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Annals of Internal Medicine | 2001

Hepatitis B Virus Infection in Children and Adolescents in a Hyperendemic Area: 15 Years after Mass Hepatitis B Vaccination

Yen-Hsuan Ni; Mei-Hwei Chang; Li-Min Huang; Huey-Ling Chen; Hong-Yuan Hsu; Tai-Yuan Chiu; Keh-Sung Tsai; Ding-Shinn Chen

Hepatitis B virus (HBV) infection is an important cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma in many parts of the world, including Taiwan (1, 2). Up to 15% to 20% of the general population in Taiwan are chronic carriers of hepatitis B surface antigen (HBsAg) (3, 4). Most chronic carriage of HBV results from infection in early childhood, especially before 2 years of age (57). Taiwan launched the worlds first nationwide universal vaccination program in 1984 to prevent infection in the early years of life (8). In addition to decreasing the proportion of carriers and the prevalence of HBV infection in the current young generation (9), the universal vaccination program has also resulted in a decreased incidence of childhood hepatocellular carcinoma (10). To study the effect of this universal vaccination program, we conducted a series of prospective seroepidemiologic surveys in Chung-Cheng District, Taipei City, Taiwan. The first survey was conducted shortly before the mass vaccination program began in 1984 (6), followed by similar surveys in 1989 (11) and 1994 (12). We report findings that extend our follow-up observations to 199915 years after the start of the program. Methods National Vaccination Program The national program of universal HBV vaccination in Taiwan began on 1 July 1984 (8). At that time, only the newborn infants of mothers who were HBsAg carriers were vaccinated. The vaccination program was extended in June 1987 to include all newborn infants and in July 1987 to cover all children of preschool age. The program was further extended to school children, teenagers, and then adults from 1988 to 1990. Since 1991, the vaccination records of first-grade children have been checked, and children without a complete set of previous vaccinations have been given catch-up HBV vaccinations. Before July 1992, four doses of plasma-derived vaccine were administered in children before 1 week of age and again at 1, 2, and 12 months of age; after July 1992, three doses of recombinant (yeast-derived) vaccine were administered before 1 week and at 1 month and 6 months of age. Since 1984, newborns whose mothers test positive for hepatitis B e antigen (HBeAg) have also received hepatitis B immunoglobulin, 0.5 mL (100 IU), within 24 hours after birth. The vaccination program has been described in greater detail elsewhere (8, 12). We defined the vaccination coverage rate as the percentage of children receiving at least three doses of HBV vaccine. We assessed the vaccination histories of the studied population by examining their vaccination cards and by taking a history from their parents. We classified the vaccination status as unknown for persons with a missing vaccination card or a vague vaccination history. Participants From March 1999 to October 1999, serum samples were collected from 1916 children and adolescents from two groups: 1) 1357 apparently healthy persons younger than 15 years of age [721 male participants and 636 female participants], who were born after the launch of the universal vaccination program, and 2) 559 persons (297 male participants and 262 female participants) 15 to 20 years of age, who were born before universal vaccination. We recruited participants for the baseline and follow-up seroepidemiologic studies in Chung-Cheng District, Taipei City. In 1999, Chung-Cheng had a population of 165 388 citizens; 35 005 of the citizens were younger than 15 years of age, and 47 565 were younger than 20 years of age. From 1994 to 1999, the population was stable, with an average annual migration rate of less than 4.8%. The annual family income,


Vaccine | 2001

Recommendations are needed for adolescent and adult pertussis immunisation: rationale and strategies for consideration

Magda Campins-Marti; H.K. Cheng; Kevin Forsyth; Nicole Guiso; Scott A. Halperin; Li-Min Huang; Jussi Mertsola; Gabriel Wolf Oselka; Joel I. Ward; C.H. Wirsing von König; Fred Zepp

