Preclinical evaluation of a plant-derived SARS-CoV-2 subunit vaccine: Protective efficacy,immunogenicity, safety,and toxicity

Coronavirus disease 2019 (COVID-19) is an acute respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The prevention of SARS-CoV-2 transmission has become a global priority. Previously, we showed that a protein subunit vaccine that was developed based on the fusion of the SARS-CoV-2 receptor-binding domain (RBD) to the Fc portion of human IgG1 (RBD-Fc), produced in Nicotiana benthamiana, and adjuvanted with alum, namely, Baiya SARS-CoV-2 Vax 1, induced potent immunological responses in both mice and cynomolgus monkeys. Hence, this study evaluated the protective efficacy, safety, and toxicity of Baiya SARS-CoV-2 Vax 1 in K18-hACE2 mice, monkeys and Wistar rats. Two doses of vaccine were administered three weeks apart on Days 0 and 21. The administration of the vaccine to K18-hACE2 mice reduced viral loads in the lungs and brains of the vaccinated animals and protected the mice against challenge with SARS-CoV-2. In monkeys, the results of safety pharmacology tests, general clinical observations, and a core battery of studies of three vital systems, namely, the central nervous, cardiovascular, and respiratory systems, did not reveal any safety concerns. The toxicology study of the vaccine in rats showed no vaccine-related pathological changes, and all the animals remained healthy under the conditions of this study. Furthermore, the vaccine did not cause any abnormal toxicity in rats and was clinically tolerated even at the highest tested concentration. In addition, general health status, body temperature, local toxicity at the administration site, hematology, and blood chemistry parameters were also monitored. Overall, this work presents the results of the first systematic study of the safety profile of a plant-derived vaccine, Baiya SARS-CoV-2 Vax 1; this approach can be considered a viable strategy for the development of vaccines against COVID-19.     

中成药联合普利或沙坦类药物治疗糖尿病肾病的网状Meta分析＊

目的 运用网状Meta分析方法，以单纯ACEI/ARB（angiotensin receptor blockers，ARB；angiotensin-converting enzyme inhibitor，ACE）治疗为共同参照，对比海昆肾喜胶囊、黄葵胶囊、尿毒清颗粒、肾衰宁胶囊、雷公藤多苷片、金水宝胶囊、百令胶囊、火把花根片对糖尿病肾病的临床疗效。方法 计算机检索有关海昆肾喜胶囊、黄葵胶囊，尿毒清颗粒、肾衰宁胶囊、雷公藤多苷片、金水宝胶囊、百令胶囊、火把花根片联合ACEI/ARB治疗糖尿病肾病的随机对照试验。由2名研究人员独立筛选，包括质量、评估，数据采用R、Gemtc、ＲevMan 5.3软件进行网状Meta分析和传统Meta分析。最终纳入86篇RCTs，共7413例患者，涉及9种干预措施。结果 Meta分析结果显示：①在综合疗效方面，金水宝胶囊、雷公藤多苷片、肾衰宁胶囊联合ACEI/ARB排序靠前，其中雷公藤多苷片联合ACEI/ARB降低24 h尿蛋白（24 h UPQ）和尿微量蛋白（UAER）的疗效最佳，肾衰宁胶囊联合ACEI/ARB降低血肌酐（Scr）、糖化血红蛋白（HBA1C）和空腹血糖（FPG）的疗效最佳；②在安全性方面，联合中成药均较单纯ACEI/ARB治疗有一定改善，因临床异质性较大无法定量合并，所有纳入研究未发生严重不良反应。由于纳入文献质量相对偏低，得出的结论尚有待临床验证。结论 结合网状Meta分析结果和文献信息，在治疗有效率方面，金水宝胶囊联合ACEI/ARB疗效最优；在降低24 h尿蛋白（24 hUPQ）和尿微量蛋白（UAER）方面，均为雷公藤多苷片联合ACEI/ARB疗效最优；在降低血肌酐（Scr）、糖化血红蛋白（HBA1C）和空腹血糖（FPG）方面，均为肾衰宁胶囊联合ACEI/ARB疗效最优。     

Proxalutamide in metastatic castration-resistant prostate cancer: Primary analysis of a multicenter,randomized, open-label,phase 2 trial

We aim to assess the safety and efficacy of proxalutamide, a novel androgen receptor antagonist, for men with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter, randomized, open-label, phase 2 trial. In our study, the enrolled mCRPC patients were randomized to 100, 200 and 300 mg dose groups at 1:1:1. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and time to PSA and radiographic progression. Safety and pharmacokinetics were also assessed. Finally, there were 108 patients from 17 centers being enrolled. By week 16, there were 13 (35.1%), 12 (36.4%) and 15 (42.9%) patients with confirmed 50% or greater PSA decline in 100 mg (n = 37), 200 mg (n = 33) and 300 mg (n = 35) groups, respectively. Among the 19 patients with target lesions at study entry, three (15.8%) had a partial response and 12 (63.2%) had stable disease. The ORRs of 20.0%, 22.2%, 0% and DCRs of 80.0%, 88.9%, 60.0% were, respectively, achieved in 100, 200 and 300 mg groups. By the maximum follow-up time of 24 weeks, there were 42.6% and 10.2% of cases experiencing PSA progression and radiographic progression, respectively. Overall, adverse events (AEs) were experienced by 94.4% of patients, most of which were mild or moderate. There were 28 patients experiencing ≥grade 3 AEs. The most common AEs were fatigue (17.6%), anemia (14.8%), elevated AST (14.8%) and ALT (13.0%), decreased appetite (13.0%). These findings preliminarily showed the promising antitumor activity of proxalutamide in patients with mCRPC with a manageable safety profile. The proxalutamide dose of 200 mg daily is recommended for future phase 3 trial (Clinical trial registration no. CTR20170177).     

Consensus summary report for CEPI/BC March 12–13, 2020 meeting: Assessment of risk of disease enhancement with COVID-19 vaccines

A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of “disease enhancement” has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.