The aim of the clinical study is to study the safety and tolerability of the live cell-based vaccine against smallpox and other orthopoxvirus infections (VAC∆6 vaccine) based on vaccinia virus, in intracutaneous administration. The research tasks are to: * evaluate the safety of various schemes for the use of the VAC∆6 vaccine using a set of clinical and laboratory-instrumental methods (thermometry, blood pressure registration, auscultation of the heart and lungs, electrocardiography (ECG), complete blood count and common urine test, biochemical, immunological, and virological studies); * evaluate the reactogenicity of various schemes for the use of the VAC∆6 vaccine (taking into account the number of local and systemic reactions, the percentage of those vaccinated with various degrees of manifestation of systemic and local reactions); * evaluate the possibility of virus shedding into the environment by volunteers; * evaluate the immunological efficacy of various vaccine administration schemes; * identify the development of undesirable reactions to the administration of the vaccine; * evaluate the cellular immune response to the introduction of various schemes for the use of the vaccine; * evaluate preliminary efficacy data in order to select an optimal scheme for the administration of the vaccine to make a decision on conducting Phase II clinical trials in an extended group of volunteers.
This study is an open-label, controlled, parallel-group clinical trial. The study included 60 healthy volunteers of both sexes aged 18-40 years who had not been vaccinated against smallpox, had no vaccine marks and anti-smallpox virus neutralizing antibodies in their sera as well as those who met the inclusion criteria and did not have any exclusion criteria. Distribution of volunteers by groups: Group 1: 15 volunteers vaccinated once intradermally at a dose of 10⁶ plaque-forming units (PFU) (0.2 ml) of the VAC∆6 vaccine in the outer surface of the shoulder 8-10 cm below the shoulder joint; Group 2: 15 volunteers vaccinated once intradermally at a dose of 10⁷ PFU (0.2 ml) of the VAC∆6 vaccine in the outer surface of the shoulder 8-10 cm below the shoulder joint; Group 3: 15 volunteers vaccinated twice spaced 28 days apart, intradermally at a dose of 10⁶ PFU (0.2 ml) of the VAC∆6 vaccine in the outer surface of the shoulder 8-10 cm below the shoulder joint; Group 4: 15 volunteers vaccinated by the two-step vaccination method: Step 1 - the first vaccination once subcutaneously with 1 dose (0.5 ml) of the inactivated smallpox vaccine OspaVir® in the area of the left shoulder 8-10 cm below the shoulder joint; Step 2 - the second vaccination once by the method of multiple puncture into the outer surface of the shoulder 8-10 cm below the shoulder joint with a live smallpox vaccine at a dose of 1x 10⁶ PFU 7 days following the first vaccination with OspaVir®. Since the product "Live cell-based vaccine against smallpox and other orthopoxvirus infections (VAC∆6 vaccine) based on vaccinia virus" was used for the first time for human vaccination, the vaccination of volunteers was started at a low dose, i.e. 1x10⁶ PFU. The first five volunteers included in Group 1 were vaccinated intradermally at a dose of 1x10⁶ PFU. The volunteers were monitored daily; 14 days after vaccination, in the absence of side effects and after the results were agreed upon, vaccination was performed for the remaining 10 Group 1 volunteers and the first 5 volunteers of Group 2 who were vaccinated at a dose of 1x10⁷ PFU. After 14 days, in the absence of adverse effects (AEs) or serious adverse effects (SAEs), the rest of the volunteers included in Group 2 were vaccinated. After receiving the results indicating the absence of AEs or SAEs in the volunteers vaccinated once with the VAC∆6 vaccine at a dose of 1x10⁶ PFU, the first vaccination of Group 3 volunteers was performed, the dose of the vaccine was 1x10⁶ PFU, and after 28 days - the second vaccination was performed. Group 4 was vaccinated with reference products: live smallpox vaccine (smallpox vaccine) and the OspaVir® vaccine, an inactivated smallpox vaccine. Vaccination was performed in two steps: * the first step: subcutaneous administration of the inactivated smallpox vaccine OspaVir®; * the second step: skin inoculation with a live smallpox vaccine.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
60
15 volunteers vaccinated once intradermally at a dose of 10⁶ PFU (0.2 ml) of the VAC∆6 vaccine in the outer surface of the shoulder 8-10 cm below the shoulder joint
15 volunteers vaccinated once intradermally at a dose of 10⁷ PFU (0.2 ml) of the VAC∆6 vaccine in the outer surface of the shoulder 8-10 cm below the shoulder joint
15 volunteers vaccinated twice spaced 28 days apart, intradermally at a dose of 10⁶ PFU (0.2 ml) of the VAC∆6 vaccine in the outer surface of the shoulder 8-10 cm below the shoulder joint
15 volunteers vaccinated by the two-step vaccination method: Step 1 - the first vaccination once subcutaneously with 1 dose (0.5 ml) of the inactivated smallpox vaccine OspaVir® in the area of the left shoulder 8-10 cm below the shoulder joint; Step 2 - the second vaccination once by the method of multiple puncture into the outer surface of the shoulder 8-10 cm below the shoulder joint with a live smallpox vaccine at a dose of 1x 106 PFU 7 days following the first vaccination with OspaVir®.
