新型冠狀病毒疫苗研究策略分析

楊利敏，田德雨，劉文軍,2

1 中國科學院微生物研究所 病原微生物與免疫學重點實驗室，北京 100101 2 中國科學院大學，北京 100049

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新型冠狀病毒疫苗研究策略分析

楊利敏1，田德雨1，劉文軍1,2

1 中國科學院微生物研究所 病原微生物與免疫學重點實驗室，北京 100101 2 中國科學院大學，北京 100049

新型冠狀病毒(SARS-CoV-2)是一種可引起人新型冠狀病毒肺炎(COVID-19)的新發(fā)呼吸道病原體，與重癥急性呼吸道綜合癥冠狀病毒(SARS-CoV)和中東呼吸綜合征冠狀病毒(MERS-CoV)同屬于β-冠狀病毒，具有較高的傳染性和一定的致死率。2019年12月在我國武漢被發(fā)現(xiàn)，隨后蔓延到我國大部分省份，給我國人民健康和經(jīng)濟發(fā)展造成巨大損失。疫苗接種是預防和控制傳染病的常規(guī)和有效手段，國內(nèi)外多個機構(gòu)已啟動COVID-19 疫苗研究工作。文中基于SARS 和MERS 疫苗研究的經(jīng)驗和教訓，對COVID-19 疫苗的研究策略和需要注意的關(guān)鍵問題進行了闡述，為相關(guān)研究人員提供參考。

新型冠狀病毒肺炎，疫苗，抗體，粘膜免疫，抗體依賴感染增強

新型冠狀病毒(SARS-CoV-2)于2019年12月初在湖北省武漢市被發(fā)現(xiàn)，呈現(xiàn)出高傳染性和快速傳播特點并可導致一定比例患者出現(xiàn)重癥新冠肺炎(COVID-19)[1-2]。2020年1月31日世界衛(wèi)生組織宣布COVID-19 疫情為“國際關(guān)注的突發(fā)公共衛(wèi)生事件”，于2月28日將疫情全球風險級別上調(diào)為“非常高”，并于3月12日將其定義為“大流行”。COVID-19 在臨床上表現(xiàn)為發(fā)熱、干咳、呼吸困難、肌肉或關(guān)節(jié)痛、腹瀉和肺炎，嚴重時可導致呼吸衰竭甚至死亡[3-4]。SARS-CoV-2 是繼SARS-CoV 和MERS-CoV 之后第3 個可引起人體嚴重急性呼吸窘迫綜合征(ARDS)的冠狀病毒，也是唯一造成全球大流行的非流感病毒。通過高效綜合防控我國疫情已被有效控制，截至2020年3月17日，我國已報告80 894 確診病例和3 122死亡病例，感染人數(shù)和傳播速度遠超前兩次冠狀病毒疫情，是建國以來最為嚴重的一次重大突發(fā)公共衛(wèi)生事件。研究證明，SARS-CoV-2 在人體內(nèi)的病毒載量變化模式不同于SARS-CoV，與流感病毒更相似[5]，且感染性更強，因此SARS-CoV-2具有長期在人間存在的潛在風險。隨著全球超過90%的國家和地區(qū)出現(xiàn)病例，其已成為全球公共衛(wèi)生機構(gòu)的一個巨大挑戰(zhàn)。

SARS-CoV-2 為單股正鏈RNA 病毒，是第7 個已發(fā)現(xiàn)可感染人的冠狀病毒。COVID-19 致死率低于SARS(9.6%)和MERS(34.4%)，但傳染性強于兩者，且存在一定數(shù)量的無癥和輕癥患者，因此防控難度也更大[6]。作為一種新發(fā)傳染病，阻隔被證明是最有效的短期防控措施，但從長遠來看，一種安全有效的疫苗對于控制疫情和防止再次暴發(fā)具有重要意義[7]。SARS-CoV-2 還沒有獲批的疫苗和治療性藥物，考慮到它與SARS-CoV和MERS-CoV 同屬β-冠狀病毒，與SARS-CoV同源性達79.5%，且細胞受體與SARS-CoV 同為血管緊張素轉(zhuǎn)化酶2(ACE2)[3]，因此前期SARS和 MERS 疫苗研究的經(jīng)驗可用于指導本次COVID-19 疫苗的研發(fā)。多個不同的疫苗平臺曾被用于SARS 和MERS 疫苗的研發(fā)，包括滅活全病毒疫苗、DNA 疫苗、亞單位疫苗、載體疫苗和減毒活疫苗，大部分尚處于臨床前研究階段，少數(shù)進入了臨床試驗階段。選擇一個適合COVID-19的疫苗研發(fā)策略將直接決定該疫苗研發(fā)的成敗。

