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針對新冠病毒的“通用疫苗”,能研發(fā)成功嗎?

Jeremy Kahn
2021-03-01

如果病毒不斷變異,就可能陷入永恒的貓捉老鼠游戲。

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南非人。巴西人。英國“肯特”。

這些聽起來沒有什么特別,有點像某種特定發(fā)型的名字。但正如病毒追蹤者所知,這些都是新冠病毒變異毒株的簡稱。變異病毒的傳染性更強,其中,英國變異病毒株可能更致命,迫使世界各國政府加緊旅行限制,有些國家還宣布了新的封鎖令。

新型變異病毒也給第一批新冠疫苗帶來了問題。目前幾乎所有獲批的疫苗都是針對冠狀病毒的刺突蛋白。蛋白突變會降低疫苗的有效性,甚至導致免疫失敗。

現(xiàn)在疫苗生產(chǎn)商和政府提出的解決方案是,開始準備新版疫苗,促使免疫系統(tǒng)產(chǎn)生針對新病毒刺突蛋白的抗體。

但如果病毒不斷變異,就可能陷入永恒的貓捉老鼠游戲。人們總要追趕最新的病毒株,全世界大部分地區(qū)每年都要接種加強疫苗。流感病毒基本上就是如此。

而且跟流感病毒一樣,研究人員經(jīng)常有可能誤判,從而忽視新出現(xiàn)并迅速傳播的變異病毒,是患者再次面臨必須住院治療甚至死亡的風險。

還有別的辦法嗎?

一些科學家認為有:要么使用更傳統(tǒng)的疫苗技術(shù),讓人們實際接觸到病毒和各種蛋白質(zhì);要么用新型信使RNA技術(shù),制造出能夠應(yīng)對當前及未來所有變異病毒的通用疫苗。

為什么變異病毒如此令人擔心

首先,多提供一點當前背景,雖然正式命名為B.1.1.7的英國“肯特”病毒的傳播性更強,也更致命,但刺突蛋白沒有明顯改變,已經(jīng)獲批的疫苗可以很好地應(yīng)對。

然而分別被正式命名為B.1.351和B.1.1.248的南非和巴西變異病毒都會導致現(xiàn)有疫苗效力降低。

牛津大學和制藥公司阿斯利康合作疫苗在南非的臨床試驗數(shù)據(jù)分析表明,疫苗不能預防B.1.351毒株導致的輕癥和普通感染,不過阿斯利康宣稱,相信能夠預防新冠重癥。

實驗室也測試了輝瑞和Moderna信使RNA疫苗接種者的血液樣本,結(jié)果也表明如果抗體要應(yīng)對變異毒株,抗體量要比應(yīng)對原始病毒高。但Moderna公司表示,相信自家疫苗可以產(chǎn)生足夠抗體,能夠預防普通型或重癥。

令人擔心的是,英國科學家發(fā)現(xiàn)B.1.1.7“肯特”病毒一個版本中也包含了跟南非和巴西毒株相同的刺突蛋白突變,即E484K。

如果一個人感染多種病毒,各病毒株的遺傳物質(zhì)混合有可能出現(xiàn)該情況,也可能是同一種突變發(fā)生不止一次的結(jié)果。

目前大多數(shù)獲批疫苗均采用相對較新的技術(shù)制造,包括信使RNA(mRNA)或改良腺病毒載體。

兩種疫苗的思路都是指導人類細胞生產(chǎn)新冠病毒的一種蛋白質(zhì),激發(fā)免疫反應(yīng)。然后身體產(chǎn)生抗體,抗體可以附著在蛋白質(zhì)上使之失效。人們還希望免疫系統(tǒng)其他部分,例如能夠殺死受感染細胞的T細胞,根據(jù)蛋白識別外來入侵者并將其清除。

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與傳統(tǒng)疫苗制造方法相比,新方法的巨大優(yōu)勢是非常安全,因此研究疫苗的研究人員合理確信疫苗不會引發(fā)嚴重副作用,這一想法在隨后的人體臨床試驗中也得到了證實。

新疫苗的另一大優(yōu)勢在于,只要病毒基因組完成測序,并有明顯的蛋白質(zhì)作為靶點,就像新冠病毒一樣,疫苗就可以迅速適應(yīng)新病毒。之所以世界衛(wèi)生組織宣布發(fā)現(xiàn)病毒不到一年后的今天,數(shù)百萬人中就能夠接種多種疫苗,主要就是因為采用了新型疫苗制造方法。

單一蛋白質(zhì)問題

不過迄今相關(guān)技術(shù)抗擊新冠病毒的一大缺點在于,疫苗只可以指導細胞制造一種病毒蛋白。因此疫苗容易受到特定蛋白質(zhì)突變影響。

新冠病毒有四個主要的結(jié)構(gòu)蛋白,其中S蛋白(刺突蛋白)最為人所知,還有N蛋白(核衣殼蛋白)、M蛋白(膜蛋白)以及E蛋白(包膜蛋白)。因此,想讓疫苗刺激免疫系統(tǒng),對某些甚至所有蛋白產(chǎn)生反應(yīng)是存在可能性的。

兩種傳統(tǒng)疫苗制造技術(shù)讓人體暴露于各種蛋白中,因為使用了真正的病毒。

其中一種方法是將活病毒“減毒”或削弱,在很難快速繁殖的環(huán)境中生長。另一種方法則是將病毒“滅活”,或者用化學方式殺死,然后進行整體注射,或是粉碎后注射。該方法可能比給人注射活病毒疫苗更安全,因為活病毒疫苗存在變成危險病原體的風險。