39 963 (in U.S. dollars), was the third highest among the 12 districts in Taipei (13). From 1985 through 1990, the HBsAg carrier rate among pregnant women14% (14)was similar to the national average (3, 4). The 1916 participants in our 1999 study consisted of 1) 157 children younger than 3 years of age enrolled from the Well-Baby Clinic of the National Taiwan University Hospital Department of Pediatrics and from two day care centers; 2) 232 children 3 to 6 years of age recruited from two kindergarten classes; 3) 763 children 7 to 12 years of age enrolled from one public elementary school; 4) 205 children and adolescents 12 to 15 years of age enrolled from one public junior high school; 5) 219 adolescents 15 to 18 years of age enrolled from one high school; and 6) 340 first-year undergraduate students at the National Taiwan University, 19 to 20 years of age. We recruited the child and adolescent participants through poster advertisements and by invitation from the health staff of the Department of Pediatrics, National Taiwan University Hospital. The university student participants and the parents of enrolled children gave written, informed consent and provided the vaccination history of the participant, according to his or her personal health booklet. (The booklet, which is used to record a persons vaccination history, is provided to the parents of all newborns by the Health Bureau of City Hall.) Serologic and Statistical Analyses We analyzed serum samples for HBsAg, HBsAg antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) by using enzyme immunoassay (Abbott Laboratories, North Chicago, Illinois). We examined between-group differences in frequency by using the chi-square test with Yates correction or the Fisher exact test, where appropriate. A P value less than 0.05 was considered significant. Data analyses were performed by using GraphPad Prism, version 3.00 (GraphPad Software, Inc., San Diego, California). Role of the Funding Source The funding source had no role in the collection, analysis, and interpretation of the data or in the decision to submit the paper for publication. Results In 1999, the vaccination coverage rate was greater than 90% among children younger than 8 years of age and 80% to 86% among children 8 to 15 years of age (Table). These figures might be underestimates because some of the participants, particularly in the older age group, had missing vaccination cards; in other cases (for 23 of the 541 children younger than 8 years of age and 63 of the 766 participants 8 to 15 years of age), the parents could not recall the vaccination history. Infants had a lower coverage rate than other age groups because some of them had not yet finished their vaccination schedule (Appendix Table). Table. Seroprevalence of Hepatitis B Surface Antigen and Its Antibody in Chung-Cheng District, Taipei City, Taiwan, in 1984, 1989, 1994, and 1999 The prevalence of HBsAg in children younger than 15 years of age, 0.7% (9 of 1357), was considerably lower than the rate of 7% (39 of 559) observed in participants older than 15 years of age, who were born before the universal vaccination program (P < 0.001). Of the 9 children who were born after the vaccination program was instituted and tested positive for HBsAg, only 1 had not received the scheduled vaccinations, and the mother of this child was also HBsAg positive. According to their vaccination cards, the 8 other participants had received at least three doses of the HBV vaccine, and the first dose had been given within 1 week of birth. Seven of these 8 participants had mothers who were HBsAg carriers, and the remaining participant was living with two grandparents who were HBsAg positive. All 9 participants tested positive for anti-HBc. Eight of these 9 HBsAg carriers had received the plasma-derived vaccine, and 1 had received the yeast-derived recombinant vaccine; however, type of vaccine did not affect the rate of HBsAg seropositivity (8 of 968 persons who received the plasma-derived vaccine were carriers vs. 1 of 389 who received the yeast-derived vaccine; P > 0.2, Fisher exact test). The overall prevalence of anti-HBs in persons younger than 15 years of age in 1999 was 75.8%. We observed the highest prevalence of anti-HBs in children younger than 5 years of age (Table). The longitudinal perspective of HBsAg carriers in cohorts 0 to 1 years of age is shown in the Figure. Figure. Longitudinal perspective of the proportion of hepatitis B surface antigen carriers among the cohorts of 0 to 1 year of age in 1984 (circles) and 1989 (squares) in Chung-Cheng District, Taipei City, Taiwan. Children in the 1984 0- to 1-year age cohort, who were born before universal vaccination in Taiwan, had a carrier rate of 5.1% in 1984, 3.9% in 1989 (at age 5 to 6 years), 4.7% in 1994 (at age 10 to 11 years), and 7.5% in 1999 (at age 15 to 16 years). These proportions are significantly higher than those observed over time in the 1989 0- to 1-year age cohort, who were born since the national vaccination program started, at the corresponding age points (from the survey years 1989, 1994, and 1999, respectively). The rate of anti-HBc seropositivity was 2.9% in persons younger than 15 years of age but was 20.6% in persons 15 years of age or older (P < 0.001). In contrast, the rate of anti-HBc seropositivity among children younger than 15 years of age was 26.2% in 1984 (6), 14.5% in 1989 (11), and 4.0% in 1994 (12). Discussion The prevalence of HBsAg among children younger than 15 years of age decreased from 9.8% to 0.7% in the 15 years since implementation of the universal vaccination program. A high coverage rate for HBV vaccination is crucial for decreasing the prevalence of HBV infection. We observed a vaccination rate of at least 80% among children younger than 15 years of age and as high as 97% among children 4 years of age or younger. A nationwide series of seroepidemiologic studies of three cohorts of children 6 years of age in 1989, 1991, and 1993 reported that the vaccination rates for HBV ( 3 doses of vaccine) were 27.8%, 60.7%, and 88.7%, respectively (9). The age of these three cohorts in 1999 correspond to the age groups of 15 to 18 years, 13 to 14 years, and 11 to 12 years in our study. The data from these three national cohort studies confirm that the vaccination rate in our sample is similar to the vac


