背景
自1986年針對新生兒實施全面性的B型肝炎疫苗接種計劃後，台灣近年來兒童慢性B型肝炎病毒帶原率由過去的10~11%下降至1~2%，兒童肝癌發生率也有顯著下降的趨勢。而國內外相關疫苗評估研究均顯示B型肝炎疫苗有良好的效力。但從1992~1993年在花蓮地區新城鄉與秀林鄉的HBV血清流行病學調查發現當地原住民兒童對疫苗有較差的免疫反應及較高的B型肝炎病毒感染率、帶原率。相較於台灣其他地區居民，當地原住民兒童是慢性B型肝炎病毒感染高危險族群，這對整個B型肝炎防疫體系而言，無疑是潛在的危機。所以本次研究選定同一區域再次進行HBV血清流行病學調查，除進一步評估疫苗在此高危險族群的長期效力與分析影響疫苗效力（efficacy）可能因素外，並藉由這次研究了解B型肝炎疫苗接種計劃在偏遠地區的實施情形。此外，慢性B型肝炎病毒帶原有家族聚集現象，由國內先前研究得知藉由疫苗產生的免疫反應存在氏族的差異與對於B型肝炎病毒的感受性（susceptibility）與預後狀況（prognosis）存在氏族與性別的差異。而國內外其他遺傳學研究顯示一些免疫遺傳因子與慢性B型肝炎病毒帶原有相關性存在，基於遺傳因素在慢性B型肝炎病毒感染扮演的重要性，本篇論文的另一個主題即是研究慢性B型肝炎病毒感染可能存在的易感受基因SCCA1。
研究對象
HBV血清流行病學調查，研究樣本包含花蓮地區新城鄉與秀林鄉共1707名7~13歲兒童。遺傳流行病學研究，研究樣本共有245個漢族家族，包含245個e抗原陽性母親、149個父親以及其480個子女共計874人，以及選取200名的漢族婦女和416名的漢族兒童做為族群對照組。在成人慢性HBV帶原病例-對照研究中樣本來源除家族性樣本的父母親之外，另增加199名HBsAg陰性的成年女性、34名HBsAg陰性的成年男性及45名HBsAg陽性的成年男性。
研究方法
HBV血清流行病學調查採用橫斷研究法（cross-sectional study），利用半結構式問卷收集研究個案的人口學資料與並依據疫苗接種紀錄卡確認個案疫苗接種狀況。B型肝炎血清學狀況是以酵素免疫測定法原理（enzyme linked immunosorbant assay；ELISA），檢測個案血清中的HBsAg、anti-HBc（IgG）與anti-HBs的效價；對於HBsAg帶原者，除以PCR檢測HBV DNA確認帶原狀況外，另測試anti-HBc IgM以排除初期感染的可能。遺傳流行病學研究採用生態學研究法（ecology study）、病例對照研究法（case-control study）和家族遺傳研究法（family study），而人口學資料、疫苗接種紀錄收集與血清學狀況確定與血清流行病學調查研究相同；研究個案的DNA在利用PCR增幅所需的片段後，以質量光譜測定法（matrix-assisted laser desorption ionization time-of-flight mass spectrometry；MALDI-TOF MS）來鑑定SCCA1基因核酸序列1069的單核甘酸多型性。
結果
血清流行病學調查顯示在離上次研究近十年後，居住在秀林鄉與新城鄉的兒童相對於都市地區兒童族群，仍然是B型肝炎病毒感染的高危險族群，其平均感染率為10%，帶原率為2.5%，保護性抗體效價陽性率為38.2%。在疫苗效力的長期評估上，比較重要的發現是關於延遲第一劑疫苗注射會增加B型肝炎病毒感染率與帶原率，而且不管是使用血清疫苗或是基因重組疫苗，B型肝炎病毒感染率與帶原率都會隨著第一劑疫苗注射延遲時間而有增加的趨勢。採用複對數迴歸分析，以血清學標記HBsAg為依變項，選擇居住地、氏族、性別、第一劑B型肝炎疫苗接種時間、年齡及疫苗類別為自變項；在控制居住地、性別、第一劑B型肝炎疫苗接種時間、年齡及疫苗類別後，原住民對於HBsAg帶原的危險比值（odds）是漢人的3.57倍（95%CI=1.04~12.30）；在控制居住地、氏族、性別、年齡及疫苗類別後，第一劑疫苗注射時間在出生4週後注射的族群對於HBsAg帶原的危險比值（odds）是於出生1週內注射族群的5.43倍（95%CI=1.75~16.87）。以HBV感染與否為依變項，選擇居住地、氏族、性別、第一劑B型肝炎疫苗接種時間、年齡及疫苗類別為自變項；在控制居住地、氏族、性別、年齡及疫苗類別後，第一劑疫苗注射時間在出生4週後的族群對於HBV感染的危險比值（odds）是於出生1週內注射族群的1.87倍（95%CI=1.07~3.27）。
排除曾感染過HBV的研究個案後，採用複線性迴歸分析，以血清學標記anti-HBs效價（titer）為依變項，並對anti-HBs效價取對數，使其呈常態分布符合統計條件後，選擇居住地、氏族、性別、第一劑B型肝炎疫苗接種時間、年齡及疫苗類別為自變項；在控制氏族、性別、第一劑B型肝炎疫苗接種時間、年齡及疫苗種類後，居住在原住民村的族群其log（anti-HBs）較非原住民村族群減少0.22（p-value=0.002）；在控制居住地、氏族、性別、第一劑B型肝炎疫苗接種時間與年齡後，施打基因重組疫苗的族群其log（anti-HBs）較施打血清疫苗的族群減少0.24（p-value=0.029）。
遺傳流行病學研究結果顯示當假設SCCA1 nucleotide 1069 allele A為隱性基因（recessive gene）時，e抗原陽性的母親族群與婦女族群對照組有顯著的統計差異存在（genotype AA vs. genotypes AG/GG, OR=1.61, 95%CI=1.04~2.50），而父親族群與婦女族群對照組同時具有趨近統計顯著的差異（genotype AA vs. genotypes AG/GG, OR=1.50, 95%CI=0.92~2.47）。在兒童族群當中，當假設SCCA1 nucleotide 1069 allele A為顯性基因（dominant gene）時，e抗原產婦所生子女族群與兒童族群對照組有統計上顯著差異（genotypes AA/AG vs. genotype GG, OR=1.44, 95%CI=1.02~2.04）。在成人慢性HBV帶原病例-對照研究中，當假設SCCA1 nucleotide 1069 allele A為隱性基因時，病例組與對照組有趨近統計上的顯著差異性存在（genotype AA vs. genotypes AG/GG, OR=1.36, 95%CI=0.93~2.00）；當假設SCCA1 nucleotide 1069 allele A為顯性基因時，女性成人病例組與對照組有顯著的統計差異（genotypes AA/AG vs. genotype GG, OR=1.71, 95%CI=0.99~2.98）。此外，在血清學HBsAg陰性且anti-HBc陽性的成人族群中，男性基因型GG比例顯著少於女性（16.2% vs. 27.8%, p-value=0.036），而基因型GG的比例亦存在有隨年齡增加而顯著減少的負相關趨勢（p-value=0.024）。
