冠状病毒病：疫苗的竞争

周可勇

Vaccines take over a decade to develop in a safe and effective manner. Vaccine candidates must first be proved to work in the lab and then tested for toxicity in animals before reaching early phase clinical trials. Once they have reached human trials， a vaccine must be tested for safety （phase I） and side effects （phase II） before entering large scale clinical trials （phase III）. There is a high level of attrition1 as vaccines pass through the various stages of clinical trials， either because they are unsafe， ineffective or both. It is difficult to fast-track vaccine development; these stages cannot be skipped.

The covid-19 pandemic is accelerating the slow process of vaccine development but how long will it be until we can effectively vaccinate populations？ This article looks at how the industry is responding to the covid-19 outbreak in the race for a vaccine.

Current vaccine candidates

According to the World Health Organisation （WHO）， there are more than 40 vaccines against SARS-CoV-2 in development， with two already at the clinical trial stage. The Coalition for Epidemic Preparedness Innovations （CEPI）， a foundation that takes donations to finance2 independent research projects to develop vaccines against emerging infectious3 diseases， is currently working with eight companies， all of which are having to adapt to accelerate their vaccine development process.

The first stage of vaccine development is research-intensive and involves the identification of natural or synthetic antigens that might help combat the disease. However， within a week of sequencing4 the SARS-CoV-2 genome， Chinese scientists had shared it publicly. Sharing the viral genome globally has allowed for an acceleration of the early development stage. Researchers at Imperial College， for example， took just two weeks from receiving the genome to producing a candidate vaccine.

Another way of accelerating the development process is to run trials in parallel. Researchers at Oxford University are currently recruiting for5 a safety trial in humans for a vaccine candidate that uses a chimpanzee adenoviral vector. Provided these go smoothly， they will move to larger trials to assess efficacy6. The same vaccine will undergo animal trials concurrently. This is unusual as animal work should normally be completed before human trials can begin. However， the chimpanzee adenoviral vector has been studied extensively and used safely in thousands of subjects in vaccines targeting over ten different disease types. This makes it easier to justify the accelerated move to human testing. Regulatory approval can also be accelerated if similar products have been approved before.

For similar reasons， many companies are also repurposing7 vaccines. Coronaviruses have caused two recent epidemics： SARS and MERS. In both cases， work started on vaccines was subsequently8 stopped when the epidemics were successfully contained. Inovio Pharmaceuticals had already started to work on a DNA vaccine for MERS prior to9 the covid-19 outbreak， allowing the company to quickly develop a potential vaccine for covid-19. Sanofi is repurposing a SARS protein vaccine and Novavax are working on several repurposed vaccines that will reportedly be ready for human trials in the spring.

As well as the more traditional techniques being used， such as live-attenuated and recombinant vaccines， new techniques are being used to develop a vaccine against SARS-CoV-2： RNA vaccines. These are faster and cheaper to develop than the more traditional vaccines as researchers dont need to grow large amounts of the virus in the lab， which overcomes both regulatory and manufacturing hurdles. However， no RNA vaccine has ever been approved for use and the safety of such vaccines is unknown at present. Moderna gave the first dose10 of their novel RNA vaccine to a human participant on 16 March and currently has 45 participants enrolled in11 in clinical trials. However， they expect the trials to continue into next year. Although the vaccine may have been quicker to develop， they cannot circumvent the necessary steps to show the vaccine is safe and effective.

One step that can potentially be fast-tracked is authorisation. The European Medicines Agency （EMA）  has regulatory mechanisms in place to speed up development and approval. The PRIME scheme was launched to provide early and enhanced scientific and regulatory support to medicines that have the potential to address unmet medical needs. Developers of medicines and vaccines benefitting from PRIME will be eligible12 for accelerated assessment， reducing the timeframe for the EMA to review applications for market authorisation. The EMA can also grant a conditional marketing authorisation for vaccines where the benefits of immediate availability outweigh the risks of less comprehensive data than normally required. Developers working on vaccines that could be used for the prevention of covid-19 are encouraged to contact the EMA and discuss their research as soon as possible.

