全球冠状病毒疫苗专利分析

冠状病毒是一类可感染人类和动物的RNA病毒,可引起严重急性呼吸综合征(SARS)和中东呼吸综合征(MERS)等严重疾病。新型冠状病毒是以前从未在人体中发现的冠状病毒新毒株,其人际传播迅速,引起了各国政府的高度重视并积极寻求疫苗防控对策。基于冠状病毒疫苗领域全景专利,在综合对比分析该领域的全部专利的发展趋势、主要国家和主要机构的专利产出的同时,重点揭示了其中的人用相关疫苗的发展与分布情况以及重点分析了人用疫苗产品的研发现状,以期为我国冠状病毒疫苗领域的科研工作者和管理决策者提供参考数据。     

新型冠状病毒致病机理及其疫苗的研发进展

新型冠状病毒(severe acute respiratory syndrome coronavirus-2, SARS-CoV-2)是一种可引起人新型冠状病毒肺炎(novel coronavirus pneumonia, NCP;亦称为COVID-19)的新发呼吸道病原体,与中东呼吸综合征冠状病毒(Middle East respiratory syndrome coronavirus, MERS-CoV)和严重急性呼吸综合征冠状病毒(severe acute respiratory syndrome coronavirus, SARS-CoV)同属β-冠状病毒,其受体与SARS-CoV的受体相同,均利用血管紧张素转化酶2(angiotensin-converting enzyme 2, ACE2)受体入侵人体细胞。SARS-CoV-2主要通过呼吸系统和消化系统感染,具有较高的传染性和致死率。目前,新冠病毒引起的肺炎已在全球范围内大规模蔓延,接种疫苗是根除病毒性传染病最有效的方法,国内外各大科研机构已快速展开COVID-19疫苗的研制工作,这是有效控制疫情的重点和难点。现就新冠病毒的致病机理、感染途径及疫苗研发作一综述,旨在为相关研究人员提供参考。     

冠状病毒疫苗的研究进展

严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)自被发现以来就引起了人们的广泛关注,开发针对该病毒的安全、有效疫苗成为近期的研究热点。本文以高致病性冠状病毒疫苗(包括灭活疫苗、重组亚单位疫苗、重组病毒载体疫苗和核酸疫苗)的研究展开综述,为研制SARS-CoV-2疫苗提供参考。     

新型冠状病毒疫苗研究策略分析

新型冠状病毒(SARS-CoV-2)是一种可引起人新型冠状病毒肺炎(COVID-19)的新发呼吸道病原体,与重症急性呼吸道综合症冠状病毒(SARS-CoV)和中东呼吸综合征冠状病毒(MERS-CoV)同属于β-冠状病毒,具有较高的传染性和一定的致死率。2019年12月在我国武汉被发现,随后蔓延到我国大部分省份,给我国人民健康和经济发展造成巨大损失。疫苗接种是预防和控制传染病的常规和有效手段,国内外多个机构已启动COVID-19疫苗研究工作。文中基于SARS和MERS疫苗研究的经验和教训,对COVID-19疫苗的研究策略和需要注意的关键问题进行了阐述,为相关研究人员提供参考。     

广谱抗冠状病毒疫苗及抗冠状病毒多肽的研究进展

由严重急性呼吸综合征冠状病毒2型(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)感染引起的2019冠状病毒病(coronavirus disease 2019,COVID-19)暴发,给人类公共卫生安全和全球经济发展造成了严重威胁。疫苗和药物是防治疫情的重要手段,但目前研发的针对冠状病毒的疫苗和药物大多以SARS-CoV-2为靶点,该病毒若发生重大突变或出现新的高致病性冠状病毒,目前研发的有效疫苗或药物可能会无效,而且疫苗和新药的研发往往比较滞后,难以在疫情发生早期投入使用。因此,亟须研发高效、安全、广谱的冠状病毒疫苗和药物,以应对未来可能出现的冠状病毒疫情。本文对广谱冠状病毒疫苗和抗冠状病毒多肽的研究进展进行综述,期望为研发此类疫苗和药物提供参考。     

严重急性呼吸综合征冠状病毒2的突变株及其疫苗

伴随着严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome-coronavirus 2,SARS-CoV-2)疫苗(也称COVID-19疫苗)在世界各地预防接种的展开,SARS-CoV-2突变株也在世界多地相继出现,其中有的突变株可能对现行SARS-CoV-2疫苗诱导的抗体产...     

