS. 16 No disease-
modifying or symptomatic treatment for AD among individu-
als with DS is currently available. Thus, there is an important
and unmet medical need for more effective treatments for AD
in this genetically predisposed population.
The ACI-24 vaccine is liposome based and intended to treat
neurological disorders caused by misfolded Aβ pathological
protein. By incorporating the first 15 amino acids of human Aβ
into a stacked β-sheet conformation on the liposome, ACI-24
induces the production of polyclonal anti-Aβ antibodies spe-
cific for soluble and insoluble aggregated forms of Aβ, includ-
ing oligomers17-19; Aβ oligomers are one of the toxic species that
create pathogenesis in both persons with AD and DS.20 Inocu-
lation of APP×PS-1 mice for AD17 or Ts65Dn mice for DS21 using
a murine version of the ACI-24 vaccine resulted in a modest,
albeit statistically insignificant, reduction of Aβ levels in the
Ts65Dn brain21 and significant decreases in soluble and in-
soluble fractions of Aβ in the APP×PS-1 brain,17 with a con-
comitant improvement in cognitive function. The present study
was designed to assess the safety, tolerability, and immuno-
genicity of the ACI-24 vaccine among human adults with DS.
Methods
Study Design and Participants
In this multicenter double-blind placebo-controlled dose-
escalation phase 1b randomized clinical trial, participants with
DS were enrolled at 3 medical centers with affiliated Down syn-
drome clinics in the US (Massachusetts General Hospital, Bos-
ton, Massachusetts; University of California, San Diego; and
Barrow Neurological Institute, Phoenix, Arizona). The study
566 JAMA Neurology June 2022 Volume 79, Number 6 (Reprinted)
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Key Points
Question Is treatment with the antiamyloid ACI-24 vaccine safe
and tolerable, and does it engage disease indicators in adults with
Down syndrome (DS) who are at risk of developing a genetic form
of Alzheimer disease?
Findings In this randomized clinical trial involving 16 adults with
DS, the ACI-24 vaccine was found to be safe and well tolerated.
The vaccine elicited immunogenicity in 4 of 12 participants and
impacted Alzheimer disease biomarkers.
Meaning This study’s findings demonstrate that interventional
clinical trials can be successfully conducted among individuals with
DS and that the ACI-24 vaccine is safe, well tolerated, and warrants
further investigation.
was conducted between March 30, 2016, and June 29, 2020,
and received institutional review board approval at each study
site before initiation. Written informed consent was obtained
from all participants and their study partners or legal repre-
sentatives before any clinical trial–related activities were per-
formed. The investigator (W.C.M., B.G.S., or A.D.B.) or a des-
ignated staff member met with the participant and the
participant’s study partner or legal representative and ex-
plained the study in sufficient detail to permit an informed de-
cision to participate. Participants provided written informed
consent after demonstrating that they understood the study
procedures. In cases in which participants could not describe
the study procedures, the study partner or legal guardian pro-
vided written consent. The study adhered to all applicable lo-
cal regulations, was conducted in accordance with the Guide-
line for Good Clinical Practice,22 and complied with ethical
standards described in the Declaration of Helsinki.23 This study
followed the Consolidated Standards of Reporting Trials
(CONSORT) reporting guideline for randomized clinical trials.
Eligible participants were men or women with a cytoge-
netic diagnosis of either trisomy 21 or complete unbalanced
translocation of chromosome 21 who were aged 25 to 45 years.
This age range was selected to minimize the presence of sub-
stantial cognitive impairment due to dementia, which would
have impaired participants’ ability to complete study proce-
dures. All participants were required to have a study partner
or legal representative with whom they had direct contact for
a minimum of 10 hours per week and who could be asked ques-
tions about the participant. Exclusion criteria included weight
less than 40 kg, IQ composite score lower than 40 (as mea-
sured by the Kaufman Brief Intelligence Test, Second
Edition24), any current psychiatric or neurological illness other
than DS, drug or alcohol misuse within the past 5 years, or the
presence of a medical condition that could impede evalua-
tion of the study drug. Additional inclusion and exclusion cri-
teria are listed in the trial protocol (Supplement 1). This small
study involving a unique population did not enroll a large num-
ber of members of underrepresented racial and ethnic minor-
ity groups, perhaps as a result of an unawareness of the op-
portunity to participate in clinical trials among these groups.
Participants were randomized between April 27, 2016, and
July 2, 2018. The study consisted of 2 cohorts of 8 partici-
pants each. In cohort 1, 6 participants were randomized to re-
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 Safety, Tolerability, and Immunogenicity of ACI-24 Vaccine in Adults With Down Syndrome
ceive ACI-24, 300 μg, and 2 participants were randomized to
receive placebo; in cohort 2, 6 participants were randomized
to receive ACI-24, 1000 μg, and 2 participants were random-
ized to receive placebo. A total of 7 subcutaneous injections
of either ACI-24 or placebo were administered at weeks 0, 4,
8, 12, 24, 36, and 48 followed by an additional 48-week
treatment-free safety follow-up period, with the last study
visit conducted at week 96. The cohorts were studied sequen-
tially in ascending dose order. Cohort 2 initiated treatment
when safety and tolerability data through week 14 of the treat-
ment period of the last participant in cohort 1 had been re-
viewed by the data safety monitoring board.
Randomization and Blinding
Investigators used a secure web-based system to randomize
