A Booster Dose of CoronaVac Increases Neutralizing Antibodies and T Cells that Recognize Delta and Omicron Variants of Concern.

CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization (WHO). Previous studies reported increased levels of neutralizing antibodies and specific T cells 2 and 4 weeks after two doses of CoronaVac; these levels were significantly reduced at 6 to 8 months after the two doses. Here, we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against the variants of concern (VOCs), Delta and Omicron, in adults participating in a phase III clinical trial in Chile. Volunteers immunized with two doses of CoronaVac in a 4-week interval received a booster dose of the same vaccine between 24 and 30 weeks after the second dose. Neutralization capacities and T cell activation against VOCs Delta and Omicron were assessed 4 weeks after the booster dose. We observed a significant increase in neutralizing antibodies 4 weeks after the booster dose. We also observed a rise in anti-SARS-CoV-2-specific CD4+ T cells over time, and these cells reached a peak 4 weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2-specific T cells induced by the booster showed activity against VOCs Delta and Omicron. Our results show that a booster dose of CoronaVac increases adults' humoral and cellular anti-SARS-CoV-2 immune responses. In addition, immunity induced by a booster dose of CoronaVac is active against VOCs, suggesting adequate protection. IMPORTANCE CoronaVac is an inactivated vaccine against SARS-CoV-2 that has been approved by WHO for emergency use. Phase III clinical trials are in progress in several countries, including China, Brazil, Turkey, and Chile, and have shown safety and immunogenicity after two doses of the vaccine. This report characterizes immune responses induced by two doses of CoronaVac followed by a booster dose 5 months after the second dose in healthy Chilean adults. The data reported here show that a booster dose increased the immune responses against SARS-CoV-2, enhancing levels of neutralizing antibodies against the ancestral strain and VOCs. Similarly, anti-SARS-CoV-2 CD4+ T cell responses were increased following the booster dose. In contrast, levels of gamma interferon secretion and T cell activation against the VOCs Delta and Omicron were not significantly different from those for the ancestral strain. Therefore, a third dose of CoronaVac in a homologous vaccination schedule improves its immunogenicity in healthy volunteers.

Safety and Non-Inferiority Evaluation of Two Immunization Schedules with an Inactivated SARS-CoV-2 Vaccine in Adults: A Randomized Clinical Trial.

Several vaccines have been developed to control the COVID-19 pandemic. CoronaVac®, an inactivated SARS-CoV-2 vaccine, has demonstrated safety and immunogenicity, preventing severe COVID-19 cases. We investigate the safety and non-inferiority of two immunization schedules of CoronaVac® in a non-inferiority trial in healthy adults. A total of 2302 healthy adults were enrolled at 8 centers in Chile and randomly assigned to two vaccination schedules, receiving two doses with either 14 or 28 days between each. The primary safety and efficacy endpoints were solicited adverse events (AEs) within 7 days of each dose, and comparing the number of cases of SARS-CoV-2 infection 14 days after the second dose between the schedules, respectively. The most frequent local AE was pain at the injection site, which was less frequent in participants aged ≥60 years. Other local AEs were reported in less than 5% of participants. The most frequent systemic AEs were headache, fatigue, and myalgia. Most AEs were mild and transient. There were no significant differences for local and systemic AEs between schedules. A total of 58 COVID-19 cases were confirmed, and all but 2 of them were mild. No differences were observed in the proportion of COVID-19 cases between schedules. CoronaVac® is safe, especially in ≥60-year-old participants. Both schedules protected against COVID-19 hospitalization.

Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy. METHODS: COVID-19 patients with moderate pneumonia (SpO2 ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO2), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions. RESULTS: A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher. CONCLUSIONS: The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered. TRIAL REGISTRATION: Clinicaltrials.jp number: JapicCTI-205238.

