Objective: Evaluation of safety and initial efficacy of a novel fusion-protein based anti-COVID19 vaccine in healthy volunteers.
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase I: safety / immunogenicity
Phase II: safety / immunogenicity and initial efficacy as expressed by
neutralizing IgG titers / seroconversion.
Secondary outcome
1. To evaluate the inhibitory/neutralization potency of the SP/RBD-specific IgG
titers induced by AKS-452 and to estimate peak titers and duration of the
response.
2. To evaluate the Th1/Th2 immune response profile.
To achieve these objectives, the following will be measured:
a. Anti-SARS-CoV-2 SP/RBD IgG titers at days 0, 28, 56, 90, and 180.
extra time points booster study: day 180+28, day 180+56.
b. Serum titer inhibition of recombinant ACE2-SP/RBD binding and/or
neutralization of live SARS-CoV-2 virus infection of live cells (Plaque
Reduction Neutralization Test, PRNT) at days 0, 28, 56, 90, and 180.
extra time points booster study: day 180+28, day 180+56.
c. T-cell responses measured ex vivo using PBMCs to measure SP/RBD-specific T
cell production of IFN-g and Th1/Th2/Th17 related cytokines via ELISpot or
other Ag-specific flowcytometric-based assays on days 0, 7, 28, 35, 56, 90, and
180.
extra time points booster study: day 180+28, day 180+56.
Background summary
Rationale: Every decade in the twenty-first century has experienced a new major
coronavirus epidemic; SARS in the 2000s, MERS in the 2010s, and now (in 2020)
Coronavirus Disease 2019 (COVID-19) caused by the SARS-COV-2 virus. This novel
COVID-19 is a severe and acute respiratory illness caused by infection with the
SARS-CoV-2 virus. The first COVID-19 case was reported in Wuhan, China in
December 2019 and as of 18 November 2020, there has been approximately 56
million (M) cases world-wide to date (quantified as SARS-Cov-2 virus confirmed
and unconfirmed *probable*), in which there are 18.5M active cases, 36M
recovered cases, and 1.3M fatal cases attributed to COVID-19 (COVID-19
Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns
Hopkins University; https://www.covidtracker.com/). Consequently, to address
this pandemic crisis, there is an immediate need for solutions that can
accurately quantify the level of neutralizing anti-SARSCoV-
2 Abs in individuals and therapeutically induce and/or amplify the level of
neutralizing anti-SARS-CoV-2 Abs across the population. The expectation of the
foreseeable future is that natural and vaccine-induced immunity most likely
will not be long-lived [4, 7-10], and therefore a cost-effective and safe
vaccine administered as frequently as every 6 months, if necessary, is required
to maintain robust immunity among the population. Due to the apparent increased
transmissibility of SARS-CoV-2, a global security priority is to advance and
stockpile coronavirus vaccines as quickly as possible, inevitably requiring
significant international funding and relaxing of regulatory paths in a
responsible manner. Given the challenges of a
recombinant SARS-Cov-2 SP subunit vaccine to induce a strong protective immune
response in an immunologically naïve human population, the SP Ag must be
modified and/or formulated with additional immune-enhancing features to
overcome the activation thresholds of naïve T and B cells. Akston, the
subsidising party of the study, has implemented the following features into its
COVID-19 vaccine that are major advantages over most other such vaccines in
development, in which the Therapeutic Product Profile (TPP) describes details
of its clinical candidate, AKS-452:
1. The use of the smaller focused antigenic portion of SP, the RBD
2. Recombinant fusion of RBD with human IgG1 Fc (SP/RBD-Fc)
3. Emulsification of SP/RBD-Fc in the water-in-oil adjuvant, Montanide ISA 720
In summary, the Fc moiety on AKS-452 is designed to act as a mild adjuvant via
inducing activation signaling to the APC via Fc*Rs and is designed to work in
concert with a strong classical adjuvant, such as Montanide ISA 720, to enhance
the duration of Ag exposure to APCs and perhaps direct Ag entry into lymph
nodes locally and systemically where additional APCs reside. As a consequence,
the Fc moiety in combination with an adjuvant is expected to create a dramatic
dose-sparing potential for both the Ag and adjuvant such that the risk of
reactogenicity (a safety concern) is dramatically reduced; i.e., too much
adjuvant that overactivates many APCs and other innate immune cells can lead a
systemic inflammatory reaction termed reactogenicity. Such reactogenicity is
induced acutely after injection and is not mediated by T and B cells.
