Thomas Verstraeten

Burden of rotavirus disease in European Union countries.

Two new rotavirus vaccines are expected to be introduced in the European Union (EU) in coming years. A human rotavirus vaccine has already been licensed in several countries worldwide, and a pentavalent bovine vaccine has been submitted for licensure in the United States and the EU. Few data exist on the burden of rotavirus disease and its associated costs within the EU. To estimate the burden of rotavirus disease in the EU, we adapted a model based on the approach developed by the Centers for Disease Control and Prevention to the European situation and applied it to recent population and mortality data from European countries. Country-specific estimates were added to obtain a global estimate of rotavirus episodes treated at home, clinic visits, hospitalization and death. We estimate that 3.6 million episodes of rotavirus disease occur annually among the 23.6 million children younger than 5 years of age in the EU. Every year, rotavirus accounts for 231 deaths, >87,000 hospitalizations and almost 700,000 outpatient visits. Rotavirus disease constitutes a large public health burden in the EU. Except for deaths, the burden of disease is not dissimilar to that in the developing world. Country-specific studies are required to more accurately understand the burden of disease caused by rotavirus. With the introduction of new rotavirus vaccines in sight, rotavirus gastroenteritis may be regarded as the single most frequent vaccine-preventable disease among children in the EU.

Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: A pooled analysis of 11 clinical trials

A pooled analysis of the safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine Cervarix™ (GlaxoSmithKline) was performed in a cohort of almost 30000 girls and women aged ≥10 years, 16142 who received at least one dose of the HPV-16/18 vaccine and 13811 who received one of three controls [Al(OH)3 or hepatitis A vaccine (720 or 360 EU)]. Data are available for a total of 45988 vaccine doses. Solicited local and general symptoms were recorded for 7 days after each dose. Serious adverse events (SAEs), pregnancies, medically significant conditions (MSCs) and new onset of chronic diseases (NOCDs), including new onset of autoimmune diseases (NOADs), were proactively monitored. Data were analyzed by vaccine group according to age (10–14, 15–25 and >25 years) and reporting period (Months 0–7, Months 7–12 and >Month 12). Rates of solicited local and general symptoms were higher in the HPV-16/18 vaccine group than in the control groups. However, compliance with the 3-dose schedule was high and did not differ between groups (93.4% for HPV-16/18 vaccine group versus 92.5% for pooled controls). No clinically relevant differences were seen between the HPV-16/18 vaccine and pooled control groups in rates of SAEs (2.8% versus 3.1%), MSCs (19.4% versus 21.4%), NOCDs (1.7% in both groups) or NOADs (0.4% versus 0.3%). Similarly, no differences in pregnancy outcomes or rates of withdrawals due to AEs or SAEs were observed between groups. In conclusion, analysis of this large database shows the HPV-16/18 AS04-adjuvanted cervical cancer vaccine to have a favorable safety profile in women of all ages.

Prospective multinational study of pertussis infection in hospitalized infants and their household contacts.

Background: Increased incidence of pertussis has been noted among infants too young to be immunized. We studied the disease burden of pertussis in pediatric intensive care units and the source of infection in several Asian, European and Latin American countries. Methods: The study was conducted in 7 countries from September 2001 to January 2004. Children <1 year of age were enrolled from pediatric intensive care units (PICU) and pediatric wards if they presented with respiratory failure, apnea, bradycardia, or cough accompanied by paroxysms, vomiting, whoop or cyanosis. Household members of pertussis-positive index cases were asked to answer a questionnaire and provide diagnostic specimens. Results: Pertussis was confirmed in 99 infants (12%) of 823 infants included in the analysis: 10 of 90 (11%) in Brazil, 9 of 88 (10%) in Costa Rica, 11 of 145 (8%) in Germany, 13 of 147 (9%) in Singapore, 29 of 67 (43%) in Spain, 2 of 86 (2%) in Taiwan and 25 of 200 (13%) in Uruguay. However, sensitivity analysis indicated that these figures were conservative. The mean (±SD) average age of infection was 2.6 ± 2.2 months. Pertussis was found among 96 of 269 (36%) of household contacts investigated. At least one household contact was identified as the source of infection in 24 of 88 (27%) of the PICU cases and mothers were identified as being the most frequent source of infection. Conclusion: Although regional differences exist, severe pertussis represents a considerable global disease burden. Since most infants are infected before vaccination and concomitant protection is completed, household contacts should be targeted for booster vaccination to reduce the pertussis reservoir.

Postmarketing surveillance of intussusception following mass introduction of the attenuated human rotavirus vaccine in Mexico.