eligible participants to study groups. A central dynamic ran-
domization model enabling a balance of treatment allocation
across study groups (3:1 active drug to placebo ratio) was used
at the overall study level due to the limited study population.
This system was programmed to ensure that the randomiza-
tion of the first 4 participants (3 to the active drug group and
1 to the placebo group) to each dose level was separated by an
interval of 7 or more days to enable a sufficient safety moni-
toring period between each participant. The ACI-24 vials were
labeled by the manufacturer (Polymun Scientific Immunbi-
ologische Forschung). The study sponsor (AC Immune), in-
vestigators, and participants were unaware of assigned treat-
ment groups during the active treatment and follow-up periods.
Blinded clinical assessments were conducted by the study in-
vestigators (W.C.M., B.G.S., and A.D.B.). Reviews of blinded
and unblinded safety data were performed on a quarterly ba-
sis by the study sponsor and the data safety monitoring board,
respectively. Blinded analysis of magnetic resonance imaging
(MRI) scans was conducted by an external clinical research
company (BioClinica).
Procedures
The study drug or placebo was administered at weeks 0, 4, 8,
12, 24, 36, and 48. The dosing time of day and relation of dos-
ing to meals were not controlled. Because the appearance of
the liquid in the vial differed between placebo and ACI-24, a
qualified unblinded person at the study site obtained the study
product from the pharmacy and administered the product.
The investigator assigned the responsibility of an unblinded
dispenser or administrator to a person or persons who did not
participate in any subjective evaluation of any participant. As-
sessment of adverse events (AEs), causality and cognitive and
behavioral test results were subjective evaluations of study par-
ticipants and were therefore not permitted to be conducted by
the unblinded dispenser or administrator. Cognitive and be-
havioral tests included the Cambridge Neuropsychological Test
Automated Battery (which measures brain function across 3
cognitive domains: visual memory, attention, and functional
components of executive function),25 the Brief Praxis Test
(which screens for early features of dementia in adults with
intellectual disability),26 the Vineland II Adaptive Behavior
Scales (which measure adaptive behaviors, including ability
to cope with environmental changes, learn new skills, and dem-
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Original Investigation Research
onstrate independence),27 the Neuropsychiatric Inventory
(which measures neuropsychiatric symptoms),28 the Clini-
cian Global Impression of Change (which measures symptom
severity, treatment response, and treatment efficacy),29 a global
assessment of tolerability (performed by W.C.M., B.G.S., and
A.D.B.), and the Columbia–Suicide Severity Rating Scale (which
measures suicidal ideation and behavior).30
The investigator, study coordinator, and any study par-
ticipants other than the unblinded dispenser or administra-
tor were not permitted to know the study product assigned to
any participant. Site monitoring of the clinical trial was un-
dertaken by a blinded monitor for all study data (with the ex-
ception of study drug accountability data), which were re-
viewed by an unblinded monitor along with the unblinded
study site personnel.
The treatment was administered by subcutaneous injec-
tion. For the cohort receiving a low dose (ACI-24, 300 μg, or
placebo), the preferred injection site was the arm, alternating
between the left and right arm for each administration. For the
cohort receiving a high dose (ACI-24, 1000 μg, or placebo),
the preferred injection site was the leg, with the study drug
administered as 2 concomitant subcutaneous injections be-
cause of the higher drug volume. The injection sites were al-
ternated from right leg to left leg between visits. Free anti–
Aβ1-42 immunoglobulin G (IgG) titers were determined using
an assay (Meso Scale Discovery Free Assay) developed in house,
then transferred to an external contract research organiza-
tion (BioAgilytix Labs) for validation of good clinical labora-
tory practice.
Outcomes
The primary objective of this study was to assess the safety,
tolerability and immunogenicity of the ACI-24 vaccine. Pri-
mary end points included AEs, global assessment of tolerabil-
ity, physical and neurological examination results, vital signs,
suicidal ideation or behavior, MRI and electrocardiographic
findings, hematological and biochemical findings from blood
and urine, inflammatory markers in blood and cerebrospinal
fluid (lumbar puncture was optional), and serum anti-Aβ an-
tibody titers.
The secondary objectives were to assess the study drug for
clinical efficacy and effects on cognition, behavior, brain struc-
ture volumes, and blood and/or cerebrospinal fluid biomark-
ers. The secondary clinical assessment end points included
change in cognition from baseline, as measured by the Clini-
cian Global Impression of Change and cognitive assessments;
change in motor control, reaction time, and paired associa-
tive learning from baseline, as measured by the Cambridge
Neuropsychological Test Automated Battery; performance on
the Brief Praxis Test; and change in behavior from baseline,
as measured by the Vineland II Adaptive Behavior Scales and
the Neuropsychiatric Inventory. The secondary biological end
points were whole brain, ventricle, and hippocampal vol-
umes assessed by MRI; T-cell activation; inflammatory cyto-
kines; and AD-related biomarkers, including levels of Aβ, total
tau protein, phosphorylated tau protein, neurofilament light,
neurogranin, and other exploratory biomarkers, such as an-
giogenic proteins and vascular injury markers.
(Reprinted) JAMA Neurology June 2022 Volume 79, Number 6 567
 Research Original Investigation
Figure 1. Study Flowchart
20 Patients with Down syndrome screeneda
4 Did not pass screening
16 Randomized
6 Randomized to receive 6 Randomized to receive 4 Randomized to
