Change in hepatitis A virus seroepidemiology in southern Taiwan: a large percentage of the population lack protective antibody

Hepatitis A, the predominant reported etiologic form of viral hepatitis in Taiwan, continues to be a disease primarily of children and young adults. A seroepidemiologic study was performed to assess the seroprevalence of hepatitis A (HAV) antibodies in the southern Taiwan general population in 1998 and is compared with results of a similar study in 1992. A total of 948 subjects (477 male and 471 female) with ages ranging from 0.3 to 63 years were stratified into 14 age-specific groups. The presence of anti-HAV antibodies was detected using a commercially available radioimmunoassay. Fifteen percent of the subjects were positive for anti-HAV antibodies, which is lower than that in 1992 (P < 0.001). Seroprevalences were 14.1% for males and 22.6% for females (P = 0.006). The pattern of anti-HAV seroprevalence was distinguishable from that found in 1992; minimum seroconversion occurred at ages ranging from 1 to 30 years. Prevalence of seropositive subjects decreased markedly for the < 1, 13-15, 16-19, 20-24, 25-29, and 30-39 year age groups in comparing 1998 with 1992. The current study demonstrates a continuing decline in the prevalence of HAV among children, adolescents, and young adults. The findings can be ascribed to the improvement of socioeconomic status and modernization of environmental sanitation. As a consequence of this changing trend of endemicity and the resulting lack hepatitis A antibodies among the general population in Taiwan, the risk of sudden major outbreaks is increased because of increasing international travel and immigration, particularly during and after natural disasters. HAV vaccination will be important for the prevention and control of HAV outbreaks in the community.     

Antibody persistence and immune memory in healthy adults following vaccination with a two-dose inactivated hepatitis A vaccine: long-term follow-up at 15 years

Long‐term persistence of vaccine‐induced immune response in adults was assessed annually for 15 years following primary immunization with a two‐dose inactivated hepatitis A vaccine. In 1992, 119 and 194 subjects aged 17–40 years and naïve for hepatitis A virus (HAV) were enrolled in two studies to receive 1,440 ELISA units (El.U) of inactivated hepatitis A vaccine (Havrix?, GlaxoSmithKline Biologicals, Belgium) according to a standard 0, 6 or an extended 0, 12 months schedule, respectively. Serum samples were taken 1 month after the second vaccine dose and every consecutive year up to 15 years after primary vaccination for measurement of anti‐HAV antibody concentrations (NCT00291876 and NCT00289757). At year 15, 100% (48/48) and 97.3% (108/111) of subjects vaccinated at 0, 6 or 0, 12 months remained seropositive for anti‐HAV antibodies, with geometric mean concentrations (GMCs) of 289.2 and 367.4 mIU/ml, respectively. An additional dose of HAV vaccine (1,440 El.U) was administered to the six subjects who had become seronegative for anti‐HAV antibodies since year 11. All subjects mounted a humoral immune response to the additional HAV challenge dose, although post‐challenge anti‐HAV antibody levels remained low in one subject. These studies represent the longest annual follow‐up of hepatitis A vaccine in healthy adults. The immune response induced by two doses of this inactivated HAV vaccine was shown to persist for at least 15 years. No difference in long‐term antibody persistence was observed between the two primary vaccination schedules, reinforcing the potential for flexibility in the timing of the second primary vaccine dose. J. Med. Virol. 83:1885–1891, 2011. © 2011 Wiley‐Liss, Inc.     

Antibody responses of adults, adolescents, and children to a plasma-derived hepatitis B vaccine in a rural African setting

A field trial of a plasma-derived hepatitis B vaccine in five rural villages in Zambia was analyzed to determine if adults in a rural African setting respond to this vaccine as well as adults in Western countries and to determine the immunogenicity of fewer than the recommended three doses; 255 residents, including 171 who were susceptible to hepatitis B, were vaccinated. Among those who received three vaccine doses, protective levels of antibody to hepatitis B surface antigen (anti-HBs) developed in 67% of adults (ages 21 to 70 years), 87% of adolescents (ages 12 to 19 years), and 100% of children (ages 0 to 11 years). The 67% of vaccinated adults who developed anti-HBs at the protective level was lower than the 96% reported among adults receiving the same vaccine at the same dose and dosage schedule in studies in Western countries. No difference was seen in the response of those receiving two doses compared with those receiving three doses among adults and adolescents, suggesting that a two-dose regimen may be acceptable in these age groups in developing countries to reduce costs and improve compliance. Use of hepatitis B vaccine in a region where prevaccination hepatitis B serologic screening was not available did not appear to increase the number of severity of adverse reactions.     

