Immunization against hepatitis A in the first year of life: priming despite the presence of maternal antibody

BACKGROUND: Maternal antibodies interfere with hepatitis A vaccination in young infants. We examined the response to a high dose hepatitis A vaccine administered concomitantly with a combination of diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine to initially seropositive vs. initially seronegative infants. METHODS: Three hundred subjects were originally planned to be enrolled at age 6 to 10 weeks and received hepatitis A vaccine (formalin-inactivated vaccine, SB-Bio, 720 enzyme-linked immunosorbent assay units) at 2, 4 and 6 months concomitantly with a diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus vaccine/H. influenzae type b vaccine. Children initially seropositive received a booster dose at 12 months of age. An additional 100 twelve-month-old infants previously not vaccinated with hepatitis A vaccine were given 1 dose, to observe the primary response at that age. Reactogenicity was recorded on diary cards for the 3 subsequent days. Immunogenicity was measured at Months 2, 4, 5, 10 and 11 after administration of the first vaccine dose. For the subjects enrolled at 12 months, blood was drawn before and 1 month after the first vaccination. RESULTS: Of 297 initially enrolled infants 36% were seronegative before vaccination (Group A). The geometric mean concentration (GMC) (milli-International Units/ml) of the seropositive infants (Group B) before immunization was 2587. The GMCs of Group A infants 1 month after each dose and at 12 months of age were 93, 518, 1656 and 786, respectively. For Group B infants, the respective GMCs were 1165, 460, 508 and 167. One hundred subjects of Group B received a booster dose at age 12 months; at Month 13 all were seropositive with a GMC of 1902. For comparison, a third group of 100 not previously immunized 12-month-old infants (Group C) were enrolled and received 1 dose of hepatitis A vaccine with pre- and postimmunization GMCs of 52 and 120, respectively. CONCLUSIONS: Our results suggest that the initially seropositive infants were primed despite maternal antibody interference. The hepatitis A vaccine was well-tolerated in this population of young infants.     

Mother-to-infant transmission of hepatitis C virus

Anti-hepatitis C virus (HCV) antibodies and HCV-RNA were measured in the sera of 22 anti-HCV positive, HIV-1 negative mothers and their infants. ELISA and RIBA II were used for anti-HCV determination. HCV-RNA was measured by a nested polymerase chain reaction. HCV-RNA was found in 12 of 22 mothers. All 22 children were followed for 12 months. All were anti-HCV positive by the fourth month; 18 became anti-HCV negative between the 8th and 12th month. HCV-RNA was detected in 5 of 22 infants in the fourth month. They remained HCV-RNA positive. All children born to HCV-RNA negative mothers were HCV-RNA negative while 5 of 12 babies born to HCV-RNA positive mothers were infected. All five infected babies were born to mothers infected through transfusions or drug use. ALT levels in mothers seemed to have no effect on mother-to-infant transmission. Hence evidence for perinatal transmission of HCV from HCV-RNA positive mothers was demonstrated in the present study.     

Hepatitis C virus infection and related liver disease in children of mothers with antibodies to the virus

Objective: To evaluate the clinical, biochemical, and virologic features associated with hepatitis C virus (HCV) infection acquired early in life from mothers with antibodies to HCV (anti-HCV).Study design: Multicenter prospective-retrospective study in Italian children.Patients: Two groups of children were investigated. Group 1 included 14 infants, born to mothers with anti-HCV but without human immunodeficiency virus infection, who became seropositive for HCV RNA during the first year of life and were thus considered infected. Group 2 included 16 children with chronic hepatitis C, aged 1 ½ to 14 years, whose mothers were the unique potential source of infection. Both groups were followed for 12 to 48 months.Methods: Alanine transaminase (ALT), anti-HCV, and HCV RNA were investigated by the polymerase chain reaction on entry to the study and during follow-up.Results: All children in group 1 had anti-HCV throughout follow-up, and all had ALT abnormalities, ranging from 1.5 to 10.5 times the normal value during the first 12 months. During further follow-up, 5 of 10 children had HCV RNA with abnormal ALT values, 3 had a return to normal of the ALT values but continued to have viremia, and 2 eventually had normal ALT values and clearance of HCV RNA. Of the 16 children in group 2, all were free of symptoms and 62% had only slight ALT elevations; 7 who underwent liver biopsy had histologic features of minimal or moderate hepatitis.Conclusions: HCV infection acquired early in life from mothers with anti-HCV is usually associated with biochemical features of liver damage during the first 12 months of life. Progression to chronicity seems to occur in the majority of cases, although HCV-associated liver disease is likely to be mild throughout infancy and childhood. (J Pediatr 1997;130:990-3)     