ACI-24, 300 μg ACI-24, 1000 μg receive placebo
0 Withdrew from study 2 Withdrew from studyb 0 Withdrew from study
6 Included in the primary 6 Included in the primary 4 Included in the primary
intention-to-treat intention-to-treat intention-to-treat
analysis analysis analysis
a
One participant was rescreened.
b
Two participants discontinued participation because they were unwilling to
attend the final study visit (week 96) due to the risk of COVID-19.
Abnormal laboratory or imaging findings and other ab-
normal clinical assessments that the study investigator (W.C.M.,
B.G.S., or A.D.B.) determined to be clinically meaningful (in-
cluding severity and causal relationship to the study drug) were
recorded if they met the definition of an AE or serious AE. The
MRI scans were conducted at the screening visit (weeks 0-4)
and at weeks 14, 26, 50, and 96; MRI scans were performed
within a 14-day period after the screening visit date (start of
visit plus 14 days) and within a 7-day period before or after the
subsequent visit date (start of visit plus or minus 7 days).
Statistical Analysis
Analyses were 2-tailed and performed as specified in the sta-
tistical analysis plan (Supplement 1), which was finalized be-
fore unblinding of treatment assignments. Evaluations of the
statistical analysis plan were performed by an external clini-
cal research organization (Synteract). The sample size was es-
tablished as 8 participants (6 receiving ACI-24 and 2 receiv-
ing placebo) per cohort. It was expected that the sample size
would be sufficient to achieve the main goals of detecting com-
mon AEs and providing information about the immunogenic-
ity of ACI-24 in this population. No statistical tests were per-
formed because the sample size did not allow for meaningful
statistical inference.
All analyses and tabulations were performed using SAS
software, version 9.4 or higher (SAS Institute Inc). Four data
sets were used for analysis: (1) all participants, which com-
prised all individuals who received initial screening; (2) safety
analysis population, which comprised all randomized partici-
pants who received at least 1 dose of the study drug or pla-
cebo and at least 1 postdosing safety assessment; (3) modi-
fied intention-to-treat population, which comprised all
randomized participants who received at least 1 dose of the
study drug or placebo and at least 1 biological or efficacy as-
sessment at any time during the study after the first dose
administration; and (4) per protocol population, which com-
prised all participants included in the modified intention-to-
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Safety, Tolerability, and Immunogenicity of ACI-24 Vaccine in Adults With Down Syndrome
treat population who completed the treatment period and
received all injections per protocol and for whom no major pro-
tocol deviation was observed. Additional details about the
statistical analysis plan are available in Supplement 1.
Results
Twenty participants were screened for eligibility; of those, 4
participants were not eligible for enrollment, and 1 partici-
pant was rescreened and deemed eligible to participate
(Figure 1). Among 16 enrolled participants, the mean (SD) age
was 32.6 (4.4) years; 9 participants (56.3%) were women, and
7 (43.7%) were men. All participants were White, and 1 par-
ticipant in the ACI-24, 1000 μg, group had Hispanic or Latino
ethnicity. The educational level was identical across all study
groups (mean [SD], 12.0 [0.0] years).
A total of 6 participants were randomized to receive ACI-
24, 300 μg, 6 participants were randomized to receive ACI-
24, 1000 μg, and 4 participants were randomized to receive
placebo. Treatment adherence was 100%; all participants
completed the treatment period (through week 48) and
received all study product administrations. All participants
in cohort 1 who were randomized to receive ACI-24, 300 μg,
or placebo completed the study through week 96 (end of
safety follow-up period); however, only 4 of 6 participants
(66.7%) in cohort 2 who were randomized to receive ACI-24,
1000 μg, completed week 96. These 2 participants (33.3%)
discontinued the study before the end of the safety
follow-up period because they were unwilling to attend the
final site visit as a result of the risk of contracting SARS-
CoV-2. No major protocol deviations occurred during the
study; consequently, all participants from the modified
intention-to-treat population were included in the per proto-
col population, which had the same composition as the
population included in the safety analysis. Most results
reported in this article refer to the modified intention-to-
treat population (with the exception of data shown in
Table 1, which includes baseline demographic information
about participants who were deemed ineligible to participate
based on initial screening results).
Baseline demographic characteristics were similar across
cohorts (Table 1). There were more male participants in the
group receiving ACI-24, 300 μg (4 individuals [66.7%]), vs
the group receiving ACI-24, 1000 μg (2 individuals [33.3%]),
and the groups receiving placebo (1 individual [25.0%]).
Body mass index (calculated as weight in kilograms divided
by height in meters squared) was slightly lower among those
receiving ACI-24, 300 μg (mean [SD], 37.0 [9.9]), vs ACI-24,
1000 μg (mean [SD], 39.9 [9.4]), and placebo (mean [SD],
43.1 [12.7]). The IQ composite score on the Kaufman Brief
Intelligence Test was slightly lower among participants
receiving ACI-24, 300 μg (mean [SD], 44.2 [5.5] points), vs
ACI-24, 1000 μg (mean [SD], 49.2 [9.5] points), and placebo
(mean [SD], 46.0 [8.0] points).
All randomized participants presented with trisomy 21.
A medical history of obesity, which is a common comorbidity
among individuals with DS, was recorded in one-half of par-
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 Safety, Tolerability, and Immunogenicity of ACI-24 Vaccine in Adults With Down Syndrome Original Investigation Research

