子宮頸癌疫苗綜論

Overview of cervical cancer vaccine

子宮頸癌是全世界主要的罹病率與死亡率的疾病，特別在缺乏完整篩檢系統的國家。1960 年代的研究者猜疑herpes simplex virus (HSV)是子宮頸癌的致病元兇，一直到 1976 年Harald zur Hausen 的研究團隊才在子宮頸癌的組織檢體發現人類乳突瘤病毒(human papilloma virus, HPV)的病毒核酸，HPV16 及HPV18的 DNA。從此陸續在將近99.7%的子宮頸癌組織內找到HPV 病毒的DNA，奠定了 HPV 是人類子宮頸癌的學理依據，也因此項偉大貢獻，zur Hausen 得到2008 年諾貝爾醫學獎的殊榮。傳統上所使用幾十年的子宮頸抹片篩檢可以早期偵測到不正常的子宮頸上皮細胞，但抹片篩檢方法僅是疾病的第二級預防(secondary prevention)，疾病真正的第一級預防(primary prevention)應該是阻斷疾病本身的發生。唯一對付病毒的第一級預防的策略是疫苗接種，目前全世界祇有 GSK 及MSD 兩大藥廠製造出抗 HPV 疫苗，分別是Cervarix 及Gardasil，全球100 個以上的國家核准使用，這是 21 世紀人類生物醫學史上的一件偉大貢獻與發明，未來影響勢必相當深遠。台大醫院婦產部很榮幸地參加世界多國跨洲的 HPV-008 子宮頸癌疫苗的臨床試驗計劃，在全部收案 18644 位中占1032 位，排名位居亞洲第1 名世界第2名。HPV-008 臨床試驗是針對HPV16 及18 兩型而設計，採用新型免疫佐劑(ASO4)，以類病毒顆粒(VLPs,virus-like particles)當抗原，皮下注射，以誘發中和抗體(neutralizing antibody)的產生，達到阻斷病毒感染的效果。Cervarix 的疫苗功效(vaccine efficacy)針對HPV16/18 而言高達98.1%，針對非注射的其他12 種HPV 的預防效果也有54.0%。二十一世紀開啟了子宮頸癌疫苗的新時代，對於全世界婦女的福祉貢獻非淺。但仍有一些問題要加以突破：(1)如何提高所有醫師及人們對於HPV 及疫苗的認知？(2)提供更多的疫苗接種的健康效益成本分析。(3)什麼時候開始接受疫苗接種？(4)國家公共衛生政策的優先次序的確定。(5)半年內施打三劑HPV 疫苗是黃金標準嗎？少於三劑的注射，其疫苗功效又如何？以上各點能獲得解決，台灣與全世界的婦女才能真正免除子宮頸癌恐懼的陰影。

Cervical cancer is the disease with major prevalence and mortality worldwide, especially in countries without comprehensive screening system. Around 1960, herpes simplex virus was thought to be the causal agent of cervical cancer. In 1976, the research team led by Dr. Harald zur Hausen discovered the presence of human papillomavirus(HPV)-DNA in 99.7% of cervical cancer tissue specimens. He was rewarded with Nobel Prize in 2008 due to his tremendous contribution in medicine. Traditional Papanicolou smear has been extensively used for several decades since 1950, which can early detect abnormal cervical epithelial cells. However, the screening method of cervical cytology examination is a method of secondary prevention. The real primary prevention of a disease is to block the disease before its occurrence. The strategy of primary prevention of a viral disease is vaccination. Nowadays, only two companies, GSK and MSD, produce anti-HPV vaccines, which are Cervarix(GSK) and Gardasil (MSD). This is a great jump and record in the history of biomedicine in 21 century. National Taiwan University Hospital (NTUH), Taipei, Taiwan was very honored to participate in the international multicenter HPV-008 cervical cancer vaccine clinical trial study during 2004-2011. HPV-008 study involved 135 medical centers among 14 countries including Taiwan. Our study-site at NTUH recruited 1032 subjects among 18,644, ranking No.1 in Asia and No. 2 in the world. HPV-008 study was designed to target HPV-16 and 18, utilizing a special adjuvant (AS04) and virus-like particles (VLPs) to induce a high level production of neutralizing antibodies in human subjects after immunization. The vaccine efficacy of Cervarix was reported to be 98.1% against HPV-16/18, and 54.0% against 12 other non-vaccinated HPV types. Though the discovery of cervical cancer vaccines in the early beginning of 21st century has made a great impact on women’s healthcare in the world, there are still several important issues which needed to be solved in the near future: (1) How to improve the awareness of HPV itself and HPV vaccine in physicians and people? (2) To provide more statistical data of cost/effectiveness analyses in HPV vaccination. (3) At what age to take the initial HPV vaccination? (4) To establish the priority of public health policy of our national vaccinetion program including HPV vaccination. (5) Is 3-doses in 6 months a golden standard of HPV vaccination schedule? How about the vaccine efficacy of fewer than 3-doses vaccination? All women in Taiwan as well as in the world will really get rid of the fear of cervical cancer when all the above concerned issues are resolved.