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標題: | 邁向B型肝炎病毒根除之路:透過全面嬰兒B型肝炎疫苗接種和給予懷孕母親惠立妥治療,並探索HBx 基因變異對免疫耐受期的影響 Moving Toward the Eradication of Hepatitis B virus: By Universal Infant HBV Vaccination and Maternal Tenofovir Treatment, and Exploring the Role of HBx Variants on Immune-tolerant phase |
作者: | 張凱琪 Kai-Chi Chang |
指導教授: | 張美惠 Mei-Hwei Chang |
關鍵字: | B型肝炎,全面B型肝炎疫苗接種,母子傳染,惠立妥,免疫耐受期,B型肝炎病毒X基因, hepatitis B virus,universal hepatitis B vaccination,mother-to-infant transmission,tenofovir,immune-tolerant phase,Hepatitis B virus X, |
出版年 : | 2024 |
學位: | 博士 |
摘要: | 世界衛生大會制訂一項全球衛生策略,希望在2030年可以根除病毒性肝炎。在所有根除B型肝炎的方法中,全面接種B型肝炎疫苗是預防感染B型肝炎最具成本效益的方法。台灣作為推動全面B型肝炎疫苗先驅,經過30多年的演進,成功使B型肝炎盛行率大幅減低。這項成功可以歸因於疫苗接種高覆蓋率和全面的B型肝炎病毒篩檢,共同建立了強大的防禦網絡。我們進行了一個大規模研究,徹底探究後疫苗時代所有可能的慢性B型肝炎傳播情況。從台北都會區招募的1611名1歲到59歲的受試者中,我們發現疫苗接種後世代的B型肝炎表面抗原跟B型肝炎核心抗體的盛行率皆遠低於疫苗接種前世代(0.4% vs 7.7%、2.2% vs 50.8% ,P < .0001)。另外值得注意的是,疫苗接種後世代中,那些被發現B型肝炎表面抗原陽性的個案都是由B型肝炎帶原母親所生。
除了全面接種B型肝炎疫苗以外,給予懷孕母親抗病毒藥物治療,為另一個對抗B型肝炎垂直感染的重要方式。經由我們第一部分的研究,確認母嬰垂直感染是B型肝炎感染的主要傳染途徑、也是為施打疫苗卻發生突破性感染的主要原因。若懷孕母親具有B型肝炎高病毒量,或e抗原陽性,代表母親體內病毒正在大量複製,則會增加突破性感染的發生率。利用抗病毒藥物治療懷孕婦女可以降低其體內的病毒量,進而減低母嬰傳染的風險。然而,這些嬰兒出生時體內是否測得到B型肝炎病毒的存在,而這對隨後的慢性B型肝炎風險到底有何影響仍不清楚。為了回答這個問題,我們招募了201名慢性B型肝炎感染並且為高病毒量的孕婦,其中有110人在第三孕程接受惠立妥(tenofovir)治療,其餘的孕婦則維持常規孕程追蹤,並未特別服用抗病毒藥。在總共208名誕生的寶寶中,惠立妥組的新生兒,其體內測得B型肝炎去氧核醣核酸(DNA)陽性率比較媽媽沒有接受惠立妥組的新生兒低(5.22%對30.11%,P < .0001),並在6個月(1.74%對11.83%,P = .003)和12個月(1.74%對10.75%,P = .007)的B型肝炎表面抗原陽性率也比較低。此外,我們發現新生兒B型肝炎病毒DNA陽性與否,在多變量分析中是預測兒童慢性B型肝炎感染的有效獨立預測因子(勝算比odds ratio = 61.89, P = .0002)。 延續母嬰垂直傳染的議題,慢性B型肝炎感染的懷孕母親若處於B型肝炎e抗原陽性的病毒活躍複製期,將病毒傳染給寶寶的機率大幅增加。此段e抗原陽性時期稱之為免疫耐受期,而它是慢性B型肝炎感染自然史中,佔據兒童、青少年、到年輕成人數十年光陰的一個階段。若我們能對免疫耐受期增加更多理解,或許能預測哪些慢性B型肝炎感染個案,當成為懷孕母親時傳染病毒給寶寶的機率較低,而哪些人又較高。 從免疫耐受期過渡到免疫廓清期(immune clearance phase),甚至成功達到B型肝炎e抗原陰轉,這些現象暗示著人類宿主的免疫力復甦,通常對長期病程的預後有益。然而,在慢性B型肝炎感染自然史中,調控免疫耐受期的機制仍然不明。粒線體抗病毒信號蛋白質(MAVS, Mitochondrial Antiviral Signaling Protein)是一個負責傳遞訊息向下,推動乙型干擾素(IFN-β)順利產生的重要物質。B型肝炎病毒X蛋白(HBx protein)已被報導會透過減少粒線體抗病毒信號蛋白質來破壞下游的乙型干擾素的生成,進而可能損害後續對抗B型肝炎病毒的後天免疫系統 (adaptive immune system)。我們分析了慢性B型肝炎患者基因變異對免疫耐受期的影響,發現臨床上帶有HBx R87G、I127V以及R87G+I127V雙重突變感染株的患者較容易突破免疫耐受期。 接著,我們進行細胞轉染,將帶有B型肝炎病毒X基因R87G和I127V變異的片段送入肝細胞株中,並且發現細胞內、外偵測到的乙型干擾素皆有顯著上升。再者,我們偵測到一旦B型肝炎病毒X蛋白出現R87G和I127V的變異,粒線體抗病毒信號蛋白質會被野生型B型肝炎病毒X蛋白附著並且進行泛素化 (ubiquitination)分解的作用將會被抵銷,此舉有助於保留住粒線體抗病毒信號蛋白質。由此推斷特定的B型肝炎病毒X基因的突變,在B型肝炎病毒跟宿主的免疫系統交互作用中扮演重要的角色,它會往下恢復乙型干擾素的產生。這個過程或許有助於逆轉原本免疫系統耗竭的情況,促進免疫耐受期的突破。 根除B型肝炎感染,除了給予患者核苷/核苷酸類似物(nucleos(t)ide analogues) 治療以外,全面讓新生兒接受B型肝炎疫苗接種、以及在第三孕程給予高風險B型肝炎帶原母親抗病毒藥物,皆有助降低傳播機率。另外,深入了解慢性B型肝炎感染的自然病程中的演進、並且探索內部的潛在機制,都有助於我們制定更全面的B型肝炎感染者的篩檢和監測,並為他們提供適當的後續追蹤和照護。 The World Health Assembly is addressing a Global Health Sector Strategy aimed at eliminating viral hepatitis by the year 2030. Of all the methods available for eradicating hepatitis B virus (HBV) infection, universal vaccination stands out as the most cost-effective approach for preventing new infections. Taiwan, as the pioneer in establishing universal HBV immunization, has demonstrated a remarkable decline in the prevalence of HBV infection over the past three decades. This success can be attributed to high vaccination coverage and comprehensive HBV screening, which have collectively contributed to the establishment of a robust healthcare network. We conducted an extended survey to thoroughly investigate all conceivable