Table 1. Baseline Demographic Characteristics

No. (%)
Treatment
Ineligible for cohort 1 Treatment cohort
study (ACI-24, 2 (ACI-24, Placebo cohorts
Characteristic Total participationa 300 μg) 1000 μg) 1 and 2
Total participants, 20 4 6 6 4
No.
Age at signing of
informed consent, y
Mean (SD) 32.9 (4.1) 34.0 (2.6) 33.5 (4.6) 31.5 (4.9) 33.0 (4.2)
Median (range) 33.5 (25.0-41.0) 34.0 (31.0-37.0) 32.5 (28.0-41.0) 33.0 (25.0-36.0) 33.0 (28.0-38.0)
Sex
Female 11 (55.0) 2 (50.0) 2 (33.3) 4 (66.7) 3 (75.0)
Male 9 (45.0) 2 (50.0) 4 (66.7) 2 (33.3) 1 (25.0)
Race
Racial minority 0 0 0 0 0
groupsb
White 20 (100) 4 (100) 6 (100) 6 (100) 4 (100)
Ethnicity
Hispanic or Latino 1 (5.0) 0 0 1 (16.7) 0
Non-Hispanic or 19 (95.0) 4 (100) 6 (100) 5 (83.3) 4 (100)
non-Latino
APOE genotype
ε3/ε3 8 (40.0) 0 3 (50.0) 3 (50.0) 2 (50.0)
ε2/ε3 2 (10.0) 0 1 (16.7) 1 (16.7) 0 Abbreviations:
APOE, apolipoprotein E; BMI, body
ε3/ε4 2 (10.0) 0 1 (16.7) 0 1 (25.0) mass index (calculated as weight in
Not reported 8 (40.0) 4 (100) 1 (16.7) 2 (33.3) 1 (25.0) kilograms divided by height in meters
BMI at screening squared); KBIT-2, Kaufman Brief
Intelligence Test, Second Edition.
Mean (SD) 40.2 (10.1) 42.8 (11.6) 37.0 (9.9) 39.9 (9.4) 43.1 (12.7) a
Ineligibility determined by initial
Median (range) 39.4 (24.3-58.3) 41.2 (30.5-58.3) 37.3 (24.3-52.0) 35.1 (31.9-53.4) 47.4 (25.1-52.4) screening results.
KBIT-2 IQ composite b
Racial minority groups include
Mean (SD) 47.8 (10.4) 52.8 (18.9) 44.2 (5.5) 49.2 (9.5) 46.0 (8.0) American Indian or Alaska Native,
Asian, and Black or African
Median (range) 42.0 (40.0-80.0) 45.5 (40.0-80.0) 42.0 (40.0-54.0) 48.5 (40.0-60.0) 43.5 (40.0-57.0)
American.

ticipants in each study group (ie, 3 participants receiving
ACI-24, 300 μg, 3 participants receiving ACI-24, 1000 μg, and
2 participants receiving placebo). However, 13 of 16 partici-
pants (81.3%) had a body mass index greater than 30, thereby
meeting the medical criterion for obesity.
A total of 14 of 20 screened participants (70.0%) reported
having sleep apnea (5 of 6 participants [83.3%] in each ACI-24
group, 1 of 4 participants [25.0%] in the pooled placebo group,
and 3 of 4 participants [75.0%] who were ineligible to partici-
pate based on screening results). Hypothyroidism was also re-
ported in 4 participants (66.7%) receiving ACI-24, 1000 μg,
compared with 2 participants (50.0%) who were ineligible for
study participation and 0 participants in the other study
groups.
Safety and Tolerability Outcomes
No deaths, serious AEs, or treatment-emergent AEs (TEAEs)
leading to study withdrawal were reported during the study.
Overall, 15 of 16 participants (93.8%) reported TEAEs; the only
participant who did not report a TEAE was in the ACI-24, 300
μg, group (Table 2). Most TEAEs were of mild intensity (110 of
132 events [83.3%]) and either unrelated or unlikely to be re-
lated to the study drug (113 of 132 events [85.6%]). Only 2 se-
rious AEs (obstructive sleep apnea and tonsillar hypertrophy)
were reported in 1 participant receiving placebo. Eight mild and
self-limiting injection site reactions were reported in 3 par-
ticipants (50.0%) receiving ACI-24, 1000 μg, with a mean (SD)
time to onset from the last study drug administration of 32.8
(4.8) hours and a mean (SD) time to resolution of 236.9 (32.7)
hours. There were no injection site reactions reported in either
the ACI-24, 300 μg, group or the placebo groups.
Cellulitis considered unrelated to the study drug was re-
ported in 3 participants (50.0%) receiving ACI-24, 300 μg, and
0 participants receiving ACI-24, 1000 μg, or placebo. Rash, in
all cases considered unrelated to the study drug, was re-
ported in 2 participants (33.3%) receiving ACI-24, 1000 μg, 1
participant (16.7%) receiving ACI-24, 300 μg, and 1 partici-
pant (50.0%) in cohort 1 receiving placebo. Headache was re-
ported by 2 participants (33.3%) in the ACI-24, 1000 μg, group
and 1 participant (50.0%) in the cohort 2 placebo group.
Angiogenic proteins and vascular injury markers (ie, vas-
cular endothelial growth factor A, C, and D; tyrosine kinase 2;
C-reactive protein; vascular cell adhesion molecule 1; intra-
cellular adhesion molecule 1, and bicinchoninic acid) were
evaluated in plasma and showed no difference across treat-
ment groups. Inflammatory cytokines (ie, interferon γ, inter-
leukins 10 and 12, and tumor necrosis factor) evaluated in
serum also showed no difference across treatment groups and

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 Research Original Investigation Safety, Tolerability, and Immunogenicity of ACI-24 Vaccine in Adults With Down Syndrome

Table 2. Treatment-Emergent Adverse Events Occurring in 50% or More of Participants in Any Study Group (Safety Analysis Population)a