沒有公司考慮新冠活疫苗,滅活疫苗倒是有幾家公司研制。

中國公司科興生產(chǎn)的疫苗就使用滅活病毒,在中國和巴西等地已經(jīng)有數(shù)十萬人接種。該公司稱,自家的疫苗能夠有效抵抗南非變異病毒,但并未公布數(shù)據(jù)。

在巴西進行的科興疫苗臨床試驗表明,這種疫苗在預防重癥方面100%有效,但在預防輕癥方面幾率僅略高于50%。

多價疫苗

與此同時,法國Valneva公司的首席執(zhí)行官托馬斯·林格爾巴克說,正在研制使用完整病毒的滅活疫苗,可能比已經(jīng)獲批的疫苗更具優(yōu)勢。由于使用完整病毒,Valneva疫苗有可能讓免疫系統(tǒng)對各種抗原表位出現(xiàn)反應(yīng),抗原表位是指免疫系統(tǒng)可以識別的病毒蛋白部分。Valneva還將滅活病毒與輔藥結(jié)合,輔藥是能夠增強人體免疫反應(yīng)的化學物質(zhì)。

更重要的是,Valneva有生產(chǎn)多價疫苗的經(jīng)驗,所以可能會生產(chǎn)針對新冠的疫苗,所謂多價疫苗是指一次注射中包含多種毒株。

林格爾巴克稱公司將努力趕上新冠候選疫苗“第三波”,相信明年春天能夠獲批提供多價疫苗。(第一波是已獲批疫苗,第二波是目前已經(jīng)進入人體臨床試驗的疫苗。)

英國政府已經(jīng)預購了1億劑Valneva疫苗,其中一些將在蘇格蘭分公司工廠生產(chǎn)。

“通用”疫苗

還有一種方法可能為通用新冠疫苗帶來希望,思路是尋找既可以引起強烈免疫反應(yīng),又對新冠病毒繁殖至關(guān)重要的抗原表位。如果相關(guān)蛋白對病毒的生命周期至關(guān)重要,那病毒就無法通過成功突變避開疫苗。

比利時初創(chuàng)公司MyNeo就選擇了該方法,利用機器學習,預測病毒哪些抗原表位可以引發(fā)強烈的免疫反應(yīng)。

該公司的首席執(zhí)行官塞德里克·博格特表示,找到之后會在各種冠狀病毒發(fā)現(xiàn)的抗原表位里尋找子集。他指出,有些抗原表位不僅在新冠所有變異中都相同,而且在引起非典(SARS)和中東呼吸綜合征(MERS)的冠狀病毒中,還有感染水貂和蝙蝠的已知冠狀病毒中都一樣。

水貂和蝙蝠均攜帶冠狀病毒,科學家認為未來病毒可能會傳給人類。生物學家稱常見蛋白片段“保存完好”,進而推測隨著時間推移,相關(guān)蛋白不會出現(xiàn)太大變化,因為蛋白正常工作對病毒生存至關(guān)重要。

特別令人感興趣的是,新冠病毒里的N蛋白,主要存在于病毒內(nèi)部,圍繞在病毒遺傳密碼RNA周圍。

業(yè)界普遍認為N蛋白在病毒感染細胞后的復制方面起著關(guān)鍵作用。各種冠狀病毒里的N蛋白部分非常相似。人類細胞中發(fā)現(xiàn)的抗體能夠識別N蛋白。

與粘附在刺突蛋白上的抗體不同,此類抗體不能阻止細胞被感染??贵w在細胞內(nèi)發(fā)現(xiàn)N蛋白后會將其分解成碎片,然后在細胞表面展示標記。人的T細胞利用標記來識別被感染的細胞,并把它清除掉。

MyNeo正在與另一家比利時公司eTheRNA合作,公司的業(yè)務(wù)開發(fā)主管麥克·馬爾奎恩表示,公司可以制造mRNA疫苗,還發(fā)明了一種名叫TriMix的專利輔藥,能夠顯著增強人體T細胞和B細胞對疫苗的反應(yīng)。MyNeo協(xié)助公司選擇一組合適的蛋白質(zhì),比如N蛋白,與疫苗中的TriMix一起使用。

馬爾奎恩認為,公司有望生產(chǎn)對預防未來各種病毒株更有效的疫苗。他介紹說,可能會在一年內(nèi)進入后期臨床試驗。

其他科學家持懷疑態(tài)度

不過也有人對類似方法持懷疑態(tài)度。

新墨西哥州立大學的生物學教授凱瑟琳·漢利研究過登革熱病毒疫苗,認為滅活病毒疫苗激發(fā)的免疫反應(yīng),跟自然感染新冠病毒的反應(yīng)差別并不大。在感染新冠肺炎的患者中,刺突蛋白似乎是出現(xiàn)免疫反應(yīng)的主要原因。

馬爾奎恩說,如果采用mRNA方法制造疫苗,可能不是什么問題。原因在于,雖然自然感染過程中,對某個特定抗原表位的免疫反應(yīng)往往占主導地位,但如果身體像注射mRNA疫苗一樣,單獨遭遇不同的抗原表位,如果再使用輔藥,就有可能引發(fā)對該特定蛋白質(zhì)強烈的免疫反應(yīng)。

