Marie Van der Wielen

Multicenter Prospective Study of the Burden of Rotavirus Acute Gastroenteritis in Europe, 2004–2005: The Reveal Study

BACKGROUND Rotavirus is recognized as a significant cause of pediatric gastroenteritis worldwide. Comprehensive data on the burden of rotavirus disease in Europe were lacking. METHODS A prospective, multicenter, observational study was conducted during the 2004-2005 season in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom, to estimate the incidence of acute gastroenteritis (AGE) and rotavirus gastroenteritis (RVGE) in children <5 years of age who require medical care in primary care, emergency department, and hospital settings. RESULTS A total of 2846 children with AGE were included in the study, and, of the 2712 children for whom ELISA results were available, 1102 (40.6%) were found to be rotavirus positive. The estimated annual incidence of RVGE was 2.07-4.97 cases/100 children <5 years of age, and it was highest among children 6-23 months of age, with 56.7%-74.2% of all RVGE cases occurring in children in this age group. Overall, RVGE was estimated to account for 27.8%-52.0% of AGE cases, and it was responsible for up to two-thirds of hospitalizations and emergency department consultations, as well as one-third of primary care consultations for AGE. CONCLUSIONS Rotavirus infections account for a significant proportion of AGE cases in children <5 years of age in Europe, many of whom require frequent primary care consultations or care in emergency department and/or hospital settings. The results of the present study suggest that routine rotavirus vaccination for infants <6 months of age could significantly reduce the substantial burden of this potentially serious childhood disease.

Costs of Community-Acquired Pediatric Rotavirus Gastroenteritis in 7 European Countries: The Reveal Study

BACKGROUND Morbidity and resource use due to rotavirus gastroenteritis (RVGE) are substantial in Europe, although comprehensive data on the economic impact of the disease are lacking. METHODS A cost study was conducted to assess health care resource use data collected during a prospective epidemiologic study of acute gastroenteritis in children <5 years of age in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom. We calculated the average cost (direct and indirect) per episode of confirmed RVGE in primary care, emergency department, and hospital settings. RESULTS The total societal cost (including direct medical, direct nonmedical, and indirect costs) per episode of RVGE ranged from 166 euros to 473 euros in the primary care setting, from 334 euros to 770 euros in the emergency department setting, and from 1525 euros to 2101 euros in the hospital setting. The majority of hospital-related costs were reimbursed by national health care payers, but the percentage of reimbursed costs declined progressively in the emergency department and primary care settings. The mean number of workdays lost by parents and other relatives varied between study areas and settings, ranging from 2.3 to 7.5 days, and this represented the major cost not reimbursed by national health care payers. CONCLUSIONS RVGE incurs considerable resource utilization in all health care settings and substantial costs for national health care payers, families of patients, and employers. Routine rotavirus vaccination in infants could significantly reduce the health and economic burden of pediatric RVGE.

Distribution of Rotavirus Genotypes in Europe, 2004–2005: The REVEAL Study

BACKGROUND Rotavirus gastroenteritis (RVGE) constitutes a significant burden of pediatric disease. Knowledge of currently cocirculating rotavirus genotypes is required to help guide immunization strategies. METHODS During the 2004-2005 RVGE season, a prospective, multicenter, observational study of RVGE was conducted in children <5 years of age seeking health care in primary care, emergency department, and hospital settings in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom. Rotavirus was identified by enzyme-linked immunosorbent assay (ELISA), and genotypes were determined by reverse-transcription polymerase chain reaction (RT-PCR) analysis of stool samples for which ELISA results were positive. RESULTS ELISA results were available for 2712 of the 2846 children with acute gastroenteritis who were recruited for the study; of these 2712 children, 1102 (40.6%) were rotavirus positive. RT-PCR results were available for 1031 children with ELISA-positive samples. G1-G4 and G9 were the most prevalent genotypes identified: G1 was identified in Spain, Sweden, and the United Kingdom; G9 in Italy, France, and Belgium; and G4 in Germany. Only the G4 and G9 genotypes were identified in all study areas. Rotavirus infections showed seasonal variation, with different patterns noted among the genotypes. CONCLUSIONS Rotavirus genotypes G1-G4 and G9 are associated with the majority of RVGE infections in the areas studied, with geographic and seasonal variation in the distributions of rotavirus strains. Rotavirus vaccines should, therefore, provide protection against all major genotypes to decrease effectively the RVGE disease burden in Europe.