Hepatology | 2004

Waning immunity to plasma-derived hepatitis B vaccine and the need for boosters 15 years after neonatal vaccination

Chun-Yi Lu; Bor-Luen Chiang; Wei-Kuang Chi; Mei-Hwei Chang; Yen-Hsuan Ni; Hsu-Mei Hsu; Shiing-Jer Twu; Ih-Jen Su; Li-Min Huang; Chin-Yun Lee

Pertussis vaccination of infants has dramatically reduced disease, complications and deaths in infancy and early childhood. But there is still a major public health challenge--to deal with the morbidity and economic burden of illness in older children, adolescents and adults. Furthermore, it is these groups that form a major source of infection for non-immunised and partially immunised infants who are at high risk of severe complications. Adult-type acellular pertussis vaccine confers safe and effective protection against pertussis. There are several strategies to consider for immunising older individuals. Universal vaccination of all age groups would be the best available strategy for protecting individuals. It would also reduce the potential for transmitting the disease to other susceptibles, particularly infants. However, such a policy may be difficult both logistically and economically at this time. More easily achievable as a first step would be a strategy of universal adolescent booster vaccination combined with a programme targeted at adults most likely to have contact with very young babies including healthcare and childcare workers, parents and close family contacts. There is also potential for offering vaccination to adults (and their carers and close contacts) whose medical conditions or advanced age may place them at increased risk of more severe pertussis disease. Specific details of immunisation programmes must be made on a country by country basis depending on local circumstances.


Pediatrics | 2009

Epidemiologic Features of Kawasaki Disease in Taiwan, 2003–2006

Wen-Chan Huang; Li-Min Huang; I-Shou Chang; Luan-Yin Chang; Bor-Luen Chiang; Pei-Jer Chen; Mei-Hwan Wu; Hung-Chi Lue; Chun-Yun Lee