Treatment Placebo
Cohort 1 Cohort 2
Total (ACI-24, 300 μg) (ACI-24, 1000 μg) Cohort 1 Cohort 2
Participants, Events, Participants, Events, Participants, Events, Participants, Events, Participants, Events,
System organ class No. (%) No. No. (%) No. No. (%) No. No. (%) No. No. (%) No.
Preferred term, No. 16 NA 6 NA 6 NA 2 NA 2 NA
Any AE 15 (93.8) 132 5 (83.3) 56 6 (100) 56 2 (100) 9 2 (100) 11
Infections and 9 (56.3) 33 5 (83.3) 18 3 (50.0) 14 1 (50.0) 1 0 0
infestations
Cellulitis 3 (18.8) 3 3 (50.0) 3 0 0 0 0 0 0
Bronchitis 2 (12.5) 3 1 (16.7) 2 0 0 1 (50.0) 1 0 0
Nervous system disorders 7 (43.8) 14 3 (50.0) 5 3 (50.0) 6 0 0 1 (50.0) 3
Headache 4 (25.0) 6 1 (16.7) 1 2 (33.3) 4 0 0 1 (50.0) 1
Dizziness 2 (12.5) 3 0 0 1 (16.7) 1 0 0 1 (50.0) 2
Respiratory, thoracic, 7 (43.8) 9 3 (50.0) 4 3 (50.0) 3 0 0 1 (50.0) 2
and mediastinal
disorders
Sleep apnea syndrome 2 (12.5) 2 0 0 1 (16.7) 1 0 0 1 (50.0) 1
Tonsillar hypertrophy 2 (12.5) 2 1 (16.7) 1 0 0 0 0 1 (50.0) 1
Gastrointestinal 6 (37.5) 11 3 (50.0) 5 1 (16.7) 3 0 0 2 (100) 3
disorders
Diarrhea 2 (12.5) 3 1 (16.7) 1 1 (16.7) 2 0 0 0 0
Vomiting 2 (12.5) 2 1 (16.7) 1 0 0 0 0 1 (50.0) 1
Abdominal hernia 1 (6.3) 1 0 0 0 0 0 0 1 (50.0) 1
Upper abdominal pain 1 (6.3) 1 0 0 0 0 0 0 1 (50.0) 1
General disorders and 6 (37.5) 13 2 (33.3) 2 2 (33.3) 9 1 (50.0) 1 1 (50.0) 1
administration site
conditions
Fatigue 3 (18.8) 3 2 (33.3) 2 0 0 0 0 1 (50.0) 1
Peripheral swelling 1 (6.3) 1 0 0 0 0 1 (50.0) 1 0 0
Investigations 6 (37.5) 8 2 (33.3) 2 2 (33.3) 3 2 (100) 3 0 0
Weight increased 2 (12.5) 2 1 (16.7) 1 0 0 1 (50.0) 1 0 0
C-reactive protein 1 (6.3) 1 0 0 0 0 1 (50.0) 1 0 0
increased
Menstruation normal 1 (6.3) 1 0 0 0 0 1 (50.0) 1 0 0
Skin and subcutaneous 5 (31.3) 13 1 (16.7) 5 3 (50.0) 7 1 (50.0) 1 0 0
tissue disorders
Rash 4 (25.0) 4 1 (16.7) 1 2 (33.3) 2 1 (50.0) 1 0 0
Eye disorders 4 (25.0) 6 2 (33.3) 4 1 (16.7) 1 1 (50.0) 1 0 0
Lacrimation increased 1 (6.3) 1 0 0 0 0 1 (50.0) 1 0 0
Injury, poisoning, and 4 (25.0) 5 2 (33.3) 2 1 (16.7) 2 0 0 1 (50.0) 1
procedural complications
Lip injury 1 (6.3) 1 0 0 0 0 0 0 1 (50.0) 1
Psychiatric disorders 3 (18.8) 3 1 (16.7) 1 1 (16.7) 1 1 (50.0) 1 0 0
Enuresis 1 (6.3) 1 0 0 0 0 1 (50.0) 1 0 0
Endocrine disorders 2 (12.5) 2 1 (16.7) 1 0 0 1 (50.0) 1 0 0
Hypothyroidism 1 (6.3) 1 0 0 0 0 1 (50.0) 1 0 0
Blood and lymphatic 1 (6.3) 1 0 0 0 0 0 0 1 (50.0) 1
system disorders
Anemia 1 (6.3) 1 0 0 0 0 0 0 1 (50.0) 1
Abbreviations: AE, adverse event; NA, not applicable. Medical Dictionary for Regulatory Activities (MedDRA) software package
a
A participant with more than 1 event in a specific category was only counted developed by the International Council for Harmonisation of Technical
once. Table is sorted by descending participant count on the preferred term Requirements for Pharmaceuticals for Human Use.
level. Preferred term is standard terminology for AE coding used in the

no increase over time (eFigure 1 in Supplement 2). No evi-
dence of T-cell activation was observed during the study.
No laboratory results were deemed clinically meaningful
throughout the study. More weight gain was observed in par-
ticipants randomized to the placebo groups vs the ACI-24
groups (gain of 5 kg vs loss of 1 kg) (eFigure 2 in Supple-
ment 2). No corrected QT intervals (measured by electrocar-
diography; calculated as the time from the start of the Q wave
to the end of the T wave) greater than 480 milliseconds were
noted at any time in any group. No clinically meaningful ab-

