藥物的研究(research, R) 與發展(development, D),雖然都是在研究藥物,但其意義與目的是不同的;前者是較偏向藥物的探索、作用與機轉之研究,是學術創新性;而後者是對具有治療應用價值之藥物進行產業化或商品化之開發,包括藥物的製造、動物的毒性到臨床藥效之觀察等。整體新藥研發(New drug R & D)的流程包括:藥的探索與價值確效、產品開發之臨床前動物試驗、臨床試驗,具有臨床療效後,才能查驗登記並上市。整體研發費時10~15 年,每一段都要花費相當龐大之研發經費,然而新藥研發一旦成功上市,其產值卻也非常龐大(圖二)。
圖二:新藥研發之流程、時間、經費與價值。IND:試驗用新藥,Investigational new drug;NDA: 新藥查驗登記,New drug application。
此階段包括產品原料藥之開發、製程、劑型及動物毒理試驗等。藥物最終目的是要在病人身上證明有效,但為了安全起見,一定要先在動物證明其具有藥效,並且安全。為達此目的,有許多試驗是在人體臨床試驗前必須完成,才能向衛生主管機構申請「試驗用新藥」(investigational new drug, IND),通過審核後再執行臨床試驗。以下簡述IND 所需完成之研發項目。
( 一) 化學、製造與監控(Chemical Manufacture and Control, CMC):含化合物的大量製造、純度分析、物化性質、安定性試驗、劑型設計等。
上述這些臨床前試驗的工作,不一定要藥廠本身執行,可以委由具有此專業設備與經驗之委託研究機構或公司,即所謂CRO(Contract Research Organization)代為執行。市場上有種種不同功能與技術之CRO公司,一個藥廠可借助多家CRO 來完成一件新藥之研發,以節省設置那麼多研究機構之經費。而當臨床前試驗執行完畢後,即可收集所有研發相關之實驗結果、文獻等資料向藥物管理機構申請IND,其資料通常包括:藥物來源組成、製造方法與規格、藥理與毒理之各種動物實驗、藥物動力學、臨床試驗計畫書與執行者等。
每個國家對於藥物的管理都有一套制度,從新藥的IND、每一期的臨床試驗、到藥品的查驗登記(NDA)與上市後的監視,都是為了保障人類的健康。美國及台灣的醫藥品主管機構都叫食品藥物管理局(Food and Drug Administration, 分別為FDA 及TFDA),歐盟則成立了歐洲藥物評審調查局(The European Medicine Agency, EMEA)。藥物的審核,是相當嚴謹,食品藥物管理局有各領域專家群,針對藥物之CMC、藥理、藥動、毒理、臨床試驗給予詳細的評審。IND 的審查,是著重在安全比藥效重要,在一至數個月內可完成審查,通過後即可進入臨床一期試驗。NDA 的審查,由於資料龐大,且需在藥效與安全之多方面考慮才准上市,因此審核相當費時。美國FDA 考量許多無藥可治或迫切需求之重症病人,因等待新藥過久而失去機會,因此制定了快速核准制度(Accelerated approval),如愛滋病用藥與罕見疾病用藥等;但必須在執行上市後,建立各項藥物安全之限制設施。
我國政府對生技醫藥之研發投資不小,尤其國科會、經濟部、衛生署都有補助藥物研發計畫之經費。國科會負責藥物探索,包括藥物來源之發掘與藥效之基礎研究,以支援上游之藥物研發;經濟部則補助各法人科專之臨床前研究及產業之藥物研發計畫;衛生署推動臨床試驗與研究中心,並責成醫藥品查驗中心(Center of Drug Evaluation, CDE)協助研發相關之法規問題,以加速藥物研發時程(圖三)。
此外,在正常的初級止血過程中,活化的血小板和內皮細胞會釋放一種叫做 Von Willebrand 因子的蛋白質,如果因子 VIII 沒辦法與其結合,就會在血液中被迅速降解;因此,若 Von Willebrand 因子缺乏或出問題,也會有類似血友病的症狀,在台灣稱為「類血友病」或「溫韋伯氏疾病」(von Willebrand disease, VWD)。
自 1965 年史丹佛大學 Judith Pool 博士發現解凍血漿留下的沈澱物富含因子 VIII,到 1990 年代基因工程培養細胞產生凝血因子;補充因子的治療方法雖可大幅改善患者生活品質,但還是有一些關鍵問題。除了終身都要持續、頻繁地從靜脈注射凝血因子外,療法非常昂貴,且只有不到一半的患者可達到零關節出血的目標。
