Protective effect of hepatitis B vaccine combined with two-dose hepatitis B immunoglobulin on infants born to HBsAg-positive mothers

Background

Despite the use of hepatitis B (HB) vaccine and hepatitis B immunoglobulin (HBIG), a portion of infants are still non- or low-responders, or even immunoprophylaxis failure. We aimed to determine the immune response in the infants from the mothers being positive for hepatitis B surface antigen (HBsAg), by which the infants received three doses of HB vaccine in combination with two-dose 200 IU HBIG injections.

Methods

In this retrospective study, 621 infants from HBsAg-positive mothers in Beijing YouAn Hospital between January 2008 and December 2009 were included. All the infants were given three doses of 10 µg HB vaccine (at 0, 1 and 6 months of age) and two-dose of 200 IU HBIG (at birth and in 2 weeks of age). Serum HBsAg and antibody to HBsAg (anti-HBs) in all the infants were determined at 7 months of age.

Results

Of the 621 infants, 2.9% were immunoprophylaxis failure (positive for HBsAg), 1.4% were non-responders (anti-HBs undetectable), 95.7% were responders. The 594 responders could be categorized into three subsets, 22 were 10 to 99 IU/L for anti-HBs levels, 191 were 100 to 999 IU/L, and 381 were ≥1000 IU/L. The immunoprophylaxis failure rate was at 0% and 5.2% for the infants of HBeAg-negative and HBeAg-positive mothers(P<0.001). Infants from mothers with detectable HBV DNA had higher incidence of immunoprophylaxis failure than those of mothers without detectable HBV DNA (P = 0.002). The factors including gender, birth weight, gestation weeks, the rates of maternal HBeAg-positive, and detectable HBV DNA did not contribute to the no response to HB vaccination.

Conclusions

Through vaccination by three doses of HB and two-dose of HBIG, majority of the infants (95.7%) achieved a protective level of anti-HBs at 7 months of age. Maternal HBeAg-positive and HBV DNA detectable were associated with the immunoprophylaxis failure, but not contribute to the non- or low-response to HB vaccination.     

Patterns of circulating hepatitis B surface antigen variants among vaccinated children born to hepatitis B surface antigen carrier and non-carrier mothers

Hepatitis B virus (HBV) variants that possessed missense mutation within the neutralization epitope of the major S antigen as defined by amino acid residues (aa#) 124–147, termed the a determinant variants, were identified through a population-based serosurvey of 2,305 children of the vaccinated birth cohorts born after 1986. Data on the 678 nucleotides encoding the S antigen of HBV were available for 75 HBV strains that were collected from 63 vaccinated children and 12 unvaccinated or incompletely vaccinated children, and 21 HBV strains from 25 unvaccinated adults. Among the diverse patterns of one to three amino acid substitutions within the a determinant, 145-Arg occurred most frequently (5/14); other variants were: 126-Ala, 127-Thr, 126-Ser/131-Asn/133-Thr, 129-His, 129-Arg, 123-Asn/131-Ile, 133-Leu, 141-Glu, and 141-Arg/144-Ala. Only one of these variants occurred in the 16 hepatitis B surface antigen (HBsAg)-carrier children born to HBsAg-negative mothers, whereas 12 of these variants occurred in the 20 (50%) children born to HBsAg-positive mothers. In addition, early administration of HBV vaccine within the noenatal period increased the likelihood of the emergence of these variants to 64.7% (11/17). Five of the 21 (23.8%) unvaccinated HBsAg-carrier adults harbored the a determinant variants possessing mutations within aa# 125–136, i.e. the putative first loop formed by the cysteine disulfide bonds. Vaccinated children were likely to harbor HBV variants possessing mutations involving altered charge of side chains and/or its hydrophobicity of amino acid residues within the putative second loop between aa#140 and 146. Our data suggest that emergence of these HBV S gene mutants in the phase of HBV vaccination program would be most common among populations in whom perinatal/vertical transmission of HBV is most common, i.e. southeast Asian and the Taiwanese.     