新型冠状病毒潜在抗体依赖增强效应的研究进展

抗体依赖增强(antibody-dependent enhancement,ADE)是关系到病毒疫苗和抗体疗法安全性的重要问题之一.临床试验表明,ADE效应是导致部分病毒疫苗(如登革热疫苗等)研发失败的重要原因.针对非典型肺炎的致病病毒严重急性呼吸综合征冠状病毒(severe acute respiratory syn...     

中东呼吸综合征冠状病毒重组疫苗研究进展

中东呼吸综合征冠状病毒(Middle East respiratory syndrome corona virus,MERS-CoV)自发现以来就引起了人们的广泛关注,研制针对该病毒的有效疫苗成为近期的研究热点。本文主要介绍该病毒重组疫苗方面的研究新进展,包括动物模型的选择以及重组亚单位疫苗、重组活载体疫苗、假病毒疫苗的构建与优化。在对该病毒重组疫苗的研究新进展做出相关总结的基础上,对进一步验证疫苗安全性和有效性等的发展方向提出展望。     

mRNA疫苗及其基于聚合物的递送系统研究进展

2019年,全球暴发了严重急性呼吸综合征冠状病毒2型(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)疫情。由SARS-CoV-2引起的传染病(Corona Virus Disease 2019,COVID-19)具有极强的传染性及较高的病死率,对人类健康及经济发展造成了极大伤害。疫苗接种是预防和控制SARS-CoV-2传播的主要途径。信使RNA(mRNA)疫苗因具有制备简单、生产周期短、细胞毒性较小等优点而备受关注;最重要的是,mRNA容易实现量产,是应对突发疫情的重要手段之一。在此将对mRNA疫苗及其作用机制、递送载体以及给药方式等进行综述,旨在为mRNA疫苗研发工作提供参考。     

中东呼吸综合征疫苗研究进展

中东呼吸综合征(Middle East respiratory syndrome,MERS)是由中东呼吸综合征冠状病毒(MERS Coronavirus,MERS-CoV)引起的一种呼吸系统疾病。目前该病已经蔓延到全球25个国家,造成1400余人感染,近500人死亡,并有4个国家报道骆驼感染MERS病例。研发相关疫苗成为预防该病非常重要的措施。研究人员在病毒载体、重组蛋白、DNAs、纳米粒子、MERS-CoV重组的基础上进行了大量的候选疫苗开发,其中一些还在实验动物身上进行了效果试验。本文就当前一些候选疫苗研究进展进行总结概括,以期更多人力物力投入到研发安全有效的疫苗当中。     

Binding and entering: COVID finds a new home

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerged as a virus with a pathogenicity closer to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and a transmissibility similar to common cold coronaviruses (CoVs). In this review, we briefly discuss the features of the receptor-binding domain (RBD) and protease cleavage of the SARS-CoV-2 spike protein that enable SARS-CoV-2 to be a pandemic virus.     

Current advances in the development of SARS-CoV-2 vaccines

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a global pandemic that has wreaked havoc globally, which has put a heavy toll on public health, lives, and the world economy. Vaccination is considered as one of the greatest successes in medical history. Based on prior experience with the development of SARS-CoV vaccines, all COVID-19 vaccines must be subjected to the tests for protective effects and harmful risks derived from antibody-dependent enhancement that may contribute to augmented infectivity and/or eosinophilic infiltration. The SARS-CoV-2 vaccine is now being developed urgently in several different ways. China is regarded as one of the world''s leading countries in SARS-CoV-2 vaccine development, up to date the last inactivated vaccine international clinical (Phase III) trial was launched in the United Arab Emirates by Sinopharm China National Biotec Group (CNBG). In this review, we outline the current status of vaccine development against clinically relevant SARS-CoV-2 strains, anticipating that such attempts would help create efficacious and sage SARS-CoV-2 vaccines.     

