新冠肺炎疫苗：研發創新與全球可及難題

文/大衛·羅賓遜（David K Robinson） 譯/史聰一

如今，全球正面臨巨大的挑戰，如何應對新冠肺炎疫情已經成為各國重要任務。《華盛頓郵報》指出，新冠肺炎疫苗的研發花費了12—18個月，這是破世界紀錄的研究速度。之前美國研制疫苗的最快時間是4年（根據1967年數據，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.

以最短時間研發出疫苗

應對新冠肺炎疫情的嚴峻挑戰需要以最短的時間研發出新冠肺炎疫苗。通常一款疫苗的研發平均需要4—30年，并經過長時間的臨床Ⅰ期、Ⅱ期及Ⅲ期試驗，才能夠上市并進行大規模的接種。臨床Ⅰ期階段需要證明其安全性，臨床Ⅱ期階段需要證明其有效性，完成Ⅲ期試驗后才能獲批上市。新冠肺炎疫苗的研發已將所有的階段都進行了壓縮、重疊并加速，從而保證能夠在最短12—18個月時間之內得到使用。這個加速階段包含了很多重要環節，首先是基于對MERS和SARS的研究基礎；其次在獲得Ⅰ期數據之前就進行了放大測試，雖然可能帶來一定的風險，但是新冠肺炎疫苗的研究人員決定將Ⅰ期和Ⅱ期以及Ⅱ和Ⅲ期試驗階段進行重疊或者合并，將某些階段壓縮，最后研究人員將小規模的臨床試驗加速進行，來保證新冠肺炎疫苗能夠在有效性試驗完成之后，即可進入到大規模生產階段。所以，在新冠肺炎疫苗全球研制的過程中，疫苗效力的研究以及各國監管的審查促成了全世界的緊急使用授權。基于過去幾十年的研究發展，重組蛋白疫苗在三十多年以前就獲得批準，LNPmRNA相關的研究已經在二十多年前進入臨床試驗階段。可以說，過去幾十年的科研工作為新冠肺炎疫苗的加速使用奠定了科研基礎。

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.

大衛·羅賓遜（美國），比爾及梅琳達·蓋茨基金會疫苗研發與監管部門副主任

新冠肺炎疫苗實施計劃是一種風險分擔機制

新冠肺炎疫苗方面的國際合作起到了非常關鍵的作用。值得一提的是新冠肺炎疫苗實施計劃（COVAX）——實際上，這是一種風險分擔機制，這種機制通過參與的各國分擔風險，從而降低全球面臨新冠肺炎疫情時的風險。

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有一系列目標：支持全球范圍內管理疫苗的供應；預計到2021年年底提供總計超過20億劑的新冠肺炎疫苗；通過提供疫苗降低確診病例的數量，并于2021年年底結束疫情的迅猛上升期；確保所有人公平可及獲得新冠肺炎疫苗。COVAX和很多不同疫苗廠家簽署了合同和合作協議，同時COVAX有一系列招投標活動。在COVAX疫苗庫中有三個來自中國的疫苗制造商，包括三葉草生物、國藥集團和科興中維；在美國、歐洲及其他國家和地區也有相應的疫苗生產商，所以COVAX是一個全球綜合性的疫苗平臺。COVAX簽署的總協議涉及的疫苗總量超過了10億劑，希望到2021年年底提供20億劑，并且能為20億人注射60億劑疫苗，這樣到2022年第三季度實現總體人口的疫苗覆蓋率達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.

加強合作，構建更穩健的疫苗供應鏈

COVAX疫苗也面臨供應問題，相應供應商生產延時、疫苗使用審批及進出口審批，都可能影響疫苗的供應。COVAX組成了一個特別行動小組來應對、改善供應鏈，以幫助在2021年扭轉整個疫情的走向。COVAX疫苗制造工作小組中一些主要成員將會關注92個參與“預先市場采購協議”國家，希望能夠增加包括疫苗和其他產品的產量并保證質量，從而形成可持續的長期的疫苗生產機制，供應更多的疫苗。

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.

疫苗的交付問題也十分值得關注。特別行動小組將和一系列貿易組織合作，共同組織疫苗的運輸與供給。COVAX的措施中包括與各個國家更緊密的合作，從而構建一個更加可持續、更加安全、更加穩健的疫苗供應鏈。目前已經看到新冠肺炎疫苗不斷擴大生產規模，世界各地疫苗生產商總計增加了20%的產能。這使總的年生產量從50億劑有望增加到100億劑甚至更多，但依然存在供給不足的問題。想要解決新冠肺炎疫苗供給的問題，COVAX項目也和一系列的市場機構展開了合作，以推動相應市場的建立，來完善整個疫苗供給；為供應商提供更廣闊的平臺獲得相應的原材料；同時更有效利用產量和庫存，并且實時調控未來的存貨量。

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.

目前的疫苗分配并沒有真正能夠滿足所有需要量。現在，COVAX已經覆蓋超過了100個國家，其中包括60個最不發達國家。疫苗分配過程中有很多不平等問題。不同國家疫苗覆蓋率有所不同，一些國家覆蓋率小于10%，而有的國家超過50%甚至60%。這與國家內部的疫苗生產能力、人口需求等一系列因素相關。如很多非洲國家并沒有足夠的疫苗生產商，但有很大需求，這加劇了疫苗供求之間的不匹配。目前，非洲疾病預防控制中心正不斷擴展疫苗合作伙伴關系。

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時會根據不同的目標或出發點選擇不同的制造工藝，目前主要有五種疫苗制造工藝?，F在全球使用較多的新冠肺炎疫苗類型是mRNA疫苗，也是第一次在全球范圍使用并驗證。另一種無細胞結合類型的疫苗，可以采用mRNA的形式，無需細胞結合，具備熱穩定的特性。在疫苗制造方面同樣有一些進步，比如佐劑和生物反應器。我們已經開始使用一次性生物反應器來進行生產，相較于傳統的不銹鋼生物反應器，一次性技術可以加快生產批次間的切換效率。

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.

在未來，期望從抗體、生物反應器乃至整個疫苗的制造過程不斷地降低疫苗研發或制造成本，制造出更適合在全球范圍內推廣的疫苗。我們對mRNA疫苗未來發展抱有期望，其生產過程中的酶和試劑成本更低，強度更高，可以通過微流體的混合來實現。

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.

總之，全球成千上萬的人員致力于疫苗研發，并通過有效的機制，確保全球疫苗的分配較為平衡，能夠保證供應鏈的穩定。通過COVAX機構的組織與配合盡可能降低全球疫苗分配的不平衡。此外，如一些欠發達地區與非洲疾病預防控制中心共同創辦了非洲疫苗生產合作計劃等，讓更多的新冠肺炎疫苗生產商參與進來，將更多新冠肺炎疫苗制造的技術應用到實際。相信新冠肺炎防控的前景將會更好。

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.