Mother-to-infant transmission of hepatitis C virus: A prospective study

To investigate the risk of mother-to-infant transmission of hepatitis C virus (HCV) and the natural course of HCV-infected infants, we prospectively studied 31 offspring of pregnant women who were anti-HCV positive and anti-HIV negative. Sera were serially tested for anti-HCV by the second-generation ELISA-test (ELISA-2) and for HCV-RNA by the polymerase chain reaction procedure. The mean period of follow up was 19 months (range 6–41 months). The presence of HCV-RNA in the mothers was associated with a high titre of anti-HCV by ELISA-2 or a positivity of the second generation recombinant immunoblot assay. At birth, 26 babies were positive for anti-HCV. Passively transferred maternal antibodies became undetectable within 2–15 months. HCV-RNA was detected in only 3 infants (9.7%) within 1–4 weeks after birth and persisted there-after. The genotype of HCV-RNA in each of the infants was consistent with that of their mother. These 3 showed chronic transaminase elevation during the follow up that started at 1–2 months of age, although they revealed no clinical symptoms. Re-elevation of anti-HCV titre was observed in the HCV-infected infants within 10 months of age, suggesting an endogenous production of anti-HCV. The mean titre of HCV-RNA in three mothers of infected infants was higher than that in the mothers of uninfected infants (10^5.3±0.3 vs 10^4.4±0.2/ml).Conclusion Our findings indicate that HCV was most likely to have been transmitted from mothers to infants at the time of delivery and that it was capable of evoking the chronic carrier state.     

Cognitive and motor development in infants at risk for human immunodeficiency virus.

To evaluate the natural course of cognitive and motor development among infants infected with human immunodeficiency virus from birth, the Bayley Scales of Infant Development were administered to 96 infants between 5.5 and 24 months of age. Infants were divided into three groups on the basis of subsequent assessment of human immunodeficiency virus serologic status: seronegative (N = 45), seropositive (N = 12), and seroreverter (N = 39). Groups did not differ in race, infant age at initial testing, maternal age, maternal education level, maternal history of intravenous drug abuse, or percentage of children in foster care placement. Significant group differences were found on the Mental Development Index and Psychomotor Development Index, with the seropositive infants scoring significantly lower than the seronegative or seroreverter infants.     

Antibody response to hepatitis A immunization among human immunodeficiency virus-infected children and adolescents

Seventy-one of 84 human immunodeficiency virus (HIV)-infected children [84.5% (95% confidence interval: 75-91.5%)] were hepatitis A virus (HAV) seropositive after 2 doses of HAV vaccine. Higher CD4% and HIV suppression were significantly associated with increased HAV seropositivity rate. In multivariate analysis, CD4 >or=25% and young age were independent predictors of HAV seropositivity. Of 7 children given a third HAV vaccine dose because of negative HAV antibody after 2 doses, 2 (29%) became seropositive.     

Immunogenicity of an inactivated hepatitis A vaccine in infants and young children

