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。841Please respect copyright.ＰＥＮＡＮＡMF4tpd9tqu
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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。841Please respect copyright.ＰＥＮＡＮＡNStZjLqvmj
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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。841Please respect copyright.ＰＥＮＡＮＡLblkFWHDLl
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下列為Sinovac製作滅活病毒疫苗的扼要流程(Ref3)841Please respect copyright.ＰＥＮＡＮＡpk1CDtZrZl
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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。841Please respect copyright.ＰＥＮＡＮＡcMEVdQvd25
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2.經過數輪實驗室細胞的培植，使病毒數量增加。841Please respect copyright.ＰＥＮＡＮＡbVwswuwNtV
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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。841Please respect copyright.ＰＥＮＡＮＡ3F9WxCVwJy
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4.將其製成可注射的疫苗。841Please respect copyright.ＰＥＮＡＮＡEsQFAYr92G
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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。841Please respect copyright.ＰＥＮＡＮＡqC4H1fUwPI
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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。841Please respect copyright.ＰＥＮＡＮＡUcWxcd3F0E
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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。841Please respect copyright.ＰＥＮＡＮＡPu8ddFJcNO
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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。841Please respect copyright.ＰＥＮＡＮＡ2oD0WGTiSg
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1.抗體與病毒的S protein合併，841Please respect copyright.ＰＥＮＡＮＡF3yvSoU5jj
防止條件1的達成。841Please respect copyright.ＰＥＮＡＮＡ8GFgVhhq8n
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2.抗體與病毒其他位置合併，841Please respect copyright.ＰＥＮＡＮＡrMzHUgkTAC
防止條件3的達成。841Please respect copyright.ＰＥＮＡＮＡ8lYWa8mZZ4
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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。841Please respect copyright.ＰＥＮＡＮＡBiA8HhqDg5
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。841Please respect copyright.ＰＥＮＡＮＡWAEOdIX5Or
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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。841Please respect copyright.ＰＥＮＡＮＡjTsoG3sGT5
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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;841Please respect copyright.ＰＥＮＡＮＡcGlglsHvct
簡單來說，就是抗體適得其反地協助病毒入侵人體細胞。841Please respect copyright.ＰＥＮＡＮＡgl1zyMSU8j
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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。841Please respect copyright.ＰＥＮＡＮＡMw7Se2t1kj
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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。841Please respect copyright.ＰＥＮＡＮＡHZASRgOP6I
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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。841Please respect copyright.ＰＥＮＡＮＡgR90beX3sB
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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。841Please respect copyright.ＰＥＮＡＮＡkoKyXcCiDz
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。841Please respect copyright.ＰＥＮＡＮＡFCOZJpQ9iX
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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。841Please respect copyright.ＰＥＮＡＮＡimqa57fKwE
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。841Please respect copyright.ＰＥＮＡＮＡxDshhajifR
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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)841Please respect copyright.ＰＥＮＡＮＡKRynCdKQrT
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。841Please respect copyright.ＰＥＮＡＮＡ68erqQpDYp
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。841Please respect copyright.ＰＥＮＡＮＡx2yh7BjFac
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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。841Please respect copyright.ＰＥＮＡＮＡKgATu8Ndry
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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)841Please respect copyright.ＰＥＮＡＮＡ5ew2nBQMtY
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武肺會否出現同樣現象，暫時尚未清楚。841Please respect copyright.ＰＥＮＡＮＡ5o94x07Bgs
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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。841Please respect copyright.ＰＥＮＡＮＡdv3bmVflQ0
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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。841Please respect copyright.ＰＥＮＡＮＡLs3FE122KM
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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！841Please respect copyright.ＰＥＮＡＮＡonFJ5HYT6Y
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Ref2:https://jamanetwork.com/journals/jama/fullarticle/2769612?fbclid=IwAR0sp9eU5V9FOzuLjz6ERw6LRFm-1yx3MJt1OEgqBDQKW1GA5mQeIIi5J7E841Please respect copyright.ＰＥＮＡＮＡqNLDA0w6tO
Ref3:https://science.sciencemag.org/content/369/6499/77?fbclid=IwAR29zOO06gVsQAC2jLU2uMJi-qcYbniz108Y4kcaWOr1iNuQyVM3jCFMHa4841Please respect copyright.ＰＥＮＡＮＡfuAgvl4cKH
Ref4:https://www.nature.com/articles/s41586-020-2538-8.pdf841Please respect copyright.ＰＥＮＡＮＡlzqQdTzWig
Ref5:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115629/841Please respect copyright.ＰＥＮＡＮＡVDprCmZUiU