B型肝炎疫苗防疫失敗的家族性因素

Abstract

自1984年開始實施新生兒接種B型肝炎疫苗計畫以來，台灣地區兒童之B型肝炎表面抗原陽性率、猛暴性肝炎/肝衰竭之發生率/死亡率、以及兒童肝細胞癌之發生率，均有明顯的下降。然而，B型肝炎疫苗合併免疫球蛋白的注射並不能完全防止B型肝炎病毒的傳染，仍有小於10%的表面抗原陽性，特別是e抗原也是陽性的母親所生下的嬰兒，無法經由注射疫苗（或加上免疫球蛋白）得到保護，而受到病毒的感染。防疫失敗的原因可能有：子宮內感染、表面基因突變的病毒感染、母體內高濃度的病毒以致於無法被免疫球蛋白所中和、以及接受疫苗注射者本身體質的因素而無法對疫苗產生抗體。本研究的目的是想知道：一位B型肝炎表面抗原及e抗原陽性的母親，若其先前生的一位孩子防疫失敗的話，和之前有一位孩子防疫成功的母親相比，她後來所生的孩子防疫失敗的機率是否較大﹖來藉此推測，B型肝炎疫苗防疫失敗是否有家族性的因素存在。 本研究收集在臺大醫院追蹤的B型肝炎帶原個案的家庭，以及在台大醫院出生，母親產前檢驗為B肝帶原者的家庭，選取其中至少有兩個孩子之家庭，且其母親在這兩個孩子出生時均為e抗原陽性，而這些子女在出生後均接受免疫球蛋白及疫苗注射。取得家長同意後，我們替這些孩子檢驗其B型肝炎血清學標記。此外，這些孩子的性別、年齡、其母親在生他們時的年齡、父親是否亦為B肝帶原者、出生方式為自然生產或剖腹生產等，也會一併分析。 本研究一共找到98個家庭，每個家庭至少有兩個孩子符合上述的收案標準。若一個家庭有不只兩個孩子符合標準，只取其中較大的兩名分析。在這98個家庭中，有9個家庭是兩個孩子都防疫失敗，有28個家庭是只有兩個孩子中的較大者防疫失敗，15個家庭是只有兩個孩子中的較小者防疫失敗，另外有46個家庭中的兩個孩子都防疫成功。在所有家庭中，兩個孩子中的較大者防疫失敗的機率（37/98, 37.8%），比兩個孩子中的較小者防疫失敗的機率（24/98, 24.5%）來得高（p = 0.0474）。至於在兩個孩子中的較大者防疫失敗的家庭中，較小的孩子也防疫失敗的機率（9/37, 24.3%），和在兩個孩子中的較大者防疫成功的家庭中，較小的孩子防疫失敗的機率（15/61, 24.6%），此兩者並沒有顯著的差別（p = 0.976）。 比較有孩子是疫苗失敗者的家庭（N=52）和完全沒有孩子是疫苗失敗者的家庭（N=46），我們發現，有孩子是疫苗失敗者的家庭，其母親在生產時的年齡明顯的比完全沒有孩子是疫苗失敗者的母親輕（p < 0.05）。 本研究也報告了另外八名防疫失敗者，其母親在生產前的e抗原檢測為陰性，這八名個案出生時沒有注射免疫球蛋白，但都有接受疫苗注射。調查這些人的兄弟姊妹的疫苗接種史及B肝血清學標記後，我們發現，可能這些人出生時，其母親正處在e抗原陰轉的過渡時期，其體內的病毒濃度還沒降低，這時候生的孩子沒有接受免疫球蛋白的注射，結果就受到感染。 總結來說，本研究的初步結果顯示，e抗原陽性的母親，若其先前有孩子防疫失敗，和先前有孩子防疫成功的母親相比，其後來生的孩子防疫失敗的機率，並無差別。不過，本研究已發現，在e抗原陽性母親的孩子中，排行在前的孩子比較可能防疫失敗；且有孩子是防疫失敗者的母親，其年齡比沒有孩子防疫失敗的母親明顯較輕。可能的原因是：母親的年紀較輕、其體內病毒濃度較高、孩子受感染的機會較大。

Since the nationwide hepatitis B vaccination program was launched in 1984, the seropositive rate of hepatitis surface antigen (HBsAg), the incidence/mortality rate of fulminant hepatitis and the incidence rate of hepatocellular carcinoma in Taiwanese children have declined significantly. However, active/passive immunoprophylaxis against hepatitis B virus (HBV) can not eradicate transmission completely. Less than 10% infants born to HBsAg positive mothers, especially e antigen (HBeAg) positive ones, will still be infected and become victims of chronic hepatitis B. Possible causes of immunoprophylaxis failure (IF) include: intrauterine infection, surface gene mutant HBV infection, high level of maternal viremia and the host factors that lead to non-response to the vaccine. The aim of the study is to compare the IF rate of the younger child of HBeAg positive mothers, whose elder child is a case of IF, to that of other HBeAg positive mothers, whose elder child is not a case of IF, to see if there is any familial cause of failed immunoprophylaxis. HBsAg positive mothers with more than one child were enrolled from mothers of HBV carrier children followed-up in our hospital and women delivered in our hospital. The mothers were HBeAg positive when the children were born. Those children who did not receive hepatitis B immunoglobulin (HBIG), or did not receive HBIG within 24 hrs after birth, or did not complete hepatitis B vaccine injection, were excluded. If more than two children in the same family fulfilled the criteria, only the first two were recruited. The HBsAg status, age, sex, delivery mode, maternal age at delivery, and paternal HBsAg status of these children were analyzed. A total of 98 families were collected. In 9 of the 98 families, both children were cases of IF. In 28 families, only the elder one was HBsAg positive. In 15, only the younger one was HBsAg positive, and in 46, both were HBsAg negative. The IF rate of the elder child (37/98, 37.8%) was significantly higher than that of the younger one (24/98, 24.5%) (p = 0.0474). However, the IF rate of the younger child in the families with an elder child who was a case of IF (9/37, 24.3%), did not differ from that in the families with an elder child who was a not case of IF (15/61, 24.6%) (p = 0.976). In addition, the maternal age at delivery was significantly younger in those families (N=52) with children infected by HBV than that in the families (N=46) without children infected by HBV (p < 0.05). We also reported other 8 cases of IF. Their mothers were HBeAg negative at delivery and there 8 cases received HBV vaccines but no HBIG. More than half of them have siblings born within 3 years of their births and the mothers were HBeAg positive when the siblings were born. It is possible that these 8 cases were born at the HBeAg seroconversion stage of their mothers and the maternal HBV DNA amount was still high although the maternal HBeAg was negative. In conclusion, our present result did not find differences between the IF rates of the younger child in the families with an elder child who was a case of IF and that in the families with an elder child who was a not case of IF. Our present finding indicated that the IF rate was higher in the older children than in the younger ones of HBeAg positive mothers. A younger maternal age at delivery was also noted in those families with children infected by HBV than that in the families without children infected by HBV. A younger maternal age at delivery may be associated with a heavier viral load and then result in failed immunoprophylaxis.