BACKGROUND: Infants with passively transferred maternal antibody, born to mothers immune to hepatitis A virus (HAV), have a blunted response to hepatitis A (HA) vaccine. We compared HA vaccine immunogenicity among infants born to immune and susceptible mothers, vaccinated on different schedules. METHODS: Infants were randomized into 3 groups, each receiving 2 doses of 720 EL.U. of HA vaccine (HAVRIX; Glaxo SmithKline): group 1 at ages 6 and 12 months, group 2 at ages 12 and 18 months and group 3 at ages 15 and 21 months. We determined mothers' antibody to HAV (anti-HAV) status and infants' anti-HAV concentrations at the first vaccine dose (baseline) and at 1, 7 and 12 months thereafter. All were tested at age 13 months for responses to recommended routine vaccinations administered during infancy. RESULTS: Of 248 participants, 140 were born to HA-susceptible mothers and 108 to immune mothers. At baseline, 34 of 36 (94%) group 1, 5 of 34 (15%) group 2 and one of 38 (3%) group 3 infants born to immune mothers were seropositive. By month 7, all participants in all groups were seropositive except group 1 infants born to immune mothers (34 of 36 [94%], seropositive). In group 1, peak geometric mean concentrations between infants born to immune (794 mIU/mL) and susceptible (2083 mIU/mL) mothers were significantly different. Across groups, peak geometric mean concentrations were similar among infants born to susceptible mothers (3166 mIU/mL, group 2; 3153 mIU/mL, group 3). Among infants born to immune mothers, the difference between groups 1 and 3 (2715 mIU/mL) was significant. There were no differences in responses to routine vaccinations. CONCLUSIONS: HA vaccine is immunogenic among infants born to HA-susceptible mothers and those born to immune mothers and vaccinated beginning > or =12 months old. Passively transferred maternal antibody persists for at least 6 months and results in a blunted response to HA vaccination.     

Impact of revaccinating children who initially received measles vaccine before 10 months of age

Two hundred fifty-four infants who had received measles vaccine at less than 10 months of age were revaccinated at greater than or equal to 15 months of age, and their immune responses were compared with 129 control infants who received their first doses of measles vaccine at greater than or equal to 15 months of age. Sera were collected at the time of revaccination (study infants) or primary vaccination (control infants), 3 weeks, and 8 months later and tested for antibody by hemagglutination inhibition (HI), enzyme-linked immunosorbent assay (ELISA), and cytopathic effect neutralization (CPEN). Of the 121 study infants who were initially HI negative, 116 (95.9%) made HI antibody 3 weeks postrevaccination compared with 126 (99.2%) of 127 control infants (P = 0.19). Of the 63 study infants with no initial detectable antibody by any of the three tests, 14 (22.2%) had a measles-specific IgM response 3 weeks postrevaccination compared with 37 of 50 (74.0%) randomly chosen control infants. By 8 months after revaccination, the 121 initially HI-negative study infants were significantly less likely to have detectable HI antibodies than control infants (52.1% v 97.6%) (P less than .001). However, 96.7% of these 121 study infants had detectable neutralizing antibody 8 months postrevaccination, an antibody thought to correlate best with protection. This study confirms the altered immune response to revaccination in infants first vaccinated prior to 10 months of age; however, the data suggest that most of these infants were successfully primed and are probably protected after revaccination.     

Seroprevalence of hepatitis B, hepatitis C and human immunodeficiency virus antibodies among multitransfused thalassaemic children in Shiraz, Iran

OBJECTIVE: To evaluate the rate of seropositivity to hepatitis B and C and human immunodeficiency virus (HIV) infections among children with beta-thalassaemia major receiving multiple transfusions in Shiraz, Iran, compared with healthy controls. METHODOLOGY: The study was performed during 1999-2000 on multitransfused children with beta-thalassaemia major registered by the Shiraz Thalassaemia Society. Hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibodies (Ab) and HIV Ab were checked using a second-generation enzyme-linked immunosorbent assay (ELISA). Positive tests were confirmed by western blots. Healthy blood donors were used for the control group. RESULTS: Hepatitis B surface antigen, anti-HCV Ab and HIV Ab were positive in four of 755 (0.53%, 95% confidence interval (CI)=0.17-1.3), 73 of 466 (15.7%; 95% CI=12.6-19.2) and none of 466 patients tested, respectively. Positive sera for HBsAg, anti-HCV Ab and HIV Ab were found in 85 (1.07%), 47 (0.59%) and 27 (0.34%) of 7879 control children, respectively. The rate of anti-HCV Ab was significantly higher in patients than in the control group (P < 0.0001). In patients, the rate of positive anti-HCV Ab was significantly higher than the rate for positive HBsAg (P < 0.0001). CONCLUSION: It is concluded that HCV is the current major problem in multitransfused children with thalassaemia major and more careful pretransfusion screening of blood for anti-HCV must be introduced in our blood banks.     

