Philippe Duclos

How best to estimate the global burden of pertussis

In most countries, pertussis surveillance is inadequate for accurately estimating numbers of cases or deaths. Good estimates are needed to help set priorities for vaccination programmes. We aimed to develop a simple, reliable, and explicit method for estimating pertussis cases and deaths for children under 15 years to calculate the global disease burden in 1999. We estimated the proportion of susceptible children becoming infected in countries with poor vaccination coverage (<70%) in 1999 at 30% by 1 year, 80% by 5 years, and 100% by 15 years of age and for countries with good coverage (> or =70%) at 10% by 1 year, 60% by 5 years, and 100% by 15 years. Vaccine efficacy was estimated at 80% for preventing infection and 95% for preventing deaths. We used UN population estimates and vaccination coverage reported to WHO (adjusted for specific survey data if available). Case fatality ratios for countries with high and low child mortality were derived from published and unpublished work. For some countries with good vital events registration we used reported deaths adjusted for underascertainment. In 1999 there were an estimated 48.5 million pertussis cases in children worldwide. Deaths from pertussis were estimated at 390000 and at 295000 after adjustment for local data sources. Based on this approach, disability-adjusted life years from pertussis (12.7 million) in 2000 exceeded those of other preventable diseases such as lung cancer (11.4 million) and meningitis (5.8 million). This simple approach yields estimates that can be used for setting vaccination programme priorities. Better data are needed on the public health importance of pertussis in high mortality countries, the benefits of incomplete vaccination, and the harm from delayed vaccination.

Epidemiological Features of Pertussis in Hospitalized Patients in Canada, 1991- 1997: Report of the Immunization Monitoring Program—Active (IMPACT)

To assess the morbidity associated with the continued high levels of pertussis, we studied all children <2 years of age who were admitted to the 11 Immunization Monitoring Program--Active (IMPACT) centers, which constitute 85% of Canadas tertiary care pediatric beds. In the 7 years preceding implementation of acellular pertussis vaccine, a total of 1,082 pertussis cases were reported, of which 49.1% were culture-confirmed. The median age of the patients was 12.4 weeks; 78.9% of cases were in children <6 months of age. Complications of pertussis were common: pneumonia was reported in 9.4% of cases, new seizures in 2.3%, and encephalopathy in 0.5%. There were 10 deaths (0.9%), all in children < or =6 months of age. Duration of hospitalization was longer (9.3 days vs. 4.9 days; P = .001) and intensive care was required more frequently (19.2% vs. 4.9%; P = .001) in infants under <6 months of age than in those > or =6 months. Pertussis continues to cause significant morbidity and occasional mortality in Canada, particularly in young infants.

The Brighton Collaboration: addressing the need for standardized case definitions of adverse events following immunization (AEFI)

UNLABELLED To further scientific progress of immunization safety, comparability of data from clinical trials and surveillance systems is essential. Comparability requires the availability of standardized case definitions for adverse events following immunization (AEFI) and guidelines for case determination, recording and data presentation. METHOD International collaborative working groups, consisting of professional volunteers from developed and developing countries, conduct systematic literature reviews to develop 50-100 AEFI definitions. Case definitions are finalized after a comment period by a reference group consisting of organizations concerned with immunization safety, and will be disseminated via the world-wide-web and other means for free world-wide use. RESULTS Literature reviews yielded substantial diversity in data collection and presentation. We have developed standardized case definitions together with guidelines for use in clinical trials and surveillance systems. CONCLUSIONS Diversity in safety methods leads to considerable loss of scientific information. We have built the necessary international network of currently about 300 participants from patient care, public health, scientific, pharmaceutical, regulatory and professional organizations to develop and assess standardized AEFI case definitions and guidelines. Evaluation studies, global implementation, ongoing definition development and a continuously growing network will be essential for the success of the collaboration.

