Safety, Tolerability and Immunogenicity of Recombinant COVID-19 Vaccine Betuvax-CoV-2

Randomized, double-blind, multicenter parallel-group clinical study of safety, tolerability and immunogenicity of the Betuvax-CoV-2 vaccine. The aim of this study is to investigate the safety, tolerability and immunogenicity of the Betuvax-CoV-2 Recombinant vaccine for the prevention of coronavirus infection caused by the SARS-CoV-2 virus, suspension for intramuscular administration, 10 μg/ml and 40 μg/ml (Ltd. Institute of New Medical Technologies, Russia) in healthy adult volunteers, aged 18 to 60 (inclusive).

Participation of the volunteers in the study includes Visit 0 (screening), Visits 1-4 and Visits 10-13 (on an inpatient basis), Visits 5-9 and Visits 14-20 (on an outpatient basis). During Visits 2 and 11, volunteers receive either a study drug (one of two dosages) or a placebo.

The study includes 116 healthy male and female volunteers aged 18 to 60 (inclusive) years who meet the inclusion criteria.

All volunteers are enrolled in two stages of the study and at each stage they are randomized into two or three groups, respectively.

Taking into account the estimated number of volunteers found by the screening results as not meeting the inclusion criteria (54 people), 170 volunteers are screened in the First and Second stage.

The vaccination course includes two intramuscular injections within a 28-day period.

The first stage of the study:

* Group 1 (10 people) will be intramuscularly administered the study drug Betuvax-CoV-2 according to the following scheme: the first injection of 20 μg (0.5 ml of suspension for intramuscular administration of 40 μg/ml), the second injection of 5 μg (0.5 ml of suspension for intramuscular injection of 10 μg/ml) in 28 days.
* Group 2 (10 people) will be intramuscularly administered the study drug Betuvax-CoV-2 according to the following scheme: the first and second injection of 20 μg (0.5 ml of solution for intramuscular injection of 40 μg/ml) within a 28-day period.

The second stage of the study:

* Group 3 (32 people) will be intramuscularly administered the study drug Betuvax-CoV-2 according to the following scheme: the first injection of 20 μg (0.5 ml of the suspension for intramuscular administration of 40 μg/ml), the second injection of 5 μg (0.5 ml of the suspension for intramuscular injection of 10 μg/ml) in 28 days.
* Group 4 (32 people) will be intramuscularly administered the study drug Betuvax-CoV-2 according to the following scheme: the first and second injection of 20 μg (0.5 ml of solution for intramuscular injection of 40 μg/ml) within a 28-day period.
* Group 5 (32 people) will receive a placebo according to the following scheme: the first and second injections (0.5 ml of sodium chloride 0.9% solution, intramuscularly) within a 28-day period.

Study participants will be closely monitored for their intended outcomes. Key safety outcomes will be centrally reviewed by the Independent Data Monitoring Committee (ICMD). Investigators will be required to report anticipated safety outcomes in a timely manner (within 24 hours if possible) and to record these outcomes in the CRF in a timely manner (within 24 hours if possible).

Eligibility Criteria:
Inclusion criteria:

1. 18 to 60 years of age.
2. Verified healthy condition according to the data of standard clinical, laboratory and instrumental examination methods.
3. For women being in an active reproductive period: Consent to adhere to appropriate methods of contraception during the entire period of the participation in the study and for 1 month after the completion of the participation in the study (appropriate methods of contraception include abstinence from sexual intercourse or any two of the following methods: an intrauterine device (intrauterine device without release and with a release of a local hormonal drug), diaphragm, spermicides, cervical caps, oral contraceptives, contraceptive sponge and/or condom); for men: Consent to adhere to appropriate dual barrier methods of contraception during the entire period of the participation in the study and 1 month after completion of the participation in the study.
4. Body mass index (BMI): 18.5≤ BMI≤30 kg/m2.
5. Negative breath alcohol test.
6. Negative laboratory blood tests for HIV, syphilis and hepatitis B and C.
7. Ability and willingness to attend all scheduled visits and undergo all procedures and examinations planned by the Protocol.
8. Signed and dated Informed Consent to participate in the study.

