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

Phase 1

Completed

Conditions: SARS Pneumonia
COVID-19 Vaccine
COVID-19 Disease
Pneumonia, Viral

Interventions: Biological: COVIVAC
Biological: Phosphate-buffered saline

Registration Number: NCT04830800

Lead Sponsor: Institute of Vaccines and Medical Biologicals, Vietnam

Brief Summary: 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)

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 120

Inclusion Criteria

Phase 1 Only:

Adult 18 through 59 years of age inclusive at the time of randomization.
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.
Has provided written informed consent prior to performance of any study-specific procedure.
Has a body mass index (BMI) of 17 to 40 kg/m2, inclusive, at screening.
Resides in study site area and is able and willing to adhere to all protocol visits and procedures.
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

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.
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.
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
History of hypersensitivity reaction to any prior vaccination or known hypersensitivity to any component of the study vaccine
History of egg or chicken allergy
History of angioedema
History of anaphylaxis
Acute illness (moderate or severe) and/or fever (body temperature measured orally ≥38°C)
Any abnormal vital sign deemed clinically relevant by the PI
Abnormality in screening laboratory test deemed exclusionary by the PI in consultation with the Sponsor
A positive serologic test for hepatitis B (HBsAg) or hepatitis C (HCV Ab)
History of confirmed HIV
History of laboratory-confirmed COVID-19
History of malignancy, excluding non-melanoma skin and cervical carcinoma in situ
Any confirmed or suspected immunosuppressive or immunodeficient state
Administration of immunoglobulin or any blood product within 90 days prior to first study injection or planned administration during the study period.
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).
History of known disturbance of coagulation or blood disorder that could cause anemia or excess bleeding. (e.g, thalassemia, coagulation factor deficiencies).
Recent history (within the past year) or signs of alcohol or substance abuse.
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.
Employee of any person employed by the Sponsor, the contract research organization (CRO), the PI, study site personnel, or site.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
COVIVAC 10mcg	COVIVAC	10mcg IVAC COVIVAC vaccine for intramuscular injection administered as two doses (0.5mL each) 28 days apart.
Placebo	Phosphate-buffered saline	Phosphate buffered saline (pH 7.2) for intramuscular injection administered as two doses (0.5mL each) 28 days apart.
COVIVAC 3mcg	COVIVAC	3mcg IVAC COVIVAC vaccine for intramuscular injection administered as two doses (0.5mL each) 28 days apart.
COVIVAC 1mcg	COVIVAC	1mcg IVAC COVIVAC vaccine for intramuscular injection administered as two doses (0.5mL each) 28 days apart.
COVIVAC 1mcg + CpG1018 1.5mg	COVIVAC	1mcg + CpG1018 IVAC COVIVAC vaccine for intramuscular injection administered as two doses (0.5mL each) 28 days apart.

Primary Outcome Measures

Name	Time	Method
Serious Adverse Event	Throughout the Study Period (until Day 197)	Number of participants with serious adverse events (SAEs)
Medical Attended Adverse Events	Throughout the Study Period (until Day 197)	Number of participants with medically-attended AEs (MAAEs)
Solicited Adverse Events	During the first 7 days after each vaccination	Percentage of participants with solicited local and systemic adverse events (AEs)
Clinical Safety Tests	At 7 days post each vaccination	Percentage of participants with clinically significant hematological and biochemical abnormalities
Unsolicited Adverse Events	During the first 28 days after each vaccination	Number of participants with any unsolicited adverse event
Adverse Event of Special Interest	Throughout the Study Period (until Day 197)	Number of participants with adverse events of special interest (AESI) , including AESI relevant to COVID-19, and potential immune-mediated medical conditions (PIMMC)

Secondary Outcome Measures

Name	Time	Method
GMT of 50% Neutralizing Antibody (NT50)	GMT of NT50 at 28 days after first vaccination, at 14 days and 6 months after the second vaccination	50% neutralizing antibody (NT50) geometric mean titer (GMT) against SARS-CoV-2 pseudovirus
Geometric Mean Fold Rise (GMFR)	GMFR at 28 days after first vaccination, at 14 days and 6 months after the second vaccination	Geometric mean fold rise (GMFR) (from baseline) in NT50 against SARS-CoV-2 pseudovirus
Seroresponse in NT50	Seroresponse at 28 days after first vaccination, at 14 days and 6 months after the second vaccination	Percentage of subjects with NT50 seroresponse against SARS-CoV-2 pseudovirus as defined by (1) a ≥ 4-fold increase from baseline, and (2) a ≥ 10-fold increase from baseline
Anti-S IgG GMC	GMC of Anti-S IgG at 28 days after the first vaccination, at 14 days and 6 months after the second vaccination	Immunogenicity outcome measurement
GMFR in Anti-S IgG GMC	GMFR at 28 days after the first vaccination, 14 days and 6 months after the second vaccination	GMFR (from baseline) in anti-S IgG GMC
Seroresponse in Anti-S IgG Concentration	Seroresponse at 28 days after the first vaccination, 14 days and 6 months after the second vaccination	Percentage of subjects with seroresponses in anti-S IgG titer as defined by (1) a ≥ 4-fold increase from baseline, and (2) a ≥ 10-fold increase from baseline