Hepatitis A vaccines

The global disease burden associated with hepatitis A virus (HAV) is expected to increase in the coming years due to a shift in the epidemiological pattern of the disease. A decrease in the prevalence of natural immunity is leading to an increased number of adolescents and adults susceptible to a disease that is associated with greater morbidity, mortality and treatment costs in older-age groups. Current HAV vaccines have been shown to be safe, highly immunogenic and confer long-lasting protection against HAV disease. Vaccine-induced antibodies persist for more than 12 years in vaccinated adults and mathematical modeling predicts antibody persistence for more than 25 years in over 95% of vaccine recipients. However, the cost of HAV vaccines has been prohibitive for some countries. Recent studies in countries with transitioning HAV endemicity indicate that the cost-benefit ratio of mass vaccination against HAV would be similar to other routine childhood vaccinations.     

Antibody persistence and immune memory in adults, 15 years after a three-dose schedule of a combined hepatitis A and B vaccine

A combined hepatitis A and B vaccine is available since 1996. Two separate open‐label primary studies evaluated the immunogenicity and safety of this hepatitis A and B vaccine (720 EI.U of HAV and 20 µg of HBsAg) in 306 healthy subjects aged 17–43 years who received three doses of the vaccine following a 0, 1, and 6 months schedule. These subjects were followed up annually for the next 15 years to evaluate long‐term persistence of anti‐HAV and anti‐HBs antibodies. The subjects whose antibody concentrations fell below the cut‐offs between Year 11 and Year 15 (anti‐HAV: <15 mIU/ml; anti‐HBs: <10 mIU/ml) were offered an additional dose of the appropriate monovalent hepatitis A and/or B vaccine. In subjects who received the additional vaccine dose, a blood sample was collected 1 month after vaccination. At the Year 15 time point, all subjects in Study A and Study B were seropositive for anti‐HAV antibodies and 89.3% and 92.9% of subjects in the respective studies had anti‐HBs antibody concentrations ≥10 mIU/ml. Four subjects (two in each study) received an additional dose of monovalent hepatitis B vaccine and mounted anamnestic responses to vaccination. No vaccine‐related serious adverse events were reported. This study confirms the long‐term immunogenicity of the three‐dose regimen of the combined hepatitis A and B vaccine, as eliciting long‐term persistence of antibodies and immune memory against hepatitis A and B for up to at least 15 years after a primary vaccination. J. Med. Virol. 84:11–17, 2011. © 2011 Wiley Periodicals, Inc.     

Current seroepidemiology of hepatitis A in Hong Kong.

The current seroepidemiology of hepatitis A in Hong Kong was examined by testing stored sera from 702 healthy subjects, collected between 1987-1989, for antibody to hepatitis A virus (anti-HAV). The overall prevalence of anti-HAV antibody was 45.6%. There were significant increases in prevalence of anti-HAV antibody with every 10-year increase in age up to age 40. The prevalence of anti-HAV antibody was 24% for subjects below age 30 and 89.2% for those above age 30 (P less than 0.0001). Socioeconomic factors did not appear to have any influence on the prevalence of anti-HAV antibody. In comparison with another study conducted in Hong Kong 10 years ago, the prevalence of anti-HAV antibody in the current study was significantly lower in every age group from 0 to 30 years. In summary, it was shown that HAV infection is no longer highly endemic in Hong Kong. In view of the changing epidemiology, postexposure prophylaxis will be necessary for young adults and children, and hepatitis A vaccine may be indicated for high risk groups when it is generally available.     