Study objective
Objective: Evaluation of safety and initial efficacy of a novel fusion-protein
based anti-COVID19 vaccine in healthy volunteers.
Study design
Study design: Single center, open-label, phase I dose-finding and safety study
combined with a phase II, safety / efficacy study, on the biological activity
against COVID-19 under study to warrant more extensive development towards a
phase III clinical study.
Intervention
We designed a phase 1 and 2 clinical study design by including 6 dosing
cohorts, with subcutaneous (s.c.) administration alone. Consequently, phase 1
will be a classical 6x3 dose-finding design, after which we will assess safety
after each dosing cohort (n=3 subjects). The following stopping-rule will be
applied (see also flow-chart): any SAE or AE <=3 (according to NCI Common
Terminology Criteria for Adverse Events [CTCAE]) attributable to AKS-452.
In case none of the included subjects has an AE<=3 or SAE attributable to
AKS-452, we will expand each dosing cohort with an additional 7 patients. After
completing the 6 cohorts with a total maximum of 10 patients each (overall 60
patients), a safety assessment during the interim analysis between Phase I and
II will be executed. On the basis of this safety assessment conducted on each
cohort and a minimum project seroconversion rate of 70% for each cohort (where
seroconversion is defined as a true positive based on the SP/RBD IgG ELISA
assay positive/negative cutoff criteria using the quantitative cut-off value
defined by the assay kit batch expressed in µg/mL. The positive/negative cutoff
value was established as 1.313 µg/mL from the validation analysis for the
current lot of assay kits, but it should be noted that for each new lot of
assay kits, Akston QC performs a re-validation of the cutoff value in order to
maintain clinical agreement from lot-to-lot), we will determine the optimal
single-dose and the optimal two-dose cohorts for the single-dose s.c. regimen
and two-dose s.c. regimen, respectively, for the Phase II study. If two dosing
cohorts are eligible for the subsequent phase 2 study, the lowest dose-regimen
will be selected. This has been modified in the Research Protocol accordingly.
The phase 1 participants who received a single dose injection (cohort 1,3,5)
will be offered to receive a booster vaccine with the 'naked' AKS-452 (without
the adjuvant Montanide ISA 720) at day 180 of the phase 1 study.
Statistical Re-assessment:
• With a seroconversion rate of 90%, 26 participants in phase 2 dosing cohort
are sufficient to reach with a confidence interval of 95% a seroconversion rate
of 70-98%. The minimal seroconversion rate of 90% is realistic since in both
selected dosis regimes (i.e. 2x45 ug and 1x90 ug) a 100% seroconversion rate in
phase 1 was observed.
• When a seroconversion rate of 100% is observed in phase II, this will be
associated with a 95% confidence interval of 87-100% seroconversion.
With the above mentioned re-assessment we conclude to include a total of 52
participants in phase 2.
Study burden and risks
The burden of participating in the study will be the number of site visits and
possible travelling for subjects in phase I/II, study investigations such as
blood samples for measurement of immunogenicity, physical examination prior to
inclusion / exclusion, and physical discomfort related to the subcutaneous
injection of AKS-452. The risk associated with exposure to a novel vaccine for
a 1st in-human phase I/II clinical study are
pain/swelling/redness/bleeding/infection/granuloma formation at the injection
site, mild fever, chills, feeling tired, headache, muscle and joint aches,
syncope, and an allergic reaction which are all well within the tolerable range
for a novel vaccine like AKS-452. The benefit, in case of a safe and sufficient
immunogenicity provoking vaccine, is for protecting health care workers, future
vulnerable and frail elderly, and patients undergoing large surgical procedures
for instance oncology, transplantation etc. Moreover, providing protection in
co-morbid citizens (I.e., diabetes, overweight, cardiovascular disease etc) and
ultimately, creating another leverage to returning societies back to their
previous health care system capacities and
economic growth world-wide.