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 Safety, Tolerability, and Immunogenicity of ACI-24 Vaccine in Adults With Down Syndrome
Figure 2. Anti–Amyloid-β (Anti-Aβ) 1-42 Immunoglobulin G Titer Values in Serum of Modified Intention-to-Treat Population by Study Visit
2500
2000
Mean absolute anti–Aβ 1-42 IgG, AU/mL
1500
1000
500
0
–500
–2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96
Values were obtained using the Meso Scale Discovery Free Assay. Whiskers represent 95% CIs. Arrows indicate time points of study drug administration.
IgG indicates immunoglobulin G; LLOQ, lower limit of quantification.
normalities and no episodes of amyloid-related imaging ab-
normalities due to vasogenic edema and sulcal effusions or
hemosiderin deposition or central nervous system inflamma-
tion were noted in MRI results at any time during the
study. No consistent changes in brain volume were noted in
participants receiving either dose of ACI-24 compared
with those receiving placebo. There were no changes in re-
sults on the Columbia–Suicide Severity Rating Scale (eTable in
Supplement 2).
Immunogenicity
Anti–Aβ1-42 IgG levels were measured at screening, before any
injections were administered, at weeks 2 and 4 after injec-
tions were administered, and at weeks 60, 72, and 96 during
the follow-up period. The mean absolute free anti–Aβ1-42 IgG
titers per treatment arm are shown in Figure 2. Increased ti-
ters were observed in 4 of 12 participants (33.3%) receiving
ACI-24 (2 receiving 300 μg and 2 receiving 1000 μg) com-
pared with 0 participants receiving placebo. Individual IgG
titers are shown in eFigure 3 in Supplement 2. The partial re-
sponse in immunogenicity may have contributed to the good
safety profile.
Amyloid-Related Biomarkers
Plasma Amyloid-β 1-40 and Amyloid-β 1-42
Similar to immunogenicity, variability in plasma Aβ levels were
observed at baseline. A greater increase in plasma Aβ1-40 and
Aβ1-42 levels was found in participants who received either
dose of ACI-24 compared with those who received placebo,
with higher levels toward the end of the safety observation pe-
riod (mean [SD] changes in plasma Aβ1-40 level: increase of
11.0 [41.5] ng/L in the placebo group; increase of 108.2 [49.2]
ng/L in the ACI-24, 300 μg, group; and increase of 112.3 [26.9]
ng/L in the ACI-24, 1000 μg, group; mean [SD] changes in
plasma Aβ1-42 level: decrease of 6.5 [9.8] ng/L in the placebo
groups; increase of 11.7 [5.0] ng/L in the ACI-24, 300 μg, group;
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Original Investigation Research
ACI-24, 300 μg
ACI-24, 1000 μg
Pooled placebo
1/2 LLOQ
Week
and increase of 13.8 [7.4] ng/L in the ACI-24, 1000 μg, group)
(Figure 3).
Exploratory Biomarkers
Exploratory analyses included measurement of serum neuro-
filament light levels in all participants and cerebrospinal fluid
tau, phosphorylated tau threonine 181, and neurogranin lev-
els in the only 3 participants (1 in the ACI-24, 300 μg, group
and 2 in the ACI-24, 1000 μg, group) who underwent cerebro-
spinal fluid sampling. In addition, whole brain volumetric
assessments were performed. No consistent changes in these
biomarkers were observed in this small sample (eFigure 4 in
Supplement 2).
Clinical and Cognitive Outcomes
Similar to the other exploratory biomarkers, no consistent
changes from baseline were noted in scores on the Brief Praxis
Test; scores on the motor control, reaction time, or paired as-
sociative learning scales on the Cambridge Neuropsychologi-
cal Test Automated Battery; or scores on the Vineland II Adap-
tive Behavior Scales (eFigure 5 in Supplement 2). No differences
in clinical or cognitive outcomes were observed; however, the
study was underpowered to detect any changes.
Discussion
In this randomized clinical trial, the ACI-24 vaccine was found
to be safe and well tolerated at the 2 subcutaneous doses (300
μg and 1000 μg) assessed. No deaths, serious AEs, or TEAEs
leading to study withdrawal were reported during the study.
There were no episodes of central nervous system inflamma-
tion or amyloid-related imaging abnormalities due to vaso-
genic edema and sulcal effusions or hemosiderin deposition.
Injection site reactions, which were mild and self-limiting in
nature, were reported in 3 of 6 participants (50.0%) in the
(Reprinted) JAMA Neurology June 2022 Volume 79, Number 6 571
 Research Original Investigation Safety, Tolerability, and Immunogenicity of ACI-24 Vaccine in Adults With Down Syndrome

Figure 3. Amyloid-β (Aβ) 1-40 and Aβ 1-42 Levels in Plasma of Modified Intention-to-Treat Population by Study Visit

A Amyloid-β 1-40 levels

300
Mean absolute Aβ1-40, ng/L

200

100

ACI-24, 300 μg
ACI-24, 1000 μg
Pooled placebo

–2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96
Week

B Aβ 1-42 levels
80

60
Mean absolute Aβ 1-42, ng/L

40

20

–20

–2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96
Week

Whiskers represent 95% CIs. Arrows indicate time points of study drug administration.