Declining hepatitis A seroprevalence among medical students in Bangkok,Thailand, 1981-2001

The severity of clinical symptoms following hepatitis A virus (HAV) infection is age dependent. Hepatitis A in children is mostly an asymptomatic disease while adolescents and adults usually show symptoms of clinical hepatitis. Improved personal hygiene and environmental sanitation has led to a decline in natural immunity acquired in childhood, creating a population of susceptible adults. In the past decade, the incidence and prevalence of hepatitis A disease in Thailand have decreased significantly. In this study, we used enzyme-linked immunosorbent assay to determine the prevalence of anti-HAV antibodies among medical students at two different time points in 1996 and 2001. We then compared these results with data from previous studies in 1981 and 1992. The seroprevalence was 73.01%, 30.23%, 16.67% and 6.67% in 1981, 1992, 1996 and 2001, respectively. A significant decline has happened over the past two decades (p < 0.001). Considering the decreasing immunity to HAV in the younger generations, more cases of symptomatic HAV infection could be anticipated. Further seroprevalence studies in other adolescence groups from different socioeconomic status are needed to elucidate the current situation of HAV infection in the young generation more comprehensively and to develop an appropriate prevention program.     

Le virus de l'hépatite A : actualités

Hepatitis A virus (HAV) is the leading cause of viral hepatitis worldwide. Infection is usually self limiting, yet, in some cases it may cause fulminant and fatal hepatitis, particularly in patients of more than 50 years old. Improved hygiene standards have led to a reduction in natural immunization allowing potentially massive outbreaks involving adults. This changing epidemiology leads to the modification of public health surveillance systems and vaccine recommendations. The diagnosis of acute infection is based on anti-HAV IgM detection. However, IgM can be detected in the absence of HAV infection, then IgG avidity may help to distinguish between acute infection and immune reactivation. Molecular epidemiology contributes to the identification of linked cases and source of contamination. The observation of the diversity of circulating strains allows to better understand HAV diffusion modes within a community or from a country to another and to adapt the tools for virus detection.     

Hepatitis A outbreak in an institution

In February 1996, four serologically confirmed cases of hepatitis A virus (HAV) occurred in one household. Investigation showed that the source was a family member with sub-clinical HAV who attended a Unit for Learning Disabilities. Reports of two further cases in the institution followed and control measures were instigated. Contacts were unwilling to accept human normal immunoglobulin (HNIG). Following salivary antibody and serological testing, hepatitis A vaccine was offered to the non-immune. An investigation found that sub-clinical infection was significantly associated with being less than 5 years old (RR = 6.07, p < 0.005) and being in one particular classroom (RR = 6.21, p < 0.0005). None of the staff in the institution became infected. In all, 31 cases of hepatitis A (18 clinical and 13 subclinical cases) occurred. This paper (a) describes an outbreak of hepatitis A (b) refers to the use of a salivary antibody test (assay performance to be published elsewhere) (c) identifies factors associated with the acquisition of HAV and (d) endeavours to assess the effectiveness of the vaccine to contain the outbreak.     

A nationwide seroprevalence of total antibody to hepatitis A virus from 2005 to 2009: age and area-adjusted prevalence rates

Background/Aims

Recent outbreak of hepatitis A in Korea is clearly related to the epidemiological shift of hepatitis A virus (HAV). However, nationwide seroprevalence data have been limited. This study estimated the nationwide, age- and area-adjusted anti-HAV prevalence from 2005 to 2009.

Methods

Retrospective analysis of the results of total anti-HAV test in 25,140 cases which were requested by 1,699 medical institutions throughout the nation to Seoul Clinical Laboratory from Jan. 1 2005 to Dec. 31 2009 was performed. The estimated seroprevalence was adjusted by area and age of the standard population based on the 2005 Census data from Korea National Statistical Office.

Results

The area-adjusted anti-HAV prevalence in the children younger than 10 years were 33.4% in 2005 and 69.9% in 2009. The most susceptible age groups to HAV infection during the last 5 years were teenagers and the young adults in their age of twenties. The area-adjusted seroprevalence in 2009 were 11.9% in the age group of 20-29 years, 23.4% in the age group of 10-19 years, 48.4% in the age group of 30-39 years. The population in 40-49 years showed geographically different seroprevalence with the lowest rate in Seoul (80%).

Conclusions

The most susceptible age group to HAV infection is 10-29 years, while the young children less than 10 years showed about 70% seropositivity. The changing seroepidemiology should be monitored continuously for the proper vaccination and patient care.     