紐約康奈爾大學威爾·康奈爾醫(yī)學院的微生物學和免疫學教授,約翰·摩爾表示,這并不能確定。

他說,雖然人體對新冠病毒出現(xiàn)免疫反應(yīng)的方式還不是很清楚,但“諸多線索顯示,中和抗體才是關(guān)鍵。”他說,T細胞和B細胞反應(yīng)可能由其他蛋白質(zhì)觸發(fā),可能會起到一定作用,但抗體才是關(guān)鍵,畢竟是抗體激發(fā)對刺突蛋白的反應(yīng)。

“S蛋白是中和抗體的唯一靶點,選擇并不多?!彼f。

即使摩爾說錯了,馬爾奎恩也還是承認MyNeo和eTheRNA研制新冠通用疫苗的方法長期來看可能有問題。

雖然理論上保存完好的抗原表位很可能對病毒的生命周期至關(guān)重要,因而不太可能成功變異,但實際上可能并非如此。此類蛋白從未經(jīng)歷重大的選擇壓力。

馬爾奎恩表示,一旦注射針對其他蛋白質(zhì)的疫苗,病毒有可能進化出躲避疫苗的方法。

古老的挑戰(zhàn)

在醫(yī)學史上,制造通用疫苗的失敗案例比比皆是。

“很長時間以來,人們研制通用流感疫苗的努力都以失敗告終?!睗h利說。她說此前嘗試過同樣的想法,在不同的毒株中尋找保存完好的抗原表位,但迄今為止都失敗了。

流感病毒的變異速度遠遠快于冠狀病毒,冠狀病毒在復制過程中有一個步驟可以校對復制的基因密碼防止出錯,從而減緩變異。

“冠狀病毒不是流感,所以有可能,但也不確定?!彼f。

有些科學家認為,研發(fā)新疫苗解決新冠變異病毒的說法為時過早。

“目前還沒有達到臨界線?!辟M城兒童醫(yī)院的傳染病??漆t(yī)師、疫苗教育中心的主任保羅·奧菲特說。

他指出,越過臨界線意味著自然感染原始病毒的人,或者注射了獲批疫苗的人再次感染新毒株,而且病情嚴重到需要住院治療。

他表示,已經(jīng)接受兩劑疫苗的人體內(nèi)抗體水平很高,這很讓人振奮,特別是輝瑞和Moderna的mRNA疫苗,說明抗體很強,即使面對新毒株也能夠繼續(xù)抵御。

他表示,由于冠狀病毒變異往往比流感少,如果在未來幾個月內(nèi),有足夠多的人接種疫苗,而且有相當多的人已經(jīng)感染新冠肺炎,病毒傳播則有望下降。只要傳播放緩,發(fā)生突變的可能性也將減小,新一代疫苗投入使用也就沒有什么問題。

摩爾對此表示贊同,他認為屆時不一定需要每年強化當前疫苗。

“計劃并加以考慮有合理性,不過當前還沒有到那一步?!彼f。

所有科學家包括研究新一代疫苗的科學家都認為,相較于應(yīng)付比英國、南非和巴西還要麻煩的病毒變異,關(guān)鍵在于要盡快推動盡可能多的人接種疫苗,從而降低病毒傳播。

他們說,如果有人宣稱不用全民接種疫苗,年輕人感染后不太可能轉(zhuǎn)為重癥,就讓病毒在年輕人群里傳播,都會變成災難的導火索。

“耐藥病毒只在特定情況下出現(xiàn),其中之一就是疫苗接種不足?!蹦栒f。

他還擔心延長兩劑之間的時間,英國就是如此(兩劑之間等待12周,以便給更多人注射第一劑)。因為輝瑞公司和Moderna的第一劑疫苗免疫應(yīng)答到底能否持續(xù)超過四周,并沒有數(shù)據(jù)支持。

他擔心的是,如果病毒發(fā)現(xiàn)宿主有某種免疫反應(yīng),又無法完全消滅病毒并阻止其復制,就會對病原體施加選擇壓力,從而出現(xiàn)成功突變。

疫苗接種不足也是流感流行的原因之一。漢利指出,盡管每年流感導致超過5萬美國人死亡,美國成人只有不到一半接種流感疫苗。

“大多數(shù)公共衛(wèi)生項目在真正成功之前,都是其自身成功的犧牲品?!彼f?!八愿≡w才如此艱難?!保ㄘ敻恢形木W(wǎng))

譯者:夏林

南非人。巴西人。英國“肯特”。

這些聽起來沒有什么特別,有點像某種特定發(fā)型的名字。但正如病毒追蹤者所知,這些都是新冠病毒變異毒株的簡稱。變異病毒的傳染性更強,其中,英國變異病毒株可能更致命,迫使世界各國政府加緊旅行限制,有些國家還宣布了新的封鎖令。

新型變異病毒也給第一批新冠疫苗帶來了問題。目前幾乎所有獲批的疫苗都是針對冠狀病毒的刺突蛋白。蛋白突變會降低疫苗的有效性,甚至導致免疫失敗。

現(xiàn)在疫苗生產(chǎn)商和政府提出的解決方案是,開始準備新版疫苗,促使免疫系統(tǒng)產(chǎn)生針對新病毒刺突蛋白的抗體。

但如果病毒不斷變異,就可能陷入永恒的貓捉老鼠游戲。人們總要追趕最新的病毒株,全世界大部分地區(qū)每年都要接種加強疫苗。流感病毒基本上就是如此。

而且跟流感病毒一樣,研究人員經(jīng)常有可能誤判,從而忽視新出現(xiàn)并迅速傳播的變異病毒,是患者再次面臨必須住院治療甚至死亡的風險。

還有別的辦法嗎?