Background: Mexico initiated mass vaccination with the attenuated human rotavirus vaccine (Rotarix) in 2006. This postlicensure study aimed to assess any potential temporal association between vaccination and intussusception in Mexican infants. Methods: Prospective, active surveillance for intussusception among infants aged less than 1 year was conducted in 221 hospitals across Mexico from the Mexican Institute of Social Security between January 2008 and October 2010. The temporal association between vaccination and intussusception was assessed by self-controlled case-series analysis. Results: Of the 753 episodes of intussusception reported in 750 infants, 701 were in vaccinated infants (34.5% post–dose 1, 65.5% post–dose 2). The relative incidence of intussusception within 31 days of vaccination was 1.75 (95.5% confidence interval [CI]: 1.24–2.48; P = 0.001) post–dose 1 and 1.06 (95.5% CI: 0.75–1.48; P = 0.75) post–dose 2. The relative incidence of intussusception within 7 days of vaccination was 6.49 post–dose 1 (95.5% CI: 4.17–10.09; P < 0.001) and 1.29 post–dose 2 (95.5% CI: 0.80–2.11; P = 0.29). Clustering of intussusception within 7 days of vaccination was observed post–dose 1. An attributable risk of 3 to 4 additional cases of intussusception per 100,000 vaccinated infants was estimated. Conclusion: This is the largest surveillance study for intussusception after rotavirus vaccination to date. A temporal increase in the risk for intussusception was seen within 7 days of administration of the first vaccine dose. It is still uncertain whether rotavirus vaccination has any impact on the overall incidence of intussusception. This finding has to be put in perspective with the well-documented substantial benefits of rotavirus vaccination.

Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split virion H1N1 (2009) pandemic influenza vaccine during pregnancy: A prospective cohort study

Infection with influenza virus during pregnancy poses a significant risk of complications for both mother and fetus. During the H1N1 2009 pandemic, pregnant women constituted one of the priority groups for vaccination in many countries, creating a need for close monitoring of the safety of the vaccine in pregnant women. We present findings from an analysis of a cohort of pregnant women (N=267) from a prospective, observational, post-authorization safety study of the AS03-adjuvanted split virion H1N1 (2009) pandemic vaccine. There were 265 known pregnancy outcomes with 261 live births, four spontaneous abortions with no congenital anomalies, and no stillbirths. There were six live births with congenital anomalies, of which one was diagnosed before vaccination. A total of 247 women (94.6%), of whom four had twin pregnancies, delivered at term, and 14 women (5.4%), of whom two had twin pregnancies, delivered preterm (between Weeks 24 and 36 of gestation), with three of them (1.1%) occurring before 32 weeks (very preterm). Twenty-one neonates (8.1%) had a low birth weight (<2.5 kg), of whom nine (3.5%) were term neonates. The prevalence of all outcomes was in line with the expected rates. The adverse events reported were consistent with the events anticipated to be reported by this study population. No adverse events of special interest were reported. The results of this analysis suggest that exposure to the AS03 adjuvanted H1N1 (2009) vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes including spontaneous abortion, congenital anomalies, preterm delivery, low birth weight neonates, or maternal complications. Although limited in size, the fully prospective nature of the safety follow-up of these women vaccinated during pregnancy is unique and offers an important degree of reassurance for the use of the AS03 adjuvanted H1N1 (2009) vaccine in this high risk group for H1N1 infection.

Rotavirus Serotype G9 Is Associated with More-Severe Disease in Latin America

The association between rotavirus serotypes and severity is not well established. Analysis of a clinical trial conducted in Latin America points at more-severe disease associated with serotype G9. Thus, demonstration of efficacy against G9 will be an important asset of any rotavirus vaccine to be introduced into a Latin American country or any country where G9 has been shown to be prevalent.

