A Trial of a Peptide-based Group A Streptococcal (GAS) Vaccine Candidate in Healthy Individuals.
Study Details
Study Description
Brief Summary
The purpose of this study is to investigate the safety and antibody (germ fighters) response of experimental (investigational) vaccine candidates against the germ group A streptococcus when injected into the arm of healthy adults.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
Group A streptococcus (GAS) is a bacteria that cause a number of different infections that range from mild illnesses to deadly diseases. It is estimated 500,000 deaths occur worldwide each year from GAS. To address these high rates of disease, the investigators want to test a new potential vaccine for safety and immune response in healthy participants.
To test the new vaccine, the investigators are proposing a two-phase study. Phase 1 of the study will be dose-escalating based on safety. 8 participants will receive 1 injection into the muscle in the phase 1 portion of the study in a 2x2x2x2 design whereby 2 participants will receive the lowest dose of vaccine and be assessed for 3 weeks. If there are no safety concerns the next 2 participants will receive the second-highest dose of vaccine and be assessed for 3 weeks. The dose increase will occur until all 8 patients have completed a 3-week assessment period for safety.
If there are no safety concerns after all 4 vaccine arms have been assessed, the study will proceed to a phase 2 double-blind randomized clinical trial. 37 healthy participants will be randomized to 1 of 5 arms of the study (1 placebo, and 4 experimental treatment arms from phase 1). Following a screening appointment, the participants will each receive 3 injections (baseline, 3 weeks, and 6 weeks) in addition to 2 follow up visits for total participation of approx 10 months.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Vaccine p*17-K4S2 (25 µg/mL) Vaccine To evaluate the safety and immunogenicity of *17-CRM197 (12.5µg) + K4S2-CRM197 (12.5µg): TOTAL 25 µg |
Biological: p*17-K4S2 (25 µg/mL)
Administer p*17-K4S2 25 μg vaccine at 0, 3, and 6 weeks and evaluate the safety and antibody levels for a total of 6 months after the last injection. All vaccines will be administered intramuscularly
|
| Experimental: Vaccine p*17-K4S2 (50 µg/mL) Vaccine To evaluate the safety and immunogenicity of p*17-CRM197 (25µg) + K4S2-CRM197 (25µg): TOTAL 50 µg |
Biological: p*17-K4S2 (50 µg/mL)
Administer p*17-K4S2 50 μg vaccine at 0, 3, and 6 weeks and evaluate the safety and antibody levels for a total of 6 months after the last injection. All vaccines will be administered intramuscularly
|
| Experimental: Vaccine p*17-K4S2 (100 µg/mL) Vaccine To evaluate the safety and immunogenicity *17-CRM197 (50µg) + K4S2-CRM197 (50µg): TOTAL 100 µg |
Biological: p*17-K4S2 (100 µg/mL)
Administer p*17-K4S2 100 μg vaccine at 0, 3, and 6 weeks and evaluate the safety and antibody levels for a total of 6 months after the last injection. All vaccines will be administered intramuscularly
|
| Experimental: J8-K4S2 (100 µg/mL ) Vaccine To evaluate the safety and immunogenicity -CRM197 (50µg) + K4S2-CRM197 (50µg): TOTAL 100 µg |
Biological: J8-K4S2 (100 µg/mL)
Administer a vaccination schedule of p*17-K4S2 25 μg vaccine at 0, 3, and 6 weeks and evaluate the safety and antibody levels for a total of 6 months after the last injection. All vaccines will be administered intramuscularly
|
| Sham Comparator: Rabavert Vaccine Comparator vaccine (RABAVERT) |
Biological: Rabavert vaccine
Administer the standard Rabavert vaccine at 0, 3, and 6 weeks and evaluate the safety and antibody levels for a total of 6 months after the last injection. All vaccines will be administered intramuscularly. The Rabavert vaccine will be used as a control comparator as it has a similar approved dosing schedule to the investigational vaccines.
|
Outcome Measures
Primary Outcome Measures
- Adverse Events [6 months after last dose of vaccine is administered]
Safety is the primary outcome, and will be measured by assessing the clinical symptoms and signs at each study visit and completing standard lab parameters (hematological and biochemical) as well as performing echocardiograms to assess for mitral regurgitation
Secondary Outcome Measures
- Immunogenicity [6 months after last dose of vaccine is administered]
Antibody titre levels will be measured prior to each vaccine dose administered as well as 2 after the last dose and 6 months after the last dose
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Able to understand the purpose and the procedures involved in this study and sign the informed consent form.