A genome-wide CRISPR screen identifies interactors of the autophagy pathway as conserved coronavirus targets

Over the past 20 years, 3 highly pathogenic human coronaviruses (HCoVs) have emerged—Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and, most recently, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)—demonstrating that coronaviruses (CoVs) pose a serious threat to human health and highlighting the importance of developing effective therapies against them. Similar to other viruses, CoVs are dependent on host factors for their survival and replication. We hypothesized that evolutionarily distinct CoVs may exploit similar host factors and pathways to support their replication cycles. Herein, we conducted 2 independent genome-wide CRISPR/Cas-9 knockout (KO) screens to identify MERS-CoV and HCoV-229E host dependency factors (HDFs) required for HCoV replication in the human Huh7 cell line. Top scoring genes were further validated and assessed in the context of MERS-CoV and HCoV-229E infection as well as SARS-CoV and SARS-CoV-2 infection. Strikingly, we found that several autophagy-related genes, including TMEM41B, MINAR1, and the immunophilin FKBP8, were common host factors required for pan-CoV replication. Importantly, inhibition of the immunophilin protein family with the compounds cyclosporine A, and the nonimmunosuppressive derivative alisporivir, resulted in dose-dependent inhibition of CoV replication in primary human nasal epithelial cell cultures, which recapitulate the natural site of virus replication. Overall, we identified host factors that are crucial for CoV replication and demonstrated that these factors constitute potential targets for therapeutic intervention by clinically approved drugs.

This study identifies essential host dependency factors for human coronavirus replication, showing that these can be directly targeted by clinically approved inhibitors and that treatment leads to effective inhibition of coronavirus replication in primary human nasal epithelial cell cultures.     

Mouse-adapted SARS-CoV-2 protects animals from lethal SARS-CoV challenge

The emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in a pandemic causing significant damage to public health and the economy. Efforts to understand the mechanisms of Coronavirus Disease 2019 (COVID-19) have been hampered by the lack of robust mouse models. To overcome this barrier, we used a reverse genetic system to generate a mouse-adapted strain of SARS-CoV-2. Incorporating key mutations found in SARS-CoV-2 variants, this model recapitulates critical elements of human infection including viral replication in the lung, immune cell infiltration, and significant in vivo disease. Importantly, mouse adaptation of SARS-CoV-2 does not impair replication in human airway cells and maintains antigenicity similar to human SARS-CoV-2 strains. Coupled with the incorporation of mutations found in variants of concern, CMA3p20 offers several advantages over other mouse-adapted SARS-CoV-2 strains. Using this model, we demonstrate that SARS-CoV-2–infected mice are protected from lethal challenge with the original Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), suggesting immunity from heterologous Coronavirus (CoV) strains. Together, the results highlight the use of this mouse model for further study of SARS-CoV-2 infection and disease.

Studying cross-protection from different coronaviruses is important to inform the research for a universal vaccine. This study uses a mouse-adapted SARS-CoV-2 strain to show that it confers protection from SARS-CoV challenge, suggesting possible immunity from heterologous challenge following natural infection.     

mRNA vaccines for COVID-19: what,why and how

The Coronavirus disease-19 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2), has impacted human lives in the most profound ways with millions of infections and deaths. Scientists and pharmaceutical companies have been in race to produce vaccines against SARS-CoV-2. Vaccine generation usually demands years of developing and testing for efficacy and safety. However, it only took less than one year to generate two mRNA vaccines from their development to deployment. The rapid production time, cost-effectiveness, versatility in vaccine design, and clinically proven ability to induce cellular and humoral immune response have crowned mRNA vaccines with spotlights as most promising vaccine candidates in the fight against the pandemic. In this review, we discuss the general principles of mRNA vaccine design and working mechanisms of the vaccines, and provide an up-to-date summary of pre-clinical and clinical trials on seven anti-COVID-19 mRNA candidate vaccines, with the focus on the two mRNA vaccines already licensed for vaccination. In addition, we highlight the key strategies in designing mRNA vaccines to maximize the expression of immunogens and avoid intrinsic innate immune response. We also provide some perspective for future vaccine development against COVID-19 and other pathogens.     