Impact of universal varicella vaccination on 1-year-olds in Uruguay: 1997–2005

Objective: Varicella vaccination was introduced at the end of 1999 into the Uruguayan immunisation schedule for children aged 12 months. Varilrix (Oka strain; GlaxoSmithKline Biologicals) has been the only vaccine used since then and coverage has been estimated to exceed 90% since the start of the universal varicella vaccination programme. We assessed the impact of the Uruguayan varicella vaccination programme during 2005, 6 years after its introduction. Methods: Information on hospitalisations was collected from the main paediatric referral hospital and information on medical consultations for varicella was collected from two private health insurance systems in Montevideo. The proportion of hospitalisations due to varicella and the proportion of ambulatory visits for varicella since the introduction of the vaccine were compared between 1999 and 2005 and 1997 and 1999 in the following age groups: <1 year, 1–4 years, 5–9 years and 10–14 years. Results: By 2005, the proportion of hospitalisations due to varicella among children, was reduced by 81% overall and by 63%, 94%, 73% and 62% in the <1, 1–4, 5–9 and 10–14 years age groups, respectively. The incidence of ambulatory visits for varicella among children was reduced by 87% overall and by 80%, 97%, 81% and 65% in the <1, 1–4, 5–9 and 10–14 years age groups, respectively. Conclusions: The burden of varicella has decreased substantially in Uruguayan children since the introduction of the varicella vaccination, including those groups outside the recommended vaccination age. It is expected to decrease further as more cohorts of children are vaccinated and herd immunity increases.

Review of 8 years of experience with Infanrix hexa™ (DTPa–HBV–IPV/Hib hexavalent vaccine)

Combination vaccines that include multiple antigens within one formulation are now widely accepted as an effective means of eliciting protection against several diseases at the same time. Owing to improvements in quality and convenient modes of administration, they have become part of routine pediatric practice. Hexavalent vaccines, including diphtheria, tetanus, pertussis, hepatitis B, polio and Haemophilus influenzae type b antigens represent the latest advance in the development of combination vaccines. Over 8 years since its first licensure, this review looks at the immunogenicity, efficacy and safety profile of the only hexavalent pediatric vaccine currently in use – Infanrix hexa™ (diphtheria, tetanus, acellular pertusis–hepatitis B virus–inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine [DTPa–HBV–IPV/Hib]; GlaxoSmithKline Biologicals, Rixensart, Belgium) – through published clinical trials and postmarketing surveillance data. These data show DTPa–HBV–IPV/Hib to be highly immunogenic and well tolerated across a range of different primary and booster vaccination schedules, as well as when administered concomitantly with other licensed vaccines (e.g., pneumococcal conjugate vaccine). Additional issues surrounding the use of hexavalent vaccines are also reviewed.

Four and one-half-year follow-up of the effectiveness of diphtheria-tetanus toxoids-acellular pertussis/Haemophilus influenzae type b and diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus/H. influenzae type b combination vaccines in Germany

Background: Recently an increase in the number of invasive Haemophilus influenzae type b (Hib) cases was observed in the United Kingdom, which coincided with a temporary change from diphtheria-tetanus toxoids-wild-type pertussis to diphtheria-tetanus toxoids-acellular pertussis (DTaP) Hib vaccines. A study in Germany based on approximately 2 years of follow-up, estimated vaccine effectiveness (VE) of DTaP/Hib and DTaP-inactivated poliovirus/Hib combination vaccines against invasive Hib disease to be high. Objectives: To assess VE of DTaP-containing Hib vaccines against Hib in Germany with the use of extended follow-up of case surveillance and vaccine uptake. Subjects and Methods: Cases with confirmed systemic Hib infections in children born between June 1, 1996 and December 31, 1998 were ascertained by a nationwide active surveillance system from January 1998 through June 2002. A representative subcohort of 667 children born in the same time frame was randomly sampled in a nationwide vaccine coverage survey. VE was determined with a case-cohort approach of Cox regression with time-dependent covariates. Results: Thirty-six cases of Hib disease were reported. Of these, 10 were vaccinated with DTaP-containing Hib vaccines only and 20 were not vaccinated. Of the 10 vaccinated cases, 4 had received an incomplete primary series (1–2 doses), and 6 had received the full primary series (3 doses), 3 of whom also received the booster dose. VE of combination vaccines against invasive Hib infection was 89.6% [95% confidence interval (CI), 67.0–96.7] for an incomplete primary series, 96.7% (95% CI 87.7–99.1) for a full primary series and 98.5% (95% CI 94.5–99.6) for a booster dose (irrespective of priming). Conclusion: Hib combination vaccines containing acellular pertussis antigens continue to be highly effective in Germany.

Vaccine safety surveillance using large linked databases: opportunities, hazards and proposed guidelines.

Combined administrative databases are referred to as ‘large linked databases’ because of their relatively large size and the need for linkage of different data sets that were created separately from each other. Such linked databases have become popular in vaccine safety surveillance. Whereas their use offers some unique opportunities, their increasingly widespread use can also lead to wrongful linkage of vaccines to adverse events. We review the opportunities and hazards of using large linked databases for vaccine safety surveillance and propose some guidelines to increase the reliability of the outcomes. We also offer our opinion on the future use of large linked databases for vaccine safety surveillance purposes.