一些科學家認為有:要么使用更傳統(tǒng)的疫苗技術(shù),讓人們實際接觸到病毒和各種蛋白質(zhì);要么用新型信使RNA技術(shù),制造出能夠應(yīng)對當前及未來所有變異病毒的通用疫苗。

為什么變異病毒如此令人擔心

首先,多提供一點當前背景,雖然正式命名為B.1.1.7的英國“肯特”病毒的傳播性更強,也更致命,但刺突蛋白沒有明顯改變,已經(jīng)獲批的疫苗可以很好地應(yīng)對。

然而分別被正式命名為B.1.351和B.1.1.248的南非和巴西變異病毒都會導致現(xiàn)有疫苗效力降低。

牛津大學和制藥公司阿斯利康合作疫苗在南非的臨床試驗數(shù)據(jù)分析表明,疫苗不能預防B.1.351毒株導致的輕癥和普通感染,不過阿斯利康宣稱,相信能夠預防新冠重癥。

實驗室也測試了輝瑞和Moderna信使RNA疫苗接種者的血液樣本,結(jié)果也表明如果抗體要應(yīng)對變異毒株,抗體量要比應(yīng)對原始病毒高。但Moderna公司表示,相信自家疫苗可以產(chǎn)生足夠抗體,能夠預防普通型或重癥。

令人擔心的是,英國科學家發(fā)現(xiàn)B.1.1.7“肯特”病毒一個版本中也包含了跟南非和巴西毒株相同的刺突蛋白突變,即E484K。

如果一個人感染多種病毒,各病毒株的遺傳物質(zhì)混合有可能出現(xiàn)該情況,也可能是同一種突變發(fā)生不止一次的結(jié)果。

目前大多數(shù)獲批疫苗均采用相對較新的技術(shù)制造,包括信使RNA(mRNA)或改良腺病毒載體。

兩種疫苗的思路都是指導人類細胞生產(chǎn)新冠病毒的一種蛋白質(zhì),激發(fā)免疫反應(yīng)。然后身體產(chǎn)生抗體,抗體可以附著在蛋白質(zhì)上使之失效。人們還希望免疫系統(tǒng)其他部分,例如能夠殺死受感染細胞的T細胞,根據(jù)蛋白識別外來入侵者并將其清除。

與傳統(tǒng)疫苗制造方法相比,新方法的巨大優(yōu)勢是非常安全,因此研究疫苗的研究人員合理確信疫苗不會引發(fā)嚴重副作用,這一想法在隨后的人體臨床試驗中也得到了證實。

新疫苗的另一大優(yōu)勢在于,只要病毒基因組完成測序,并有明顯的蛋白質(zhì)作為靶點,就像新冠病毒一樣,疫苗就可以迅速適應(yīng)新病毒。之所以世界衛(wèi)生組織宣布發(fā)現(xiàn)病毒不到一年后的今天,數(shù)百萬人中就能夠接種多種疫苗,主要就是因為采用了新型疫苗制造方法。

單一蛋白質(zhì)問題

不過迄今相關(guān)技術(shù)抗擊新冠病毒的一大缺點在于,疫苗只可以指導細胞制造一種病毒蛋白。因此疫苗容易受到特定蛋白質(zhì)突變影響。

新冠病毒有四個主要的結(jié)構(gòu)蛋白,其中S蛋白(刺突蛋白)最為人所知,還有N蛋白(核衣殼蛋白)、M蛋白(膜蛋白)以及E蛋白(包膜蛋白)。因此,想讓疫苗刺激免疫系統(tǒng),對某些甚至所有蛋白產(chǎn)生反應(yīng)是存在可能性的。

兩種傳統(tǒng)疫苗制造技術(shù)讓人體暴露于各種蛋白中,因為使用了真正的病毒。

其中一種方法是將活病毒“減毒”或削弱,在很難快速繁殖的環(huán)境中生長。另一種方法則是將病毒“滅活”,或者用化學方式殺死,然后進行整體注射,或是粉碎后注射。該方法可能比給人注射活病毒疫苗更安全,因為活病毒疫苗存在變成危險病原體的風險。

沒有公司考慮新冠活疫苗,滅活疫苗倒是有幾家公司研制。

中國公司科興生產(chǎn)的疫苗就使用滅活病毒,在中國和巴西等地已經(jīng)有數(shù)十萬人接種。該公司稱,自家的疫苗能夠有效抵抗南非變異病毒,但并未公布數(shù)據(jù)。

在巴西進行的科興疫苗臨床試驗表明,這種疫苗在預防重癥方面100%有效,但在預防輕癥方面幾率僅略高于50%。

多價疫苗

與此同時,法國Valneva公司的首席執(zhí)行官托馬斯·林格爾巴克說,正在研制使用完整病毒的滅活疫苗,可能比已經(jīng)獲批的疫苗更具優(yōu)勢。由于使用完整病毒,Valneva疫苗有可能讓免疫系統(tǒng)對各種抗原表位出現(xiàn)反應(yīng),抗原表位是指免疫系統(tǒng)可以識別的病毒蛋白部分。Valneva還將滅活病毒與輔藥結(jié)合,輔藥是能夠增強人體免疫反應(yīng)的化學物質(zhì)。