The seroepidemiology of primary varicella-zoster virus infection in Flanders (Belgium)

Abstract. The age-specific seroprevalence of varicella-zoster virus (VZV) antibodies was assessed in a sample of the Flemish (Belgian) population. ELISA tests were used to analyse 1673 sera from subjects aged 1 to 44 years (October 1999 – April 2000). Chickenpox infections in Flanders appear to affect children at a younger age than in other European countries since 47.37% (95% CI: 37.33–57.41) is already immune at 2 years of age. For older age-groups, the prevalence is similar to that of most European countries: 80.19% (95% CI: 72.60–87.78) at 5 years, 92.52% (95% CI: 87.54–97.51) at 9 years and 100%≥40 years. The accuracy of non-positive recollections of varicella histories among Flemish 10 to 17-year olds was examined on the basis of a second (residual) serum bank. In this group, VZV seroprevalence was almost always 100% (or nearly 100%), irrespective of age, degree of reliability (negative or uncertain answers) or level of ascertainment (child personally or parents). The limited size of this second data set did not allow for an accurate assessment of the negative predictive value of such recollections. Conclusion: since varicella-zoster virus predominantly affects very small children and is generally perceived as benign, the required high coverage rate of a universal childhood varicella vaccination programme may be hard to attain. Adolescent strategies can minimise the population risks involved but the accuracy of non positive antecedents of chickenpox needs to be documented to assess the efficiency of such strategies.

Immunogenicity of a single dose of tetravalent meningococcal serogroups A, C, W-135, and Y conjugate vaccine administered to 2- to 10-year-olds is noninferior to a licensed-ACWY polysaccharide vaccine with an acceptable safety profile

Background: Meningococcal disease remains an important cause of invasive bacterial infections in children less than 5 years of age. Immunogenicity and safety of the investigational ACWY vaccine conjugated with tetanus toxoid (ACWY-TT, GlaxoSmithKline Biologicals) were evaluated in 1501 healthy 2- to 10-year-old children in the Philippines, India, Lebanon, and Saudi Arabia. Methods: Children were randomized (3:1) to receive ACWY-TT or licensed tetravalent meningococcal polysaccharide vaccine (Mencevax, GlaxoSmithKline, Men-PS). Diary cards were used to collect solicited symptoms for 4 days after vaccination. Serious adverse events were reported for 6 months. Serum bactericidal activity (rSBA, rabbit complement) was measured before and 1 month after vaccination in the first 75% of subjects enrolled in each country. Results: The statistical criteria for noninferiority in terms of rSBA vaccine responses were reached. Exploratory analyses showed that postvaccination rSBA titers ≥1:8 and ≥1:128 were significantly higher after ACWY-TT than Men-PS for serogroups C, W-135, and Y, and rSBA vaccine responses and geometric mean antibody titers were significantly higher for all 4 serogroups after administration of ACWY-TT. Noninferiority in terms of incidences of grade 3 general symptoms was not demonstrated. ACWY-TT was well tolerated with grade 3 events reported in <1% of subjects per group. No serious adverse events were considered related to vaccination. Conclusion: ACWY-TT was immunogenic in children between 2 to 10 years of age with a clinically acceptable safety profile that resembled licensed Men-PS. These data support a positive benefit/risk ratio for the ACWY-TT vaccine.

Impact of community-acquired paediatric rotavirus gastroenteritis on family life: data from the REVEAL study.