另外,由於病患沒有因子 VIII 或 IX,他們的免疫系統就有可能把補充進來的凝血因子當成外來的病原,因而產生抗體;儘管這種現象通常只出現在重度患者身上且比例不高,但要是遇上這種情況就非常棘手,病患出血頻率會較高、也更容易關節損壞。通常醫生會使用繞徑藥物(bypassing agent),繞過需要 VIII 跟 IX 因子的凝血路徑來止血,但效果並不如直接補充凝血因子。
美國食品藥物管理局(US Food and Drug Administration)在 2022 年 11 月批准了一種治療血友病的新藥——Hemgenix:為一種基因療法,透過改造過的腺相關病毒 AAV,將基因運送到患者的肝臟細胞後,就能靠自己製造出凝血因子 IX,讓中重度 B 型血友病患者恢復凝血功能,同時兼顧安全性跟有效性。
基於對 54 名患者的臨床實驗資料,在一次性的靜脈注射後,7~8 個月左右,幾乎所有病患體內的因子 IX 水平都穩定了,預估效果起碼能維持八年以上,甚至更長。即使臨床實驗裡,有患者製造的因子 IX 比較低,但都達到足以避免自發性出血的程度。注射後的副作用很輕微,例如常見的頭痛或輕微的感冒症狀,而追蹤 24 個月之後,跟治療有關的不良反應則是零。
看時間:數據是2022年6~8月的數據,已能獲得充沛疫苗資源的國家來說該國國民絕大多數都有接種疫苗,以澳洲公布的數據來看16歲以上的澳洲人98%有接種一劑疫苗,兩劑為96.3%,三劑為71.7%,而New South Wales的人口數根據Population Australia這個網站上顯示在2022年6月底可能會達到 826萬人,而該地區16歲以上居民97%有接種一劑疫苗,兩劑為95.4%,三劑為69.6%(數據來源)
2. 分母要選對:在做如該信提到的感染機率比較時,我們必須要有施打疫苗者跟有施打疫苗者比,沒施打疫苗者跟沒施打疫苗者比,為什麼?因為你要比的是施打疫苗者跟沒施打疫苗者各自的感染機率,而以澳洲數據來看16歲以上施打至少一劑疫苗者有98%(20,209,451人),換而言之沒施打疫苗者大約是2%(412,428人);而在New South Wales16歲以上施打至少一劑疫苗者有97%(約8,017,050人),未施打疫苗者大約3%(大約247,950人)如果沒選對分母,算出來的數據會大錯特錯。
中和性抗體需要不短的成熟期,不可能在疫苗接種後幾週內產生[49][50],除非你已經是接種超過一劑疫苗,接著在第二或是第三劑疫苗施打後幾週內產生中和性抗體那可能還說得過去。而 mRNA 疫苗可以有效刺激與誘導 T 細胞與 B 細胞已在過往實驗中獲得證實[51],對於其導致心肌炎、心包炎與過敏等的可能機制也有不少研究團隊分析討論[52][53],並針對其安全性與哪些族群可能施打有較高的風險有所研究[52–54]。
Amoutzias GD, Nikolaidis M, Tryfonopoulou E, Chlichlia K, Markoulatos P, Oliver SG. The remarkable evolutionary plasticity of coronaviruses by mutation and recombination: insights for the COVID-19 pandemic and the future evolutionary paths of SARS-CoV-2. Viruses. 2022 Jan 2;14(1):78.
Schwarzendahl, F.J., Grauer, J., Liebchen, B. and Löwen, H., 2022. Mutation induced infection waves in diseases like COVID-19. Scientific Reports, 12(1), pp.1–11.
Pathan, R.K., Biswas, M. and Khandaker, M.U., 2020. Time series prediction of COVID-19 by mutation rate analysis using recurrent neural network-based LSTM model. Chaos, Solitons & Fractals, 138, p.110018.