更重要的是,Valneva有生產(chǎn)多價疫苗的經(jīng)驗,所以可能會生產(chǎn)針對新冠的疫苗,所謂多價疫苗是指一次注射中包含多種毒株。

林格爾巴克稱公司將努力趕上新冠候選疫苗“第三波”,相信明年春天能夠獲批提供多價疫苗。(第一波是已獲批疫苗,第二波是目前已經(jīng)進入人體臨床試驗的疫苗。)

英國政府已經(jīng)預購了1億劑Valneva疫苗,其中一些將在蘇格蘭分公司工廠生產(chǎn)。

“通用”疫苗

還有一種方法可能為通用新冠疫苗帶來希望,思路是尋找既可以引起強烈免疫反應(yīng),又對新冠病毒繁殖至關(guān)重要的抗原表位。如果相關(guān)蛋白對病毒的生命周期至關(guān)重要,那病毒就無法通過成功突變避開疫苗。

比利時初創(chuàng)公司MyNeo就選擇了該方法,利用機器學習,預測病毒哪些抗原表位可以引發(fā)強烈的免疫反應(yīng)。

該公司的首席執(zhí)行官塞德里克·博格特表示,找到之后會在各種冠狀病毒發(fā)現(xiàn)的抗原表位里尋找子集。他指出,有些抗原表位不僅在新冠所有變異中都相同,而且在引起非典(SARS)和中東呼吸綜合征(MERS)的冠狀病毒中,還有感染水貂和蝙蝠的已知冠狀病毒中都一樣。

水貂和蝙蝠均攜帶冠狀病毒,科學家認為未來病毒可能會傳給人類。生物學家稱常見蛋白片段“保存完好”,進而推測隨著時間推移,相關(guān)蛋白不會出現(xiàn)太大變化,因為蛋白正常工作對病毒生存至關(guān)重要。

特別令人感興趣的是,新冠病毒里的N蛋白,主要存在于病毒內(nèi)部,圍繞在病毒遺傳密碼RNA周圍。

業(yè)界普遍認為N蛋白在病毒感染細胞后的復制方面起著關(guān)鍵作用。各種冠狀病毒里的N蛋白部分非常相似。人類細胞中發(fā)現(xiàn)的抗體能夠識別N蛋白。

與粘附在刺突蛋白上的抗體不同,此類抗體不能阻止細胞被感染。抗體在細胞內(nèi)發(fā)現(xiàn)N蛋白后會將其分解成碎片,然后在細胞表面展示標記。人的T細胞利用標記來識別被感染的細胞,并把它清除掉。

MyNeo正在與另一家比利時公司eTheRNA合作,公司的業(yè)務(wù)開發(fā)主管麥克·馬爾奎恩表示,公司可以制造mRNA疫苗,還發(fā)明了一種名叫TriMix的專利輔藥,能夠顯著增強人體T細胞和B細胞對疫苗的反應(yīng)。MyNeo協(xié)助公司選擇一組合適的蛋白質(zhì),比如N蛋白,與疫苗中的TriMix一起使用。

馬爾奎恩認為,公司有望生產(chǎn)對預防未來各種病毒株更有效的疫苗。他介紹說,可能會在一年內(nèi)進入后期臨床試驗。

其他科學家持懷疑態(tài)度

不過也有人對類似方法持懷疑態(tài)度。

新墨西哥州立大學的生物學教授凱瑟琳·漢利研究過登革熱病毒疫苗,認為滅活病毒疫苗激發(fā)的免疫反應(yīng),跟自然感染新冠病毒的反應(yīng)差別并不大。在感染新冠肺炎的患者中,刺突蛋白似乎是出現(xiàn)免疫反應(yīng)的主要原因。

馬爾奎恩說,如果采用mRNA方法制造疫苗,可能不是什么問題。原因在于,雖然自然感染過程中,對某個特定抗原表位的免疫反應(yīng)往往占主導地位,但如果身體像注射mRNA疫苗一樣,單獨遭遇不同的抗原表位,如果再使用輔藥,就有可能引發(fā)對該特定蛋白質(zhì)強烈的免疫反應(yīng)。

紐約康奈爾大學威爾·康奈爾醫(yī)學院的微生物學和免疫學教授,約翰·摩爾表示,這并不能確定。

他說,雖然人體對新冠病毒出現(xiàn)免疫反應(yīng)的方式還不是很清楚,但“諸多線索顯示,中和抗體才是關(guān)鍵?!彼f,T細胞和B細胞反應(yīng)可能由其他蛋白質(zhì)觸發(fā),可能會起到一定作用,但抗體才是關(guān)鍵,畢竟是抗體激發(fā)對刺突蛋白的反應(yīng)。

“S蛋白是中和抗體的唯一靶點,選擇并不多?!彼f。

即使摩爾說錯了,馬爾奎恩也還是承認MyNeo和eTheRNA研制新冠通用疫苗的方法長期來看可能有問題。

雖然理論上保存完好的抗原表位很可能對病毒的生命周期至關(guān)重要,因而不太可能成功變異,但實際上可能并非如此。此類蛋白從未經(jīng)歷重大的選擇壓力。

馬爾奎恩表示,一旦注射針對其他蛋白質(zhì)的疫苗,病毒有可能進化出躲避疫苗的方法。

古老的挑戰(zhàn)