Neonatal immunization with hepatitis B (HB) vaccine is highly effective; however, more needs to be learned about the duration of protection and indications for boosters. We measured antibody to HB core antigen (anti‐HBc), HB surface antigen (HBsAg), and pre‐ and postbooster titers of HBsAg antibody (anti‐HBs) 15 years after primary neonatal immunization with plasma‐derived HB vaccines in 2 cohorts of 15‐year‐old children. Group A consisted of 78 children who were born to HB e antigen–positive HBsAg carrier mothers and had developed protective levels of anti‐HBs antibodies (≥10 mIU/mL) following HB immunization. Group B consisted of 113 apparently healthy children whose anti‐HBs titers after vaccination were unknown. Anti‐HBs was undetectable (antibody titer <10 mIU/mL) in 29.9% in group A and 62.4% in group B (P < .001). Anti‐HBc was detected in 33.3 % in group A and 4.4 % in group B (P < .001). After a single booster dose of HB vaccine, 2.7% in group A and 3.3% in group B remained anti‐HBs–negative. A blunted serological response was noted in approximately 20% in both groups. One HBsAg carrier was detected in group A (1.3%) and 4 in group B (3.5%). Fifteen years after neonatal immunization with plasma‐derived HB vaccine, a large proportion of children exhibited waning immunity. This poses the risk of breakthrough infection. A single booster augmented the serological response to the vaccine in most but not all subjects. In conclusion, our findings suggest that one or more booster immunizations are needed in seronegative subjects by at least 15 years following neonatal immunization with plasma‐derived HB vaccine. (HEPATOLOGY 2004;40:1415–1420.)


Pediatric Infectious Disease Journal | 2007

Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia.

John S. Tam; Maria Rosario Capeding; Lucy Chai See Lum; Tawee Chotpitayasunondh; Zaifang Jiang; Li-Min Huang; Bee Wah Lee; Yuan Qian; Rudiwilai Samakoses; Somsak Lolekha; K Pillai Rajamohanan; S Noel Narayanan; Chellam Kirubakaran; Ruth Rappaport; Ahmad Razmpour; William C. Gruber; Bruce D. Forrest

OBJECTIVE. Kawasaki disease is the leading cause of acquired heart disease in children worldwide. This study characterizes the epidemiology of Kawasaki disease in Taiwan between 2003 and 2006. METHODS. Using Taiwans 2003–2006 national health insurance claims, we investigated the epidemiologic features of Kawasaki disease (ICD-9-CM code 446.1) and coronary artery aneurysm formation (International Classification of Diseases, Ninth Revision, Clinical Modification code 414.11) and compared the incidences of these diseases with those occurring between 1996 and 2002 in Taiwan and those reported by other countries. RESULTS. During our 4-year study period, 3877 children and adolescents <20 years of age were hospitalized for Kawasaki disease. Ninety percent of these children were <5 years of age, and the male/female ratio was 1.62:1. The annual incidence of Kawasaki disease was 153 in 100000 children <1 year of age, 111 in children 1 year of age, 58 in children 2 years of age, 30 in children 3 years of age, 19 in children 4 years of age, and 5.2 in children 5 to 9 years of age. The overall incidence was 69 cases per 100000 for children <5 years of age. Kawasaki disease recurred in 1.5% of all cases. Kawasaki disease occurred most frequently in the summer and least frequently in the winter. Coronary artery aneurysm occurred in 7.2% (279 of 3877) of all Kawasaki disease cases. CONCLUSIONS. The overall incidence of Kawasaki disease was 69 in 100000 children <5 years of age between 2003 and 2006 in Taiwan, comparable with the incidence of 66 in 100000 children between 1996 and 2002. Taiwan has the third highest incidence of Kawasaki disease in the world, after Japan and Korea. In Taiwan, it occurs more frequently during the summer.


