科普專欄–薯不揀單 - <<深入淺出–中國兩隻臨床Phase3中疫苗的潛在反效果>>

至今中國總共有三間生物公司的疫苗踏入Phase3狀態，包括為Cansino、Sinovac及Sinopharm。862Please respect copyright.ＰＥＮＡＮＡVsGZ9WuY3C
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其中Sinovac (Phase 3地點:巴西）及國營的Sinopharm(Ref2) (Phase 3地點:阿聯酋）兩間均用上滅活病毒疫苗(Inactivated Virus Vaccine)設計，本文將會就此作深入探討。862Please respect copyright.ＰＥＮＡＮＡOvw049i5ca
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（圖1）滅活病毒疫苗，顧名思義就是將病毒除去感染能力，當作疫苗之用。862Please respect copyright.ＰＥＮＡＮＡdKim3g8ruw
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下列為Sinovac製作滅活病毒疫苗的扼要流程(Ref3)862Please respect copyright.ＰＥＮＡＮＡStCOYagToE
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1.從一名進入深切治療部的中國病患肺部體液中抽取病毒。862Please respect copyright.ＰＥＮＡＮＡk5vUJNYxAD
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2.經過數輪實驗室細胞的培植，使病毒數量增加。862Please respect copyright.ＰＥＮＡＮＡ9UISBX88JN
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3.加入化學物消減病毒的感染力和多重過濾，取得弱化的武肺病毒。862Please respect copyright.ＰＥＮＡＮＡyHTcoRXqdv
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4.將其製成可注射的疫苗。862Please respect copyright.ＰＥＮＡＮＡBP7oyqOjZV
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（圖2）將滅活病毒疫苗注射到身體後，身體的免疫細胞便會製作對應弱化病毒的抗體。862Please respect copyright.ＰＥＮＡＮＡGWquc7eszX
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在繼續講述抗體之前，可先閱覽（圖3）溫故知新一下武肺入侵人體細胞的簡要過程，又或者可以到之前我所寫的文章觀看略為詳細的版本。862Please respect copyright.ＰＥＮＡＮＡQhcaO7wiR5
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（圖4）抗體（Antibody)頂多只能阻礙病毒進入細胞或者指示其他免疫細胞前來清滅病毒，並無獨立能力清滅病毒。862Please respect copyright.ＰＥＮＡＮＡGxw4mXjctx
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而能夠阻礙病毒進入細胞的抗體，我們將稱之為Neutralizing Antibody，而圖中已列出其中的兩款機制。862Please respect copyright.ＰＥＮＡＮＡBEgOcHkHPq
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1.抗體與病毒的S protein合併，862Please respect copyright.ＰＥＮＡＮＡnkVV1MOIiX
防止條件1的達成。862Please respect copyright.ＰＥＮＡＮＡ1VAp6baXE2
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2.抗體與病毒其他位置合併，862Please respect copyright.ＰＥＮＡＮＡB95i2yWdOm
防止條件3的達成。862Please respect copyright.ＰＥＮＡＮＡEahLdzhJLa
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（圖5）用上滅活病毒疫苗的話，抗體的製作便會針對病毒的各個位置而進行。862Please respect copyright.ＰＥＮＡＮＡw2EYSrNDsp
基於並非所有抗體也能夠拼合在病毒的關鍵位置，不能夠阻礙病毒進入細胞的抗體，我們將稱之為Non-Neutralizing Antibody。862Please respect copyright.ＰＥＮＡＮＡWxVmlelkzO
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不過，就算是Non-Neutralizing Antibody，它亦能有能力標示病毒，指引其他免疫細胞前來清滅病毒。862Please respect copyright.ＰＥＮＡＮＡjm2XrsJ35E
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（圖6）Non-Neutralizing Antibody的出現，將會引伸出一個名為Antibody Dependent Enhancement(ADE)的重要問題;862Please respect copyright.ＰＥＮＡＮＡesDyI2lgFq
簡單來說，就是抗體適得其反地協助病毒入侵人體細胞。862Please respect copyright.ＰＥＮＡＮＡR2nvzjwU8L
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免疫細胞的表面上，有著接收器識辨抗體的某個區域。862Please respect copyright.ＰＥＮＡＮＡ9fsP3Ql2cr