Role of hepatitis B immunoglobulin in infants born to hepatitis B e antigen-negative carrier mothers in Taiwan

BACKGROUND: The efficacy of hepatitis B immunoglobulin (HBIG) in infants of hepatitis B e antigen (HBeAg)-negative hepatitis B surface antigen (HBsAg) carrier mothers in Taiwan is not clear. OBJECTIVE: To describe the responses of infants born to HBeAg-negative carrier mothers receiving HBIG combined with hepatitis B vaccine. METHODS: Term babies born to HBeAg-negative carrier mothers were assigned based on chart number to 1 of the 2 treatment groups. Group A infants (n = 94) received 0.5 ml (145 IU) of HBIG within 24 h of birth and 3 subsequent doses of recombinant hepatitis B virus (HBV) vaccine at 3 to 5 days, 1 month and 6 months of age. Group B infants (n = 122) received 3 doses of vaccines only. Infants (n = 19) born to HBeAg-positive carrier mothers were treated like those in Group A and are referred to as Group C. Sera obtained from infants at 2 and 7 months of age were tested for hepatitis B virus (HBV) markers. RESULTS: There were 2 (1%; one in Group A and one in Group B) subclinical breakthrough hepatitis B infections among studied infants. One (5%) child of Group C had asymptomatic HBV infection at the age of 7 months and became a chronic carrier. The rate of protective anti-hepatitis B surface antibody (anti-HBs) titers achieved (>10 mIU/ml) by 2 months of age was significantly higher in Group A than that in Group B (98% vs. 57%, P < 0.001). However, it was not different by 7 months of age. Infants (Group A) immunized with HBIG and vaccine had a significantly higher geometric mean titer (GMT, milli-International Units/ml) of anti-HBs than those (Group B) with vaccines only at 2 months of age (P < 0.001). Conversely at 7 months of age, the GMT of anti-HBs was significantly higher in infants who received vaccine only (P = 0.001). CONCLUSIONS: A protective level of antibodies was achieved earlier in those infants receiving both passive and active immunizations. However, infants receiving active immunizations alone achieved a higher GMT at 7 months of age. There was no clear benefit of passive-active vs.active immunization alone for chronic HBV infection in infants of HBsAg-positive, HBeAg-negative mothers.     

Mother-to-Infant transmission of hepatitis C virus (HCV) in Brazil

Sixty-one women with anti-HCV antibodies, detected by a third-generation enzyme immunoassay (EIA3), were prospectively recruited for investigation of vertical HCV transmission during child-birth, at the University Hospital of the Catholic University of Campinas, Brazil, between January 1994 and July 1998. Six of the women presented coinfection with the human immunodeficiency virus type 1 (HIV-1). All of the 72 children born in this period were followed at least until they were 18 months of age. Analyses of anti-HCV, HCV RNA, and alanine aminotransferase were performed in a minimum of two blood samples during follow-up. One (2.4 per cent; 95 per cent CI, 2.2-7) of the 42 children born to HCV viremic mothers was both anti-HCV and HCV RNA-positive, with altered ALT levels. Passively transferred maternal anti-HCV antibodies became undetectable within 9-12 months. None of the nine infants born to HIV-1 infected mothers were infected either by HIV or HCV. Thus, the mother-infant HCV transmission rate is low and seems to be associated with maternal HCV RNA positivity.     

Prospective study of mother-to-infant transmission of hepatitis C virus

BACKGROUND: Mother-to-infant transmission of hepatitis C virus (HCV) could become the main route of HCV infection in the future because there are no methods available to prevent vertical infection. The aim of this study was to determine the incidence of mother-to-infant transmission in infants born to mothers who tested positive for anti-HCV antibodies and to elucidate associated risk factors for transmission. METHODS: Screening was conducted for 16,800 pregnant women with an anti-HCV antibodies test, and 154 mothers were positive. From the positive group 141 mothers were enrolled in the study and their 147 infants were followed from birth for serum alanine aminotransferase activity, anti-HCV antibodies and HCV RNA. HIV infection was tested in 73 of 141 mothers, all of whom were negative. RESULTS: Thirty-three infants were dropped from the study because they were followed for <6 months or were not tested adequately. Of the 114 infants finally evaluated 9 (7.8%) had detectable HCV RNA. The transmission rate was not influenced by the mode of delivery [vaginal delivery, 8 of 90 vs. cesarean section, 1 of 24 (P = 0.396)] or by the type of feeding [9 of 98 for breast-fed infants vs. 0 of 16 for formula-fed infants (P = 0.243)]. All infected infants were born to mothers who had HCV viremia at the delivery (P = 0.040) and to those with a high viral load (P = 0.019). CONCLUSIONS: Our prospective study showed that the transmission rate of mother-to-infant HCV infection was 7.8% in anti-HCV antibody-positive mothers. Risk was related to the presence of maternal HCV viremia at delivery and a high viral load in the mothers.     