Federal State Budgetary Healthcare Institution - Medical and Sanitary Unit No. 163 of the Federal Medical and Biological Agency (FGBUZ MSCH-163, FMBA Russia)
Novosibirsk, Koltsovo, Novosibirsk Region, Russia
Changes in the percentage of vaccinees with a titer of virus-neutralizing antibodies to vaccinia virus ≥1:40, at specified time intervals.
On control days, the percentage of the vaccinees with a titer of virus-neutralizing antibodies to vaccinia virus ≥1:40 is recorded in the neutralization test in embryonated chicken eggs. Value changes of this indicator between time points are assessed.
Time frame: Groups 1, 2, 3: at days 0, 21, 30, 60, 90, 180. Group 4: at days 0, 5, 12, 21, 28, 37, 67, 97, 187.
Recording the number of local reactions.
On control days, the sum of local reactions is recorded: formation of inoculation elements (redness, swelling and papulo-nodules, pustules, vesicles, erythema, induration). Value changes of this indicator between time points are assessed. Evaluation criteria for local reactions: 1. The intensity or severity of adverse reactions should be assessed on a 4-point scale: 0 - none (no symptoms); 1 - mild (presence of mild symptoms); 2 - medium (symptoms that noticeably impair normal daily activities); 3 - severe (symptoms that interfere with normal daily activities). 2. The severity of local reactions was assessed according to the following criteria: * Hyperemia \< 50.0 mm (⌀) or an infiltrate \< 25.0 mm (⌀) - weak; * Hyperemia ≤ 50.0 mm (⌀) or an infiltrate 26.0-50.0 mm (⌀) - medium; * Infiltrate \> 50.0 mm (⌀) - strong.
Time frame: Groups 1, 2: at days 0 - 14, 21. Group 3: at days 0 - 14, 21, 28 - 42, 49. Group 4: at days 0 - 22, 29.
Changes in the activity of delayed-type hypersensitivity (DTH) effectors to vaccinia virus at specified time intervals.
On control days, the changes in the activity of DTH effectors to vaccinia virus are assessed. The assessment of the activity of specific DTH effectors in vitro should be carried out according to the migration index (MI), which characterizes the migration activity of leukocytes; according to the migration inhibition index (MII), which characterizes the intensity of lymphokine production, and according to the integral indicator of the effector functions (IEF). The reaction is considered positive if the difference between the experimental and control values is greater than 20%.
Time frame: Groups 1, 2: at days 1, 30, 90. Groups 3, 4: at days 1, 30, 60, 90.
Changes in the content of Class A, M, G, and E immunoglobulins.
On control days, the changes in the content of Class A (in mg/ml), M (in mg/ml), G (in mg/ml), and E (in IU/ml) immunoglobulins is assessed.
Time frame: Groups 1, 2, 3: at days 0, 5, 14, 21, 30, 60, 90, 180. Group 4: at days 0, 5, 12, 21, 28, 37, 67, 97, 187.
Changes in the content of T cells and their subpopulations: cluster of differentiation 3 (CD3+), cluster of differentiation 4 (CD4+), cluster of differentiation 8 (CD8+), CD4+/CD8+.
On control days, the changes in the content of T cells and their subpopulations is assessed: CD3+ (in % in relation to the total number of lymphocytes), CD4+ (in % in relation to CD3+), CD8+ (in % in relation to CD3+), CD4+/CD8+.
Time frame: Groups 1, 2, 3: at days 0, 5, 14, 21, 30, 60, 90, 180. Group 4: at days 0, 5, 12, 21, 28, 37, 67, 97, 187.
Recording the number of systemic reactions.
Recording the number of systemic reactions (malaise, headache, rise in body temperature, weakness, sweating, sleep and appetite disorders, nausea, vomiting, abdominal pain, etc.). Evaluating criteria for systemic reactions: 1. The intensity or severity of adverse reactions should be assessed on a 4-point scale: 0 - none (no symptoms); 1 - mild (presence of mild symptoms); 2 - medium (symptoms that noticeably impair normal daily activities); 3 - severe (symptoms that interfere with normal daily activities). 2. The temperature response should be evaluated according to the following categories in °С: 0 (none) ≤ 37 °C; 1 (weak) \> 37 °С - ≤ 37.5 °С; 2 (medium) \> 37.5 °С - ≤ 38.5 °С; 3 (strong) \> 38.5°C.
Time frame: Groups 1, 2: at days 0 - 14, 21. Group 3: at days 0 - 14, 21, 28 - 42, 49. Group 4: at days 0 - 22, 29.
Recording of the percentage of the vaccinated with various degrees of manifestation of systemic and local reactions.
Recording of the percentage of the vaccinated with various degrees of manifestation of systemic and local reactions.
Time frame: Groups 1, 2: at days 0 - 14, 21. Group 3: at days 0 - 14, 21, 28 - 42, 49. Group 4: at days 0 - 22, 29.
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