我國已對COVID-19 的檢測、疫苗和治療性藥物的研發(fā)進行了重要部署，多個研究機構(gòu)在抓緊進行相關(guān)研究開發(fā)。本文基于前期 SARS 和MERS 疫苗研究過程中積累的經(jīng)驗和教訓，將從疫苗研發(fā)平臺的選擇、研發(fā)中需著重注意的幾個關(guān)鍵問題入手，分析探討 COVID-19 疫苗研發(fā) 策略，旨在為正在進行疫苗研發(fā)的同仁提供一些參考。

1 疫苗研發(fā)平臺

SARS 和MERS 候選疫苗誘導的中和抗體滴 度與試驗動物肺部感染指數(shù)和存活率直接相關(guān)[8]，但僅靠血清中和抗體并不能產(chǎn)生足夠保護[9-10]，細胞免疫對于病毒和感染細胞的清除起到至關(guān)重要的作用[11-12]，而且記憶性T 細胞在SARS 康復病人體內(nèi)的維持時間明顯長于中和抗體[13]，提示細胞免疫是實現(xiàn)疫苗長效保護不可或缺的。因此COVID-19 疫苗的設計需兼顧體液免疫和細胞免疫。另外，COVID-19 主要通過呼吸道和接觸傳播[3]，因此粘膜免疫在防止病毒感染中的作用要引起足夠重視。病毒包含4 個結(jié)構(gòu)蛋白：棘突蛋白(Spike，S)、包膜蛋白(Envelope，E)、膜蛋白(Membrane/ matrix，M)和核衣殼蛋白(Nucleocapsid，N)，S 蛋白通過位于 S1 亞基上的受體結(jié)合區(qū)(Receptor- binding domain，RBD)與特異受體結(jié)合導致病毒感染細胞[14-16]，針對S 蛋白的中和抗體可阻斷這一過程從而防止病毒侵入[17]，S 蛋白還可有效刺激T 細胞免疫應答[18]，因此是疫苗設計最重要的靶抗原，而N 和M 也被證明可誘導機體產(chǎn)生高效細胞免疫反應[19-21]。前期多個疫苗平臺被用于SARS 和MERS 疫苗的研發(fā)，其中滅活病毒疫苗、DNA 疫苗和載體疫苗已進入臨床試驗[22-26]，盡管還沒有疫苗上市，但依然為COVID-19 疫苗的設計積累了豐富經(jīng)驗，如何選擇適合COVID-19 的研發(fā)平臺是疫苗研發(fā)人員需要面臨的首個問題。

1.1 滅活病毒疫苗

滅活疫苗是最為經(jīng)典的疫苗形式，易于制備且能高效引起體液免疫應答，往往是新發(fā)傳染病的首選疫苗方案。滅活疫苗主要通過甲醛、β-丙內(nèi)酯和紫外3 種滅活方式獲得。SARS 和MERS滅活疫苗可引起小鼠、倉鼠、雪貂和猴子產(chǎn)生高滴度中和抗體[10,27-34]，而且SARS 滅活疫苗已完成Ⅰ期臨床試驗，證明了在人體上是安全的，且能誘導生成中和抗體[23]。但是滅活疫苗引起的T細胞免疫應答普遍偏弱，前期有研究證明SARS和MERS 滅活疫苗無法有效刺激機體產(chǎn)生細胞免疫應答[35-36]，即使產(chǎn)生高滴度血清中和抗體，保護效力也并不滿意[10,28]，而且還有研究發(fā)現(xiàn)MERS滅活疫苗會導致小鼠肺部過敏性病理反應[37]，另外疫苗生產(chǎn)需要操作高濃度活病毒，具有一定的生物安全風險，因此該疫苗策略需謹慎考慮。