-
Male or non-pregnant female adults, 18-45 years of age inclusive.
-
Non-smoker and in good general health, as determined by medical screening evaluation, performed by PI or delegated sub-investigator no greater than 28 days before the first dose in the form of medical history, clinical laboratory tests and physical examination.
-
Normal Electrocardiogram (ECG).
-
Echocardiogram (ECHO) that is normal or with findings that are considered trivial and clinically insignificant such as 'Clinically insignificant/trivial mitral regurgitation
-
Women must agree not to become pregnant during the trial. If they are sexually active, they must use an effective method of birth control, e.g. insertable, injectable, transdermal, or combination oral contraceptive approved by Health Canada combined with a barrier contraceptive and have negative results on a serum or urine pregnancy test done before administration of study medication.
-
Intention to reside in the geographical area for next 10 months and not intending to travel overseas for at least 30 days following the last study vaccine administration.
-
Agree not to participate in any other clinical trial during the trial.
-
Agree not to donate blood for the duration of the trial.
-
Agree to restrain from intensive physical exercise i.e. exercise that varies significantly from an everyday exercise routine, 3 days before and after (± 3 days) administration of each dose, including each interim visit for blood sample collection.
Exclusion Criteria:
-
Personal or family history of post-streptococcal disease (rheumatic fever or glomerulonephritis), or collagen-vascular disease
-
Evidence of increased cardiovascular disease risk (defined as >10%, 10- year risk using Framingham score - see Appendix 5). Risk factors include sex, age, systolic blood pressure (mm Hg), smoking status, body mass index (BMI, kg/m2), reported diabetes status and blood pressure
-
Previous use of phentermine (appetite suppressant of the amphetamine and phenethylamine class), fenfluramine or dexfenfluramine known as Fen-Phen, anti-obesity medications (possible association with cardiac valvular abnormalities);
-
Clinical diagnosis or evidence of recent group A streptococcal infection as measured by anti-streptolysin O or anti-DNase B levels exceeding 200 units;
-
Positive group A streptococcus throat culture at screening or rapid antigen test on day of study product administration;
-
Presence of significant acute infection requiring systemic antibiotic treatment within the 14 days prior to each product administration;
-
Pregnant or breast feeding (all women will have a negative pregnancy test result prior to each study product administered);
-
Immunized or intent to immunize with any vaccine or investigational agents within 30 days prior to enrolment through to 30 days following the last study vaccine administration, with the exception of licensed inactivated influenza vaccines and COVID-19 vaccines;
-
Past significant reaction following any previous vaccination;
-
History of hypersensitivity to any diphtheria toxoid or CRM197 containing vaccine;
-
Presence of acute infectious disease or fever (e.g., sub-lingual temperature 38.5°C) within the five days prior to study product administration;
-
Presence of current or suspected serious chronic diseases such as cardiac or autoimmune disease (HIV or other immunodeficiencies), insulin dependent diabetes, progressive neurological disease, severe malnutrition, acute or progressive hepatic disease, acute or progressive renal disease, psoriasis, rheumatoid arthritis, asthma, epilepsy or obsessive compulsive disorder, skin carcinoma excluding non-spreadable skin cancers such as basal cell and squamous cell carcinoma;
-
Evidence and any history of leukaemia, lymphoma or neoplasm;
-
Presence or suspicion of impaired immune system function. Currently receiving or having within the past three years received immunosuppressive therapy, including systemic steroids, ACTH or inhaled steroids in dosages that are associated with hypothalamic-pituitary-adrenal axis suppression, such as 1mg/kg/day of prednisone or its equivalent or chronic use of inhaled high potency corticosteroids [budesonide 800 µg per day or fluticasone 750 µg];
-
Received blood, blood products or a parenteral immunoglobulin preparation in the past 12 weeks;
-
Evidence of bleeding diathesis or any condition that may be associated with a prolonged bleeding time;
-
Known inherited genetic anomaly (known as cytogenic disorders) e.g., Down's syndrome;
-
Evidence of any condition that, in the opinion of the clinical investigator, might interfere with the evaluation of the study objectives or pose excessive risks to participants;
-
Findings of definite, probable or possible rheumatic heart disease (RHD), definite or probable acute rheumatic fever (ARF).