transmission of chronic hepatitis B (CHB) infection in the post-vaccination era. Among the 1611 subjects recruited from Taipei metropolitan area, we found the prevalences of HBsAg and anti-HBc in the vaccinated birth cohort were lower than those born before 1984 (0.4% vs 7.7%, and 2.2% vs 50.8%, P < .0001; respectively). Notably, all three vaccine-failure carriers all were born to HBsAg carrier mothers. Mother-to-infant transmission (MTIT) is the primary avenue for HBV acquisition, accounting for the majority of instances of immunoprophylaxis failure. Maternal High viral load or positive hepatitis B e antigen, indicating active viral replication, both contribute to breakthrough infection. The utilization of maternal antiviral therapy can effectively reduce the HBV viral load in mothers with high viremia, consequently diminishing the risk of MTIT. Nevertheless, the impact of neonatal viremia in these infants on subsequent HBV infection remains unclear. To answer this question, we recruited 201 HBV carrier pregnant mothers who had high viral load, and 110 of them received tenofovir during the third trimester. Of the 208 children, those in the tenofovir group had a lower rate of neonatal HBV DNA seropositivity at birth (5.22% versus 30.11%, P < .0001), and HBsAg seropositivity at 6 months (1.74% versus 11.83%, P = .003) and 12 months (1.74% versus 10.75%, P = .007). In addition, we found neonatal HBV DNA positivity was a strong independent influence variable in multivariate analysis to predict children’s CHB infection (odds ratio = 61.89, P = .0002). Transitioning from the immune-tolerant phase to the immune clearance phase, and even achieving HBeAg seroconversion, which implies host immune restoration, usually confers a favorable prognosis. However, the immunologic mechanisms underlying the immune-tolerant phase of CHB infection remain unknown. The Hepatitis B virus X (HBx) protein disrupts IFN-β induction by downregulating mitochondrial antiviral signaling protein (MAVS) and may impair subsequent HBV-specific adaptive immunity. We analyzed the impacts of genetic variability of CHB patients on the immune-tolerant phase, and found patients carrying HBx R87G, I127V, and R87G+I127V double mutations exhibited higher cumulative incidences of immune-tolerant phase breakthrough. Cells transfected with HBx R87G and I127V mutants and pHBV1.3-B6.3 replicons containing the HBx R87G and I127V mutations exhibited statistically increased level of IFN-β as well. HBx R87G and I127V mutants also helped to preserve Flag-MAVS, by diminishing its ubiquitination which was stimulated by HA-HBx wild-type. Specific HBx mutants are implicated in the interaction between HBV and components of host innate immunity, rescuing the production of IFN-β. This may be helpful to restore exhausted immune responses to achieve immune-tolerant phase breakthrough. Gaining a deeper understanding of the behaviors and potential mechanisms inherent in the natural course of HBV infection can help us to set a more comprehensive screening and monitoring protocol for HBV-infected persons, and provide them with appropriate follow-up and care. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91669 |
DOI: | 10.6342/NTU202400359 |
全文授權: | 同意授權(限校園內公開) |
顯示於系所單位: | 臨床醫學研究所 |
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