A randomized, double-blind, placebo-controlled phase III clinical trial to evaluate the efficacy and safety of SARS-CoV-2 vaccine (inactivated, Vero cell): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The primary objective is to evaluate the efficacy of an inactivated and aluminium hydroxide adsorbed SARS-CoV-2 vaccine (Sinovac, China) in voluntary participants after 14 days of the second dose against RT-PCR confirmed symptomatic COVID-19 cases. The secondary objectives include evaluating the efficacy after at least one dose of the vaccine against RT-PCR confirmed symptomatic COVID-19 cases; the efficacy of two doses of the vaccine on the rates of hospitalization and death; the safety of the vaccine including adverse reactions up to one year after the 2nd dose of vaccination; and the immunogenicity of the vaccine and its duration up to 120 days. TRIAL DESIGN: This is a phase III, randomized, double-blind, placebo-controlled case driven clinical trial to assess the efficacy and safety of the vaccine. The study is planned to be carried out within two separate cohorts in voluntary participants aged between 18-59 years old. The first cohort includes healthcare professionals actively working in healthcare units, who are assumed to have higher risk of acquiring COVID-19, and the second cohort includes other immunocompetent subjects in the same age group, who are at a regular risk for COVID-19 disease. In Cohort 1, healthcare professionals will be randomized to receive two intramuscular doses of investigational product or the placebo in a 1:1 ratio and they will be monitored for 12 months by active surveillance of COVID-19. In Cohort 2, immunocompetent subjects will be randomized to receive vaccine or the placebo in a 2:1 ratio. PARTICIPANTS: Healthcare professionals of both genders, including medical doctors, nurses, cleaners, hospital technicians, and administrative personnel who work in any department of a healthcare unit and immunocompetent individuals of both genders are included. Pregnant (confirmed by positive beta-hCG test) and breastfeeding women as well as those intending to become pregnant within three months after vaccination are excluded. Other exclusion criteria include history of COVID-19 test positivity (PCR or immunoglobulin test results), any form of immunosuppressive therapy including corticosteroids within 6 months, history of bleeding disorders, asplenia, and administration of any form of immunoglobulins or blood products within 3 months. Exclusion criteria for the second dose include any serious adverse events related with the vaccine, anaphylaxis or hypersensitivity after vaccination, or any confirmed or suspected autoimmune or immunosuppressive disease (including HIV infection). Participants are only included after signing the voluntary informed consent form, ensuring cooperation in visits, undergoing screening for evaluation, and conforming to all the inclusion and exclusion criteria. All clinical sites are located in Turkey. INTERVENTION AND COMPARATOR: The vaccine was manufactured by Sinovac Research & Development Co., Ltd. It is a preparation made from a novel coronavirus (strain CZ02) grown in the kidney cell cultures (Vero Cell) of the African green monkey and contains inactivated SARS-CoV-2 virus, aluminium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride. A dose of 0.5 mL contains 600 SU of SARS-CoV-2 virus antigen. The placebo contains aluminium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride (0.5mL/dose). Scheduled visits and additional unscheduled weekly visits will be performed for the first 13 weeks and neutralizing antibody test, IgG test, T-Cell activation test, pregnancy test, and RT-PCR tests along with total antibody test will be performed. Adverse events and serious adverse events during the follow-up will be recorded on diary cards. Diary cards will collect information on the timing and severity of COVID-19 symptoms and solicited adverse events recorded by the subjects during one-year follow-up period. All serious adverse events will be managed and necessary treatment will be ensured according to the local regulations. All serious adverse events following vaccination will be reported to the ethics committee, the Ministry of Health, and the study sponsor within 24 hours of detection. MAIN OUTCOMES: The primary efficacy endpoint is the incidence of symptomatic cases of COVID-19 disease confirmed by RT-PCR two weeks after the second dose of vaccination. Secondary efficacy endpoints are the incidence of hospitalization/mortality rates among one or two dose regimens, duration of immunogenicity rates up to 120 days, the seroconversion rate, the seropositivity rate, neutralizing antibody titer, and IgG levels 14 days after each dose of vaccination. The primary safety endpoint is the severity and frequency of local and systemic adverse reactions during the period of one week after vaccination. The study would be terminated if more than 15% of the subjects have grade ≥3 adverse events related to vaccination including local reactions. RANDOMISATION: Eligible subjects will be randomized at their Study Day 0 to two study groups using an Interactive Web Response System (IWRS; developed by Omega CRO, Ankara, Turkey) in both risk groups. The IWRS system customizes the randomization algorithm. After enrolment in the study, each participant will be randomly assigned to either of the two treatment arms at a ratio of 1:1 in the high-risk group and at a ratio of 2:1 in the normal risk group. Each enrolled participant will be assigned to a code and will receive the treatment labelled with the code. BLINDING (MASKING): The trial is a double-blind study to avoid introducing bias. The blinding may be broken by the investigator in the event of a medical emergency in which knowledge of the identity of the study vaccine is critical for management of the subject's immediate treatment. The Data and Safety Monitoring Board is to be contacted in case of breaking the blinding for a study object. The blood samples will be taken from both placebo and vaccinated groups, in order not to break the blinding. