Hypothesis: A booster dose of the naked (i.e. non-adjuvanted) 5x concentrated AKS-452X vaccine, will provide an enhanced immune response after vaccination with any of the registered vaccines, either as primary vaccin or booster vaccin, against COVID…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Enhanced immune response rate defined as i) at least 80% of all participants
demonstrate any increase in IgG titers between Day 0 and Day 28 and ii) the
geometric mean ratio of titers from Day 28 to Day 0 should be at least three
(3x) times.
Secondary outcome
Safety evaluation for local and systemic adverse events after injection every
pre-defined scheduled follow-up (post intervention). Participants will continue
to be followed passively for additional safety events out to 9 months
post-intervention.
To achieve these objectives, the following will be measured:
o Anti-SARS-CoV-2 SP RBD IgG titers at days 0, 28, 56, 91, 182 and 273
post-boostering.
o 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, and 182
o T-cell responses measured ex vivo using PBMCs to measure SP/RBD-specific T
cell production of IFN-* and Th1/Th2/Th17 related cytokines via ELISpot or
other Ag-specific flow cytometric-based assays on days 0, 28, and 182.
Background summary
Every decade in the twenty-first century has experienced a new major
coronavirus epidemic; SARS in the 2000s, MERS in the 2010s, and now (2020 and
onwards) 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 October 5th, 2021, the moment of
initiation of this study, there has been approximately 236 million (M) cases
world-wide to date (quantified as SARS-Cov-2 virus confirmed and unconfirmed
*probable*), in which there are around 4.8 M 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-SARS-CoV-2 antibodies (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 (boostering), 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 Spike Protein (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 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
(only primary vaccine - which is not part of the booster vaccine)
In summary, the Fc moiety on AKS-452 is designed to act as a mild adjuvant via
inducing activation signaling to the antigen-presenting cell (APC) via
FcypsilonRs 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 is expected to create a dramatic
dose-sparing potential for both the Ag such that the risk of reactogenicity (a
safety concern) is dramatically reduced; i.e., too much adjuvant that
over-activates 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
Hypothesis: A booster dose of the naked (i.e. non-adjuvanted) 5x concentrated
AKS-452X vaccine, will provide an enhanced immune response after vaccination
with any of the registered vaccines, either as primary vaccin or booster
vaccin, against COVID-19
To determine the immunogenicity 4-6 weeks after subcutaneous injection of a
booster dose of 90 µg AKS-452X vaccine in people who have previously received
any of the registered vaccines against COVID-19 for primary or booster
immunization (i.e. Pfizer [ Comirnaty], Moderna [Spikevax], Janssen
[Ad26.COV2.S], AstraZeneca [Vaxzevria]) in human healthy volunteers.
Secondary objective: Vaccine safety and side effects after booster
vaccination.
Study design
Single center, open-label, safety and efficacy study on the biological activity
of a SP/RBD-Fc antigen booster vaccine (AKS-452X) against COVID-19.
Intervention
One booster dose-level of naked AKS-452X (90 µg) will be administered via s.c.
route to 72 subjects who have only received a primary vaccin, divided in 4
cohorts (one cohort per registered vaccin). Furthermore, a cohort of 150
participants will be included, who have received a primary and booster vaccin.
Safety parameters and neutralizing IgG titers will be reviewed after the
booster dose of 90 µg s.c.
Main study parameters/endpoints: Enhanced immune response rate defined as i)
at least 80% of all participants demonstrate any increase in IgG titers between
Day 0 and Day 28 and ii) the geometric mean ratio of titers from Day 28 to Day
0 should be at least three (3x) times.
Secondary endpoints:
Safety evaluation for local and systemic adverse events after injection every
pre-defined scheduled follow-up (post intervention). Participants will continue
to be followed passively for additional safety events out to 9 months
post-intervention.
To achieve these objectives, the following will be measured:
o Anti-SARS-CoV-2 SP RBD IgG titers at days 0, 28, 56, 91, 182 and 273
post-boostering.
o 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, and 182
o T-cell responses measured ex vivo using PBMCs to measure SP/RBD-specific T
cell production of IFN-* and Th1/Th2/Th17 related cytokines via ELISpot or
other Ag-specific flow cytometric-based assays on days 0, 28, and 182.
Study burden and risks
The burden of participating in the study will be the number of site visits and
possible travelling for subjects, 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-452X. The majority of AEs associated with exposure to the AKS-452X vaccine,
based on the observations of a first in-human phase I/II clinical study using
the same AKS-452 vaccine and adjuvant Montanide ISA-720 (ClinicalTrials.gov:
NCT04681092) are *injection site reaction,* and *injection site nodule*. All
registered AEs are likely to subside within days to weeks after appearance. The
future benefit, in the case of a safe and sufficient immunogenicity provoking
booster 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, i.e. low- and middle income countries, capacities
and economic growth world-wide.
100 Cummings Center Suite 454C
Beverly MA 01915
US
100 Cummings Center Suite 454C
Beverly MA 01915
US
Listed location countries
Age
Inclusion criteria
- Age 18-85 years (extremes included), males and females.
- 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, or vital signs
- No clinically significant laboratory abnormalities as determined by the
investigator
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
- All participants must have received a completed (registered) vaccine or
booster at least three months before inclusion in this study (i.e. Pfizer
[Comirnaty], Moderna [Spikevax], Janssen [Ad26.COV2.S], AstraZeneca
[Vaxzevria]).
- 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)
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 the dosing visit, 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 at day 0.
- 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. Participants will be screened for SARS-Cov-2 with an
EUA-approved PCR test at screening, and at day 0.
- 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-452X. 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 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
- 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 | EUCTR2021-005509-28-NL |
| CCMO | NL79397.000.21 |