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但若果有過多Non-Neutralizing Antibody黏在病毒裡頭的話，病毒就有機會可以無視之前那3條法則，不需要經過ACE2，而是透過免疫細胞的表面上識辨抗體的接收器進入細胞。862Please respect copyright.ＰＥＮＡＮＡFiIW9g0bFH
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換句話說，抗體在這情況下變相成為幫兇或者25仔，輔助病毒進入細胞，這現象我們稱之為ADE。862Please respect copyright.ＰＥＮＡＮＡ3xFEcqUN78
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（圖7）武肺病毒進入細胞後，需要切割S protein才能夠開始進行繁殖工作。862Please respect copyright.ＰＥＮＡＮＡMeIjBZ7EOK
所以就算有Non-Neutralizing antibody做25仔，如果病毒幸運地有Neutralizing antibody保護S protein免受切割的話，病毒依舊無法作惡。862Please respect copyright.ＰＥＮＡＮＡRvJfeJsMo4
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但若果無Neutralizing antibody保護的話，病毒就會利用免疫細胞作為寄主，避開一切免疫機制，大量製造病毒。862Please respect copyright.ＰＥＮＡＮＡ1KpQbL50Lp
情形就好像本身理應維護法紀的警察，突然之間搖身一變成為罪惡的溫床，窩藏及協助罪犯（病毒）滋生，導致情況一發不可收拾。862Please respect copyright.ＰＥＮＡＮＡdHmr1wqbfx
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（圖8）ADE這現象，科學家一直以來均有記錄及研究。（Ref4)862Please respect copyright.ＰＥＮＡＮＡUvKe5ZHE0M
以登革熱為例，病人染上登革熱病毒(Dengue Virus)的話，身體便會製造登革熱病毒抗體。862Please respect copyright.ＰＥＮＡＮＡQC4mJZHxsp
但基於登革熱病毒與寨卡病毒(Zika Virus)有頗為相似的地方，某部份的登革熱病毒抗體「幸運地」便成為寨卡病毒的Non-Neutralizing Antibody，透過ADE幫忙寨卡病毒入侵人體。862Please respect copyright.ＰＥＮＡＮＡu47jUikONJ
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亦即是說，擁有登革熱病毒抗體的人反而更有機會受到寨卡病毒入侵。862Please respect copyright.ＰＥＮＡＮＡS2nIaUZT7v
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（圖9）有研究指出，03年SARS病毒亦會依靠未曾上市的疫苗所產生出的Non-Neutralizing Antibody，不需經過ACE2便能入侵免疫細胞。（Ref5)862Please respect copyright.ＰＥＮＡＮＡToDUsWpLTn
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武肺會否出現同樣現象，暫時尚未清楚。862Please respect copyright.ＰＥＮＡＮＡMIKGSkxUIs
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只不過各國進行Phase3中的疫苗，大多也是針對著武肺病毒S protein位置而設計，故此出現Non-Neutralizing antibody將會比用上整個武肺病毒而作為疫苗設計的那兩間公司為低，ADE的機率亦相對減少。862Please respect copyright.ＰＥＮＡＮＡTPp25ErnWd
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當然，另一方面來看，中國那兩間公司因為用上整個武肺病毒來設計疫苗，理論上所產生的抗體數量及濃度亦會為高，抵抗的效果亦會相對顯著，但ADE的機率出現亦會相對為高。862Please respect copyright.ＰＥＮＡＮＡPb2Lf3wkWp
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美國Moderna已表示Phase3的報告將會探討ADE的可能，但願中國Sinovac及國營Sinopharm的Phase3報告，也會在ADE方面進行深入探討吧！862Please respect copyright.ＰＥＮＡＮＡzOSxPj1cQg
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Ref2:https://jamanetwork.com/journals/jama/fullarticle/2769612?fbclid=IwAR0sp9eU5V9FOzuLjz6ERw6LRFm-1yx3MJt1OEgqBDQKW1GA5mQeIIi5J7E862Please respect copyright.ＰＥＮＡＮＡ2wyqePtGCm
Ref3:https://science.sciencemag.org/content/369/6499/77?fbclid=IwAR29zOO06gVsQAC2jLU2uMJi-qcYbniz108Y4kcaWOr1iNuQyVM3jCFMHa4862Please respect copyright.ＰＥＮＡＮＡEcvOmWB9hN
Ref4:https://www.nature.com/articles/s41586-020-2538-8.pdf862Please respect copyright.ＰＥＮＡＮＡhuqXVLB74v
Ref5:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115629/862Please respect copyright.ＰＥＮＡＮＡuYK4ehtbHG