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
- Age 18-85 years (extremes included), males and females
- SARS-CoV-2 serology (an anti-SARS-Cov-2 SP-specific IgG ELISA):
o Tests negative for IgG titer and no known prior SARS-Cov-2 infection
- Body mass index (BMI) between 19.0 and 30.0 kg/m2, inclusive
- General good health, without significant medical illness, as determined via
physical exam findings, ECG or vital signs
o Note: one retest of vital functions and ECG is allowed within the screening
window
- No clinically significant laboratory abnormalities as determined by the
investigator
o Note: one retest of lab tests is allowed within the screening window
- Informed Consent Form signed voluntarily before any study-related procedure
is performed, indicating that the subject understands the purpose and
procedures required for the study and is willing to participate in the study
- Willing to adhere to the prohibitions and restrictions specified in this
protocol
- For phase I: No invitation is received to get a registered vaccine
within the first 2 months after the moment of participation in this study.
For phase II this criterium will be abandoned as the whole population
will have received an invitation to get a registered vaccine. Therefore, a
participant should agree not to receive a registered vaccine within 28
days after receiving the last AKS-452 vaccine. For the booster study with
the naked AKS-452 (non-adjuvanted), the participants should waive
their right to receive a registered vaccine within the first 56 days after
receiving the booster vaccine.
- Negative hepatitis panel (including hepatitis B surface Ag and anti-hepatitis
C virus Abs) and negative human immunodeficiency virus Ab and Ag screens at
screening
- Female subjects should fulfil one of the following criteria:
o At least 1 year post-menopausal (amenorrhea >12 months and/or
follicle-stimulating hormone >30 mIU/mL) at screening;
o Surgically sterile (bilateral oophorectomy, hysterectomy, or tubal ligation);
o Will use adequate forms of contraceptives from screening to discharge.
- Female subjects of childbearing potential and male subjects who are sexually
active with a female partner of childbearing potential must agree to the use of
an effective method of birth control from screening to discharge
o Note: medically acceptable methods of contraception that may be used by the
subject and/or partner include combined oral contraceptive, contraceptive
vaginal ring, contraceptive injection, intrauterine device, etonogestrel
implant, double barrier, sterilization and vasectomy
- Female subject has a negative pregnancy test at screening and upon check-in
at the clinical site.
o Note: pregnancy testing will consist of a serum pregnancy test at screening
and urine pregnancy tests at other (dosing) visits, in all women.
Exclusion criteria
- Pregnant or breast feeding females
- Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic,
hematologic, rheumatologic, endocrine, autoimmune, or renal disease
- Any laboratory test which is abnormal, and which is deemed by the
Investigator(s) to be clinically significant
- Behavioral or cognitive impairment or psychiatric disease that in the opinion
of the investigator affects the ability of the subject to understand and
cooperate with the study protocol
- Current alcohol/illicit drug/nicotine abuse or addiction: history or evidence
of current drug use or addiction (positive drug screen for amphetamines,
barbiturates, benzodiazepines, cannabinoids, cocaine, or opiates) or signs of
excessive use of alcohol at screening and Day -2.
- Presence of any febrile illness (T > = 38.0°C or lab confirmed viral disease
(PCR)) or symptoms suggestive of a viral respiratory infection within 1 weeks
prior to vaccination
- Use of corticosteroids (excluding topical preparations for cutaneous or nasal
use) or use of immunosuppressive drugs within 30 days before inoculation
- A history of anaphylaxis, history of allergic reaction to vaccine, known
allergy to one of the components in AKS-452. Mild allergies without angio-edema
or treatment need can be included if deemed not to be of clinical significance
(including but not limited to allergy to animals or mild seasonal hay fever)
- A history of asthma within the past 10 years, or a current diagnosis of
asthma or reactive airway disease associated with exercise
- Receipt of a licensed vaccine within 4 weeks prior to viral inoculation
- Received any (experimental) SARS-CoV-2 vaccine or drug
- Receipt of blood or blood-derived products (including immunoglobulin) within
6 months prior to vaccination.
- Receipt of another investigational agent within 30 days or 5 times the
product half-life (whichever is longest) prior to vaccination
- Shares household with/works with immunocompromised individual(s), adults with
significant cardiopulmonary disease, persons with significant asthma,
institutionalized elderly or elderly with functional disability
- Deprived of freedom by an administrative or court order or in an emergency
setting
- Any condition that in the opinion of the principal investigator (PI) would
jeopardize the safety or rights of a person participating in the trial or would
render the person unable to comply with the protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005997-82-NL |
| ClinicalTrials.gov | NCT04681092 |
| CCMO | NL76321.000.20 |