新冠肺炎疫苗：研发创新与全球可及难题

文/大卫·罗宾逊（David K Robinson） 译/史聪一

如今，全球正面临巨大的挑战，如何应对新冠肺炎疫情已经成为各国重要任务。《华盛顿邮报》指出，新冠肺炎疫苗的研发花费了12—18个月，这是破世界纪录的研究速度。之前美国研制疫苗的最快时间是4年（根据1967年数据，腮腺炎疫苗研制需要4年），而艾滋病疫苗的研制可能至少需要36年。

Currently, the world is facing significant challenges, and how to deal with COVID–19 Pandemic has become an essential task for all countries. As the

Washington Post

indicated, the COVID–19 vaccines were developed within 12 to 18 months, which would be a world record. Previously, the fastest time to create a vaccine in the United States was in four years (mumps vaccine, from scientific concept to approval in 1967), while an HIV vaccine quest could take 36 years and continuing.

以最短时间研发出疫苗

应对新冠肺炎疫情的严峻挑战需要以最短的时间研发出新冠肺炎疫苗。通常一款疫苗的研发平均需要4—30年，并经过长时间的临床Ⅰ期、Ⅱ期及Ⅲ期试验，才能够上市并进行大规模的接种。临床Ⅰ期阶段需要证明其安全性，临床Ⅱ期阶段需要证明其有效性，完成Ⅲ期试验后才能获批上市。新冠肺炎疫苗的研发已将所有的阶段都进行了压缩、重叠并加速，从而保证能够在最短12—18个月时间之内得到使用。这个加速阶段包含了很多重要环节，首先是基于对MERS和SARS的研究基础；其次在获得Ⅰ期数据之前就进行了放大测试，虽然可能带来一定的风险，但是新冠肺炎疫苗的研究人员决定将Ⅰ期和Ⅱ期以及Ⅱ和Ⅲ期试验阶段进行重叠或者合并，将某些阶段压缩，最后研究人员将小规模的临床试验加速进行，来保证新冠肺炎疫苗能够在有效性试验完成之后，即可进入到大规模生产阶段。所以，在新冠肺炎疫苗全球研制的过程中，疫苗效力的研究以及各国监管的审查促成了全世界的紧急使用授权。基于过去几十年的研究发展，重组蛋白疫苗在三十多年以前就获得批准，LNPmRNA相关的研究已经在二十多年前进入临床试验阶段。可以说，过去几十年的科研工作为新冠肺炎疫苗的加速使用奠定了科研基础。

Develop vaccine in the shortest time

In response to the severe challenges of COVID–19 pandemic, it is necessary to develop a new type of COVID–19 vaccine in the shortest time. Generally, the standard paradigm for developing a vaccine is some 4 to 30 years. After a long period of clinical phase I, phase II, and phase III trials, respectively, it can be marketed and vaccinated on a large scale. The researchers should prove the vaccine’s safety in clinical phase I, verifying its efficacy in phase II. After the trial of clinical phase III, it can be approved for marketing. The development of the vaccine was accelerated in all phases to ensure that it could be used within a 12 to 18 months window. This acceleration phase contains many vital links. Firstly, it is based on the research foundation of MERS and SARS. In addition, the scale-up test was carried out before obtaining the data from Phase I, though it may bring certain risks. However, the COVID–19 vaccine researchers decided to overlap or combine phases I and II, phase II and III, and compress certain phases. Researchers have accelerated the small-scale clinical trials to ensure that the COVID–19 vaccine can enter the large-scale manufacturing and distribution stage after the efficacy test is completed. Therefore, it can be seen that in the global development of the COVID–19 vaccine, both the efficacy research and the entire national review have obtained the world’s emergency use authorization. Also, based on the research and development of the past few decades, the recombinant protein vaccine was approved over 30 years ago. When we mentioned that LNPmRNA-related research has entered the clinical trial phase more than 20 years ago, it can be said that the scientific research in the past decade has laid the corresponding scientific research foundation for our current accelerated use of the COVID–19 vaccine.

大卫·罗宾逊（美国），比尔及梅琳达·盖茨基金会疫苗研发与监管部门副主任

新冠肺炎疫苗实施计划是一种风险分担机制

新冠肺炎疫苗方面的国际合作起到了非常关键的作用。值得一提的是新冠肺炎疫苗实施计划（COVAX）——实际上，这是一种风险分担机制，这种机制通过参与的各国分担风险，从而降低全球面临新冠肺炎疫情时的风险。

COVID–19 Vaccine Global Access Facility

International cooperation on COVID–19 vaccines has also played a key role in its global expansion. It is worth mentioning that the COVID–19 Vaccine Global Access Facility (COVAX) —in effect, is a risk-sharing mechanism that reduces the risk of COVID–19 globally by sharing the dangers of the countries involved.