結論
本篇研究綜合評估B型肝炎疫苗注射計劃在偏遠鄉村地區的施行情形，由於偏遠地區有較延緩的社會經濟發展而不利於的B型肝炎疫苗注射計劃的施行，所以當地兒童容易延遲施打第一劑疫苗與有較低的疫苗完成率。我們的研究資料同時指出於新生兒及早施打疫苗可顯著減少往後的HBV的感染率與帶原率，雖然延遲施打疫苗也會產生較佳的免疫抗體反應，不過顯然的減少HBV感染與帶原遠比增加抗體要重要。在遺傳研究上，我們推測SCCA1 nucleotide 1069 allele A/G為半顯性（semi-dominance）基因，SCCA1只要帶有單一個allele A時，就具有B型肝炎病毒結合蛋白的功能，能增加B型肝炎病毒的感染能力；而帶有SCCA1 nucleotide 1069 genotype AA的族群，SCCA1抑制半胱胺酸蛋白酵素活性的能力較佳、產生免疫反應的能力較好，但容易因免疫功能的高度表現成為長期的HBsAg帶原者。

Background
The national vaccination program against hepatitis B virus（HBV）to immunize every newborn was launched in Taiwan in July 1986 that has resulted in a significant reduction of chronic HBV infection in children or a decreased incidence of childhood hepatocellular carcinoma. Although many studies evaluated the immunogenicity and long-term efficacy of hepatitis B(HB) vaccination, however, during 1992~1993, the HBV seroepidemiologic survey performed in Xincheng and Xiulin villages, Hualien indicated the vaccinated children of indigenous origin not only mounted to a lower protective antibody response, but also had higher rates of HBV infection and chronic carrier. The opinion about the aboriginal children as having higher risk for HBV vaccine failure and HBV chronic infection, that warrants a close monitoring. Consequently, in the year 2001 through 2002, we conducted a community-based seroepidemiologic survey in the same villages to follow up the so called “high risk group” children for HBV chronic infection and to evaluate the efficacy of HB vaccination. There is strong evidence in HBV infection that host genetic factors play a major role in determining the outcome of infection and we believe genetic association may provide clues to functional questions about the pathogenesis of an organism and lead to new therapeutic avenues. Therefore, we also conducted the study of genetic epidemiology about clinical outcomes caused by infection with HBV.
Subjects
In the the HBV seroepidemiologic survey, 1707 children, aged 7~13 years old, were recruited from the elementary schools of Xincheng and Xiulin villages in Hualien. In the genetic epidemiology study, 245 families（total 874 participants）of Han race selected from the FY&MJ hospitals were recruited, including 245 HBeAg positive mothers, 149 fathers and 480 children. Besides, 200 female adults and 416 children were selected for Han race reference population groups. In addition to the adults selected from families, we further to add 199 female subjects with HBsAg negative, 34 male subjects with HBsAg negative and 45 male subjects with HBsAg negative in our adult case-control study of chronic hepatitis B infection.