Sharif, N. and Dey, S.K., 2021. Impact of population density and weather on COVID-19 pandemic and SARS-CoV-2 mutation frequency in Bangladesh. Epidemiology & Infection, 149.
Mishra, M., Zahra, A., Chauhan, L.V., Thakkar, R., Ng, J., Joshi, S., Spitzer, E.D., Marcos, L.A., Lipkin, W.I. and Mishra, N., 2022. A Short Series of Case Reports of COVID-19 in Immunocompromised Patients. Viruses, 14(5), p.934.
Maponga, T.G., Jeffries, M., Tegally, H., Sutherland, A.D., Wilkinson, E., Lessells, R., Msomi, N., van Zyl, G., de Oliveira, T. and Preiser, W., 2022. Persistent SARS-CoV-2 infection with accumulation of mutations in a patient with poorly controlled HIV infection. Available at SSRN 4014499.
Hoffman, S.A., Costales, C., Sahoo, M.K., Palanisamy, S., Yamamoto, F., Huang, C., Verghese, M., Solis, D.A., Sibai, M., Subramanian, A. and Tompkins, L.S., 2021. SARS-CoV-2 neutralization resistance mutations in patient with HIV/AIDS, California, USA. Emerging Infectious Diseases, 27(10), p.2720.
Focosi, D., Maggi, F., Franchini, M., McConnell, S. and Casadevall, A., 2021. Analysis of immune escape variants from antibody-based therapeutics against COVID-19: a systematic review. International journal of molecular sciences, 23(1), p.29.
Nel, A.E. and Miller, J.F., 2021. Nano-enabled COVID-19 vaccines: meeting the challenges of durable antibody plus cellular immunity and immune escape. ACS nano, 15(4), pp.5793–5818.
Riddell, S., Goldie, S., Hill, A., Eagles, D. and Drew, T.W., 2020. The effect of temperature on persistence of SARS-CoV-2 on common surfaces. Virology journal, 17(1), pp.1–7.
Pulliam, J.R., van Schalkwyk, C., Govender, N., von Gottberg, A., Cohen, C., Groome, M.J., Dushoff, J., Mlisana, K. and Moultrie, H., 2022. Increased risk of SARS-CoV-2 reinfection associated with emergence of Omicron in South Africa. Science, 376(6593), p.eabn4947.
Reynolds, C.J., Pade, C., Gibbons, J.M., Otter, A.D., Lin, K.M., Muñoz Sandoval, D., Pieper, F.P., Butler, D.K., Liu, S., Joy, G. and Forooghi, N., 2022. Immune boosting by B. 1.1. 529 (Omicron) depends on previous SARS-CoV-2 exposure. Science, 377(6603), p.eabq1841.
Morens, D.M., Folkers, G.K. and Fauci, A.S., 2022. The concept of classical herd immunity may not apply to COVID-19. The Journal of Infectious Diseases.
Eichhorn, Adolph. Contagious abortion of cattle. №790. US Department of Agriculture, 1917.
Smith, A., 2000. Oxford dictionary of biochemistry and molecular biology: Revised Edition. Oxford University Press.
Alberts, B., 2017. Molecular biology of the cell. WW Norton & Company.
Waldman, A.D., Fritz, J.M. and Lenardo, M.J., 2020. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nature Reviews Immunology, 20(11), pp.651–668.
Lin, L.Y., Carapito, R., Su, B. and Moog, C., 2022. Fc receptors and the diversity of antibody responses to HIV infection and vaccination. Genes & Immunity, pp.1–8.
Zhu, Y., Lu, Y., Tang, L., Zhou, C., Liang, R., Cui, M., Xu, Y., Zheng, Z., Cheng, Z. and Hong, P., 2022. Finite neutralisation breadth of omicron after repeated vaccination. The Lancet Microbe.
Suryawanshi, R. and Ott, M., 2022. SARS-CoV-2 hybrid immunity: silver bullet or silver lining?. Nature Reviews Immunology, pp.1–2.
Janeway, C.A., Travers, P., Walport, M. and Capra, D.J., 2001. Immunobiology (p. 600). UK: Garland Science: Taylor & Francis Group.
De Andrea, M., Ravera, R., Gioia, D., Gariglio, M. and Landolfo, S., 2002. The interferon system: an overview. European Journal of Paediatric Neurology, 6, pp.A41-A46.