Once a safe and effective vaccine has been developed， there are further hurdles such as large-scale manufacturing. Many organisations researching a vaccine dont have the required manufacturing capacity. Vaccine development is high risk， with many candidates failing to reach clinical application. Further， manufacturing facilities tend to be tailored to13 specific vaccines. Scaling these facilities up when the future deployment14 of a vaccine is still in the uncertain early stages is not commercially viable15. However， CEPI can shoulder16 some of that risk by providing funding not only to research facilities developing vaccine candidates but also to manufacturing facilities in parallel. At the same time as clinical trials are taking place in Oxford， production of the vaccine is being scaled up ready for larger trials and possible future deployment. By starting the scale up at an early stage， researchers are ensuring that sufficient doses will be available as soon as possible if the trials prove that the vaccine is safe and effective.

Current issues

Researchers in Beijing studied the viral genome from 103 infected patients and identified two types of the virus， S and L. At present， scientists do not know how the underlying genetic differences in the two strains relate to disease severity. Genetic analysis of a man in the US who tested positive in January has shown that it is possible to be infected by both strains. Any vaccine candidate will have to target features present in both strains in order to be effective. The genetic differences between the two strains are small at present and unlikely to affect the production of proteins， so as not to change the way the virus works. Genetic diversity doesnt necessarily mean the virus is changing however we can expect more strains to emerge.

It is generally agreed that， once infected， individuals are unlikely to be infected again， unless the virus mutates to overcome host immunity. It is possible that this selection pressure will lead to an outbreak of a new strain， in a similar fashion to seasonal flu. As is the case with flu， new variants can emerge that infect individuals， whether or not they have been infected in the past. This will clearly have an impact on the long-term efficacy of vaccines currently in development.

以安全有效的方式研發疫苗一般需要十多年的时间。候选疫苗必须首先在实验室中证明有效;之后，在进入早期临床试验之前，要在动物身上测试其毒性。一旦进入人体试验阶段，疫苗必须先进行安全性（第一阶段）和副作用（第二阶段）测试，然后才能开展大规模临床试验（第三阶段）。在临床试验的各个阶段，疫苗损耗非常大，要么由于疫苗不安全，要么由于疫苗无效，再或者两者都有。疫苗研发难以快速推进，上述这些阶段都不可省略。

2019冠状病毒病大流行加速了原本缓慢的疫苗研发进程，但究竟需要多长时间才能有效地为人们接种疫苗呢？本文探讨的就是疫苗行业在疫苗研发竞争中如何应对2019冠状病毒病的暴发。

现有的候选疫苗

根据世界卫生组织的消息，针对新型冠状病毒，目前研发中的疫苗有40多种，其中2种已进入临床试验阶段。流行病预防创新联盟（CEPI）是一个基金会，接受捐款用于资助针对新发传染病开发疫苗的独立研究项目。该基金会目前正与8家公司合作，所有公司都不得不根据现状加以调整，加速疫苗研发进程。

疫苗研发的第一阶段是研究密集型的，着眼于识别可能有助于对抗新冠病毒病的天然抗原或人工合成抗原。然而，中国科学家在对新冠病毒基因组进行测序后的一周之内就公开分享了测序结果。新冠病毒基因组全球共享使研发的第一阶段得以加速展开。例如，英国帝国理工学院的研究人员在获得基因组以后，仅花两周就制作出了一个候选疫苗。

加速疫苗研发进程的另一种方法是进行平行试验。牛津大学的研究人员目前正在招募志愿者测试一个候选疫苗的安全性，该疫苗使用的是黑猩猩腺病毒载体。如果进展顺利，他们将进行更大规模的试验来评估其效果。同样的疫苗将同时进行动物试验。牛津大学这种操作很不寻常，因为动物试验通常应该在人体试验启动之前完成。不过，科学家已对黑猩猩腺病毒载体进行过广泛研究，并在数以千计的疫苗试验对象身上安全使用过，涉及十多种不同的疾病类型。这使上述候选疫苗加速进入人体测试环节的理由更加充分。如果类似产品之前已经获得批准，监管部门的审批速度还可能加快。