1.2 核酸疫苗

核酸疫苗包括DNA 疫苗和mRNA 疫苗兩種。由于研發(fā)周期短，每當出現(xiàn)新發(fā)疫情時采用該策略可最快速地獲得候選疫苗[40-43]。目前已有包括SARS 和MERS 在內(nèi)的多個DNA 疫苗進入臨床試驗階段[24,26,44-45]，而且部分DNA 疫苗已經(jīng)上市，包括動物用流感、西尼羅病毒等[46]。相比DNA疫苗需要進入細胞核，mRNA 疫苗僅需進入細胞質(zhì)即可實現(xiàn)靶抗原的表達，因此理論上更為安全。近些年mRNA 疫苗得到迅速發(fā)展，狂犬病毒和流感病毒mRNA 疫苗已完成Ⅰ期臨床評價[45-46]，但免疫效果并不令人滿意，接種人員出現(xiàn)了較高比例的頭痛、疲勞和肌肉痛等副反應，疫苗生成的免疫保護在一年內(nèi)即迅速下降，而且未檢測到細胞免疫應答，因此還需進一步改善mRNA 疫苗的免疫效力和長期保護力。截止目前還沒有mRNA疫苗上市。SARS 和MERS DNA 疫苗可使小鼠和猴子產(chǎn)生體液和細胞免疫反應[19-21,38-39,47-52]，而且臨床試驗證明在人體上也是安全有效的[22,24]。國內(nèi)外多個機構(gòu)已迅速啟動了COVID-19 DNA 疫苗和mRNA 疫苗的研發(fā)工作，美國國家過敏和傳染病研究所(National Institute of Allergy and Infectious Diseases，NIAID)與Moderna 公司合作開發(fā)的mRNA 疫苗已率先啟動了Ⅰ期臨床試驗。DNA 疫苗可像病毒感染一樣進入細胞利用宿主蛋白翻譯系統(tǒng)生成靶抗原，作為一種內(nèi)生免疫原可同時誘導體液和細胞免疫應答，而且生產(chǎn)成本低廉、容易量產(chǎn)、無需冷鏈運輸，但相比蛋白疫苗方便的接種方式，DNA 疫苗的接種方式限制了其應用。接種DNA 疫苗主要包括3 種方式：直接肌肉注射、基因槍接種和電穿孔儀接種。盡管肌肉注射操作方便，但由于疫苗接種后主要分布于細胞間隙，僅有極少量能夠進入胞內(nèi)生成蛋白免疫原，因此免疫效果大打折扣。而基因槍和電穿孔儀接種增加了免疫成本，且臨床試驗報告顯示受試者普遍反映痛感較高，因此當前DNA 疫苗應用存在瓶頸。本團隊前期在研究埃博拉和拉沙熱病毒DNA 疫苗過程中開發(fā)了一種無針皮下接種DNA 疫苗的方式，免疫效果與基因槍和電穿孔儀接種無顯著差異，且成本低廉易于推廣。該技術(shù)可用于COVID-19 DNA 疫苗的接種，從而打破DNA 疫苗的接種瓶頸。盡管核酸疫苗可有效誘導全身性免疫應答，但由于免疫原性偏弱，且不易產(chǎn)生粘膜免疫應答，與其他疫苗聯(lián)合使用會達到更好的免疫效果[53]。鑒于核酸疫苗的優(yōu)勢，推薦其單獨使用或與其他平臺的疫苗聯(lián)合使用。

1.3 亞單位疫苗

亞單位疫苗由純化的重組蛋白構(gòu)成，被認為是最安全的疫苗，目前已有多個亞單位疫苗上市，包括乙型肝炎、戊型肝炎和人乳頭瘤病毒疫苗。SARS 和MERS 亞單位疫苗可使小鼠產(chǎn)生高滴度中和抗體，通過鼻腔或口腔接種還可以誘導粘膜免疫反應，從而更有效地阻斷病毒通過呼吸道傳播，數(shù)據(jù)也證明了粘膜接種途徑保護效力優(yōu)于肌肉接種[54-68]。然而作為一種非內(nèi)生抗原，亞單位疫苗不能通過MHC-Ⅰ遞呈，也就不能有效產(chǎn)生致敏細胞毒性T 細胞(CTL)，考慮到細胞免疫在清除冠狀病毒感染中的關(guān)鍵作用，針對COVID-19的亞單位疫苗最好與其他平臺疫苗配合使用，而且建議包含鼻腔、口腔粘膜接種途徑以激活粘膜免疫應答。另外亞單位疫苗免疫原性相對較弱，將其設計成多聚體或病毒樣顆粒(Virus like particle，VLP)結(jié)構(gòu)可有效增強其免疫原性。合適的疫苗佐劑對于增強免疫效率也是至關(guān)重要的，鋁佐劑是一種應用廣泛的人用疫苗佐劑，但是該佐劑不能有效誘導Th1 型免疫應答(介導細胞免疫)，而Th1 型免疫反應在清除病毒感染中處于重要地位。基于角鯊烯成分的佐劑，如MF59、AS03、AF03，被證明可更均衡地誘導亞單位疫苗的體液及細胞免疫應答，而且能誘導更廣泛的交叉反應[69]，相對更適合于COVID-19 亞單位疫苗。

