Safety and Immunogenicity of Betuvax-CoV-2, an RBD-Fc-Based SARS-CoV-2 Recombinant Vaccine: Preliminary Results of the First-in-Human, Randomized, Double-Blind, Placebo-Controlled Phase I/II Clinical Trial.

COVID-19, being a life-threatening infection that evolves rapidly, remains a major public health concern calling for the development of vaccines with broad protection against different pathogenic strains and high immunogenicity. Aside from this, other concerns in mass immunization settings are also the scalability of production and relative affordability of the technology. In that regard, adjuvanted protein vaccines with particles mimicking the virus stand out among known vaccine technologies. The "Betuvax-CoV-2" vaccine, developed on the basis of a recombinant protein and an adjuvant, has already been tested in preclinical studies and has advanced to clinical evaluation. Open, double-blinded, placebo-controlled, randomized phase I/II clinical trial of the "Betuvax-CoV-2," recombinant protein subunit vaccine based on the S-protein RBD fused with the Fc-fragment of IgG, was conducted to evaluate safety and immunogenicity in response to the vaccination. METHODS: In the phase I/II clinical trial, 116 healthy adult men and women, ages 18-58, were enrolled: 20 in Stage I, and 96 in Stage II. In Stage I, 20 µg of the vaccine was administered intramuscularly on day 2, and either 5 µg (group 1) or 20 µg (group 2) on day 30. In Stage II, 20 µg of the vaccine was administered intramuscularly on day 2, and either 5 µg (group 3) or 20 µg (group 4) on day 30. In group 5, both injections were replaced with placebo. The primary outcome measures were safety (number of participants with adverse events throughout the study) and antigen-specific humoral immunity (SARS-CoV-2-specific antibodies measured by ELISA and CMIA). Antigen-specific cell-mediated immunity and changes in neutralizing antibodies (detected with a SARS-CoV-2 neutralization assay) were measured as a secondary outcome. The trial is registered with ClinicalTrials.gov (Study Identifier: NCT05270954). FINDINGS: Both vaccine formulations (20 µg + 5 µg and 20 µg + 20 µg) were safe and well tolerated. Most adverse events were mild, and no serious adverse events were detected. On day 51,anti-SARS-CoV-2 total and IgG antibody titers and anti-SARS-CoV-2 neutralizing antibodies were significantly higher in the vaccine groups (both formulations) than in the placebo. A more pronounced CD4+-mediated immune response was observed in the group of volunteers administered with the 20 + 20 µg vaccine formulation. INTERPRETATIONS: RBD-Fc-based COVID-19 "Betuvax-CoV-2" vaccine in doses (20 + 5 µg and 20 + 20 µg) demonstrated an excellent safety profile and induced a strong humoral response. Further research on the protective effectiveness of the "Betuvax-CoV-2" vaccine for the prevention of COVID-19 is on its way.

Efficacy and safety of favipiravir in a complex therapy of mild to moderate COVID-19

Material and methods. An open-labeled, randomized, active-controlled multicenter trial of favipiravir in out- and hospitalized patients with mild to moderate COVID-19 was conducted. Eligible patients were aged 18-60 years and had laboratory confirmed by PCR test infection of SARS-CoV-2. Patients were randomly assigned in a 2:1 ratio to receive either favipiravir (1800 mg BID on day 1, followed by 800 mg BID for 9 days), or standard of care (SOC) treatment (umifenovir + intranasal interferon alpha-2b, or hydroxychloroquine for up to 10 days). In needed, patients received concomitant symptomatic medication. The co-primary outcomes were the time to clinical improvement and the time to viral clearance. Results and discussion. It was found that the median time to clinical improvement was 6.0 [interquartile range (IQR) 4.0;9.3] days in favipiravir group and 10.0 (IQR 5.0;21.0) days in SOC group;the median difference was 4 days [hazard ratio (HR) 1.63;95% confidence interval (CI) 1.14-2.34, p=0.007]. The rate of clinical improvement in the favipiravir group on day 7 was 1.5-fold higher compared to SOC: 52.7% vs 35.7% [risk ratio (RR) 1.50;95% CI 1.02-2.22;p=0.020]. Despite an absence of statistically significant difference between the median time to viral elimination, the rates of viral elimination on day 3 and day 5 were significantly higher in favipiravir group: on the day 3 viral elimination was observed for in 71.4% of patients, who received favipiravir vs 57.1% in SOC group (RR 1.27;95% CI 0.99-1.64;p=0.030), on the day 5 81.2 vs 67.9%, respectively (RR 1.22;95% CI 1.00-1.48;р=0.022). Favipiravir was well tolerated: most of the adverse events (AE) were mild. The most common AEs were asymptomatic hyperuricemia, transient elevation of ALT & AST, and gastrointestinal disorders (diarrhea, nausea, abdominal pain). Цель исследования - оценка эффективности и безопасности фавипиравира для лечения новой коронавирусной инфекции (COVID-19) легкого и среднетяжелого течения. Материал и методы. Проведено открытое рандомизированное многоцентровое клиническое исследование с активным контролем у амбулаторных и госпитализированных пациентов с COVID-19 легкого и среднетяжелого течения. В исследовании приняли участие 168 пациентов в возрасте 18-60 лет с подтвержденной инфекцией SARS-CoV-2 (методом полимеразной цепной реакции мазков из рото- и носоглотки). Пациенты были рандомизированы в соотношении 2:1 в группы терапии фавипиравиром (по 1800 мг 2 раза в 1-й день, по 800 мг 2 раза в день - со 2-го по 10-й дни) либо стандартной терапии (умифеновир + интраназальный интерферон альфа-2b или гидроксихлорохин, длительность - до 10 дней). Пациенты также получали необходимую сопутствующую симптоматическую терапию. Комбинированная первичная конечная точка включала оценку медиан времени до улучшения клинического статуса и элиминации вируса. Результаты и обсуждение. Установлено, что в группе фавипиравира клиническое улучшение наступало на 4 дня быстрее, чем в группе стандартной терапии: медианы времени до клинического улучшения составили 6,0 [межквартильный диапазон (МКД) 4,0;9,3] дня и 10,0 (МКД 5,0;21,0) дней соответственно [hazard ratio (HR) 1,63;95% доверительный интервал (ДИ) 1,14-2,34, р=0,007]. Частота клинического улучшения на 7-й день в группе фавипиравира была в 1,5 раза выше по сравнению с группой стандартной терапии: 52,7 против 35,7% [risk ratio (RR) 1,50;95% ДИ 1,02-2,22;р=0,020]. Достоверной разницы медиан времени до элиминации вируса не наблюдалось. Однако частота элиминации вируса на 3-й и 5-й день в группе фавипиравира была значимо выше: на 3-й день она наблюдалась у 71,4% пациентов в группе фавипиравира против 57,1% в группе стандартной терапии (RR 1,27;95% ДИ 0,99-1,64;р=0,030), а на 5-й день у 81,2 против 67,9% соответственно (RR 1,22;95% ДИ 1,00-1,48;р=0,022). Фавипиравир хорошо переносился пациентами, а большинство нежелательных явлений имели легкую степень тяжести. Среди наиболее частых нежелательных явлений отмечали бессимптомную гиперурикемию, транзиторное повышение уровней аланин- и аспартат-аминотрансферазы и желудочно-кишечные нарушения (диарея, тошнота, боль в животе). Полученные результаты подтверждают преимущество фавипиравира по сравнению со стандартной этиотропной терапией при применении у пациентов с COVID-19 легкого и среднетяжелого течения.