- 學位論文
新冠病毒變種的威脅及疫苗發展的因應策略
The Threat of Variants of SARS-CoV-2 Virus and The Coping Strategies of Vaccine Development
摘要
為了因應 SARS-CoV-2 所引起的人類感染大流行，在滾動式審查過程和緊急授權（EUA）政策下，來自多個平台的多項候選疫苗得以快速開發及提供民眾施打。除了腺病毒載體疫苗和 mRNA 疫苗外，蛋白次單元疫苗隨後也在此次新冠疫情上扮演一定程度的角色。雖然人類快速發展出新冠疫苗，但更多的挑戰接踵而至。例如，疫苗在世界各地的供應短缺，各廠牌或各平台未必都能及時生產運送到位；接種完標準兩劑疫苗後，抗體效價還是會逐步下降；尤其是變種病毒層出不窮的出現，從 Alpha/Beta/Gamma 變種，到橫掃全球的 Delta 及 Omicron 變種，不但傳播性可能更強，疫苗所能提供的免疫力也可能會有所下降，而可能發生突破性感染。 我在網路上各大生物醫學資料庫，以預設的關鍵字，例如 “immunogenicity”, “efficacy”, “effectiveness”, “variant”, “Covid-19 vaccine”, 及在 “2021-2022” 期間所發表的文獻，系統性的大量搜尋並閱讀新冠病毒及其變種，及新冠疫苗等相關資料，試圖從我的角度，整理出幾項人類目前希望克服這些挑戰的疫苗發展方向及應變策略應用，並將於文中詳加討論。 結果發現，世界衛生組織、各衛生學術機構、各相關研究團隊，針對前述挑戰，所採取的應變策略，主要為以下幾項。首先，混打接種政策的組合方式及評估。在各種組合的混合接種試驗結果發現，mRNA 與 AZ 腺病毒疫苗的混打，中和抗體效價可以遠高於兩劑 AZ；蛋白疫苗的混打，則是提高接種安全性及不亞於 mRNA 疫苗的細胞性免疫。藉由對各種混打的可行性及優缺點的了解，讓各地區能靈活運用所取得的疫苗，提高全球施打率，以期減少變種病毒的出現。 其次是施打的劑數。在兩劑完整接種後，中和抗體雖能達到高峰，但會隨著時間逐漸下降；第三劑疫苗的施打，不僅可重新拉高抗體的數量，而且還可超越前兩劑接種所能達到的高峰；更重要的是，抗體對抗 Omicron variant 的中和效價也更加提升，並且之後抗體濃度可維持更久。至於第四劑新冠疫苗的接種，可將中和抗體量重新拉回第三劑所能達到的量，但無明顯更加提升；雖然仍然安全，但大約只多提供了30 %的保護效力來對抗 Omicron 的感染；打滿四劑仍感染的人，依然有相當的傳染性；不論是否有施打第四劑，得到 Omicron variant 感染皆為輕症。從此看來，我認為將來透過固定時間的反覆施打，來與病毒共存的趨勢已相當明確。既然需要每年的反覆施打，最安全且最能普及的蛋白次單位疫苗，在人類需長期與病毒共存的未來，將扮演關鍵的角色。 另外，以南非變種的棘蛋白為基礎所設計的 S-2P，所製作而成的次世代疫苗，在動物試驗已呈現出能對新冠變種病毒提升免疫生成性及攻毒試驗中的保護力，目前也已進入初步人體試驗。新加坡團隊也在已感染過SARS又接種過新冠疫苗的人身上，發現極廣效中和抗體的存在，因此我認為人類研發出可同時對抗所有變種病毒的通用型疫苗，是指日可待的。 因此，綜上所述，雖然人類已無可逃避與新冠病毒的共存，也無法阻止新冠病毒層出不窮的出現，但人類已同時有多項疫苗發展的因應對策，來因應這場與新冠病毒的長期抗戰。
並列摘要
In response to the SARS-CoV-2 pandemic, many vaccine candidates from several platforms have been developed rapidly under the rolling review process and EUA policy. In addition to adenovirus-vectored vaccines and mRNA vaccines that were introduced to help control the infectious disease pandemic, protein-based vaccines were developed. However, despite the availability of a variety of vaccines, human beings continue to face more challenges, such as the equity and shortage of vaccine supply, the phenomenon of antibody decline after the standard 2-dose vaccination, the emergence of viral variants that have strong transmissibility and are refractory to immune protection from vaccination, and subsequent breakthrough infections. I conducted an extensive literature review from a preset search strategy and selection criteria to search academic reports containing the terms “immunogenicity”, “efficacy”, or “effectiveness”, and “COVID-19 vaccines” in adult populations. From the literature review, I tried to analyze and then propose a whole picture of how human beings face these new challenges, especially the coping strategies of vaccine development. In this master’s thesis, I will introduce and discuss the feasibility of these strategies from my perspective. I found that the WHO, health institutes, and research teams have enacted several policies to face the challenges mentioned above. The first is the assessment of the combination of homologous and/or heterologous vaccination. The studies showed that the immunogenicity of heterologous vaccination with mRNA and AZ adenovirus-vectored vaccine (ChAd) was superior to that of homologous ChAd vaccination; in addition, heterologous vaccination with protein-based vaccination could provide a high level of safety and good cellular immunity. The understanding and application of heterologous vaccination could lead to widespread vaccination and decrease the risk of the emergence of viral variants. The second is the times of vaccination. The antibody titers increased markedly after two vaccinations, but the titers declined gradually. The third dosing policy could increase the antibody titers up to levels even higher than those achieved through two-dose vaccination. Furthermore, not only antibody titers but also neutralizing capacity against the Omicron variant and much better antibody persistence could be achieved by the third dosing. However, although the fourth dose could level up the declined antibody titers after the third dose, it failed to increase the peak levels when compared to those achieved with the third dose. The fourth dose is well tolerated and safe but has only approximately 30% efficacy against infection by the Omicron variant. Low vaccine efficacy against infections as well as relatively high viral loads suggest that those who were infected were infectious. Thus, a fourth vaccination may have only marginal benefits. In my opinion, a repeated annual vaccination will fail to eradicate the virus but remains necessary to control the pandemic. Protein-based vaccines may play a critical role in the long-term because of their high level of safety and availability. In addition, a next-generation vaccine based on the modified S-2P from the beta variant has been developed. An animal study with a hamster model showed improved immunogenicity against viral variants, including Omicron, and provided good protection in the virus challenge test. Clinical trials have already begun. Furthermore, extremely broad-spectrum neutralizing antibodies against coronaviruses have been identified in persons who were infected with SARS and vaccinated with BNT. This finding makes universal COVID-19 vaccine development against all variants possible. In summary, in my opinion, based on the currently available evidence, living with SARS-CoV-2 and facing the threat of the emergence of viral variants are inevitable; however, people have prepared coping strategies for vaccine development to fight against these challenges.