COVAX有一系列目标：支持全球范围内管理疫苗的供应；预计到2021年年底提供总计超过20亿剂的新冠肺炎疫苗；通过提供疫苗降低确诊病例的数量，并于2021年年底结束疫情的迅猛上升期；确保所有人公平可及获得新冠肺炎疫苗。COVAX和很多不同疫苗厂家签署了合同和合作协议，同时COVAX有一系列招投标活动。在COVAX疫苗库中有三个来自中国的疫苗制造商，包括三叶草生物、国药集团和科兴中维；在美国、欧洲及其他国家和地区也有相应的疫苗生产商，所以COVAX是一个全球综合性的疫苗平台。COVAX签署的总协议涉及的疫苗总量超过了10亿剂，希望到2021年年底提供20亿剂，并且能为20亿人注射60亿剂疫苗，这样到2022年第三季度实现总体人口的疫苗覆盖率达30%。

There are series of goals for COVAX: to support the global management of the entire vaccine supply; it is expected to provide a total of more than 2 billion doses of COVID–19 vaccines by the end of 2021. Second, to reduce the number of confirmed cases by providing vaccines and ending the pandemic's rapid rise by the end of 2021; ensure fair access to the COVID–19 vaccine for everyone. COVAX has signed contracts and cooperation agreements with many different vaccine manufacturers and has a series of bidding activities. In the COVAX vaccine library, there are three vaccine manufacturers from China, including Clover Biopharmaceuticals, Sinopharm, and Sinovac; there are corresponding vaccine manufacturers in the United States, Europe, or other places. COVAX is a comprehensive vaccine platform globally. The total amount of vaccines involved in the total agreement signed by COVAX exceeds 1 billion doses. It is expected to provide 2 billion doses by the end of 2021 (as mentioned before), and 2 billion people will be injected with 6 billion vaccine doses. As a response, the vaccine coverage rate of the total population will reach 30% in the third quarter of 2022.

加强合作，构建更稳健的疫苗供应链

COVAX疫苗也面临供应问题，相应供应商生产延时、疫苗使用审批及进出口审批，都可能影响疫苗的供应。COVAX组成了一个特别行动小组来应对、改善供应链，以帮助在2021年扭转整个疫情的走向。COVAX疫苗制造工作小组中一些主要成员将会关注92个参与“预先市场采购协议”国家，希望能够增加包括疫苗和其他产品的产量并保证质量，从而形成可持续的长期的疫苗生产机制，供应更多的疫苗。

Supply, delivery, and distribution of COVID–19 Vaccine

The COVAX vaccine and the related supply issues, including the production delay of the related supplier, the approval for the use of the vaccine, and the approval of import and export, are all issues that may affect the supply. Therefore, COVAX formed a special action team to improve the supply chain to help reverse the trend of the entire pandemic in 2021. Members of the COVAX vaccine manufacturing working group will focus on 92 countries that participate in the “Pre-market Purchase Agreement,” hoping to increase the production of vaccines. They also hope to increase the use of other products to ensure quality and thereby form a sustainable long-term vaccine production mechanism to provide more needed vaccines in the future.

疫苗的交付问题也十分值得关注。特别行动小组将和一系列贸易组织合作，共同组织疫苗的运输与供给。COVAX的措施中包括与各个国家更紧密的合作，从而构建一个更加可持续、更加安全、更加稳健的疫苗供应链。目前已经看到新冠肺炎疫苗不断扩大生产规模，世界各地疫苗生产商总计增加了20%的产能。这使总的年生产量从50亿剂有望增加到100亿剂甚至更多，但依然存在供给不足的问题。想要解决新冠肺炎疫苗供给的问题，COVAX项目也和一系列的市场机构展开了合作，以推动相应市场的建立，来完善整个疫苗供给；为供应商提供更广阔的平台获得相应的原材料；同时更有效利用产量和库存，并且实时调控未来的存货量。

Currently, the delivery of vaccines is also worthy of attention. The special operation team may cooperate with trade organizations to jointly organize the transportation and vaccines supply. There are series of measures by COVAX, including closer cooperation with every country to build a more sustainable, safer, and more robust vaccine supply chain. We have seen the large-scale production of the COVID–19 vaccine, which involves a total of 20% increase in vaccine production capacity worldwide. Thus, the annual output of total doses is from 5 billion doses to 10 billion doses or more, but there is still a problem of short supply in the market. The COVAX project has cooperated with a series of market institutions to promote the establishment of improved market supply and solve any supply and distribution problems of the COVID–19 vaccines. The COVAX project will overhaul the entire vaccine supply chain: provide suppliers with a broader platform to obtain related raw materials and develop more effective output and inventory with realtime control of future stock.

