An Experimental Medicine Multicenter Trial to Evaluate the Safety and Immunogenicity of Experimental Versus Authorized SARS-CoV-2 Vaccine Candidates as a Booster Dose in Healthy Participants Previously Vaccinated With Authorized mRNA SARS-CoV-2 Vaccines.

An Experimental Medicine Multicenter Trial to Evaluate the Safety and Immunogenicity of Experimental Versus Authorized SARS-CoV-2 Vaccine Candidates as a Booster Dose in Healthy Participants Previously Vaccinated With Authorized mRNA SARS-CoV-2 Vaccines.

The SOLVE-01 trial is a study evaluating four SARS-CoV-2 vaccines as booster injections: two experimental vaccines (CD40.RBDv and CD40.Pan.CoV, both combined with the Hiltonol® adjuvant) and two authorised vaccines (Comirnaty® and NuvaxovidTM). This trial is designed for healthy adults aged 18 to 65 at the time of signing the informed consent form.

The main objectives of this trial are:

• to evaluate the safety of the two experimental vaccines,
• to determine the antibody response induced by the vaccines and its durability.

Participants will:

• Receive one injection of vaccine and two intradermal skin tests
• Come to the hospital 10 visits for medical exams and blood and saliva sample collection
• Keep a diary of their symptoms and the treatments taken

Inclusion Criteria:

1. Male and female subjects aged 18 to 65 years inclusive at the time of the screening visit

2. Having received at least two doses of COVID-19 mRNA vaccines in the past with the last dose received more than 6 months prior to IMP administration in the trial

3. In healthy condition or with stable health status which is defined as an existing disease that has not required a significant change in treatment or hospitalization for worsening before enrolment, and for which neither a significant change in treatment or hospitalization for worsening is expected in the near future.

4. For woman of childbearing potential: a negative Beta-HCG blood test measure during the screening visit, and a negative highly sensitive pregnancy urinary test the day of the vaccination visit

   • if heterosexually active female, consistently using a highly effective method of contraception with partner from at least 21 days prior to enrolment through 4 months after the IMP administration. Highly effective contraception is defined as using any of the following methods:

     • Combined hormonal contraception with inhibition of ovulation (estrogen and progesterone containing);
     • Intrauterine device (IUD);
     • Intrauterine hormone releasing system (IUS);
     • Hormonal contraception (progesterone only);
     • Successful vasectomy in the male partner (considered successful if a participant reports that a male partner has (i) documentation of azoospermia by microscopy, or (ii) a vasectomy more than 2 years ago with no resultant pregnancy despite unprotected sexual activity post vasectomy);
     • Or not be of reproductive potential, such as having reached menopause (no menses for 1 year without an alternative medical cause) or having undergone hysterectomy, bilateral oophorectomy, or tubal ligation.

   • Agree not to seek pregnancy including through alternative methods, such as artificial insemination or in vitro fertilization until 4 months after the IMP administration.

5. Participant who was born male, if heterosexually active male, using an effective method of contraception with their partner from the IMP administration until 4 months thereafter. All male participants also agree not to donate sperm during this period.

6. Negative nasopharyngeal antigenic test for SARS-CoV-2 on the day of screening and before randomisation

7. Participant who has normal biological values:

   • Hemoglobin ≥ 11.0 g/dL for participants who were born female, ≥ 13.0 g/dL for participants who were born male;
   • White blood cell count = 3,300 to 12,000 cells/mm3;
   • Total lymphocyte count ≥ 800 cells/mm3;
   • Platelets = 125,000 to 550,000/mm3;
   • ALT, AST, and alkaline phosphatase < 1.25 times the institutional upper limit of normal;
   • Creatinine <1.1x institutional upper limit of normal of the laboratory;
   • Normal urine test: absence of glucose, protein and haemoglobin
   • Negative HIV antigen/antibody test;
   • Negative Hepatitis B surface antigen (HBsAg);
   • Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase chain reaction (PCR) if the anti-HCV is positive;

8. Willingness to undertake SARS-CoV-2 testing according to study protocol, and receive SARS-CoV-2 test results

9. Willingness and availability to be followed for the planned duration of the study in one of the dedicated trial centres

10. Informed and signed written consent form before performance of any trial-related screening procedures

11. Agree to be registered in the French Health Ministry computerised file (for France only)

12. Being covered by Health Insurance (for France only)

Exclusion Criteria:

1. Acute febrile infection (body temperature ≥ 38.0°C) within the previous 72 hours and/or presenting symptoms suggestive of COVID-19 or SARS-CoV-2 infection within the previous 28 days or having been in contact with an infected individual for the last 14 days before the inclusion visit

2. Any medical condition that could impair the immune response: clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. A clinically significant condition or process includes but is not limited to:

   • A process that would affect the immune response;
   • A process that would require medication that affects the immune response;
   • Any contraindication to repeated injections or blood draws;
   • A condition that requires active medical intervention or monitoring to avert grave danger to the participant's health or well-being during the study period;
   • A condition or process for which signs or symptoms could be confused with reactions to vaccine, or
   • Any condition specifically listed among the exclusion criteria below.