出于类似的原因，许多公司也在将已有疫苗改作新用。冠状病毒造成了最近的两种流行病：非典（SARS）和中东呼吸综合征（MERS）。针对这两种流行病所进行的疫苗研发工作在疫情得到成功控制后都相继停止了。在2019冠状病毒病暴发之前，伊诺维奥制药公司已经开始为MERS患者研发DNA疫苗，这使公司能够迅速开发出针对2019冠状病毒病的候选疫苗。赛诺菲公司正在改造一种SARS蛋白疫苗，而诺瓦瓦克斯医药公司也正改造几种疫苗。据报道，这些疫苗将在明年春季准备好开始人体试验。

除了减毒活疫苗和重组疫苗这些正在使用的比较传统的技术外，人们也在利用新技术开发针对新冠病毒的核糖核酸疫苗（RNA疫苗）。与传统的疫苗技术相比，这些新技术的研发速度更快、成本也更低，因为研究人员不需要在实验室中培养大量的病毒，从而避开了监管和生产两方面的障碍。然而，目前还没有RNA疫苗得到过使用批准，而且这种疫苗的安全性目前尚不清楚。莫德纳公司于3月16日给一名志愿者首次注射了他们的新型RNA疫苗，目前已有45人参与了这项临床试验。但是，他们预计试验将持续到明年。虽然疫苗的研发速度也许更快了，但他们仍然无法绕过证明疫苗安全且有效的必要环节。

一个有可能快速推进工作进程的做法是官方授权。欧洲药品管理局（EMA）有适当的调控机制，可以加快疫苗的研发和审批。机制之一是PRIME项目，最初设置是针对可能满足某些无药可用的医疗需求的药品，希望尽早为这类药品的研发加强科学及监管支持。受益于PRIME项目的药品和疫苗研发机构将有资格获得加速评估，从而缩短EMA审批上市的时间。临床数据不像通常要求的那样充分全面会带来风险，但如果尽快推出疫苗带来的益处大于风险，EMA还可能为这类疫苗授予有条件的上市许可。EMA鼓励正在研发2019新冠病毒病疫苗的机构尽快与EMA联系并讨论他们的研发工作。

一款安全而有效的疫苗研发出来后，还会遭遇其他的问题，例如大批量生产的问题。许多研发疫苗的机构不具备必要的生产能力。疫苗研发风险很大，许多候选疫苗进入不到临床应用阶段。另外，生产设备往往是为特定的疫苗量身定制的。倘若一种疫苗还处于日后投放使用尚不确定的初期研发阶段，那么扩大生产设备的规模就很不划算。但是，CEPI既可以为研发候选疫苗的机构提供资助，也可以为生产部门提供支持，从而分担一部分风险。在牛津大学进行临床试验的同时，这种疫苗的生产规模也在扩大，以便为更大规模的试验和未来可能的疫苗投放做好准备。在研发初期就开始扩大生产规模，研究人员可以确保，一旦试验证明疫苗安全有效就能尽快向市场供应充足的疫苗。

当前的问题

北京的研究人员对103名感染者的病毒基因组进行了研究，发现了S型和L型两种类型的病毒。目前，科学家还不了解这两类毒株潜在的遗传差异与疾病严重程度之间的关系。美国一名男子在1月的病毒检测中呈阳性，基因分析显示，他可能同时感染了这两类毒株。任何候选疫苗都必须靶向这两类才算有效。这两类毒株目前的遗传差异很小，不大可能影响蛋白质的生成，因此不会改变病毒的感染机制。基因多样性并不一定意味着病毒在变异，但很可能会有更多类型的毒株出现。

一般认为，除非病毒发生变异并战胜宿主的免疫系统，否则感染过的个体不太可能再次感染。这种选择压力可能导致病毒新毒株的暴发，正如季节性流感一样。与流感类似，病毒可能出现新型变异并感染人类个体，无论他们过去是否被感染过。这一情况显然将影响目前研发中的疫苗的长期疗效。

（译者单位：北京四中）