BackgroundRotavirus is the leading cause of acute gastroenteritis (AGE) and the most frequent cause of severe diarrhoea in children aged less than 5 years. Although the epidemiology of rotavirus gastroenteritis (RVGE) is well documented, there are few data on the impact of RVGE on the families of affected children.MethodsData associated with the burden of RVGE, including number of working days lost, levels of parental stress, the need for alternative childcare arrangements and additional nappies used, were extracted from questionnaires completed by parents of children participating in a prospective, multicentre, observational study (Rotavirus gastroenteritis Epidemiology and Viral types in Europe Accounting for Losses in public health and society, REVEAL), conducted during 2004-2005 in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom to estimate the incidence of RVGE in children aged less than 5 years seeking medical care as a result of AGE.Results1102 children with RVGE were included in the present analysis. The proportion of RVGE cases that required at least one parent or other person to be absent from work was 39%-91% in the hospital setting, 44%-64% in the emergency department, and 20%-64% in primary care. Self-reported levels of parental stress were generally high (mean stress levels, ≥ 5 on a 10-point visual analogue scale). Additional childcare arrangements were required in up to 21% of RVGE episodes. The mean number of nappies used per day during RVGE episodes was approximately double that used when the child was not ill.ConclusionsPaediatric RVGE cases cause disruption to families and parental stress. The burden of RVGE on children and their families could be substantially reduced by routine rotavirus vaccination of infants.

Rotavirus vaccines: considerations for successful implementation in Europe

A group of European experts in infectious diseases and vaccinology has met on several occasions to assess the rationale for universal vaccination against rotavirus infection of infants in Europe. On the basis of the available data, we concluded that vaccination was the best approach to prevent severe rotavirus gastroenteritis, and that European countries should consider implementing rotavirus vaccination in their routine immunisation programmes. The main barrier to the implementation of rotavirus vaccination in Europe is a general lack of awareness of stakeholders, policymakers, health-care professionals, and parents about rotavirus disease and the advantages of vaccination. Further studies on the cost of the disease and the benefit of vaccination, together with raising awareness are necessary steps to ensure successful implementation of rotavirus vaccination in Europe.

A two dose schedule for combined hepatitis A and hepatitis B vaccination in children ages one to eleven years

RATIONALE A combined hepatitis A and B vaccine, Twinrix, containing at least 720 enzyme-linked immunosorbent assay units of hepatitis A antigen and 20 microg of hepatitis B antigen in the adult formulation and half those doses in the pediatric formulation, has been available in many countries since 1997. This vaccine is administered on a three dose schedule: 0, 1 and 6 months. A reduction in the number of doses would add convenience for the vaccinees and reduce administration-associated costs. We investigated the safety and immunogenicity profile of the adult formulation administered at 0 and 6 months in children ages 1 to 11 years. METHODS A total of 237 children of both sexes were enrolled. Blood sampling was performed at 0 and 1, 2, 6 and 7 months. Seropositivity for anti-hepatitis A virus was defined as > or = 33 mIU/ml and seroprotection against hepatitis B virus as > or =10 mIU/ml. Data on solicited and unsolicited adverse events were collected on diary cards. RESULTS The vaccine was well-tolerated in all subjects. At Month 7 all subjects had seroconverted for anti-hepatitis A virus antibodies with a high geometric mean concentration (11 543 mIU/ml). We observed a continuous increase in anti-hepatitis B surface antibody (anti-HBs) seroconversion rates and seroprotection rates until Month 6. After the second dose (Month 7), all subjects seroconverted for anti-HBs antibodies with a high geometric mean concentration (8056 mIU/ml) and 98.5% of the subjects were considered seroprotected. CONCLUSION The two dose adult formulation could be an alternative to prevent hepatitis A and hepatitis B infection in children ages 1 to 11 years.