Specific, passive prevention of hepatitis B perinatal transmission to infants born to mothers with HBs antigenemia]

The study aimed at evaluating an infectiousness of HBV-positive mothers and mothers with the acute hepatitis B to their progeny in various periods of their lives, and elaborating the effective ways of HBV infection prevention during the first two years of child life as well as evaluating HBIG in prophylaxis. It was found, that prophylaxis should be carried out in children of HBs-positive mothers independent of a routine system. An infection is usually asymptomatic in the first two years of life. It seems, that routinely used prevention methods are insufficient. Three HBIG doses should be given every 4 months. However, the best way to prevent HBV infection is passive-active immunization.     

Weight growth in infants born to mothers who smoked during pregnancy.

OBJECTIVE--To determine whether maternal smoking during pregnancy causes impairment in growth after birth. DESIGN--Longitudinal study. SETTING--Six medical university centres of six towns of north, central, and south Italy. SUBJECTS--12,987 babies (10,238 born from non-smoking mothers, 2276 from mothers smoking one to nine cigarettes a day, and 473 from mothers smoking > or = 10 cigarettes a day) entered the study. MAIN OUTCOME MEASURES--Difference in weight gain between children born to smoking mothers and those born to non-smoking mothers. Weight was measured at birth and at 3 and 6 months of age. Maternal smoking habit was derived from interview on third or fourth day after delivery. RESULTS--Compared with children born to mothers who did not smoke during pregnancy, the birth weights of children born to mothers who smoked up to nine cigarettes a day were 88 g (girls) and 107 g (boys) lower; in children born to mothers who smoked > or = 10 cigarettes a day weights were 168 g and 247 g lower. At six months of age for the first group the mean weight for girls was 9 g (95% confidence interval -47 g to 65 g) higher and for boys 64 g (-118 g to -10 g) lower than that of children born to mothers who did not smoke. The corresponding figures for the second group were 28 g (-141 g to 85 g) lower for girls and 24 g (-136 g to 88 g) lower for boys. CONCLUSIONS--The deficits of weight at birth in children born to mothers who smoked during pregnancy are overcome by 6 months of age. These deficits are probably not permanent when smoking habit during pregnancy is not associated with other unfavourable variables (such as lower socioeconomic class).     

Neonatal complications in infants born to mothers with diabetes mellitus

Health status of 53 babies delivered by diabetic mothers are discussed. Neonatal period was uncomplicated only in 12 cases. The remaining babies suffered from respiratory disorders, edema, neurological disturbances, prolonged jaundice, infections etc. Metabolic disorders in diabetic female are unfavourable for the development of pregnancy and neonate health. it may be improved by the proper diagnostico-therapeutical management prior to and during pregnancy and by intensive care of neonates after delivery. It requires, however, the establishment of health institution with highly qualified teams well equipped which will be able to carry out diagnosis and therapy of diabetes mellitus in females in the reproductive age, during pregnancy as well as proper care of the neonates.     

The prediction of thyroid function in infants born to mothers with chronic thyroiditis

To elucidate the relationship between the mother's TSH-receptor antibody activities and the status of thyroid dysfunction in their offspring, blood was taken from 5 mothers with chronic thyroiditis with potent thyrotropin (TSH)-receptor blocking activity, and the potency of TBII and TSBAb activity was assayed more quantitatively. In those mothers whose infants suffered from neonatal hypothyroidism, the 50% inhibition of binding of labeled TSH to its receptors was obtained at more than 30 to 50-fold dilution, while in those mothers whose infants had transiently increased TSH or were euthyroid, the titers were of less than 30-fold dilution. Similarly, in those mother whose infants suffered from neonatal hypothyroidism, the 50% inhibition of TSH-induced cAMP accumulation was obtained at approximately 400 to 3000-fold dilution, while in those mothers whose infants had transiently increased TSH or were euthyroid, the titers were of less than 50-fold dilution. On the other hand TBII activity was much less potent in serum from patients with Graves' disease. These results suggested that the titration of serum with dilution to obtain 50% inhibition of labelled TSH binding to its receptor may be the simplest way to predict thyroid dysfunction of the newborn infants born to mothers with chronic thyroiditis.     