1.4 載體疫苗

載體疫苗是利用病毒或細菌為載體，將疫苗靶基因整合入載體基因組中制備的疫苗，分為復制型和非復制型兩種。載體疫苗可感染細胞并在細胞質(zhì)內(nèi)表達靶抗原，因此可高效誘導機體產(chǎn)生體液及細胞免疫應答，由于具有天然粘膜嗜性，通過鼻腔或口腔接種還能誘導粘膜免疫反應，是近幾年發(fā)展最為迅速的疫苗研發(fā)平臺。有多個載體可供選擇，包括腺病毒、水泡性口炎病毒、痘苗病毒、麻疹病毒、副流感病毒、新城疫病毒、狂犬病毒以及減毒沙門氏菌等。其中基于水泡性口炎病毒的埃博拉載體疫苗被用于非洲剛果金埃博拉疫情的防控，展示了良好的安全性和保護效力[70]，而我國也已批準了首個埃博拉腺病毒載體疫苗?；诙鄠€不同載體研制的SARS 和MERS疫苗可使小鼠、雪貂和猴子產(chǎn)生高效體液和細胞免疫應答，尤其是通過鼻腔或口腔接種可以誘導良好的粘膜免疫反應[10,71-95]。研究顯示SARS 腺病毒載體疫苗鼻腔接種產(chǎn)生的血清中和抗體水平低于肌肉接種途徑，但由于可在粘膜表面生成高滴度IgA 抗體，保護效力反而優(yōu)于肌肉接種[10,73]，提示單靠高滴度血清中和抗體的保護效力是不完整的。兩個分別基于痘苗病毒和腺病毒的MERS體疫苗也已完成Ⅰ期臨床研究[25-26]，確認了其安全性和免疫原性。但是設計腺病毒載體疫苗時需著重考慮其預存免疫影響，建議選用在人群中低血清陽性率的人源(如Ad26、Ad35)或非人靈長動物源腺病毒載體。另外采用多途徑接種方式(肌肉、鼻腔接種)，或增加接種劑量和次數(shù)在動物實驗中證明可避開預存免疫影響，但在人體上還沒有相關(guān)證據(jù)?？傮w來說，載體疫苗策略在COVID-19 疫苗開發(fā)中具有較大優(yōu)勢。

1.5 減毒活疫苗

減毒活疫苗是一種通過病毒關(guān)鍵蛋白點突變或缺失引起病毒毒力降低，但不影響其免疫原性和復制能力的疫苗，該疫苗方案具有非常好的免疫原性，可誘導全身性免疫和粘膜免疫應答，且免疫力持久。已有多個減毒活疫苗上市，包括黃熱病、天花、麻疹、脊髓灰質(zhì)炎、腮腺炎、風疹、水痘等。SARS-CoV E 蛋白缺失減毒活疫苗證明可在小鼠和倉鼠上誘導產(chǎn)生體液和細胞免疫應答，而且可實現(xiàn)攻毒部分保護[96-101]，有研究人員通過缺失E 蛋白或突變NSP16 蛋白制備了MERS減毒活疫苗。然而，研究證明SARS 減毒活疫苗在細胞或小鼠體內(nèi)連續(xù)傳代后會恢復毒力[101]，提示該疫苗方案存在較大的生物安全風險。在沒有足夠證據(jù)確保減毒活疫苗不會返強的情況下，該策略暫不建議用于COVID-19 疫苗開發(fā)。