甲型肝炎减毒活疫苗及灭活疫苗灌胃免疫小鼠后的抗体应答

目的 :测定甲肝减毒活疫苗及灭活疫苗灌胃免疫小鼠后的抗体应答效应。方法 :将活或灭活的甲肝疫苗加或不加明胶 ,经胃免疫小鼠 ,于末次免疫后 2w取血清及肠液 ,用间接ELISA法分别检测其中的特异性IgG和IgA抗体水平 ,并与空白及肌注组比较。结果 :实验组特异抗体水平明显高于肌注组 (P <0 0 1) ;加明胶组的免疫效果较不加者好 (IgG :P <0 0 0 1,IgA :P <0 0 5 )。结论 :甲肝活疫苗及灭活疫苗经消化道免疫小鼠后 ,均可诱导全身及局部的抗体应答 ;明胶有增强抗体产生的作用 ,可作为一种安全、廉价的粘膜佐剂被进一步开发与利用。     

Comparison of memory B cell, antibody-secreting cell, and plasma antibody responses in young children, older children, and adults with infection caused by Vibrio cholerae O1 El Tor Ogawa in Bangladesh

Children bear a large component of the global burden of cholera. Despite this, little is known about immune responses to cholera in children, especially those under 5 years of age. Cholera vaccine studies have demonstrated lower long-term protective efficacy in young children than in older children and adults. Memory B cell (MBC) responses may correlate with duration of protection following infection and vaccination. Here we report a comparison of immune responses in young children (3 to 5 years of age; n = 17), older children (6 to 17 years of age; n = 17), and adults (18 to 60 years of age; n = 68) hospitalized with cholera in Dhaka, Bangladesh. We found that young children had lower baseline vibriocidal antibody titers and higher fold increases in titer between day 2 and day 7 than adults. Young children had higher baseline IgG plasma antibody levels to Vibrio cholerae antigens, although the magnitudes of responses at days 7 and 30 were similar across age groups. As a surrogate marker for mucosal immune responses, we assessed day 7 antibody-secreting cell (ASC) responses. These were comparable across age groups, although there was a trend for older age groups to have higher levels of lipopolysaccharide-specific IgA ASC responses. All age groups developed comparable MBC responses to V. cholerae lipopolysaccharide and cholera toxin B subunit at day 30. These findings suggest that young children are able to mount robust vibriocidal, plasma antibody, ASC, and MBC responses against V. cholerae O1, suggesting that under an optimal vaccination strategy, young children could achieve protective efficacy comparable to that induced in adults.     

Incidence of hepatitis A virus (HAV) infection in rural Liberia

To provide background for future hepatitis A vaccine trials, sera were collected from 0- to 4-year-old Liberian infants and their mothers on two occasions an average of 14.75 months apart and tested for antibody to hepatitis A virus (anti-HAV). The prevalence of anti-HAV rose from 2.5% in infants 0-6 months of age to 70% in children 3-4 years of age and did not differ between male and female infants. The annual incidence of new infections was slightly lower in the first year of life (35%) than in the subsequent 3 years, when it averaged 45%. The presence of HBV infection did not affect the incidence of HAV seroconversion. No clinical hepatitis was recognized in the subjects who seroconverted. Dual hepatitis A and B virus infection were observed; these were all clinically inapparent. The extraordinary incidence of HAV infection documented in the present study offers an opportunity for vaccine efficacy trials requiring minimal numbers of subjects.     

Use of vaccine in the era of antimicrobial resistance: need of effective pneumococcal vaccines

Streptococcus pneumoniae is an important pathogen causing invasive infections particularly in children. Penicillin-nonsusceptible pneumococci are very prevalent in Korea and a difficult problem in antimicrobial treatment. Immunization with effective vaccines including viral and bacterial vaccines has proven to be the most effective and reliable method to prevent the target disease. Universal immunization to infants with Haemophilus influenzae type b conjugate vaccine has dramatically proven to be very effective in reducing invasive Hib diseases and also the carriage rate. The 23-valent pneumococcal polysaccharide vaccine is effective in preventing invasive diseases in young adults and covers most of the penicillin-nonsusceptible types. It has not proven very effective in the prevention of otitis media, and is unable to elicit adequate antibody response in children younger than 2 years of age. Recently a new polysaccharide-protein conjugate vaccine was developed which can elicit antibody response in children younger than 2 years of age. However, the vaccine is only 8-valent at the moment. Studies are required to determine the possible idiotypic modulation and nonproductive immune response when polysaccharide vaccine is administered to infants. Part of the problem of antimicrobial-resistant pneumococcal infection may be solved in the future with the use of improved vaccine. Preventing pneumococcal infections with safe and effective vaccines will not only reduce the development of antibiotic resistance, but could also be the most cost-effective method to control pneumococcal disease.     