The Journal of Infectious Diseases | 2008

Humoral and Cellular Immune Responses to a Hepatitis B Vaccine Booster 15–18 Years after Neonatal Immunization

Chun-Yi Lu; Yen-Hsuan Ni; Bor-Luen Chiang; Pei-Jer Chen; Mei-Hwei Chang; Luan-Yin Chang; Ih-Jen Su; Hsu-Sung Kuo; Li-Min Huang; Ding-Shinn Chen; Chin-Yun Lee

Background: This study was designed to evaluate the efficacy and safety of cold-adapted influenza vaccine, trivalent (CAIV-T) against culture-confirmed influenza in children 12 to <36 months of age during 2 consecutive influenza seasons at multiple sites in Asia. Methods: In year 1, 3174 children 12 to <36 months of age were randomized to receive 2 doses of CAIV-T (n = 1900) or placebo (n = 1274) intranasally ≥28 days apart. In year 2, 2947 subjects were rerandomized to receive 1 dose of CAIV-T or placebo. Results: Mean age at enrollment was 23.5 ± 7.4 months. In year 1, efficacy of CAIV-T compared with placebo was 72.9% [95% confidence interval (CI): 62.8–80.5%] against antigenically similar influenza subtypes, and 70.1% (95% CI: 60.9–77.3%) against any strain. In year 2, revaccination with CAIV-T demonstrated significant efficacy against antigenically similar (84.3%; 95% CI: 70.1–92.4%) and any (64.2%; 95% CI: 44.2–77.3%) influenza strains. In year 1, fever, runny nose/nasal congestion, decreased activity and appetite, and use of fever medication were more frequent with CAIV-T after dose 1. Runny nose/nasal congestion after dose 2 (year 1) and dose 3 (year 2) and use of fever medication after dose 3 (year 2) were the only other events reported significantly more frequently in CAIV-T recipients. Conclusions: CAIV-T was well tolerated and effective in preventing culture-confirmed influenza illness over multiple and complex influenza seasons in young children in Asia.


Vaccine | 2009

Safety and efficacy of human rotavirus vaccine during the first 2 years of life in Asian infants: Randomised, double-blind, controlled study

Kong Boo Phua; Fong Seng Lim; Yu-Lung Lau; E. A. S. Nelson; Li-Min Huang; Seng Hock Quak; Bee Wah Lee; Yee Leong Teoh; Haiwen Tang; Boudville Ic; Lidia Oostvogels; P.V. Suryakiran; Igor Smolenov; H.H. Han; Hans L. Bock

BACKGROUND Whether hepatitis B (HB) vaccine-conferred immunity persists into adulthood is unknown. We aimed to investigate long-term HB immunity in adolescents. METHODS In 2004-2005, 6156 high school students (15-21 years old) who had been vaccinated with plasma-derived HB vaccine as infants were recruited for HB seromarker screening. The immune response to an HB vaccine booster was evaluated in 872 subjects who were seronegative. HB surface antibody (anti-HBs) titers and levels of HB surface antigen (HBsAg)-specific interferon (IFN)-gamma- or interleukin (IL)-5-secreting peripheral blood mononuclear cells (PBMCs; measured by enzyme-linked immunospot assay) were determined 4 weeks later. RESULTS Although the vaccine remained highly efficacious in reducing the HBsAg positivity rate, 63.0% of the vaccinees had no protective anti-HBs. After the booster, anti-HBs remained undetectable in 28.7% (158/551) of the subjects who had received complete HB vaccination (4 doses) during infancy. We estimated that 10.1% of the total population had lost their HB vaccine-conferred booster response. HBsAg-specific IFN-gamma- or IL-5-secreting PBMCs remained negative in 27.2% (25/92) of subjects after the booster. CONCLUSIONS A notable proportion of fully vaccinated adolescents had lost immune memory conferred by a plasma-derived HB vaccine 15-18 years later. This decay of immune memory may raise concerns about the need for a booster vaccine for high-risk groups in the long run.


Clinical Infectious Diseases | 2004

Clinical manifestations and molecular epidemiology of necrotizing pneumonia and empyema caused by Streptococcus pneumoniae in children in Taiwan.