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The study is planned to be carried out with two separate cohorts. The Cohort 1 includes healthcare professionals working in healthcare units and the Cohort 2 consists of immunocompetent subjects having normal risk for COVID-19 disease. The Cohort 2 will be initiated after the evaluation of the interim safety report of the Cohort 1 by the Data and Safety Monitoring Board. Both cohorts will be followed-up via RT-PCR to confirm symptomatic COVID-19 cases. If the clinical efficacy of the vaccine is shown in the Cohort 1 or 2, the subjects randomized into the placebo arm will also be vaccinated. In the Cohort 1, 588 subjects should be included in both arms with the assumption that the risk of infection with COVID-19 will be 5% for the placebo arm and 2% for the vaccine arm in the high-risk group. Considering 10% of drop-out rate and 5% of seropositivity or PCR positivity at baseline, 680 subjects should be screened at both arms of the Cohort 1. Group sample sizes of 7545 SARS-CoV-2 vaccine and 3773 placebo suits at a two-sided 95% confidence interval for the difference in population proportions with a width equal to 1.0%, when the estimated incidence rate for vaccinated group is 1.0% and the estimated incidence rate for placebo group is 2.0%. Drop-out rate is assumed to be 10% and seropositivity or PCR positivity at baseline is assumed to be 5%; accordingly, 13000 participants are needed to be enrolled totally in both cohorts. The remaining 11640 subjects will be screened in the Cohort 2 and eligible subjects will be randomized at a ratio of 2:1. TRIAL STATUS: Protocol version 6.0 - 15 October 2020. Recruitment started on 15.09.2020 and is expected to end on February 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04582344 . Registered 8 October 2020 FULL PROTOCOL: The full protocol of the trial is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Double-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial to Evaluate the Efficacy and Safety of treating Healthcare Professionals with the Adsorbed COVID-19 (Inactivated) Vaccine Manufactured by Sinovac - PROFISCOV: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: To evaluate the efficacy of two doses of the adsorbed vaccine COVID-19 (inactivated) produced by Sinovac in symptomatic individuals, with virological confirmation of COVID-19, two weeks after the completion of the two-dose vaccination regimen, aged 18 years or older who work as health professionals providing care to patients with possible or confirmed COVID-19. To describe the occurrence of adverse reactions associated with the administration of each of two doses of the adsorbed vaccine COVID-19 (inactivated) produced by Sinovac up to one week after vaccination in Adults (18-59 years of age) and Elderly (60 years of age or more). TRIAL DESIGN: This is a Phase III, randomized, multicenter, endpoint driven, double-blind, placebo-controlled clinical trial to assess the efficacy and safety of the adsorbed vaccine COVID-19 (inactivated) produced by Sinovac. The adsorbed vaccine COVID-19 (inactivated) produced by Sinovac (product under investigation) will be compared to placebo. Voluntary participants will be randomized to receive two intramuscular doses of the investigational product or the placebo, in a 1: 1 ratio, stratified by age group (18 to 59 years and 60 years or more) and will be monitored for one year by active surveillance of COVID-19. Two databases will be established according to the age groups: one for adults (18-59 years) and one for the elderly (60 years of age or older). The threshold to consider the vaccine efficacious will be to reach a protection level of at least 50%, as proposed by the World Health Organization and the FDA. Success in this criterion will be defined by sequential monitoring with adjustment of the lower limit of the 95% confidence interval above 30% for the primary efficacy endpoint. PARTICIPANTS: Healthy participants and / or participants with clinically controlled disease, of both genders, 18 years of age or older, working as health professionals performing care in units specialized in direct contact with people with possible or confirmed cases of COVID-19. Participation of pregnant women and those who are breastfeeding, as well as those intending to become pregnant within three months after vaccination will not be allowed. Participants will only be included after signing the voluntary Informed Consent Form and ensuring they undergo screening evaluation and conform to all the inclusion and exclusion criteria. All the clinical sites are located in Brazil. INTERVENTION AND COMPARATOR: Experimental intervention: The vaccine was manufactured by Sinovac Life Sciences (Beijing, China) and contains 3 µg/0.5 mL (equivalent to 600 SU per dose) of inactivated SARS-CoV-2 virus, and aluminium hydroxide as adjuvant. Control comparator: The placebo contains aluminium hydroxide in a 0.5 mL solution The schedule of both, experimental intervention and placebo is two 0.5 mL doses IM (deltoid) with a two week interval. MAIN OUTCOMES: The primary efficacy endpoint is the incidence of symptomatic cases of virologically confirmed COVID-19 two weeks after the second vaccination. The virological diagnosis will be confirmed by detection of SARS-CoV-2 nucleic acid in a clinical sample. The primary safety endpoint is the frequency of solicited and unsolicited local and systemic adverse reactions during the period of one week after vaccination according to age group in adult (18-59 years old) and elder (60 years of age or older) subjects. Adverse reactions are defined as adverse events that have a reasonable causal relationship to vaccination. RANDOMISATION: There will be two randomization lists, one for each age group, based on the investigational products to be administered, i.e., vaccine or placebo at a 1: 1 ratio. Each randomization list will be made to include up to 11,800 (18-59 year-old) adults, and 1,260 elderly (60 y-o and older) participants, the maximum number of participants needed per age group. An electronic central randomization system will be used to designate the investigational product that each participant must receive. BLINDING (MASKING): This trial is designed as a double-blind study to avoid introducing bias in the evaluation of efficacy, safety and immunogenicity. The clinical care team, the professionals responsible for the vaccination and the participants will not know which investigational product will be administered. Only pharmacists or nurses in the study who are responsible for the randomization, separation and blinding of the investigational product will have access to unblinded information. The sponsor's operational team will also remain blind. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The total number of participants needed to evaluate efficacy, 13,060 participants, satisfies the needed sample size calculated to evaluate safety. Therefore, the total number obtained for efficacy will be the number retained for the study. Up to 13,060 participants are expected to enter the study, with up to 11,800 participants aged 18 to 59 years and 1,260 elderly participants aged 60 and over. Half of the participants of each group will receive the experimental vaccine and half of them will receive the placebo. The recruitment of participants may be modified as recommended by the Data Safety Monitoring Committee at time of the interim unblinded analysis or blind assessment of the COVID-19 attack rate during the study. TRIAL STATUS: Protocol version 2.0 - 24-Aug-2020. Recruitment started on July 21st, 2020. The recruitment is expected to conclude in October 2020. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0445659 . Registry on 2 July 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Feasibility, Reliability, and Value of Remote Video-Based Trial Visits in Parkinson's Disease.