Kinetics of maternal hepatitis a antibody decay in infants: implications for vaccine use

We conducted a seroepidemiologic study to evaluate the kinetics of maternal hepatitis A antibody decay in infants. Serum samples obtained from 200 infants at 2 and 4 months of age were tested for hepatitis A antibody. Seventy-six infants (38%) were hepatitis A antibody-positive with a geometric mean antibody titer of 2634 mIU/ml. Samples collected at 4, 6 and/or 12 months of age showed seropositivity rates of 100, 95 and 39%, respectively. These data indicate that maternal antibody levels remained high through the first 6 months of life but decayed significantly by 12 months of age.     

Effect of maternal antibody on immunogenicity of hepatitis A vaccine in infants

OBJECTIVE: To determine the effect of maternal antibody on hepatitis A vaccine immunogenicity in infants.Study design Infants of mothers negative for antibody to hepatitis A virus (anti-HAV; group 1) were administered hepatitis A vaccine at 2, 4, and 6 months of age, and infants of anti-HAV-positive mothers were randomized to receive either hepatitis A vaccine (group 2) or hepatitis B vaccine (group 3) on the same schedule. Group 3 infants subsequently received hepatitis A vaccine at 8 and 10 months of age. RESULTS: At 15 months of age, 100% of infants in group 1, 93% in group 2, and 92% in group 3 had protective levels of antibody. However, there were significant differences in the geometric mean concentration (GMC) of anti-HAV between groups. Group 1 GMC was 231 mIU/mL, compared with 85 mIU/mL for group 2 and 84 mIU/mL for group 3 (P<.001, group 1 vs group 3). CONCLUSIONS: Passively acquired maternal anti-HAV resulted in a significantly lower final antibody response when infants were administered hepatitis A vaccine at 2, 4, and 6 months of age or at 8 and 10 months of age.     

Risks of seroconversion of hepatitis B, hepatitis C and human immunodeficiency viruses in children with multitransfused thalassaemia major

OBJECTIVES: To estimate the risks of seroconversion of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency viruses (HIV) in children with multitransfused thalassaemia at a thalassaemic clinic in Kuala Lumpur, Malaysia. METHODS: Seventy-two children (39 males, median age 11.3 years, 2.5th-97.5th centile: 1.4-19.2 years) with thalassaemia major were studied. The risks of seroconversion of HBV, HCV and HIV were estimated by comparing the seroprevalences of hepatitis B surface antigen (HBsAg), anti-HCV and anti-HIV between a defined starting point and an end point. The end point was the point when latest serological results were available while the starting point was when regular transfusion was commenced, or approximately 5 years before the end point when the duration of transfusion was longer. RESULTS: The median duration of the study was 49 months (range 8-69 months, total 2953 patient-months). There were 2605 transfusion episodes and 4154 units of blood transfused (0.88 transfusion episode/patient per month, 1.41 units of blood transfused/patient per month). There were three new seroconversions for anti-HCV but none for HBsAg and anti-HIV. The risk of seroconversion for HCV was one in 1384 units of blood transfused (95% CI: 4000-472). The seroprevalence rates at the starting and end points were: HBsAg (1%, 1%), anti-HCV (10%, 13%) and anti-HIV (0%, 0%), respectively. CONCLUSIONS: The estimated risk of acquiring HCV infection in children receiving multiple blood transfusions in this study is surprisingly higher than the generally accepted estimated risk. Other routes of transmission may be important. A prospective, multicentre study to estimate such risks more precisely is needed.     