Methods
In the HBV seroepidemiologic survey, we adopted the cross-sectional study. All HBV serological markers were examined by enzyme linked immunosorbant assay（ELISA）and HBV DNA from plasma was detected by polymerase chain reaction （PCR）for re-checking the status of HBV carrier. In the genetic epidemiology, we adopted the designs of the ecology, case-control and family studies. The polymorphisms of SCCA1 nucleotide 1069 were genotyped by mass spectrometry（matrix-assisted laser desorption ionization time-of-flight mass spectrometry；MALDI-TOF MS）.
Results
After about 10 years from the last HBV seroepidemiologic survey, in contract with the urban children, the children living in Xincheng and Xiulin villages still have higher rates of HBV infection and chronic carrier, and lower protective antibody response. The rates of HBV infection, HBV carrier and protective antibody are 10%, 2.5%, 38.2%, respectively. The new finding by evaluating the efficacy of HBV vaccination is that the age of receiving 1st HBV vaccine can affect rates of HBV infection and chronic carrier. In spite of types of HBV vaccine, there is positive correlation between the age of receiving 1st HBV vaccine and the rate of HBV infection or carrier. The logistic regression analysis for evaluating the status of HBV carrier yielded significant effects of ancestral origin and age of receiving 1st HBV vaccine（OR=3.57, 95% CI=1.04-12.30 for aborigine vs. Han race, OR=5.43, 95% CI=1.75-16.87 for age of receiving 1st HBV vaccine ＞4 weeks vs. 1 week, C statistic=0.82 and p-value of Hosmer-Lemeshow Goodness-of-fit Test=0.959）. The results of logistic regression analysis for evaluating the status of HBV natural infection found significant effect of age of receiving 1st HBV vaccine（OR=1.87, 95% CI=1.07-3.27 for age of receiving 1st HBV vaccine ＞4 weeks vs. 1 week, C statistic=0.64 and p-value of Hosmer-Lemeshow Goodness-of-fit Test=0.789）. The linear regression model for evaluating the logarithm of anti-HBs titer showed that living area and age of receiving 1st HBV vaccine were statistically significant（R2=0.04, F-test for R, DF=（7, 825）, p-value＜0.001）.
In the ecology study of SCCA1 gene, as presuming that SCCA1 nucleotide 1069 allele A is a recessive gene, the frequency of SCCA1 nucleotide 1069 genotype is statistically significant different between HBeAg-positive “mothers” and female reference population（genotype AA vs. genotypes AG/GG, OR=1.61, 95%CI=1.04~2.50）, and approximating to statistically significant different between “fathers” and female reference population（genotype AA vs. genotypes AG/GG, OR=1.50, 95%CI=0.92~2.47）. As presuming that SCCA1 nucleotide 1069 allele A is a dominant gene, the frequency of SCCA1 nucleotide 1069 genotype is statistically significant different between children born to HBeAg-positive mothers and children's reference population（genotypes AA/AG vs. genotype GG, OR=1.44, 95%CI=1.02~2.04）.In adult case-control study of chronic hepatitis B infection, as presuming that SCCA1 nucleotide 1069 allele A is a recessive gene, the frequency of SCCA1 nucleotide 1069 genotype is approximating to statistically significant different between case and control groups（genotype AA vs. genotypes AG/GG, OR=1.36, 95%CI=0.93~2.00）. As presuming that SCCA1 nucleotide 1069 allele A is a dominant gene, the frequency of SCCA1 nucleotide 1069 genotype is statistically significant different between female case and control groups（genotypes AA/AG vs. genotype GG, OR=1.71, 95%CI=0.99~2.98）. The proportion of SCCA1 nucleotide 1069 genotype GG in the male adults is statistically significant less than female adults in the same status of serological HBsAg negative and anti-HBc positive（16.2% vs. 27.8%, p-value=0.036）. Furthermore, we also find that the proportion of SCCA1 nucleotide 1069 genotype GG would decrease significantly by increasing age（p-value=0.024）。
Conclusion
The comprehensive field evaluation of universal HBV vaccination program in children residing in remote rural villages, where social and economic developments lag behind and implementation of an immunization program has been known to be more difficult. Therefore, these children easier to delay receiving 1st HBV vaccine and had lower complete rate of HBV vaccination. Our data indicate that administering HBV vaccine early in life reduces the likelihood of chronic HBV infection and is more important than a higher level of anti-HBs titer which may be achieved if vaccine is administered later in the infancy. In the genetic study, by comparing different risk groups and case-control study, we proposed a hypothesis that SCCA1 nucleotide 1069 allele A/G is a semi-dominance gene. While SCCA1 has nucleotide 1069 allele A, it has normal function of HBV binding protein and can increase the rate of HBV infection. While SCCA1 nucleotide 1069 is genotype AA, SCCA1 has a high activity to inhibit cysteine proteinase and brings about hyperfunction of immunity which may be caused chronic HBsAg carrier.

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