2 疫苗設計需注意的問題

前期SARS 疫苗研究發(fā)現(xiàn)如果候選疫苗誘導產(chǎn)生針對病毒的非中和抗體，會引起抗體依賴感染增強效應(Antibody-dependent enhancement,ADE)，機制是病毒特異抗體Fc 段通過與巨噬細胞Fc 受體結(jié)合，從而使得SARS-CoV 可以感染不含ACE2 受體的巨噬細胞，增強了病毒的感染性，出現(xiàn)疫苗接種反而加重病毒感染的問題，而中和抗體水平越低感染越嚴重[102-106]，該現(xiàn)象在其他冠狀病毒中較為常見[107]，而且也在登革病毒、人類免疫缺陷病毒(HIV)和埃博拉病毒等病原上存在[108-111]?？紤]到SARS-CoV-2 與SARS-CoV同源度較高，因此COVID-19 疫苗設計時必須高度關(guān)注ADE 問題，這將直接關(guān)系到疫苗的臨床安全性。防止發(fā)生ADE 效應的一個關(guān)鍵措施就是選擇合適的靶抗原，盡量減少非中和抗體誘導區(qū)。冠狀病毒S 蛋白由S1 和S2 兩個亞基組成，S1 包含RBD 區(qū)，相比全長S 蛋白，單獨免疫S1 區(qū)段或者RBD 區(qū)同樣可以獲得很好的免疫保護[53,112]。因此應選擇優(yōu)勢中和抗體誘導區(qū)(S1 或 RBD區(qū))，排除可能產(chǎn)生非中和抗體的抗原區(qū)段，同時優(yōu)化免疫策略產(chǎn)生高滴度中和抗體以降低ADE發(fā)生風險，從而保證疫苗的安全性。細胞免疫反應在清除冠狀病毒和被感染細胞過程中起著關(guān)鍵作用，而且粘膜免疫反應相比血清中和抗體在機體保護中更具優(yōu)勢。因此，COVID-19 疫苗的設計研發(fā)策略需要兼顧全身性免疫(體液和細胞免疫)和粘膜免疫。SARS 疫苗研究證明單一疫苗策略無法有效形成對實驗動物的完全保護，為了提高疫苗的免疫保護效力，我們可以考慮采用多個不同平臺的疫苗聯(lián)合免疫，同時采用多種途徑接種，這樣可充分利用不同平臺疫苗的優(yōu)勢，補齊技術(shù)短板，有望獲得更好的免疫保護效果。

3 展望與思考

COVID-19 是新中國成立以來我們遇到的傳播速度最快、感染范圍最廣、防控難度最大的重大突發(fā)公共衛(wèi)生事件。疫情在全球肆虐，全世界各研究機構(gòu)也全力開展了疫苗和藥物的研發(fā)工作。一個好的疫苗需要同時具備安全和有效兩個特性，在設計之初就要盡量避免潛在的安全風險?？紤]到滅活病毒疫苗可能存在的ADE 效應，且短期內(nèi)不易被發(fā)現(xiàn)，選擇該策略需加倍謹慎。而減毒活疫苗由于存在毒力返強風險，不建議用于COVID-19 疫苗研發(fā)。DNA 疫苗、亞單位疫苗和載體疫苗策略被證明是安全的。前期 SARS 和MERS 疫苗研究經(jīng)驗證明，高滴度血清中和抗體并不能提供足夠保護，需要CTL 協(xié)助清除病毒和感染細胞，而且通過鼻腔接種誘導的IgA 抗體在冠狀病毒感染中表現(xiàn)出的保護效力優(yōu)于其他接種途徑誘導的血清中和抗體 IgG[12,68,73]。因此COVID-19 疫苗設計應能夠激發(fā)機體廣泛的免疫應答：全身免疫(體液免疫和細胞免疫)和粘膜免疫。載體疫苗能夠滿足這個要求，可惜已上市的載體疫苗數(shù)量非常有限，大范圍人群接種的長期安全性仍需觀察，而且載體的選擇需要考驗疫苗設計人員的智慧，既要達到高效的免疫效力又要規(guī)避預存免疫。DNA 疫苗可誘導生成體液和細胞免疫，亞單位疫苗可誘導體液免疫和粘膜免疫，這兩個策略也非常適合用于 COVID-19 疫苗研發(fā)，盡管兩者可被各自開發(fā)為單獨的疫苗，但如果能夠?qū)烧呓Y(jié)合起來，有望彌補各自不足，高效激發(fā)全身免疫和粘膜免疫應答使機體獲得最佳保護。前期研究發(fā)現(xiàn)感染SARS 康復人員體內(nèi)的中和抗體水平僅能維持較短時間[13]，因此期待通過感染而獲得群體免疫的策略是缺乏理論依據(jù)的，只有接種安全有效的疫苗才能更好地獲得免疫保護。