在醫(yī)學史上,制造通用疫苗的失敗案例比比皆是。

“很長時間以來,人們研制通用流感疫苗的努力都以失敗告終。”漢利說。她說此前嘗試過同樣的想法,在不同的毒株中尋找保存完好的抗原表位,但迄今為止都失敗了。

流感病毒的變異速度遠遠快于冠狀病毒,冠狀病毒在復制過程中有一個步驟可以校對復制的基因密碼防止出錯,從而減緩變異。

“冠狀病毒不是流感,所以有可能,但也不確定。”她說。

有些科學家認為,研發(fā)新疫苗解決新冠變異病毒的說法為時過早。

“目前還沒有達到臨界線?!辟M城兒童醫(yī)院的傳染病??漆t(yī)師、疫苗教育中心的主任保羅·奧菲特說。

他指出,越過臨界線意味著自然感染原始病毒的人,或者注射了獲批疫苗的人再次感染新毒株,而且病情嚴重到需要住院治療。

他表示,已經(jīng)接受兩劑疫苗的人體內(nèi)抗體水平很高,這很讓人振奮,特別是輝瑞和Moderna的mRNA疫苗,說明抗體很強,即使面對新毒株也能夠繼續(xù)抵御。

他表示,由于冠狀病毒變異往往比流感少,如果在未來幾個月內(nèi),有足夠多的人接種疫苗,而且有相當多的人已經(jīng)感染新冠肺炎,病毒傳播則有望下降。只要傳播放緩,發(fā)生突變的可能性也將減小,新一代疫苗投入使用也就沒有什么問題。

摩爾對此表示贊同,他認為屆時不一定需要每年強化當前疫苗。

“計劃并加以考慮有合理性,不過當前還沒有到那一步?!彼f。

所有科學家包括研究新一代疫苗的科學家都認為,相較于應(yīng)付比英國、南非和巴西還要麻煩的病毒變異,關(guān)鍵在于要盡快推動盡可能多的人接種疫苗,從而降低病毒傳播。

他們說,如果有人宣稱不用全民接種疫苗,年輕人感染后不太可能轉(zhuǎn)為重癥,就讓病毒在年輕人群里傳播,都會變成災難的導火索。

“耐藥病毒只在特定情況下出現(xiàn),其中之一就是疫苗接種不足?!蹦栒f。

他還擔心延長兩劑之間的時間,英國就是如此(兩劑之間等待12周,以便給更多人注射第一劑)。因為輝瑞公司和Moderna的第一劑疫苗免疫應(yīng)答到底能否持續(xù)超過四周,并沒有數(shù)據(jù)支持。

他擔心的是,如果病毒發(fā)現(xiàn)宿主有某種免疫反應(yīng),又無法完全消滅病毒并阻止其復制,就會對病原體施加選擇壓力,從而出現(xiàn)成功突變。

疫苗接種不足也是流感流行的原因之一。漢利指出,盡管每年流感導致超過5萬美國人死亡,美國成人只有不到一半接種流感疫苗。

“大多數(shù)公共衛(wèi)生項目在真正成功之前,都是其自身成功的犧牲品?!彼f。“所以根除病原體才如此艱難。”(財富中文網(wǎng))

譯者:夏林

The South African. The Brazilian. The U.K.’s “Kent.”

They sound like they could be the names of some new hairstyle. But, as most virus trackers know, they are common shorthand for the new strains of SARS-CoV-2, the coronavirus behind the global pandemic. More transmissible, and in the case of the U.K. strain apparently more deadly, the new variants have forced governments around the world to impose tougher travel restrictions and, in some cases, new lockdowns.

The new variants also pose a problem for the first crop of vaccines. That’s because almost all the vaccines approved so far target the coronavirus’s spike protein. Mutations in this protein can reduce the vaccines’ effectiveness, potentially even negating any immunity.

So far, the solution vaccine makers and governments have proposed is to begin preparing updated versions of the existing vaccines that will prompt the immune system to make antibodies to the modified spike protein found in the new variants.

But if the virus keeps mutating, the world may find it is stuck in a perpetual game of cat and mouse, always trying to catch up with the latest strains of the virus, with a large portion of the world requiring an annual booster vaccination. This is essentially what happens with the flu virus now. And, as with the flu virus, there is a constant risk that researchers will misjudge and fail to spot an emerging and fast-spreading variant that will once again put many people at risk of hospitalization or death.

Might there be another way?

Some scientists think there is: either using more traditional vaccine technology that exposes people to the real virus and all of its proteins, or using new messenger RNA technology to create a universal SARS-CoV-2 vaccine that would be effective against all current and future strains.

Why the variants are so worrisome

First, a little more background on the current situation: While the U.K. “Kent” strain, which is formally designated B.1.1.7, incorporates changes that make it easier to spread and may make it more deadly, the spike protein is not significantly changed, and the approved vaccines work well against it.