Combining hepatitis A and B vaccination in children and adolescents

Abstract Hepatitis A and B are common infections worldwide and their severity is related to the individuals age upon initial infection. Furthermore, when hepatitis B infection occurs in infants, the risk of becoming a chronic carrier is 90%. For hepatitis A, the lower incidence of disease arising from an improvement in living conditions leaves a greater number of children, adolescents and young adults susceptible to residual circulating virus. Consequently, initial infection occurs later in life when clinical illness is more frequent and the rate of morbidity and mortality higher. Although both viruses differ greatly, including their modes of transmission, the overlap in their epidemiology warrants the combination of hepatitis A and B vaccination. The immune response elicited by the combined hepatitis A and B vaccine following a three-dose schedule compares well with the anti-hepatitis A virus (HAV) and anti-hepatitis B sero-responses obtained with monovalent vaccines. In addition, it was shown that the seroprotection rate for anti-hepatitis B increased more rapidly with the administration of the combined vaccine, with values of more than 80% within 1 month after the first two doses (schedule, 0, 1 and 6 months). Currently, according to the World Health Organization recommendations, more than 116 countries are vaccinating their infants and/or adolescents against hepatitis B. Recently, several countries were considering or have decided to begin mass vaccination against HAV (more than fifteen states in the US, Spain (Catalonia), Italy (Puglia)). For these countries, the combination of hepatitis A and B antigens in one single vaccine offers the following advantages: fewer injections for protection against two infections, better compliance, lower implementation costs, and fewer missed vaccination opportunities. Further simplification of the schedule, by reducing the number of doses, would improve the compliance rate as well as being more convenient for the vaccinee. This should translate into a reduction in costs associated with vaccine administration. In some recent vaccine studies, the immunogenicity and safety profile of a two-dose schedule (0 and 6 months) of the adult formulation of the combined hepatitis A and B vaccine was investigated in children aged 1–11 years, as well as in adolescents aged 12–15 years. Current results indicate that this two-dose schedule of the adult formulation could be considered a viable alternative for immunization of children and adolescents.

Immunogenicity and safety of a pediatric dose of a virosome-adjuvanted hepatitis a vaccine : A controlled trial in children aged 1-16 years

Background: The availability of pediatric formulations of hepatitis A virus (HAV) vaccines would facilitate the introduction of universal mass vaccination against HAV. The objective of this study was to compare a pediatric dose (0.25 mL) of Epaxal, a virosomal, aluminum-free HAV vaccine, to 0.5 mL standard dose, and to alum-adsorbed HAV vaccine. Methods: Subjects aged 1–16 years, stratified for age, were randomized (2:2:1) into group A (0.25 mL Epaxal), group B (0.5 mL Epaxal), or group C (Havrix Junior). Vaccines were administered at months 0, 6. Seroprotection rates (≥10 mIU/mL anti-HAV antibodies) were assessed for noninferiority, defined as lower limit of 1-sided 97.5% CI >−10%. Incidence of local solicited adverse events and unsolicited adverse events were recorded. Results: Mean age of 308 enrolled subjects was 8.9 years (range, 1.0–17.0 years). All 3 vaccines were highly immunogenic. Noninferiority of group A versus group B and group C with regard to seroprotection was demonstrated after both vaccine doses for the entire study group and for all age subgroups (11–23 months, 2–4, 5–7, 8–10, 11–13, 14–16 years). One month after first vaccination, geometric mean antibody concentrations were 69.0, 83.5, and 50.5 mIU/mL for the 3 groups, respectively (A versus B, P = 0.0208; A versus C, P = 0.0015). Local injection site pain occurred more frequently in group C than in groups A and B. No subjects withdrew from study or reported any vaccine-related serious adverse event. Conclusion: In children aged 1–16 years, 0.25 mL dose of Epaxal is as immunogenic as standard 0.5 mL dose and Havrix Junior. The aluminum-free vaccine compares favorably to comparator vaccine regarding local reactogenicity.