-
Echocardiographic findings such as: Cardiac Chambers: left ventricular dilatation (based on LV diameter > 29mm/m2 to BSA); left ventricular dysfunction (Ejection Fraction < 50%; left ventricular hypertrophy (LV wall thickness > 11mm); Right ventricular dysfunction or dilatation (Subjective assessment);
-
Cardiac Valves/Haemodynamic Findings: Clinically significant mitral regurgitation defined: at the discretion of the cardiologist and/or effective regurgitant orifice area of >10mm2; Any degree of valvular stenosis or left ventricular outflow tract obstruction; Pulmonary hypertension (defined as an estimated right ventricular systolic pressure of >30 mmHg, calculated using the peak tricuspid regurgitant jet velocity method);
-
Any aortic regurgitation;
-
Pericardium: greater than trivial pericardial fluid (trivial defined as < 5mm and not circumferential);
-
Pre-existing significant structural valve disease (for example, but not limited to bicuspid aortic valve regardless of haemodynamic effect, mitral valve prolapse regardless of severity of regurgitation, pulmonary stenosis);
-
Other significant congenital lesions (for example, but not limited to aortic coarctation, septal defect, excluding patent foramen ovale (NOTE: findings considered normal developmental variation, specifically including patient foramen ovale and prominent Eustachian valve will not be considered exclusion criteria;
-
Clinical or sub-clinical acute post-streptococcal glomerulonephritis (APSGN),
-
Clinical significant abnormal laboratory results e.g., CBC with differential and platelets, AST, ALT, creatinine, fasting blood sugar, electrolytes (including sodium, potassium, chloride and bicarbonate);
-
The participant has a diagnosis of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis;
-
The participant has been hospitalized within the past 5 years prior to enrollment for psychiatric illness, history of suicide attempt or confinement for danger to self or others;
-
The participant is receiving psychiatric drugs but their psychiatric conditions is not stabilized. Participants who are receiving a single antidepressant drug and are stable for at least 3 months prior to enrollment without decompensating are allowed enrollment into the study; *aripiprazole, clozapine, ziprasidone, haloperidol, molindone, loxapine, thioridazine, thiothixene, pimozide, fluphenazine, risperidone, mesoridazine, quetiapine, trifluoperazine, trifluopromazine, chlorprothixene, chlorpromazine, perphenazine, olanzapine, carbamazepine, divalproex sodium, lithium carbonate or lithium citrate. This is not an absolute contra-indication and clinician judgment will be used to assess the likelihood that this will compromise trial participation and follow-up.
-
The participant has a history of alcohol or drug abuse in the 5 years prior to enrollment. This is not an absolute contra-indication and clinician judgment will be used to assess the likelihood that this will compromise trial participation and follow-up.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Alberta Hospital | Edmonton | Alberta | Canada | T6G 2B7 |
Sponsors and Collaborators
- University of Alberta
- Griffith University
Investigators
- Principal Investigator: Michael Hawkes, MD, PhD, University of Alberta
- Principal Investigator: Michael Good, MD, PhD, Griffith University
- Principal Investigator: Michael Houghton, PhD, University of Alberta
- Principal Investigator: Lorne Tyrrell, MD PhD, University of Alberta
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Pro00089919