Immunogenicity of hepatitis B vaccine in term and preterm infants

Some studies have suggested that decreased seroconversion rates might be found in premature infants with low birthweight (< 2000 g) following administration of hepatitis B vaccine at birth. The aim of the present investigation was to evaluate possible differences in seropositive rates between full-term and preterm infants after primary vaccination, in particular when gestational age or birthweight is very low. Two-thousand and nine neonates born to HBs Ag-negative mothers were vaccinated with 10 μg of recombinant hepatitis B virus (HBV) vaccine, from May 1991 to October 1994. Children with infections, congenital malformations or serious illnesses were excluded. HBV vaccine was administered intramuscularly, on the fourth day of life and again at 1 and 6 months of age. A 1-ml blood sample was drawn from each infant 1 month after the third vaccine dose for determination of the level of anti-HBs antibody. The response to HBV vaccination was evaluated in 241 preterm (gestational age < 38 weeks) infants and 1727 term neonates. No statistical difference was observed in the distribution of anti-HBs antibody level, either between preterm infants (< 38 weeks) and newborns of normal gestational age, or between low birthweight (< 2500 g) and normal weight infants. The results suggest that preterm and low birthweight infants (< 2500 g) respond to HBV vaccine in the same measure as normal-term infants.     

Measles antibody levels in 3 to 9 months old infants

Measles HI antibody titre was estimated in 248 infants aged 3 to 9 months. A total of 129 (52.02%) infants were seropositive (HI antibody titre more than 1:8). Geometric mean titre (GMT) and percentage of seropositive infants decreased with age and was minimum i.e., 5.52 and 22.22% respectively at the age of 7 months. After the age of 7 months the GMT and percentage of seropositive infants increased indicating that optimum age-of measles immunization in the area studied is around 7 months. Percentage of seropositivity did not differ significantly in relation to sex, socio-economic status and national status of infant.     

Post-transfusion chronic hepatitis C in children

Two hundred and twenty-six patients who received blood products for open-heart surgery in childhood were screened by a second-generation enzyme-linked immunosorbent assay and with surrogate markers for hepatitis C virus (HCV) infection, such as alanine aminotransferase (ALT). Twenty-two (14%) of the 161 recipients who received blood products before 1989 and none of the subjects who had received blood products after 1990 (the year that the blood bank began to screen for HCV antibody) were HCV seropositive. Virologic and histologic studies showed that 10 (45%) of 24 seropositive patients had persistent hepatitis C virus infection, many with ongoing hepatitis. The remaining 12 seropositive patients with absent HCV RNA had normal ALT levels, indicating resolved hepatitis C infection. Enrolment in screening is important to detect chronic hepatitis C in children who received blood products prior to screening of blood donors for HCV antibody.     

Sequelae of maternally derived cytomegalovirus infections in premature infants

Eighteen of 106 (17%) infants of seropositive mothers, with birth weights less than 1500 gm, acquired cytomegalovirus from a maternal source. Neutropenia, lymphocytosis, thrombocytopenia, and hepatosplenomegaly developed in some infants concomitant with the onset of CMV excretion. Infected infants who excreted CMV at less than 7 weeks of age had longer oxygen requirements than infants who did not excrete CMV until they were older. Passively derived maternal antibody to CMV fell more rapidly over the first few months of life in sick premature infants than would be expected in term infants. Among six infected premature infants, five had undetectable antibody titers when CMV excretion began. Loss of passively acquired antibody and early excretion of virus appear to be associated with symptomatic CMV infections in premature infants of seropositive mothers.     

Fulminant hepatitis in children in Taiwan: the important role of hepatitis B virus

In a recent period of 64 months, fulminant hepatitis was diagnosed in 17 children at National Taiwan University Hospital. Eleven patients were younger than 12 months of age. Hepatitis A IgM antibody and delta-antibody were negative in all 17. Eleven (65%) patients had hepatitis B core IgM antibody, fulminant hepatitis B. Two to 5 months before onset of hepatitis. Five of the 11 children had received blood transfusions. Three of the five donors had hepatitis B e antibody (anti-HBe) and were hepatitis B virus DNA-negative hepatitis B surface antigen (HBsAg) carriers; another two were HBsAg negative, screened by a less sensitive reverse passive hemagglutination method. The mothers of all six infants younger than 6 months of age had HBsAg. HBe antigen and antibody were studied in five of these six mothers; all five had anti-HBe. We conclude that hepatitis B virus is the most important cause of fulminant hepatitis in children in Taiwan.