A Trial of a Peptide-based Group A Streptococcal (GAS) Vaccine Candidate in Healthy Individuals.

Inclusion Criteria:

• Able to understand the purpose and the procedures involved in this study and signthe 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 screeningevaluation, performed by PI or delegated sub-investigator no greater than 28 daysbefore the first dose in the form of medical history, clinical laboratory tests andphysical examination.

• Normal Electrocardiogram (ECG).

• Echocardiogram (ECHO) that is normal or with findings that are considered trivialand clinically insignificant such as 'Clinically insignificant/trivial mitralregurgitation

• Women must agree not to become pregnant during the trial. If they are sexuallyactive, they must use an effective method of birth control, e.g. insertable,injectable, transdermal, or combination oral contraceptive approved by Health Canadacombined with a barrier contraceptive and have negative results on a serum or urinepregnancy test done before administration of study medication.

• Intention to reside in the geographical area for next 10 months and not intending totravel overseas for at least 30 days following the last study vaccineadministration.

• 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 variessignificantly from an everyday exercise routine, 3 days before and after (± 3 days)administration of each dose, including each interim visit for blood samplecollection.

• Up to date on seasonal influenza vaccine and recommended COVID-19 vaccines andbooster doses at the time of study enrolment.

Exclusion Criteria:

1. Personal or family history of post-streptococcal disease (rheumatic fever orglomerulonephritis), or collagen-vascular disease

2. Evidence of increased cardiovascular disease risk (defined as >10%, 10- year riskusing Framingham score - see Appendix 5). Risk factors include sex, age, systolicblood pressure (mm Hg), smoking status, body mass index (BMI, kg/m2), reporteddiabetes status and blood pressure

3. Previous use of phentermine (appetite suppressant of the amphetamine andphenethylamine class), fenfluramine or dexfenfluramine known as Fen-Phen,anti-obesity medications (possible association with cardiac valvular abnormalities);

4. Clinical diagnosis or evidence of recent group A streptococcal infection as measuredby anti-streptolysin O or anti-DNase B levels exceeding 200 units;

5. Positive group A streptococcus throat culture at screening or rapid antigen test onday of study product administration;

6. Presence of significant acute infection requiring systemic antibiotic treatmentwithin the 14 days prior to each product administration;

7. Pregnant or breast feeding (all women will have a negative pregnancy test resultprior to each study product administered);

8. Immunized or intent to immunize with any vaccine or investigational agents within 30days prior to enrolment through to 30 days following the last study vaccineadministration, with the exception of licensed inactivated influenza vaccines andCOVID-19 vaccines;

9. Past significant reaction following any previous vaccination;

10. History of hypersensitivity to any diphtheria toxoid or CRM197 containing vaccine;

11. Presence of acute infectious disease or fever (e.g., sub-lingual temperature 38.5°C)within the five days prior to study product administration;

12. Presence of current or suspected serious chronic diseases such as cardiac orautoimmune disease (HIV or other immunodeficiencies), insulin dependent diabetes,progressive neurological disease, severe malnutrition, acute or progressive hepaticdisease, acute or progressive renal disease, psoriasis, rheumatoid arthritis,asthma, epilepsy or obsessive-compulsive disorder, skin carcinoma excludingnon-spreadable skin cancers such as basal cell and squamous cell carcinoma;

13. Evidence and any history of leukaemia, lymphoma, or neoplasm;

14. Presence or suspicion of impaired immune system function. Currently receiving orhaving within the past three years received immunosuppressive therapy, includingsystemic steroids, ACTH or inhaled steroids in dosages that are associated withhypothalamic-pituitary-adrenal axis suppression, such as 1mg/kg/day of prednisone orits equivalent or chronic use of inhaled high potency corticosteroids [budesonide 800 µg per day or fluticasone 750 µg];

15. Received blood, blood products or a parenteral immunoglobulin preparation in thepast 12 weeks;

16. Evidence of bleeding diathesis or any condition that may be associated with aprolonged bleeding time;

17. Known inherited genetic anomaly (known as cytogenic disorders) e.g., Down'ssyndrome;

18. Evidence of any condition that, in the opinion of the clinical investigator, mightinterfere with the evaluation of the study objectives or pose excessive risks toparticipants;

19. Findings of definite, probable, or possible rheumatic heart disease (RHD), definiteor probable acute rheumatic fever (ARF).

20. Inadequate echocardiographic windows for assessment.

21. Echocardiographic findings such as: Cardiac Chambers: left ventricular dilatation (based on LV diameter > 29mm/m2 to BSA); left ventricular dysfunction (EjectionFraction < 50%; left ventricular hypertrophy (LV wall thickness > 11mm); Rightventricular dysfunction or dilatation (Subjective assessment);

22. Cardiac Valves/Haemodynamic Findings: Clinically significant mitral regurgitationdefined: at the discretion of the cardiologist and/or effective regurgitant orificearea of >10mm2; Any degree of valvular stenosis or left ventricular outflow tractobstruction; Pulmonary hypertension (defined as an estimated right ventricularsystolic pressure of >30 mmHg, calculated using the peak tricuspid regurgitant jetvelocity method);

23. Any aortic regurgitation;

24. Pericardium: greater than trivial pericardial fluid (trivial defined as < 5mm andnot circumferential);

25. Pre-existing significant structural valve disease (for example, but not limited tobicuspid aortic valve regardless of haemodynamic effect, mitral valve prolapseregardless of severity of regurgitation, pulmonary stenosis);

26. Other significant congenital lesions (for example, but not limited to aorticcoarctation, septal defect, excluding patent foramen ovale (NOTE: findingsconsidered normal developmental variation, specifically including patient foramenovale and prominent Eustachian valve will not be considered exclusion criteria;

27. Clinical or sub-clinical acute post-streptococcal glomerulonephritis (APSGN),

28. Clinically significant abnormal laboratory results e.g., CBC with differential andplatelets, AST, ALT, creatinine, fasting blood sugar, electrolytes (includingsodium, potassium, chloride, and bicarbonate);

29. The participant has a diagnosis of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis;

30. The participant has been hospitalized within the past 5 years prior to enrollmentfor psychiatric illness, history of suicide attempt or confinement for danger toself or others;

31. The participant is receiving psychiatric drugs but their psychiatric conditions isnot stabilized. Participants who are receiving a single antidepressant drug and arestable for at least 3 months prior to enrollment without decompensating are allowedenrollment 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, lithiumcarbonate or lithium citrate. This is not an absolute contra-indication andclinician judgment will be used to assess the likelihood that this will compromisetrial participation and follow-up.

32. The participant has a history of alcohol or drug abuse in the 5 years prior toenrollment. This is not an absolute contra-indication and clinician judgment will beused to assess the likelihood that this will compromise trial participation andfollow-up.