目前的疫苗分配并没有真正能够满足所有需要量。现在，COVAX已经覆盖超过了100个国家，其中包括60个最不发达国家。疫苗分配过程中有很多不平等问题。不同国家疫苗覆盖率有所不同，一些国家覆盖率小于10%，而有的国家超过50%甚至60%。这与国家内部的疫苗生产能力、人口需求等一系列因素相关。如很多非洲国家并没有足够的疫苗生产商，但有很大需求，这加剧了疫苗供求之间的不匹配。目前，非洲疾病预防控制中心正不断扩展疫苗合作伙伴关系。

The current vaccine distribution has not indeed met all the demands. COVAX has covered more than 100 countries, including 60 least developed countries, and there are many inequalities in vaccine distribution. In different countries, vaccine coverage is different. The coverage rates in some countries are less than 10%, while some are more than 50% or even 60%. Related factors include the country’s internal vaccine production capacity and population demand. For example, many African countries do not have enough vaccine manufacturers, but there is great demand, exacerbating the mismatch between vaccine supplies. Currently, the African Centers for Disease Control and Prevention (ACDC) is continuously expanding vaccine partnerships.

不同的疫苗制造商在制造疫苗时会根据不同的目标或出发点选择不同的制造工艺，目前主要有五种疫苗制造工艺。现在全球使用较多的新冠肺炎疫苗类型是mRNA疫苗，也是第一次在全球范围使用并验证。另一种无细胞结合类型的疫苗，可以采用mRNA的形式，无需细胞结合，具备热稳定的特性。在疫苗制造方面同样有一些进步，比如佐剂和生物反应器。我们已经开始使用一次性生物反应器来进行生产，相较于传统的不锈钢生物反应器，一次性技术可以加快生产批次间的切换效率。

When manufacturing vaccines, different manufacturers will choose other manufacturing processes according to different goals or purposes. Currently, there are mainly five vaccine manufacturing processes. The most commonly used type of COVID–19 vaccine now in the world is the mRNA vaccine, and it is also the first time that it has been used and verified on a global scale. Another type of cell-free vaccine without cell binding can be in the form of mRNA and have the characteristics of stability under heat. There are also some advances in vaccine manufacturing, such as adjuvants. In addition, with the advancement of bioreactors, we have begun to use disposable bioreactors for production. Compared with traditional stainless steel bioreactors, Singleuse bioreactors can speed up the switching efficiency between production batches. Furthermore, by joint efforts of multiple parties, it will ensure the vaccines supply globally.

在未来，期望从抗体、生物反应器乃至整个疫苗的制造过程不断地降低疫苗研发或制造成本，制造出更适合在全球范围内推广的疫苗。我们对mRNA疫苗未来发展抱有期望，其生产过程中的酶和试剂成本更低，强度更高，可以通过微流体的混合来实现。

In the future, it is expected that the production process of antibodies, bioreactors, and even the entire vaccine can continuously reduce the cost of R&D and manufacturing; to produce vaccines that are more suitable for global promotion. In addition, we can see the prospects for the future development of mRNA. In the first place, the enzymes and reagents in the production process are lower in cost and higher in strength, which can be achieved by mixing microfluidics.

总之，全球成千上万的人员致力于疫苗研发，并通过有效的机制，确保全球疫苗的分配较为平衡，能够保证供应链的稳定。通过COVAX机构的组织与配合尽可能降低全球疫苗分配的不平衡。此外，如一些欠发达地区与非洲疾病预防控制中心共同创办了非洲疫苗生产合作计划等，让更多的新冠肺炎疫苗生产商参与进来，将更多新冠肺炎疫苗制造的技术应用到实际。相信新冠肺炎防控的前景将会更好。

In short, thousands of people are committed to vaccine research and development worldwide. Therefore, effective mechanisms to ensure that the global vaccine distribution is more balanced can stabilize our supply chain and minimize imbalances in global vaccine distribution through COVAX. In addition, in some less developed regions, if they could cooperate with ACDC and jointly establish the African Vaccine Production Cooperation Program, it would get more COVID–19 vaccine manufacturers involved and apply more COVID–19 vaccine manufacturing technology into practice. As a result, it is believed that the future of COVID–19 vaccines will be better.