A Phase 1/2 Safety and Immunogenicity Trial of COVID-19 Vaccine COVIVAC (Phase 1)

A Phase 1/2 Randomized, Placebo-controlled, Observer-blind Trial to Assess the Safety and Immunogenicity of COVIVAC Vaccine Produced by IVAC in Adults Aged 18-60 Years in Vietnam

This prospective, single-center, randomized, placebo-controlled, observer-blind Phase 1/2 study includes two separate parts.

Part 1 is a first-in-human, Phase 1 study designed to evaluate the safety, tolerability and immunogenicity of the COVIVAC vaccine at three different dose levels (1, 3, and 10 µg) without adjuvant, and at one dose level (1 µg) with the adjuvant CpG 1018, in a total of 120 subjects aged 18-59 years. (Part 2 will be registered in a separate record)

This prospective, single-center, randomized, placebo-controlled, observer-blind Phase 1/2 study includes two separate parts.

Part 1 is a first-in-human, Phase 1 study designed to evaluate the safety, tolerability and immunogenicity of the COVIVAC vaccine at three different dose levels (1, 3, and 10 µg) without adjuvant, and at one dose level (1 µg) with the adjuvant CpG 1018, in a total of 120 subjects aged 18-59 years.

An interim analysis of Phase 1 data conducted after the last subject last visit for V6 (D57) will serve as the basis for decisions about down selection and advancing to Part 2 of the study (Phase 2). Down selection and advancement to Part 2 (Phase 2) will be based on the following parameters:

• Post-dose 2 immunogenicity results at the aggregate treatment level

  o A threshold immune response at Visit 5 (D43) will be required: the observed seroresponse rate in a treatment group (defined as the percentage of subjects with at least a 4-fold rise from baseline in 80% neutralizing antibody titers) will need to be ≥52% at the LL of the 95% CI for that treatment (vaccine formulation) to be considered for advancement to Phase 2.

• Post-dose 1 and post dose 2 safety results including all solicited and unsolicited adverse events, serious adverse events, and clinical laboratory results.

The following process will be followed for the decision about down selection and advancing to Part 2 (Phase 2):

• The DSMB will review the unblinded safety data and provide a recommendation to the Sponsor on whether the safety profile is acceptable for advancing a formulation to Phase 2.

• The Sponsor will review the DSMB recommendation in conjunction with the immunogenicity data and select two formulations to advance to Phase 2.

  o If multiple formulations achieve the threshold immune response (as well as have an adequate safety and tolerability profile per the DSMB), the Sponsor will select two formulations to advance to Phase 2 based on consideration of such factors as the relative functional immunogenicity of these formulations, opportunity for dose sparing, and opportunity to limit cost and possible supply constraints associated with use of the CpG adjuvant.

• The selection and recommendation to advance to Phase 2 along with the interim report will be jointly reviewed by NIHE's IRB and MoH prior to Phase 2 enrollment.

Inclusion Criteria:

Phase 1 Only:

1. Adult 18 through 59 years of age inclusive at the time of randomization.
2. Healthy, as defined by absence of clinically significant medical condition, either acute or chronic, as determined by medical history, physical examination, screening laboratory test results, and clinical assessment of the investigator.
3. Has provided written informed consent prior to performance of any study-specific procedure.
4. Has a body mass index (BMI) of 17 to 40 kg/m2, inclusive, at screening.
5. Resides in study site area and is able and willing to adhere to all protocol visits and procedures.
6. If a woman is of childbearing potential, must not be breastfeeding or be pregnant (based on a negative urine pregnancy test at screening and during the 24 hours prior to receipt of the first dose of IP), must plan to avoid pregnancy for at least 28 days after the last dose of IP, and be willing to use an adequate method of contraception consistently and have a repeated pregnancy test prior to the second (last) dose of IP.

Exclusion Criteria:

1. Use of any investigational medicinal product within 90 days prior to randomization or planned use of such a product during the period of study participation.

2. History of administration of any non-study vaccine within 28 days prior to administration of study vaccine or planned vaccination within 3 months after enrolment.

   Note: receipt of any COVID-19 vaccine that is licensed or granted Emergency Use Authorization in Vietnam during the course of study participation is not exclusionary if administered after Visit 5.

3. Previous receipt of investigational vaccine for SARS or MERS, or any investigational or licensed vaccine that may have an impact on interpretation of the trial results

4. History of hypersensitivity reaction to any prior vaccination or known hypersensitivity to any component of the study vaccine

5. History of egg or chicken allergy

6. History of angioedema

7. History of anaphylaxis

8. Acute illness (moderate or severe) and/or fever (body temperature measured orally ≥38°C)

9. Any abnormal vital sign deemed clinically relevant by the PI

10. Abnormality in screening laboratory test deemed exclusionary by the PI in consultation with the Sponsor

11. A positive serologic test for hepatitis B (HBsAg) or hepatitis C (HCV Ab)

12. History of confirmed HIV

13. History of laboratory-confirmed COVID-19

14. History of malignancy, excluding non-melanoma skin and cervical carcinoma in situ

15. Any confirmed or suspected immunosuppressive or immunodeficient state

16. Administration of immunoglobulin or any blood product within 90 days prior to first study injection or planned administration during the study period.

17. Administration of any long-acting immune-modifying drugs (e.g., infliximab or rituximab) or the chronic administration (defined as more than 14 days) of immunosuppressants within six months prior to first study injection, or planned administration during the study period (includes systemic corticosteroids at doses equivalent to ≥ 0.5 mg/kg/day of prednisone; the use of topical steroids including inhaled and intranasal steroids is permitted).

18. History of known disturbance of coagulation or blood disorder that could cause anemia or excess bleeding. (e.g, thalassemia, coagulation factor deficiencies).

19. Recent history (within the past year) or signs of alcohol or substance abuse.

20. Any medical, psychiatric or behavior condition that in the opinion of the PI may interfere with the study objectives, pose a risk to the subject, or prevent the subject from completing the study follow-up.

21. Employee of any person employed by the Sponsor, the contract research organization (CRO), the PI, study site personnel, or site.