Hepatitis B vaccination in a school age population: a feasibility study

There remains no consensus on whether to adopt a universal hepatitis B vaccination strategy in the United Kingdom, where the endemicity of hepatitis B virus (HBV) is considered to be very low in the general population. To assess the feasibility and acceptance of a school-based adolescent vaccination approach, 11-13 years old pupils in local secondary schools in the London Borough of Camden and Islington were contacted and offered a three-dose hepatitis B vaccination course using a 0, 1, and 12 months schedule. The adult dose of hepatitis B vaccine (Engerix B GlaxoSmithKline) containing 20 mug recombinant hepatitis B surface antigen (HBsAg) in 1 ml suspension was administered. This dosage is normally intended for adults and children older than 15 years of age, but can be administered in 10-15 years old children when compliance may be low, since a higher proportion of those vaccinated develop protective antibody levels following administration of only two doses of vaccine. Overall, a total of 528 pupils were contacted, with 122 (23%) consenting to be vaccinated. Of these, 117 (96%) received the complete three-dose regimen according to the schedule (four did not receive vaccine: three were non-attendees and one was previously vaccinated; one withdrew following a flu-like adverse event). The results of this study show that it is feasible and practical to administer hepatitis B vaccination to adolescents in a school setting, and that it is possible to achieve high rates of uptake for the complete three-dose course among adolescents. However, in order to attain and sustain high coverage rates among pupils, this would require additional general health promotion, including health education and provision of information, targeting of teachers, pupils, and parents in order to increase participation in a school-based hepatitis B vaccination programme. A further requirement includes the availability of good local health support within schools so as to allow for an efficient vaccine delivery system to maximize vaccination in this setting.     

A seroepidemiologic study of Helicobacter pylori and hepatitis A virus infection in primary school students in Taipei.

Helicobacter pylori and hepatitis A virus (HAV) share a common fecal-oral transmission route. The aim of this study was to investigate the prevalence of and risk factors for H. pylori and HAV infection in primary school students in Taiwan. We studied 289 Grade 1 to 6 students from a single primary school in Taipei County in 2003. The students volunteered for blood tests for H. pylori immunoglobulin G (IgG) antibody and anti-hepatitis A antibody after consent from their parents. Questionnaires were administered to the parents to investigate possible risk factors. The seroprevalence rates of H. pylori IgG antibody and anti-hepatitis A antibody were 21.5% (62/289) and 1.4% (4/289), respectively. No statistically significant relationship was found between seropositivity for H. pylori and for HAV. If parents had knowledge of H. pylori and HAV, their children were significantly more likely to be seronegative for H. pylori (p=0.020, odds ratio [OR] 2.1, 95% confidence interval [CI] 1.2-3.7) and HAV (p=0.012, OR 11.2, 95% CI 1.5-83.4). Students whose family members had no history of HAV infection were significantly less likely to be seropositive for HAV (p=0.001, OR 0.04, 95% CI 0.004-0.5). No other factors were found to be significantly associated with seropositivity, including blood type; age; gender; family members' history of H. pylori infection; travel to China; parents' educational level; sources of water supply; family members' use of tobacco, alcohol, or betel nut; family members' history of peptic ulcer or gastritis; and students' history of recurrent abdominal pain. Lack of public health knowledge appears to be related to seroprevalence of H. pylori in primary school students. The low seroprevalence of anti-HAV antibodies demonstrates the lack of protection against this infection in school-age children in Taiwan and suggests that universal administration of HAV vaccine would be wise.     