Fajgenbaum, D.C. and June, C.H., 2020. Cytokine storm. New England Journal of Medicine, 383(23), pp.2255–2273.
Elrefaey, A.M., Hollinghurst, P., Reitmayer, C.M., Alphey, L. and Maringer, K., 2021. Innate immune antagonism of mosquito-borne flaviviruses in humans and mosquitoes. Viruses, 13(11), p.2116.
Ntita, M., Inoue, S.I., Jian, J.Y., Bayarsaikhan, G., Kimura, K., Kimura, D., Miyakoda, M., Nozaki, E., Sakurai, T., Fernandez-Ruiz, D. and Heath, W.R., 2022. Type I interferon production elicits differential CD4+ T-cell responses in mice infected with Plasmodium berghei ANKA and P. chabaudi. International Immunology, 34(1), pp.21–33.
Kidd, P., 2003. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Alternative medicine review, 8(3), pp.223–246.
Espinosa, V., Dutta, O., McElrath, C., Du, P., Chang, Y.J., Cicciarelli, B., Pitler, A., Whitehead, I., Obar, J.J., Durbin, J.E. and Kotenko, S.V., 2017. Type III interferon is a critical regulator of innate antifungal immunity. Science immunology, 2(16), p.eaan5357.
Hermant, P. and Michiels, T., 2014. Interferon-λ in the context of viral infections: production, response and therapeutic implications. Journal of innate immunity, 6(5), pp.563–574.
Goldstein, D. and Laszlo, J., 1988. The role of interferon in cancer therapy: a current perspective. CA: a cancer journal for clinicians, 38(5), pp.258–277.
Zaidi, M.R., 2019. The interferon-gamma paradox in cancer. Journal of Interferon & Cytokine Research, 39(1), pp.30–38.
Dunn, G.P., Ikeda, H., Bruce, A.T., Koebel, C., Uppaluri, R., Bui, J., Chan, R., Diamond, M., Michael White, J., Sheehan, K.C. and Schreiber, R.D., 2005. Interferon-γ and cancer immunoediting. Immunologic research, 32(1), pp.231–245.
Regev-Yochay, G., Gonen, T., Gilboa, M., Mandelboim, M., Indenbaum, V., Amit, S., Meltzer, L., Asraf, K., Cohen, C., Fluss, R. and Biber, A., 2022. Efficacy of a fourth dose of COVID-19 mRNA vaccine against omicron. New England Journal of Medicine, 386(14), pp.1377–1380.
Boucau, J., Marino, C., Regan, J., Uddin, R., Choudhary, M.C., Flynn, J.P., Chen, G., Stuckwisch, A.M., Mathews, J., Liew, M.Y. and Singh, A., 2022. Duration of Shedding of Culturable Virus in SARS-CoV-2 Omicron (BA. 1) Infection. New England Journal of Medicine, 387(3), pp.275–277.
Junqueira, C., Crespo, Â., Ranjbar, S., de Lacerda, L.B., Lewandrowski, M., Ingber, J., Parry, B., Ravid, S., Clark, S., Schrimpf, M.R. and Ho, F., 2022. FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation. Nature, pp.1–9.
Pontelli, M.C., Castro, I.A., Martins, R.B., La Serra, L., Veras, F.P., Nascimento, D.C., Silva, C.M., Cardoso, R.S., Rosales, R., Gomes, R. and Lima, T.M., 2022. SARS-CoV-2 productively infects primary human immune system cells in vitro and in COVID-19 patients. Journal of molecular cell biology, 14(4), p.mjac021.
Joseph, M., Wu, Y., Dannebaum, R., Rubelt, F., Zlatareva, I., Lorenc, A., Du, Z.G., Davies, D., Kyle-Cezar, F., Das, A. and Gee, S., 2022. Global patterns of antigen receptor repertoire disruption across adaptive immune compartments in COVID-19. Proceedings of the National Academy of Sciences, 119(34), p.e2201541119.
André, S., Picard, M., Cezar, R., Roux-Dalvai, F., Alleaume-Butaux, A., Soundaramourty, C., Cruz, A.S., Mendes-Frias, A., Gotti, C., Leclercq, M. and Nicolas, A., 2022. T cell apoptosis characterizes severe Covid-19 disease. Cell Death & Differentiation, pp.1–14.