But mutations associated with the South African and Brazilian variants of the virus, formally called B.1.351 and B.1.1.248, respectively, render existing vaccines less effective. An analysis of data from the South African clinical trial of the University of Oxford and pharmaceutical company AstraZeneca vaccine showed that it could not prevent mild to moderate illness in those infected with the B.1.351 strain, although the company says it believes the vaccine probably still protects against severe COVID-19. Lab tests using blood samples from those vaccinated with Pfizer’s and Moderna’s messenger RNA-based vaccines also showed that higher antibody levels were needed to defeat the mutant strain than the original virus. But Moderna says it is confident its vaccine produces enough antibodies that it will still protect against moderate or severe disease.

Worryingly, scientists in the U.K. have now discovered a version of the B.1.1.7 “Kent” virus that also incorporates the same spike protein mutation, known as E484K, that the South African and Brazilian strains exhibit. This could have happened if a single person was infected with multiple strains of the virus, which then had a chance to mix their genetic material; or it could be that same mutation occurred spontaneously more than once.

Most of the COVID vaccines that have been approved for use so far were created with relatively new techniques: messenger RNA (mRNA) or modified adenovirus vectors. In both cases, the idea is to instruct human cells to produce one of the coronavirus’s proteins so that it prompts an immune response. The body then produces antibodies that can attach themselves to that protein and disable it. It is also hoped that other parts of the immune system—such as T-cells, which can kill infected cells—learn to recognize the protein as a sign of a foreign invader and kill those cells.

These technologies have some big advantages over traditional vaccine-making methods: They have excellent safety profiles, so the researchers working on the vaccines were reasonably sure they would not cause severe side effects—something which has been borne out in subsequent human clinical trials. The other good thing about them is that they can be tailored to a new virus very quickly, provided that virus has had its genome sequenced and there is an obvious protein to target, as was the case with SARS-CoV-2. The entire reason we have multiple vaccines in millions of people today, less than a year after the World Health Organization declared a pandemic, is largely because of these newer methods for creating vaccines.

The single-protein problem

But one downside of the way these techniques have been used to combat SARS-CoV-2 so far is that they instruct the cells to make a single virus protein. As a result, they are always going to be vulnerable to mutations in that particular protein. SARS-CoV-2 has four main structural protein groups: The S protein, or spike protein, is the best known. But it also has a nucleocapsid or N protein, a membrane or M protein, and an envelope or E protein. It might be possible to create vaccines that prompt an immune response to some or even all of these.

Two traditional vaccine-making techniques expose the body to all of these proteins because they use the actual virus itself. In one method, a living virus is “attenuated,” or weakened, by growing it in a way that makes it hard for the virus to rapidly reproduce. In another, the virus is “inactivated,” or killed using a chemical treatment, and then either administered whole, or sometimes broken into pieces. This is potentially safer than giving someone a living virus vaccine, which have a nasty habit of evolving back into dangerous pathogens.

No one is considering making a live SARS-CoV-2 vaccine, but several companies are working on inactivated ones. The Chinese company Sinovac’s vaccine uses the inactivated virus, and it has already been given to hundreds of thousands of people in China and in places like Brazil. The company says it is effective against the South African variant, but it has not published the data to support that claim. Meanwhile, clinical trials of the Sinovac vaccine in Brazil have shown it is 100% effective at preventing severe disease but may be only slightly more than 50% effective at preventing very mild illness.

Multivalent vaccines

French company Valneva, meanwhile, is working on an inactivated vaccine using the whole virus that might have advantages over those already approved, Thomas Lingelbach, the company’s chief executive officer, says. Because it uses the complete virus, the Valneva vaccine enables the immune system to potentially form a response to all possible epitopes—a term for the portions of the virus’s proteins that the immune system can recognize. Valneva also combines the inactivated virus with an adjuvant, a chemical substance that boosts the body’s immune response. What’s more, Valneva has experience producing multivalent vaccines—those that incorporate multiple virus strains in a single shot—and it could potentially produce one for SARS-CoV-2 too.

Lingelbach calls his company’s efforts the “third wave” of COVID-19 vaccine candidates. He believes they could have a multivalent version of Valneva’s vaccine authorized and available by next spring. (The first wave are those vaccines already approved, and the second wave are those currently in human clinical trials.) The U.K. government has already preordered 100 million doses of Valneva’s vaccine, some of which will be produced at the company’s manufacturing facility in Scotland.

The “universal” vaccine

Another approach may hold out the promise of a universal SARS-CoV-2 vaccine. The idea is to find epitopes that are both capable of eliciting a strong immune response and which are essential for the coronavirus’s reproduction. The idea is that if these proteins are essential for the virus’s life cycle, the virus won’t be able to escape the vaccine through successful mutations.

One company working on this approach is Belgian startup MyNeo. It uses machine learning to try to predict which virus epitopes will trigger the strongest immune response. It then looks for the subset of those epitopes that are found across all coronaviruses, says Cedric Bogaert, the company’s chief executive. He notes there are certain epitopes that are the same across not just all the SARS-CoV-2 variants, but also across the coronaviruses that cause SARS and MERS, as well as those known to infect minks and bats, two species that harbor coronaviruses and from which scientists think future strains may make the leap to humans. These common protein segments are what biologists call “well conserved,” and the speculation is that they don’t change much over time because their function is somehow essential to the virus’s viability.

Of particular interest is the SARS-CoV-2’s N protein, which is found inside the virus, wrapped around its RNA, the virus’s genetic code. It is thought the N protein plays a key role in helping the virus replicate after it has infected a cell. Portions of the N protein are very similar across all coronaviruses. And there are antibodies found within human cells that can recognize the N protein. Unlike the antibodies that latch on to the spike protein, these antibodies don’t prevent the cell from being infected. But when they find the N protein inside the cell, they break it into pieces, which the cell then displays on its surface. The body’s T-cells use these markers to identify the cell as infected and destroy it.

