Germaine Hanquet

Pediatric Pneumococcal Serotypes in 4 European Countries

After heptavalent pneumococcal conjugate vaccine (PCV7) was marketed in France, Spain, Belgium, and England and Wales (United Kingdom), invasive disease from non-PCV7 serotypes (NVT) increased. Adjusted serotype-specific incidences among children <15 years of age were compared between 1999-2002 (prevaccine) and 2005-2006 (postmarketing). Vaccine coverage increased to approximately 32%-48% in France, Spain, and Belgium but remained <1% in England and Wales. Serotype 1 incidence rose in all age groups and countries (incidence rate ratio [IRR] 1.3-4.2; p<0.004), independently of PCV7 use, but incidence of serotypes 7F and 19A increased most in France, Spain, and Belgium (IRR 1.9-16.9 in children <5 years; p<0.001), where PCV7 coverage was greater. Vaccine-induced replacement of PCV7 serotypes possibly contributed to NVT increases, as did secular trends. New vaccines targeting these serotypes are available, but serotype dynamics needs further exploration that accounts for underreporting and prevaccine trends.

Vaccine effects and impact of vaccination programmes in post-licensure studies

Once a vaccine is licensed and introduced in the population, post-licensure studies are required to measure vaccine effectiveness and impact of vaccination programmes on the population at large. However, confusion still prevails around these concepts, making it difficult to discern which effects are measured in such studies and how their findings should be interpreted. We review from the public health evaluation perspective the effects of vaccine-related exposures, describe the methods used to measure them and their assumptions. We distinguish effects due to exposure to individual vaccination from those due to exposure to a vaccination programme, as the latter depends on vaccine coverage, other population factors and includes indirect effects as well. Vaccine (direct) effectiveness is estimated by comparing vaccinated and unvaccinated individuals exposed to the same vaccination programme. The impact of a vaccination programme, defined here as the population prevented fraction when exposure is the programme, is measured by comparing populations with and without a vaccination programme, most commonly the same population before and after vaccination. These designs are based on a number of assumptions for valid inference. In particular, they assume that vaccinees and non-vaccinees do not differ in terms of susceptibility and exposure to the disease or in ascertainment of vaccination and disease status. In pre and post-vaccination design, the population is assumed to have similar baseline transmission, case detection and reporting, risk factors and medical practices in both periods. These principles are frequently violated in post-licensure studies. Potential confounding and biases must be minimized in study design and analyses, or taken into account during result interpretation. It is also essential to define which exposure is evaluated (individual vaccination or vaccination programme) and which effect is measured. This may help decision-makers clarify which type of study is needed and how to interpret the results.

Impact of rotavirus vaccination on laboratory confirmed cases in Belgium

Rotavirus vaccines were introduced in Belgium in 2006 and recommended in the universal schedule in January 2007. We measured the impact of rotavirus vaccination through an active laboratory-based surveillance system. In 2008, the number of laboratory confirmed rotavirus cases declined by 61.4% (95% CI 60.2-62.6%) compared to the 2005-2006 pre-vaccination period, with the highest decline in children<1 year (80.1%; 95% CI 78.7-81.4%). The rotavirus season was delayed compared to pre-vaccination seasons. Laboratory data provide a crude estimation of vaccination impact, but analysis of in-patient data will be needed to assess the impact on severe disease.

Impact of conjugate 7-valent vaccination in Belgium: Addressing methodological challenges

In Belgium, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the national schedule in 2007. The early impact of PCV7 vaccination on paediatric invasive disease was estimated by comparing pre- and post-vaccination incidence from national surveillance. In children <2 year-olds, vaccine-serotype incidence declined by 96% but non-vaccine-types increased 2-3-fold. Overall invasive disease decreased by 23-46%, depending on adjustment for under-reporting and pre-vaccine trends. Non-vaccine-types 1 and 19A had increased before PCV7 use, suggesting the contribution of other factors. Estimation of PCV7 impact comparing pre- and post-vaccination data should adjust for pre-vaccine trends, and serotype dynamics need further exploration.

Lessons learnt from pandemic A(H1N1) 2009 influenza vaccination. Highlights of a European workshop in Brussels (22 March 2010).

This European workshop identified a number of lessons learnt in the field of vaccine licensure, prioritization of target groups, communication on pandemic vaccines, implementation of vaccination and safety monitoring. The mild severity of the pandemic A(H1N1) 2009 influenza virus influenced the perception of pandemic vaccines, as previous pandemic preparedness had anticipated a more virulent virus. This vaccination experience provides an important opportunity for research on the long-term immunogenicity and safety of pandemic vaccines in pregnant women and children, as well as on the long-term safety of adjuvants. Preparedness for future pandemics could involve improved decision-making on target groups and increased communication on vaccine safety.

Methods for Health Economic Evaluation of Vaccines and Immunization Decision Frameworks: A Consensus Framework from a European Vaccine Economics Community