Woodruff, M.C., Ramonell, R.P., Haddad, N.S. et al. Dysregulated naïve B cells and de novo autoreactivity in severe COVID-19. Nature (2022). https://doi.org/10.1038/s41586-022-05273-0
Feng, S. and De Carvalho, D.D., 2022. Clinical advances in targeting epigenetics for cancer therapy. The FEBS Journal, 289(5), pp.1214–1239.
Abrantes, R., Duarte, H.O., Gomes, C., Wälchli, S. and Reis, C.A., 2022. CAR‐Ts: new perspectives in cancer therapy. FEBS letters, 596(4), pp.403–416.
Petitprez, F., de Reyniès, A., Keung, E.Z., Chen, T.W.W., Sun, C.M., Calderaro, J., Jeng, Y.M., Hsiao, L.P., Lacroix, L., Bougoüin, A. and Moreira, M., 2020. B cells are associated with survival and immunotherapy response in sarcoma. Nature, 577(7791), pp.556–560.
Helmink, B.A., Reddy, S.M., Gao, J., Zhang, S., Basar, R., Thakur, R., Yizhak, K., Sade-Feldman, M., Blando, J., Han, G. and Gopalakrishnan, V., 2020. B cells and tertiary lymphoid structures promote immunotherapy response. Nature, 577(7791), pp.549–555.
Moore, P.L., Williamson, C. and Morris, L., 2015. Virological features associated with the development of broadly neutralizing antibodies to HIV-1. Trends in microbiology, 23(4), pp.204–211.
Gray, E.S., Madiga, M.C., Hermanus, T., Moore, P.L., Wibmer, C.K., Tumba, N.L., Werner, L., Mlisana, K., Sibeko, S., Williamson, C. and Abdool Karim, S.S., 2011. The neutralization breadth of HIV-1 develops incrementally over four years and is associated with CD4+ T cell decline and high viral load during acute infection. Journal of virology, 85(10), pp.4828–4840.
Hogan, M.J. and Pardi, N., 2022. mRNA Vaccines in the COVID-19 Pandemic and Beyond. Annual Review of Medicine, 73, pp.17–39.
Heymans, S. and Cooper, L.T., 2021. Myocarditis after COVID-19 mRNA vaccination: clinical observations and potential mechanisms. Nature Reviews Cardiology, pp.1–3.
Risma, K.A., Edwards, K.M., Hummell, D.S., Little, F.F., Norton, A.E., Stallings, A., Wood, R.A. and Milner, J.D., 2021. Potential mechanisms of anaphylaxis to COVID-19 mRNA vaccines. Journal of Allergy and Clinical Immunology, 147(6), pp.2075–2082.
Anand, P. and Stahel, V.P., 2021. The safety of Covid-19 mRNA vaccines: A review. Patient safety in surgery, 15(1), pp.1–9.
Park, K.S., Sun, X., Aikins, M.E. and Moon, J.J., 2021. Non-viral COVID-19 vaccine delivery systems. Advanced drug delivery reviews, 169, pp.137–151.
Heiser, A., Coleman, D., Dannull, J., Yancey, D., Maurice, M.A., Lallas, C.D., Dahm, P., Niedzwiecki, D., Gilboa, E. and Vieweg, J., 2002. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. The Journal of clinical investigation, 109(3), pp.409–417.
Halstead, S.B. and Katzelnick, L., 2020. COVID-19 vaccines: should we fear ADE?. The Journal of infectious diseases, 222(12), pp.1946–1950.
Li, M., Wang, H., Tian, L., Pang, Z., Yang, Q., Huang, T., Fan, J., Song, L., Tong, Y. and Fan, H., 2022. COVID-19 vaccine development: milestones, lessons and prospects. Signal transduction and targeted therapy, 7(1), pp.1–32.
Maemura, T., Kuroda, M., Armbrust, T., Yamayoshi, S., Halfmann, P.J. and Kawaoka, Y., 2021. Antibody-dependent enhancement of SARS-CoV-2 infection is mediated by the IgG receptors FcγRIIA and FcγRIIIA but does not contribute to aberrant cytokine production by macrophages. MBio, 12(5), pp.e01987–21.