Frequency of finding hepatitis B viral markers in young children born of mothers carrying the HBs-antigen

The present communication deals with the results of investigations on the frequency of HBsAg-carriership among expectant mothers in Fergana (the Uzbek SSR) and on the risk for their children to be infected with hepatitis B virus. To detect the markers of hepatitis B virus, the passive hemagglutination test, the enzyme immunoassay, and the radioimmunoassay were used. The incidence rate of HBsAg-carriership among expectant mothers was rather high (5.1 +/- 0.52%) in comparison with the control group (3.5 +/- 0.70%). The detection of HBsAg in children 3 months after their birth, i.e. at the term corresponding to the possible incubation period of hepatitis B, suggested that the children were infected at birth. As noted in the course of this investigation, the risk for a newborn to be infected was directly related to the titer of HBsAg, as well as to the presence of HBeAg, in the blood of the carrier mother. A high detection rate of HBsAg was registered among children born to HBsAg-carrier mothers, which makes it possible to consider these children as a high risk group with respect to hepatitis B virus infection and necessitates the development of the system of antiepidemic and prophylactic measures for preventing newborns to be infected with hepatitis B.     

Incidence of low birth weight infants born to mothers with multiple risk factors

Low birth weight (LBW) is associated with a large number and variety of risk conditions during pregnancy. The number and types of risk conditions per pregnancy were determined in 1,864 white and 872 black mothers delivered at the University of Kansas Medical Center between 1975 and 1978. The incidence of LBW infants increased steadily among white and black mothers as the number of risk factors increased from none to three or four per pregnancy. Among pregnancies without spontaneous premature rupture of membranes (PROM), 51 percent of the LBW infants were born to mothers who had multiple risk factors associated with their pregnancies, even though only 18 percent of these pregnancies were associated with multiple risk factors. Among pregnancies with PROM, 72 percent were associated with multiple risk conditions, and 31 percent resulted in LBW infants. About 90 percent of LBW infants from PROM pregnancies had mothers with multiple risk factors. For all numbers of risk conditions, black mothers had a higher incidence of LBW infants than white mothers. Among black mothers without spontaneous premature rupture of membranes (PROM), the incidence of LBW infants increased from 3.2 percent (10/308) in low (zero)-risk condition pregnancies to 33 percent (16/49) among mothers with three or four risk conditions during the pregnancy. Among white mothers without PROM, the incidence of LBW infants increased from 1.7 percent (12/708) in low (zero)-risk condition pregnancies to 30 percent (19/64) in pregnancies with three or four risk conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatocellular carcinoma in urban born blacks: frequency and relation to hepatitis B virus infection.

Chronic hepatitis B virus infection is far less common in urban born than in rural born southern African blacks, who also have a high incidence of hepatocellular carcinoma. A case-control study was carried out to determine the relative frequency of hepatocellular carcinoma and its relation to hepatitis B virus infection in urban born blacks. Three hundred and ninety two black patients with hepatocellular carcinoma and matched controls seen at two city hospitals were classified by questioning as urban born or rural born. The ratio of rural born to urban born blacks among the controls was 1.1:1.0 (207/185), whereas in the patients with cancer the ratio was 4.8:1.0 (324/68) (p less than 0.0001). Analysis of the prevalence of hepatitis B markers in 62 urban born and matched rural born blacks with hepatocellular carcinoma showed no differences in the frequency of current or past hepatitis B virus infection. It is concluded that urban born blacks are less likely than rural born blacks to develop hepatocellular carcinoma, but when they do the tumour is equally likely to be related to infection with hepatitis B virus. The findings lend further support to an important role for chronic hepatitis B virus infection in the aetiology of hepatocellular carcinoma.     