AbstractBackgroundIncremental cost-effectiveness and cost-utility analyses [health economic evaluations (HEEs)] of vaccines are routinely considered in decision making on immunization in various industrialized countries. While guidelines advocating more standardization of such HEEs (mainly for curative drugs) exist, several immunization-specific aspects (e.g. indirect effects or discounting approach) are still a subject of debate within the scientific community.ObjectiveThe objective of this study was to develop a consensus framework for HEEs of vaccines to support the development of national guidelines in Europe.MethodsA systematic literature review was conducted to identify prevailing issues related to HEEs of vaccines. Furthermore, European experts in the field of health economics and immunization decision making were nominated and asked to select relevant aspects for discussion. Based on this, a workshop was held with these experts. Aspects on ‘mathematical modelling’, ‘health economics’ and ‘decision making’ were debated in group-work sessions (GWS) to formulate recommendations and/or—if applicable—to state ‘pros’ and ‘contras’.ResultsA total of 13 different aspects were identified for modelling and HEE: model selection, time horizon of models, natural disease history, measures of vaccine-induced protection, duration of vaccine-induced protection, indirect effects apart from herd protection, target population, model calibration and validation, handling uncertainty, discounting, health-related quality of life, cost components, and perspectives. For decision making, there were four aspects regarding the purpose and the integration of HEEs of vaccines in decision making as well as the variation of parameters within uncertainty analyses and the reporting of results from HEEs. For each aspect, background information and an expert consensus were formulated.ConclusionsThere was consensus that when HEEs are used to prioritize healthcare funding, this should be done in a consistent way across all interventions, including vaccines. However, proper evaluation of vaccines implies using tools that are not commonly used for therapeutic drugs. Due to the complexity of and uncertainties around vaccination, transparency in the documentation of HEEs and during subsequent decision making is essential.

Surveillance of invasive pneumococcal disease in 30 EU countries: Towards a European system?

In this era of new pneumococcal conjugate vaccines (PCV), we described and compared surveillance of invasive pneumococcal disease (IPD) and PCV policies in 30 European countries to provide guidance for Europe-wide surveillance. We confirmed the heterogeneity of surveillance systems and case definitions across countries but identified elements common to all countries, such as the availability of serotyping and the surveillance of pneumococcal meningitis. PCV impact was monitored in 11/15 countries using it. We propose steps for the monitoring of incidence rates and serotype distribution at EU level, to assess the need to introduce PCV and monitor its impact once introduced.

Immunologic response of unvaccinated workers exposed to anthrax, Belgium.

To determine immunologic reactivity to Bacillus anthrax antigens, we conducted serologic testing of workers in a factory that performed scouring of wool and goat hair. Of 66 workers, ≈10% had circulating antibodies or T lymphocytes that reacted with anthrax protective antigen. Individual immunity varied from undetectable to high.

Effect of high-valency pneumococcal conjugate vaccines on invasive pneumococcal disease in children in SpIDnet countries: an observational multicentre study

BACKGROUND The Streptococcus pneumoniae Invasive Disease network (SpIDnet) actively monitors populations in nine sites in seven European countries for invasive pneumococcal disease. Five sites use 13-valent pneumococcal conjugate vaccine (PCV13) alone and four use the ten-valent PCV (PCV10) and PCV13. Vaccination uptake is greater than 90% in six sites and 67-78% in three sites. We measured the effects of introducing high-valency PCVs on the incidence of invasive pneumococcal disease in children younger than 5 years. METHODS We compared the incidence of invasive pneumococcal disease in each of the 4 years after the introduction of PCV13 alone or PCV10 and PCV13 with the average incidence during the preceding period of heptavalent PCV (PCV7) use, overall and by serotype category. We calculated incidence rate ratios (IRRs) and 95% CIs for each year and pooled the values for all sites in a random effects meta-analysis. FINDINGS 4 years after the introduction of PCV13 alone or PCV10 and PCV13, the pooled IRR was 0·53 (95% CI 0·43-0·65) for invasive pneumococcal disease in children younger than 5 years caused by any serotype, 0·16 (0·07-0·40) for disease caused by PCV7 serotypes, 0·17 (0·07-0·42) for disease caused by 1, 5, and 7F serotypes, and 0·41 (0·25-0·69) for that caused by 3, 6A and 19A serotypes. We saw a similar pattern when we restricted the analysis to sites where only PCV13 was used. The pooled IRR for invasive pneumococcal disease caused by non-PCV13 serotypes was 1·62 (1·09-2·42). INTERPRETATION The incidence of invasive pneumococcal disease caused by all serotypes decreased due to a decline in the incidence of vaccine serotypes. By contrast, that of invasive pneumococcal disease caused by non-PCV13 serotypes increased, which suggests serotype replacement. Long-term surveillance will be crucial to monitor the further effects of PCV10 and PCV13 vaccination programmes in young children. FUNDING European Centre for Disease Prevention and Control, Czech National Institute of Public Health, French National Agency for Public Health, Irish Health Services Executive, Norwegian Institute of Public Health, Public Health Agency of Catalonia, Public Health Department of Community of Madrid, Navarra Hospital Complex, Public Health Institute of Navarra, CIBER Epidemiology and Public Health, Institute of Health Carlos III, Public Health Agency of Sweden, and NHS Scotland.

Cost-effectiveness of seasonal influenza vaccination in pregnant women, health care workers and persons with underlying illnesses in Belgium.

Risk groups with increased vulnerability for influenza complications such as pregnant women, persons with underlying illnesses as well as persons who come into contact with them, such as health care workers, are currently given priority (along with other classic target groups) to receive seasonal influenza vaccination in Belgium. We aimed to evaluate this policy from a health care payer perspective by cost-effectiveness analysis in the three specific target groups above, while accounting for effects beyond the target group. Increasing the coverage of influenza vaccination is likely to be cost-effective for pregnant women (median €6589 per quality-adjusted life-year (QALY) gained [€4073-€10,249]) and health care workers (median €24,096/QALY gained [€16,442-€36,342]), if this can be achieved without incurring additional administration costs. Assuming an additional physicians consult is charged to administer each additional vaccine dose, the cost-effectiveness of vaccinating pregnant women depends strongly on the extent of its impact on the neonates health. For health care workers, the assumed number of preventable secondary infections has a strong influence on the cost-effectiveness. Vaccinating people with underlying illnesses is likely highly cost-effective above 50 years of age and borderline cost-effective for younger persons, depending on relative life expectancy and vaccine efficacy in this risk group compared to the general population. The case-fatality ratios of the target group, of the secondary affected groups and vaccine efficacy are key sources of uncertainty.