Bat origin of human coronaviruses

Bats have been recognized as the natural reservoirs of a large variety of viruses. Special attention has been paid to bat coronaviruses as the two emerging coronaviruses which have caused unexpected human disease outbreaks in the 21st century, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), are suggested to be originated from bats. Various species of horseshoe bats in China have been found to harbor genetically diverse SARS-like coronaviruses. Some strains are highly similar to SARS-CoV even in the spike protein and are able to use the same receptor as SARS-CoV for cell entry. On the other hand, diverse coronaviruses phylogenetically related to MERS-CoV have been discovered worldwide in a wide range of bat species, some of which can be classified to the same coronavirus species as MERS-CoV. Coronaviruses genetically related to human coronavirus 229E and NL63 have been detected in bats as well. Moreover, intermediate hosts are believed to play an important role in the transmission and emergence of these coronaviruses from bats to humans. Understanding the bat origin of human coronaviruses is helpful for the prediction and prevention of another pandemic emergence in the future.     

COVID-19疫苗研究现状*

2019年底于中国武汉暴发的新型冠状病毒肺炎疫情来势凶猛,迅速蔓延全球,并被世界卫生组织列为“国际关注的突发公共卫生事件”,给全人类的健康及经济发展造成难以估量的损害。新型冠状病毒对人群普遍易感且传染性强,在无特效药物及治疗手段的情况下,疫苗接种是防控COVID-19疫情最有效且最经济的途径。目前全球疫苗研发正在加速进行,各国之间通力合作,共同应对此次疫情。主要对目前正在研发的针对SARS-CoV-2的灭活疫苗、病毒载体疫苗、基因工程重组亚单位疫苗、核酸疫苗的研究进展进行综述。     

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Emergence,history, basic and clinical aspects

In late December 2019, the world woke to a reality of a pandemic of Coronavirus Disease (COVID-19), elicited by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which belongs to a group of β-coronavirus. The potential to cause life-threatening respiratory failure and rapid transmission puts COVID-19 in the list of Public Health Emergency of International Concern (PHEIC). In the last two decades, this is the 3rd deadliest Coronavirus pandemic, following SARS which lasted between 2002 and 2003 and Middle East Respiratory Syndrome (MERS) from 2012 till date. Globally and as of April 23rd 2020, COVID-19 has affected 2,544,792 individuals in over 200 countries, causing 175,694 fatalities. While the SARS-CoV-2 originated in China with 84,302 confirmed cases and 4642 deaths as at the time of writing this review, the rapid transmission of SARS-CoV-2 has resulted in exponential increase in the number of cases outside of China to about 10 times the report case and death in mainland China. SARS-CoV-2 is suspected to be zoonotic in nature as genetic studies have shown sequence similarity to viruses originating from bats. Extreme precautionary measures, such as curfew, shutting of borders and quarantining of individuals suspected to be infected have been instituted with immediate effect; however, due to individuals that are asymptomatic, uncontrolled human-to-human transmission has resulted in exponential infection rate and numerous loss of lives even with this lockdown measures. This review article summarizes the developing situation surrounding the SARS-CoV-2 pandemic with respect to its epidemiology, unique genomic structure, possible origins, transmission, pathogenesis, comparison with other deadly species of Coronaviruses (CoV) and emerging treatment strategies built on informed literature.     

Computational Identification of Small Interfering RNA Targets in SARS-CoV-2

With the epidemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) worldwide and in the absence of any effective vaccine, there is an urgent need to find a specific anti- SARS-CoV-2 agent. In this study, by analyzing the secondary structures of the SARS-CoV-2 genome (MN908947), several 21~25 base-long segments were obtained and selected as the potential targets of small interfering RNA duplexes. Moreover, it was also found that these targets are conserved among different strains. We hope the results will contribute to the pharmaceutical research and therapy of the SARS-CoV-2.