ACI-24, 1000 μg, group, and no injection site reactions were
observed in the ACI-24, 300 μg, group or the placebo groups.
Four of 12 individuals who received ACI-24 (2 in each dose
cohort) showed anti-Aβ IgG response compared with 0 indi-
viduals in the placebo group. The interpretation of this find-
ing is complicated by the existing baseline levels of anti–
Aβ1-42 IgG in this group, which is thought to reflect a response
to the Aβ protein in individuals with DS.31 Notably, there was
evidence for peripheral target engagement with time in the ac-
tively treated groups, as assessed by an increase in plasma
Aβ1-40 and Aβ1-42 levels (Figure 3).
The lack of performance decline on the cognitive scales
among participants randomized to the placebo groups could
be explained by the relatively young age of the participants
(ie, younger than the onset of the clinical stage of AD, which
is expected only after age 40 years32). This finding confirms
the importance of including older participants in future
studies examining effects on cognitive decline. In addition,
the duration of this phase 1b study (ie, 96 weeks) may not
have been sufficient to detect clinical or cognitive changes
among individuals in this age range. The scales proved fea-
sible for use among the study participants, despite their
intellectual impairment. It should be noted that an original
plan to include the Repeatable Battery for the Assessment of
Neuropsychological Status33 was abandoned early in the
study when it became clear that many participants could not
complete the assessment because of the amount of time
required.
Evidence of immunogenicity was observed in 4 of 12 par-
ticipants who received treatment with this T-cell indepen-
dent vaccine, as were pharmacodynamic and target engage-
ment effects, which were reflected by a greater increase in
plasma Aβ1-40 and Aβ1-42 levels in treatment groups com-
pared with placebo groups. Notably, the anti-Aβ antibody ti-
ters observed were not associated with any adverse findings,
which supports the performance of future clinical trials to

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 Safety, Tolerability, and Immunogenicity of ACI-24 Vaccine in Adults With Down Syndrome Original Investigation Research

assess the effect of an optimized vaccine formulation among
individuals with DS.
Strengths and Limitations
This study has strengths. To our knowledge, the study is the
first randomized clinical trial of an antiamyloid vaccine among
adults with DS. The study also demonstrated that it is pos-
sible to successfully conduct multicenter clinical trials of an-
tiamyloid immunotherapies among adults with DS. Further-
more, evidence of pharmacodynamic and peripheral target
engagement suggests the generation of a polyclonal antibody
response to the vaccine target.
The study also has limitations. First, currently available
assays are limited in their ability to detect this polyclonal re-
sponse. Second, amyloid positron emission tomographic
imaging was not incorporated into the design of this small study
given the expected lack of power to discern difference in treat-
ment arms. However, it is notable that, despite clear signs of
vaccine-induced immune response, none of the participants
showed any adverse safety findings.
Conclusions
In this randomized clinical trial of adults with DS, the T-cell
independent antiamyloid ACI-24 vaccine was safe, well toler-
ated, and able to induce an anti-Aβ IgG response in 4 of 12 adults
with DS at the 2 doses of study drug tested. These findings sup-
port the further development of an optimized formulation of
ACI-24 for the treatment of adults with DS, with the goal of im-
proving immunogenicity and consistency of response as a po-
tential avenue for the prevention of AD in individuals with DS.