中國采取的史無前例的綜合非藥物性干預措施有效控制了疫情傳播，為研制疫苗及驗證治療方法爭取到寶貴的時間。病毒沒有國界，全世界不同研究機構(gòu)根據(jù)各自所長分別選用了不同疫苗研發(fā)策略，這是一場與時間賽跑的研究，最終會使我們對冠狀病毒的研究水平上升到一個新的高度，杜絕類似悲劇的再次發(fā)生。盡管SARS-CoV-2 與SARS-CoV 的受體相同，但是兩者RBD 區(qū)多個關(guān)鍵氨基酸存在差異，而且針對SARS-CoV 的絕大部分中和抗體不能識別SARS-CoV-2，因此前期研究的SARS 候選疫苗并不能用于COVID-19的防疫。美國已將一個尚未完成臨床前動物實驗的mRNA 疫苗提前啟動臨床實驗，這種打破常規(guī)疫苗研發(fā)程序的方式是為了應對當前疫情緊急態(tài)勢的應急措施。但是將一種還沒有在動物上證明安全性和有效性的疫苗倉促用于人體測試是否存在倫理問題，還需疫苗從業(yè)人員的進一步深入探討。鑒于近些年我國多個機構(gòu)建立了相對成熟的疫苗研發(fā)平臺，COVID-19 疫苗是非常有希望能夠研發(fā)成功的?？紤]到冠狀病毒變異較為頻繁，且目前已發(fā)現(xiàn)病毒開始出現(xiàn)少量變異，尤其是病毒RBD 區(qū)出現(xiàn)了一些氨基酸變異，因此建議將研制成功的疫苗作為一個類似季節(jié)性流感疫苗的平臺技術(shù)產(chǎn)品，即使病毒發(fā)生變異，我們也可在最短時間內(nèi)對現(xiàn)有疫苗進行調(diào)整后快速應用。前期的疫苗研發(fā)能力儲備為本次疫情應急響應提供了有力技術(shù)支撐，后續(xù)我們?nèi)孕韪叨汝P(guān)注病毒可能的變異，必要時調(diào)整疫苗方案，用一種安全有效的疫苗打贏這場抗疫戰(zhàn)爭。

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Strategies for vaccine development of COVID-19

Limin Yang1,Deyu Tian1,and Wenjun Liu1,2

1CAS Key Laboratory of Pathogenic Microbiology and Immunology,Institute of Microbiology,Chinese Academy of Sciences,Beijing100101,China
2Chinese Academy of Sciences University,Beijing100049,China

An epidemic of acute respiratory syndrome in humans,which appeared in Wuhan,China in December 2019,was caused by a novel coronavirus(SARS-CoV-2).This disease was named as “Coronavirus Disease 2019”(COVID-19).SARS-CoV-2 was first identified as an etiological pathogen of COVID-19,belonging to the species of severe acute respiratory syndrome-related coronaviruses(SARSr-CoV).The speed of both the geographical transmission and the sudden increase in numbers of cases is much faster than SARS and Middle East respiratory syndrome(MERS).COVID-19 is the first global pandemic caused by a coronavirus,which outbreaks in 211 countries/territories/areas.The vaccine against COVID-19,regarded as an effective prophylactic strategy for control and prevention,is being developed in about 90 institutions worldwide.The experiences and lessons encountered in the previous SARS and MERS vaccine research can be used for reference in the development of COVID-19 vaccine.The present paper hopes to provide some insights for COVID-19 vaccines researchers.

COVID-19,vaccine,antibody,mucosal immunization,antibody-dependent enhancement

March 2,2020;

March 30,2020

Supported by:National Key Research and Development Program of China(Nos.2018YFC1200502,2018YFC1200602),National Key Technologies Research and Development Program of China(Nos.2016ZX10004222-006,2018ZX10734-404).

Limin Yang.Tel:+86-10-64807503; E-mail:lmyang@im.ac.cn

國家重點研發(fā)計劃(Nos.2018YFC1200502，2018YFC1200602)，“艾滋病和病毒性肝炎等重大傳染病防治”科技重大專項(Nos.2016ZX10004222-006，2018ZX10734-404)資助。

2020-04-17

http://kns.cnki.net/kcms/detail/11.1998.Q.20200416.1203.001.html

10.13345/j.cjb.200094

楊利敏,田德雨,劉文軍.新型冠狀病毒疫苗研究策略分析.生物工程學報,2020,36(4):593–604.

Yang LM,Tian DY,Liu WJ.Strategies for vaccine development of COVID-19.Chin J Biotech,2020,36(4):593–604.

(本文責編 郝麗芳)