3. Pregnancy or breastfeeding that is currently ongoing, or positive pregnancy test at screening visit and the day of the vaccination

4. Immunodeficiency

5. Asthma: a condition that requires active medical intervention or monitoring to avert grave danger to asthma other than mild, well-controlled asthma. (Symptoms of asthma severity as defined in the most recent National Asthma Education and Prevention Program (NAEPP) Expert Panel report). Exclude a participant who:

   • Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or
   • Uses moderate/high dose inhaled corticosteroids, or
   • In the past year has either of the following: (i) Greater than 1 exacerbation of symptoms treated with oral/parenteral corticosteroids or (ii) Needed emergency care, urgent care, hospitalization, or intubation for asthma.

6. Diabetes type 1 or type 2, including cases controlled with diet alone. (Not excluded: history of isolated gestational diabetes).

7. Thyroidectomy, or thyroid disease requiring medication during the last 12 months

8. Hypertension:

   • If a person has been diagnosed with hypertension, exclude for blood pressure that is not well controlled (well-controlled blood pressure is defined as consistently ≤ 140 mm Hg systolic and ≤ 90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be ≤ 150 mm Hg systolic and ≤ 100 mm Hg diastolic). For these participants, blood pressure must be ≤ 140 mm Hg systolic and ≤ 90 mm Hg diastolic at enrolment;
   • If a person has NOT been diagnosed with hypertension, exclude for systolic blood pressure ≥ 150 mm Hg at enrolment or diastolic blood pressure ≥ 100 mm Hg at enrolment. (the measurement must be performed on a person who has been lying down for at least 5 minutes and repeat at the end of the consultation, if appropriated). Tension must be confirmed outside the clinical site to rule out hypertension.

9. Contraindication to the IMPs including hypersensitivity

10. BMI ≥ 40 kg/m2; ≤ 18 kg/m2; or BMI ≥ 35 kg/m2 with 2 or more of the following: age > 45, systolic blood pressure > 140 mm Hg, diastolic blood pressure > 90 mm Hg, current smoker, known hyperlipidemia

11. Bleeding disorder diagnosed (e.g., coagulation factor deficiency, coagulopathy, or platelet disorder requiring special precautions)

12. Malignancy (Not excluded: volunteer who has had malignancy excised surgically and who, in the investigator's estimation, has a reasonable assurance of sustained cure, or who is unlikely to experience recurrence of malignancy during the period of the study)

13. Asplenia: any condition resulting in the absence of a functional spleen

14. Seizure disorder: History of seizure(s) within past three years. Also excluded if volunteer has used medications in order to prevent or treat seizure(s) at any time within the past 3 years.

15. History of hereditary angioedema, acquired angioedema, or idiopathic angioedema.

16. History of myocarditis, pericarditis, cardiomyopathy, congestive heart failure with permanent sequelae, clinically significant arrhythmia (including arrhythmia requiring medication, treatment, or clinical follow-up)

17. History of autoimmune disease

18. Any medical, psychiatric, occupational, or other condition that, in the judgment of the investigator, would interfere with or serve as a contraindication to protocol adherence, assessment of safety, or a volunteer's ability to give informed consent

19. Psychiatric condition that precludes compliance with the protocol. Specifically excluded are persons with psychoses within the past 3 years, ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years.

20. History of serious adverse reactions to vaccines including anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain. (Not excluded: a volunteer who had a non-anaphylactic adverse reaction to pertussis vaccine as a child)

21. Investigational research agents received within 30 days before IMP administration

22. Experimental vaccine(s) received within the last 5 years in a prior vaccine trial

23. Live attenuated vaccines (e.g., measles, mumps, and rubella (MMR); oral polio vaccine (OPV); varicella; yellow fever) received within 30 days before IMP administration or scheduled within 28 days after the injection scheduled within the protocol

24. Vaccines that are not live attenuated vaccines and were received within 21 days prior to IMP administration (e.g., tetanus, pneumococcal, Hepatitis A or B)

25. Blood-derived products or immunoglobulin received within 6 months before IMP administration*

26. Current anti-tuberculosis (TB) prophylaxis or therapy received within 3 months before IMP administration *

27. Allergy treatment with antigen injections within 30 days before IMP administration or that are scheduled within 14 days after IMP administration*

28. Immunosuppressive medications or immunomodulators (such as cytokines or interferons) received within last three months before IMP administration. (Not excluded: (1) corticosteroid nasal spray; [2] topical corticosteroids for mild, uncomplicated dermatitis; or (2) a single course of oral/parenteral corticosteroids at doses < 2 mg/kg/day and length of therapy < 11 days with completion at least 30 days prior to enrolment) or low dose oral corticosteroids (≤10 mg prednisone/day) or corticosteroids for the treatment of immune-related adverse events*

29. Other prohibited medications: Corticosteroids > 10 mg prednisone equivalent/day (not excluded: topical preparations) *

30. Person participating in another research involving the human person or participating in another research involving the human person with an exclusion period still in progress at screening

31. Intent to participate in another study of an investigational research agent during the planned duration of the study

32. Participants who are not able to understand and to follow all required study procedures for the whole period of the study in the judgment of the investigator

33. Under tutorship (only for France), guardianship, or deprived of liberty by a juridical or administrative decision

34. Planned absence that could affect participation in the study (travel abroad, relocation, impending professional mutation...)

    • The scheduled use of these treatments up to 6 months after the injection also represents a contraindication