BACKGROUND: There is rising interest in remote clinical trial assessments, particularly in the setting of the COVID-19 pandemic. OBJECTIVE: To demonstrate the feasibility, reliability, and value of remote visits in a phase III clinical trial of individuals with Parkinson's disease. METHODS: We invited individuals with Parkinson's disease enrolled in a phase III clinical trial (STEADY-PD III) to enroll in a sub-study of remote video-based visits. Participants completed three remote visits over one year within four weeks of an in-person visit and completed assessments performed during the remote visit. We evaluated the ability to complete scheduled assessments remotely; agreement between remote and in-person outcome measures; and opinions of remote visits. RESULTS: We enrolled 40 participants (mean (SD) age 64.3 (10.4), 29% women), and 38 (95%) completed all remote visits. There was excellent correlation (ICC 0.81-0.87) between remote and in-person patient-reported outcomes, and moderate correlation (ICC 0.43-0.51) between remote and in-person motor assessments. On average, remote visits took around one quarter of the time of in-person visits (54 vs 190 minutes). Nearly all participants liked remote visits, and three-quarters said they would be more likely to participate in future trials if some visits could be conducted remotely. CONCLUSION: Remote visits are feasible and reliable in a phase III clinical trial of individuals with early, untreated Parkinson's disease. These visits are shorter, reduce participant burden, and enable safe conduct of research visits, which is especially important in the COVID-19 pandemic.

Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence.

The novel coronavirus infection that initially found at the end of 2019 has attracted great attention. So far, the number of infectious cases has increased globally to more than 100 thousand and the outbreak has been defined as a pandemic situation, but there are still no "specific drug" available. Relevant reports have pointed out the novel coronavirus has 80% homology with SARS. In the difficulty where new synthesized drug cannot be applied immediately to patients, "conventional drug in new use" becomes a feasible solution. The first medication experience of the recovered patients in the US has led remdesivir to be the "specific drug". China has also taken immediate action to put remdesivir into clinical trials with the purpose of applying it into clinical therapeutics for Corona Virus Disease 2019 (COVID-19). We started from the structure, immunogenicity, and pathogenesis of coronavirus infections of the novel coronavirus. Further, we analyzed the pharmacological actions and previous trials of remdesivir to identify the feasibility of conducting experiments on COVID-19.