MyNeo is working with another Belgian company, eTheRNA, which has the ability to manufacture mRNA vaccines and also has created a proprietary adjuvant, which it calls TriMix that can significantly boost the body’s T-cell and B-cell response to a vaccine, Mike Mulqueen, eTheRNA’s head of business development, says. With help from MyNeo in selecting the right set of proteins, such as the N protein, to use with the TriMix in a vaccine, Mulqueen thinks they have a shot at producing a vaccine that will be much more effective against all future virus strains. The companies could have a vaccine in late-stage clinical trials within a year, he says.

Other scientists are skeptical

But there are skeptics of these approaches. Kathryn Hanley, a professor of biology at New Mexico State University who has worked on a dengue virus vaccine, says that there’s no reason to think that an inactive virus vaccine would create an immune response that is markedly different from what people experience with a natural COVID-19 infection. And in people with COVID-19, the spike protein seems to be principally responsible for the immune reaction.

This might be less of a problem for an mRNA-based approach, Mulqueen says. That’s because while it is true that in natural infections, the immune response to one particular epitope tends to dominate, if the body is presented with a different epitope in isolation—as could be the case with an mRNA vaccine—it is possible to elicit a strong immune response to that particular protein, particularly if an adjuvant is used.

John Moore, a professor of microbiology and immunology at Cornell University’s Weill Cornell Medical College in New York, isn’t so sure. He says that while the way the body forms an immune response to SARS-CoV-2 is still not very well understood, there are “so many bread crumbs that say neutralizing antibodies are what matters.” The T-cell and B-cell responses, which may be triggered by other proteins, could play a role, he says, but it is antibodies that are critical, and they form in response to the spike protein. “The S protein is the only target for neutralizing antibodies, so there is not a lot of choice,” he says.

Even if Moore is wrong, Mulqueen acknowledges one potential longer-term problem with MyNeo’s and eTheRNA’s approach to a universal COVID-19 vaccine: While in theory the well-conserved epitopes are more likely to be essential to the virus’s life cycle and thus less likely to mutate successfully, that might not be true. Those proteins have never been subjected to significant selective pressure. Once a vaccine is introduced that targets these other proteins, it is possible, Mulqueen says, that the virus will evolve a way to evade it too.

An age-old challenge

The history of medicine is littered with failed attempts to create universal vaccines. “People have been breaking their hearts trying to develop a universal influenza vaccine for a long time,” Hanley says. She says they have even tried the same idea—finding conserved epitopes across strains—and it has so far failed. Influenza viruses mutate far faster than coronaviruses, which have a step in their replication process that essentially proofreads the copied genetic code for errors, slowing the introduction of mutations. “Coronavirus is not influenza, so it may be possible, but it’s not a sure thing,” she says.

Some scientists also believe that any talk of the need for a new crop of vaccines to address the new variants of SARS-CoV-2 is premature. “So far a critical line hasn’t been crossed,” says Paul Offit, a pediatrician specializing in infectious diseases at the Children’s Hospital of Philadelphia and director of the Vaccine Education Center. Offit says crossing that line would mean people who were naturally infected with the original virus, or who had been immunized with the approved vaccines, were becoming reinfected with the new strains and becoming so ill from them that they needed hospitalization. He says he is encouraged by the high levels of antibodies seen in those who have received two doses of the current vaccines, particularly the mRNA ones from Pfizer and Moderna, and thinks those antibodies may be robust enough to continue to protect against severe disease even in the face of new strains.

He said he was hopeful, given that coronaviruses tend to mutate less than influenza, that if enough of the population can be vaccinated in the next several months—and given the fairly high number of people who have already had COVID-19—that transmission of the virus will start to drop off. With lower transmission, there is less chance for mutations that would be significant enough to warrant another generation of vaccines.

Moore shares this view, saying we’re not even sure that annual boosters to the current crop of vaccines will be necessary. “It is reasonable to plan and think about those things, but we’re not there yet," he says.

All the scientists, including those working on the next-wave vaccines, agreed that the key to preventing mutant strains even more troubling than the current U.K., South African, and Brazilian variants is to drive transmission of the virus down as low as possible by vaccinating as many people with the existing vaccines as quickly as possible. They say any discussion of not vaccinating countries’ whole populations and letting the virus run rampant through younger demographic groups, who are unlikely to become seriously ill from COVID-19, is a recipe for disaster.

“Resistant viruses arise under certain circumstances, and one of them is undervaccination,” Moore says. He also worries about extending the time between doses, as the U.K. has done (it is waiting 12 weeks between doses in order to give first doses to as many people as possible). That’s because there is no data from the Pfizer and Moderna vaccines on how long the immune response from the first dose lasts beyond the first four weeks. His concern is that if a virus finds a host with some immune response, but not enough to totally wipe it out and prevent replication, it puts selective pressure on the pathogen to find successful mutations.

Undervaccination is part of the reason why influenza has become endemic; even though flu kills more than 50,000 Americans each year, less than half of adults in the U.S. get the flu jab, Hanley notes. “Most public health programs become victims of their own success before they are truly successful,” she says. “That is why we have such trouble eradicating pathogens.”

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