HBsAg阳性儿童和健康儿童对国产甲型肝炎灭活疫苗免疫原性和安全性的观察

目的：观察HBsAg阳性儿童对国产甲型肝炎灭活疫苗的免疫原性和安全性。方法：随机选取121名1－10岁健康儿童和10名同龄的HBsAg阳性儿童，抗－HAV均阴性，接种唐山怡安生物工程有限公司研制的甲型肝炎灭活疫苗。接种剂量为500U／剂和1000U／剂两组，免疫程序为0和6个月，并在初免后30d，第二针后30和180d用ELISA方法检测抗－HAV。结果：HBsAg阳性儿童和健康儿童接种500U／剂和1000U／剂甲型肝炎灭活疫苗后抗体阳转率均为100％。第二针免疫后30d抗体平均几何滴度500U／剂组分别为4684．9mIU和4535．6mIU；1000U／剂组分别为5399．8mIU和7347．1mIU。二者比较差异无显著性，免疫后亦未见异常反应，初免后1年抗体水平仍然很高。结论：HBsAg阳性儿童接种国产甲型肝炎灭活疫苗具有良好的免疫应答，同时也是安全的。     

Seroepidemiology of hepatitis A in Korea: changes over the past 30 years

This study aimed to assess the immune status of the Korean population against hepatitis A virus (HAV). Residual serum samples from 2008 to 2010 were collected from diagnostic laboratories and a total of 1,872 samples were analyzed. Anti-HAV seroprevalence was 57.3% in subjects aged 1-4 yr, 69.8% at 5-9 yr and decreased to 38.8% at 10-14 yr, 13.0% at 15-19 yr, and 11.7% at 20-29 yr. Seroprevalence increased with increasing age: 52.2% at 30-39 yr, 83.2% at 40-49 yr, 81.4% at 50-59 yr, 93.2% at 60-69 yr, and 95.1% at 70-79 yr. The most susceptible age group consisted of subjects aged 10-29 yr, especially those aged 20-29 yr. This pattern is markedly different from that in the past 3 decades, where the most susceptible group had consisted of children aged less than 10 yr and almost all subjects aged more than 20 yr had developed anti-HAV antibodies. Because of improvements in hygiene and introduction of hepatitis A vaccine, the age demographic of the susceptible population has shifted. These data are important for creating new prevention measures, including vaccination policies, to prevent and control outbreaks of hepatitis A in Korea.     

Tdap5 Vaccine (Covaxis®)

Covaxis (also licensed as Triaxis or Adacel in individual countries) is a combined tetanus toxoid, reduced diphtheria toxoid, five component acellular pertussis (namely detoxified pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3) vaccine for the prevention of diphtheria, tetanus, and pertussis. It is approved for use in Europe as a single intramuscular booster dose in children (aged ≥ 4 years), adolescents, and adults, and in the US it is approved for use in individuals aged 11-64 years. In large, randomized, controlled clinical trials conducted in the UK and North America, a single intramuscular booster dose of Covaxis induced robust immune responses for all of its component antigens when given to children (aged ≥ 4 years), adolescents, and adults. In addition, Covaxis vaccine was safe and generally well tolerated in terms of solicited and unsolicited local injection-site and systemic adverse events, most of which were of mild intensity and resolved without sequelae. Furthermore, the immunogenicity of each individual component and the reactogenicity of Covaxis vaccine in children, adolescents, and adults was generally similar to that of comparator vaccines. Despite being a vaccine-preventable disease and having >90% primary vaccination coverage worldwide, pertussis remains uncontrolled, particularly amongst adolescents and adults. Given the changing epidemiology of pertussis and the requirement to reduce infection in adolescents and adults (including healthcare workers) and thereby prevent transmission of the disease from these individuals to very young infants, the new 'cocoon strategy' recommended in current vaccination guidelines has become a key strategy in the management of morbidity and mortality associated with pertussis. This strategy focuses on the immunization of healthcare workers, and the parents and family members of infants who are too young to have undergone primary immunization, so as to prevent the transmission of pertussis to these young at-risk infants. The implementation of the 'cocoon strategy' may finally give countries the ability to control pertussis infections in these at-risk infants and ultimately provide the desired herd immunity against pertussis. In line with this strategy, a booster dose of Covaxis vaccine provides a valuable option to reduce pertussis morbidity and mortality, and to maintain seroprotection against diphtheria and tetanus in children (aged ≥ 4 years), adolescents, and adults.