Yu-Chia Hsieh; Po-Ren Hsueh; Chun-Yi Lu; Ping-Ing Lee; Chin-Yun Lee; Li-Min Huang

This study evaluates the safety and efficacy against severe rotavirus gastroenteritis of the oral live attenuated human rotavirus vaccine RIX4414 (Rotarix) during the first 2 years of life in Asian infants from high-income countries. Healthy infants were enrolled to receive 2 doses of RIX4414 (N=5,359) or placebo (N=5,349). From 2 weeks post-dose 2 to 2 years of age, vaccine efficacy was 96.1% (95%CI:85.1%; 99.5%) against severe rotavirus gastroenteritis, 100% (95%CI:80.8%; 100%) against wild-type G1P[8] and 93.6% (95%CI:74.7%; 99.3%) against circulating non-G1 rotavirus types. No intussusception cases were reported within 31 days post-vaccination. RIX4414 shows a good safety profile and offers high protection during the first 2 years of life with potentially significant public health impact in this population.


Nature Genetics | 2012

Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis

Yi-Ching Lee; Ho-Chang Kuo; Jeng-Sheng Chang; Luan-Yin Chang; Li-Min Huang; Ming-Ren Chen; Chi-Di Liang; Hsin Chi; Fu-Yuan Huang; Meng-Luen Lee; Yhu-Chering Huang; Betau Hwang; Nan-Chang Chiu; Kao-Pin Hwang; Pi-Chang Lee; Li-Ching Chang; Yi-Min Liu; Ying-Ju Chen; Chien-Hsiun Chen; Yuan-Tsong Chen; Fuu Jen Tsai; Jer-Yuarn Wu

Recently, there have been increasing numbers of pneumococcal pneumonia cases, with their associated complications. We conducted a retrospective review to increase the understanding of childhood pneumococcal pneumonia. Seventy-one patients with pneumococcal pneumonia were identified. Forty (56.3%) of them developed complicated pneumonia. Multivariate analysis showed that presence of immature polymorphonuclear leukocytes in peripheral blood (odds ratio [OR], 3.67; 95% confidence interval [CI], 1.08-12.63), high C-reactive protein levels (>12 mg/dL) (OR, 5.24; 95% CI, 1.10-24.93), and no underlying disease at presentation (OR, 5.48; 95% CI, 1.06-28.25) were independent predictors of the occurrence of necrosis or/and abscess. Fourteen isolates (35%), which were genotypically identical and had the same pulsed-field gel electrophoresis pattern (serogroup 14, with MICs of penicillin of 0.1-0.5 mu g/mL), were significantly associated with complicated pneumonia (P=.047). Whether the virulence of antibiotic-resistant pneumococci is evolving deserves further investigation.


Journal of The Formosan Medical Association | 2006

Influenza Pandemics: Past, Present and Future

Yu-Chia Hsieh; T. C. Wu; Ding-Ping Liu; Pei-Lan Shao; Luan-Yin Chang; Chun-Yi Lu; Chin-Yun Lee; Fu-Yuan Huang; Li-Min Huang

To find new candidate loci predisposing individuals to Kawasaki disease, an acute vasculitis that affects children, we conducted a genome-wide association study in 622 individuals with Kawasaki disease (cases) and 1,107 controls in a Han Chinese population residing in Taiwan, with replication in an independent Han Chinese sample of 261 cases and 550 controls. We report two new loci, one at BLK (encoding B-lymphoid tyrosine kinase) and one at CD40, that are associated with Kawasaki disease at genome-wide significance (P < 5 × 10−8). Our findings may lead to a better understanding of the role of immune activation and inflammation in Kawasaki disease pathogenesis.

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Luan-Yin Chang

National Taiwan University

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Chun-Yi Lu

National Taiwan University

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Chin-Yun Lee

National Taiwan University

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Ping-Ing Lee

National Taiwan University

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Pei-Lan Shao

National Taiwan University

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Po-Ren Hsueh

National Taiwan University

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Chuan-Liang Kao

National Taiwan University

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Jong-Min Chen

National Taiwan University

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Mei-Hwei Chang

National Taiwan University

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