Exclusion criteria:

1. Contact with COVID-19 patients during 14 days before the start of the study.
2. PCR SARS-CoV-2 positive test.
3. Titer of the total specific anti-SARS-CoV-2 antibodies (ELISA) more than 1:10.
4. Drug allergies, hereditary angioedema.
5. Hypersensitivity to any component of the vaccine or any excipients of Betuvax-CoV-2 or allergy to the components of the vaccine.
6. Intolerance to any of the components or any excipients of the vaccine Betuvax-CoV-2.
7. Allergic reaction to previous immunizations.
8. Serious post-vaccination reactions/complications associated with previous immunizations.
9. For women of childbearing potential - lactation period, pregnancy or suspicion of it, early postpartum period.
10. Women in the premenopausal period (last menstrual period \<1 year prior to signing informed consent) who are not surgically sterile and women who have childbearing potential but do not use or plan to use appropriate methods of contraception throughout the study and do not agree to perform a urine pregnancy test while participating in a study.
11. Men who serve in the military by conscription.
12. Individuals in custody in pre-trial detention centers and those serving sentences in places of deprivation of liberty.
13. Children under 18 years of age.
14. Chronic diseases (including oncological and autoimmune), diseases of the cardiovascular, bronchopulmonary, neuroendocrine systems, as well as the gastrointestinal tract, liver, kidneys, blood, central nervous system; surgical interventions on the gastrointestinal tract (with the exception of appendectomy).
15. Active tuberculosis at the time of screening (based on history and physical examination).
16. Mental illness, current or in history.
17. Decompensated neuropsychiatric diseases, including schizophrenia, multiple sclerosis, Parkinson's disease, dementia, endogenous depression, etc., which complicate the participation of a volunteer in the study.
18. Acute infectious from less than 3 months before the start of the study.
19. Acute infectious or non-infectious diseases, exacerbation of chronic diseases from less than 4 weeks before the start of the study.
20. Symptoms of any diseases at the time of enrollment or if less than 4 weeks have passed since recovery.
21. Hepatic or renal failure, currently or in history.
22. Current or history of oncological diseases.
23. Major surgery, major trauma less than 6 months prior to study initiation.
24. History of splenectomy.
25. Other comorbidities that, in the opinion of the investigator, may interfere with the evaluation of the objectives of the study.
26. Blood pressure: systolic blood pressure less than 100 mmHg or above 130 mmHg and diastolic blood pressure over 90 mmHg or less than 70 mmHg.
27. Heart rate less than 60 beats/min or more than 90 beats/min.
28. Deviations from the normal values according to standard clinical, laboratory (general and biochemical blood tests, urinalysis) and instrumental methods (including ECG) examination.
29. Long-term use (more than 14 days) of immunosuppressants, systemic glucocorticosteroids or immunomodulatory drugs during the 6 months before the start of the study.
30. Any vaccination within one month prior to the start of the clinical trial.
31. Taking medications containing immunoglobulin or blood products during the last 3 months before the start of the study.
32. Donation of blood (450 ml of blood or plasma and more) less than 2 months before the start of the study.
33. Participation in another clinical study less than 3 months before the start of the study.
34. Consumption of more than 10 units of alcohol (1 unit of alcohol is equivalent to 1/2 liter of beer, 200 ml of wine or 50 ml of spirits) per week or history of alcoholism, drug addiction, drug abuse.
35. Smoking more than 10 cigarettes a day.
36. Special diet (for example, vegetarian, vegan, with limited salt intake) or a special lifestyle (work at night, extreme physical activity).
37. Positive urine test result for psychotropic and narcotic substances, psychoactive drugs (barbiturates, benzodiazepines, methadone, phencyclidine).
38. Unwillingness or inability to follow the recommendations and procedures prescribed by this protocol.