ARTICLE INFORMATION
Accepted for Publication: February 11, 2022.
Published Online: May 9, 2022.
doi:10.1001/jamaneurol.2022.0983
Author Affiliations: Alzheimer’s Therapeutic
Research Institute, Keck School of Medicine,
University of Southern California, San Diego, San
Diego (Rafii); AC Immune SA, Lausanne,
Switzerland (Sol, Delpretti, Beth, Fournier, Gray,
dos Santos, Hliva, Vukicevic, Kosco-Vilbois, Streffer,
Pfeifer); Department of Neuroscience, University of
California, San Diego, San Diego (Mobley, Rissman);
Down Syndrome Program, Division of Medical
Genetics and Metabolism, Department of
Pediatrics, Massachusetts General Hospital, Boston
(Skotko, Pulsifer, C. Evans); Barrow Neurological
Institute, Phoenix, Arizona (Burke, Sabbagh);
Department of Neurology, University of Minnesota,
Minneapolis (Yuan); Department of Neuroscience,
University of California, San Diego, San Diego
(A. C. Evans, Feldman); Alzheimer’s Disease
Cooperative Study, University of California,
San Diego, San Diego (Feldman).
Author Contributions: Drs Rafii and Sol had full
access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Rafii, Sol, Gray, Pfeifer.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: Rafii, Sol, Burke,
Rissman, Beth, Gray, Vukicevic, Kosco-Vilbois,
Streffer, Pfeifer, Feldman.
Critical revision of the manuscript for important
intellectual content: Rafii, Sol, Mobley, Delpretti,
Skotko, Burke, Sabbagh, Yuan, Rissman, Pulsifer,
C. Evans, A.C. Evans, Fournier, Gray, Melo dos
Santos, Hliva, Vukicevic, Kosco-Vilbois, Streffer,
Pfeifer, Feldman.
Statistical analysis: Rafii, Pulsifer, Fournier, Streffer.
Obtained funding: Rafii, Feldman.
Administrative, technical, or material support: Rafii,
Sol, Mobley, Delpretti, Yuan, Rissman, C. Evans,
A.C. Evans, Beth, Gray, Melo dos Santos, Hliva,
Pfeifer, Feldman.
Supervision: Rafii, Sol, Mobley, Skotko, Yuan, Hliva,
Kosco-Vilbois, Streffer, Pfeifer.
Conflict of Interest Disclosures: Dr Rafii reported
receiving grants from the National Institutes of
Health (NIH) and personal fees from AC Immune
during the conduct of the study and personal fees
from Alzheon and Keystone Bio outside the
submitted work. Dr Sol reported receiving personal
fees from AC Immune outside the submitted work.
Dr Mobley reported receiving grants from AC
Immune, the LuMind IDSC Foundation, and the NIH
and personal fees from AC Immune during the
conduct of the study; grants from AC Immune,
Annovis Bio, and Samumed (now Biosplice
Therapeutics); personal fees from AC Immune,
Alzheon, Annovis Bio, Cortexyme, Pfizer, and
Samumed (now Biosplice Therapeutics); serving as
a board member of ProMIS Neurosciences; owning
stock options in CuraSen Therapeutics; and owning
a patent for a gamma secretase modulator (licensed
to the University of California, San Diego [UCSD])
outside the submitted work. Dr Delpretti reported
receiving grants from the LuMind IDSC Foundation
and the NIH and personal fees from AC Immune
during the conduct of the study and receiving
personal fees from AC Immune outside the
submitted work. Dr Skotko reported receiving
grants from UCSD during the conduct of the study;
grants from F. Hoffmann-La Roche and the LuMind
IDSC Foundation; personal fees from the Gerson
Lehrman Group; and royalties from Woodbine
House and serving on the honorary board of
directors of the Massachusetts Down Syndrome
Congress and the professional advisory committee
of the National Center for Prenatal and Postnatal
Down Syndrome Resources outside the submitted
work. Dr Sabbagh reported receiving personal fees
from Biogen, Cortexyme, Eisai Co, Eli Lilly and
Company, Qynapse, Renew Research, Roche, and
T3D Therapeutics and owning stock in Alzheon,
Athira Pharma, Cognoptix, and uMethodHealth
outside the submitted work. Dr Evans reported
receiving grants from the LuMind IDCS Foundation
during the conduct of the study. Dr Beth reported
receiving grants from the LuMind IDCS Foundation
and the NIH and personal fees from AC Immune
during the conduct of the study and receiving
personal fees from AC Immune outside the
submitted work. Dr Fournier reported receiving
grants from the LuMind IDSC Foundation and the
NIH and personal fees from AC Immune during the
conduct of the study and receiving personal fees
from AC Immune outside the submitted work.
Dr Gray reported receiving grants from AC Immune,
the LuMind IDSC Foundation and the NIH and
personal fees from AC Immune during the conduct
of the study and receiving personal fees from AC
Immune outside the submitted work. Dr Melo dos
Santos reported receiving grants from the LuMind
IDSC Foundation and the NIH and personal fees
from AC Immune during the conduct of the study
and receiving personal fees from AC Immune
outside the submitted work. Dr Hliva reported
receiving grants from the LuMind IDSC Foundation
and the NIH and personal fees from AC Immune
during the conduct of the study and receiving
personal fees from AC Immune outside the
submitted work. Dr Vukicevic reported receiving
grants from the LuMind IDSC Foundation and the
NIH and personal fees from AC Immune during the
conduct of the study and receiving personal fees
from AC Immune outside the submitted work.
Dr Kosco-Vilbois reported receiving grants from the
LuMind IDSC Foundation and the NIH and personal
fees from AC Immune during the conduct of the
study. Dr Streffer reported receiving grants from
the LuMind IDSC Foundation and the NIH and
personal fees from AC Immune during the conduct
of the study and receiving personal fees from AC
Immune outside the submitted work. Dr Pfeifer
reported receiving personal fees from AC Immune
during the conduct of the study and outside the
submitted work. Dr Feldman reported receiving
grants from AC Immune and the NIH during the
conduct of the study and receiving grants from
Annovis Bio, Biohaven Pharmaceutical Holding
Company, the LuMind IDSC Foundation, and
Vivoryon Therapeutics and personal fees from the
World Events Forum and serving as a consultant for
Arkuda Therapeutics, Axon Neuroscience, Biosplice
Therapeutics, Janssen Pharmaceuticals, Novo
Nordisk, Roche/Genentech, Samus Therapeutics,
and the Tau Consortium outside the submitted
work. No other disclosures were reported.
Funding/Support: This study was sponsored by
AC Immune and supported by grant R01AG047922
from the NIH (Dr Rafii).
Role of the Funder/Sponsor: AC Immune
participated in study design, study research, data
collection, data analysis, and data interpretation
and writing, review, and approval of the
manuscript. All authors had full access to the data,
participated in the development and review of the
manuscript, take full responsibility for the content,

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 Research Original Investigation
and approved the manuscript for submission for
publication.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank the
participants and their caregivers who participated
in this study. We also thank Wolfgang Barth, PhD, of
AC Immune; the late Michael Harpold, PhD, of the
LuMind IDSC Foundation; and the late Andreas
Muhs, PhD, of AC Immune. The study investigators
express their appreciation to members of the
clinical trial data safety monitoring board, including
Dan Weintraub, MD, chair; Serge Gauthier, MD;
Richard Kryscio, PhD; and Andrew Feigin, MD. The
Massachusetts General Hospital thanks Amy Torres,
BS, Vasiliki Patsiogiannis, BS, Kelsey Haugen, BS,
and Kavita Krell, BS, who served as clinical research
coordinators. Stephanie Santoro, MD, of
Massachusetts General Hospital, also assisted with
some physical examinations. The sponsor, AC
Immune, provided project management and
medical monitoring support and used Synteract for
data collection and statistical analyses. Imaging was
managed by BioClinica. Safety laboratory analyses
were processed by ICON Central Laboratories. The
Alzheimer’s Disease Cooperative Study provided
clinical trial coordination, project management,
regulatory and medical safety support, and site
monitoring for this study. Clinical trial progress was
reviewed regularly with the Alzheimer’s Disease
Cooperative Study Steering Committee and Laurie
Ryan, PhD, chief, Clinical Interventions and
Diagnostic Branch, Division of Neurosciences,
National Institute of Aging, whose support is
gratefully acknowledged.
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