Transient hypothyroidism in infants born to mothers with chronic thyroiditis--a nationwide study of twenty-three cases. The Transient Hypothyroidism Study Group

To define the difference in prognosis and the clinical features of transient neonatal hypothyroidism in infants born to mothers with chronic thyroiditis, we conducted a nationwide study of this condition. Sixteen mothers with chronic thyroiditis and twenty-three of their offspring with transient hypothyroidism were registered and reported in this paper. Five (group A) of twenty-two live infants showed physical, mental and/or psychomotor developmental delay (IQ below 80). No significant difference between TSH-binding inhibitor immunoglobulin (TBII) or thyroid-stimulation blocking antibody (TSBAb) activities in groups A and B (normal development) were noted. Moreover, there was no significant difference in thyroid function in the newborn period, ages at the start of thyroid medication or the dose and duration of treatment in the two groups. A striking difference observed between the two groups was the thyroid function of their mothers during pregnancy. In group A, four mothers were hypothyroid during pregnancy, and another mother discontinued thyroid medication in the last trimester and her baby was most delayed at the start thyroid medication. On the other hand, the mothers of only two of seventeen live cases in group B had mild hypothyroidism during pregnancy. There were two sets of siblings whose mother received inadequate treatment during the first pregnancy and adequate treatment during the second pregnancy. The psychomotor, physical and mental developmental delay were observed in their first babies. These findings suggested that maternal thyroid function during pregnancy might be an important factor in the prognosis of infants born to mothers with chronic thyroiditis.     

Activation of a heterogeneous hepatitis B (HB) core and e antigen-specific CD4+ T-cell population during seroconversion to anti-HBe and anti-HBs in hepatitis B virus infection.

Overcoming hepatitis B virus infection essentially depends on the appropriate immune response of the infected host. Among the hepatitis B virus antigens, the core (HBcAg) and e (HBeAg) proteins appear highly immunogenic and induce important lymphocyte effector functions. In order to investigate the importance of HBcAg/HBeAg-specific T lymphocytes in patients with acute and chronic hepatitis B and to identify immunodominant epitopes within the HBcAg/HBeAg, CD4+ T-cell responses to hepatitis B virus-encoded HBcAg and HBcAg/HBeAg-derived peptides were studied in 49 patients with acute and 39 patients with chronic hepatitis B. The results show a frequent antigen-specific CD4+ T-cell activation during acute hepatitis B infection, a rare HBcAg/HBeAg-specific CD4+ T-cell response among HBeAg+ chronic carriers, and no response in patients with anti-HBe+ chronic hepatitis. An increasing CD4+ T-cell response to HBcAg/HBeAg coincides with loss of HBeAg and hepatitis B virus surface antigen (HBsAg). Functional analysis of peptide-specific CD4+ T-cell clones revealed a heterogeneous population with respect to lymphokine production. Epitope mapping within the HBcAg/HBeAg peptide defined amino acids (aa) 1 to 25 and aa 61 to 85, irrespective of the HLA haplotype, as the predominant CD4+ T-cell recognition sites. Other important sequences could be identified in the amino-terminal part of the protein, aa 21 to 45, aa 41 to 65, and aa 81 to 105. The immunodominant epitopes are expressed in both proteins, HBcAg and HBeAg. Our findings lead to the conclusion that activation of CD4+ T lymphocytes by HBcAg/HBeAg is a prerequisite for viral elimination, and further studies have to focus on the question of how to enhance or induce this type of T-cell response in chronic carriers. The immunodominant viral sequences identified may have relevance to synthetic vaccine design and to the use of peptide T-cell sites as immunotherapeutic agents in chronic infection.