Global immunization: status, progress, challenges and future

Vaccines have made a major contribution to public health, including the eradication of one deadly disease, small pox, and the near eradication of another, poliomyelitis.Through the introduction of new vaccines, such as those against rotavirus and pneumococcal diseases, and with further improvements in coverage, vaccination can significantly contribute to the achievement of the health-related United Nations Millennium Development Goals.The Global Immunization Vision and Strategy (GIVS) was developed by WHO and UNICEF as a framework for strengthening national immunization programmes and protect as many people as possible against more diseases by expanding the reach of immunization, including new vaccines, to every eligible person.This paper briefly reviews global progress and challenges with respect to public vaccination programmes. The most striking recent achievement has been that of reduction of global measles mortality from an estimated 750,000 deaths in 2000 down to 197,000 in 2007. Global vaccination coverage trends continued to be positive. In 2007 most regions reached more than 80% of their target populations with three doses of DPT containing vaccines. However, the coverage remains well short of the 2010 goal on 90% coverage, particularly in the WHO region of Africa (estimated coverage 74%), and South-East Asia, (estimated coverage 69%). Elements that have contributed to the gain in immunization coverage include national multi-year planning, district-level planning and monitoring, re-establishment of outreach services and the establishment of national budget lines for immunization services strengthening. Remaining challenges include the need to: develop and implement strategies for reaching the difficult to reach; support evidence-based decisions to prioritize new vaccines for introduction; strengthening immunization systems to deliver new vaccines; expand vaccination to include older age groups; scale up vaccine preventable disease surveillance; improve quality of immunization coverage monitoring and use the data to improve programme performance; and explore financing options for reaching the GIVS goals, particularly in lower-middle income countries. Although introduction of new vaccines is important,this should not be at the expense of sustaining existing immunization activities. Instead the introduction of new vaccine introduction should be viewed as an opportunity to strengthen immunization systems, increase vaccine coverage and reduce inequities of access to immunization services.Vaccines have made a major contribution to public health, including the eradication of one deadly disease, small pox, and the near eradication of another, poliomyelitis.Through the introduction of new vaccines, such as those against rotavirus and pneumococcal diseases, and with further improvements in coverage, vaccination can significantly contribute to the achievement of the health-related United Nations Millennium Development Goals.The Global Immunization Vision and Strategy (GIVS) was developed by WHO and UNICEF as a framework for strengthening national immunization programmes and protect as many people as possible against more diseases by expanding the reach of immunization, including new vaccines, to every eligible person.This paper briefly reviews global progress and challenges with respect to public vaccination programmes.The most striking recent achievement has been that of reduction of global measles mortality from an estimated 750,000 deaths in 2000 down to 197,000 in 2007. Global vaccination coverage trends continued to be positive. In 2007 most regions reached more than 80% of their target populations with three doses of DPT containing vaccines. However, the coverage remains well short of the 2010 goal on 90% coverage, particularly in the WHO region of Africa (estimated coverage 74%), and South-East Asia, (estimated coverage 69%). Elements that have contributed to the gain in immunization coverage include national multi-year planning, district-level planning and monitoring, re-establishment of outreach services and the establishment of national budget lines for immunization services strengthening.Remaining challenges include the need to: develop and implement strategies for reaching the difficult to reach; support evidence-based decisions to prioritize new vaccines for introduction; strengthening immunization systems to deliver new vaccines; expand vaccination to include older age groups; scale up vaccine preventable disease surveillance; improve quality of immunization coverage monitoring and use the data to improve programme performance; and explore financing options for reaching the GIVS goals, particularly in lower-middle income countries.Although introduction of new vaccines is important,this should not be at the expense of sustaining existing immunization activities. Instead the introduction of new vaccine introduction should be viewed as an opportunity to strengthen immunization systems, increase vaccine coverage and reduce inequities of access to immunization services.

The Global Burden of Measles in the Year 2000—A Model that Uses Country‐Specific Indicators

The estimation of the global burden of measles is challenging in the absence of reliable and comparable surveillance systems worldwide. A static model is described that enables estimation of measles morbidity, mortality, and disability for the year 2000 on the basis of country-specific information (i.e., demographic profile, vaccine coverage, and estimates of case-fatality ratios). This approach estimated a global incidence of 39.9 million measles cases, 777,000 deaths, and 28 million disability-adjusted life years. The World Health Organization regions of Africa and Southeast Asia had 70% of incident cases and 84% of measles-related deaths; 11 countries alone (Afghanistan, Burkina Faso, Democratic Republic of the Congo, Ethiopia, India, Indonesia, Niger, Nigeria, Pakistan, Somalia, Uganda) account for 66% of deaths. This approach quantifies the measles burden by considering country-specific indicators, which can be updated, permitting an assessment of country, regional, and global changes in the burden associated with measles infection.

Vaccine Safety Controversies and the Future of Vaccination Programs

In the years following the hepatitis B vaccination/multiple sclerosis controversy, a number of new issues regarding vaccine safety have been raised, in some cases leading to more debate and confusion. Against this background, an international group of experts was convened to review the current points of view concerning the use of thimerosal as a preservative and its potential risks; the suggested link between thimerosal-containing vaccines and acute lymphoblastic leukemia; the alleged association between aluminum-containing vaccines/macrophagic myofasciitis and general systemic complaints; a possible link between vaccination and autoimmune pathology; and a hypothetical link between measles-mumps-rubella vaccination and autism. At present, there are no data to conclude that childhood vaccines, and in particular hepatitis B vaccine, pose a serious health risk or justify a change in current immunization practice. However, vaccine “scares” continue to have an international impact on immunization coverage. Creating a positive environment for immunization can be achieved by repositioning the value of vaccines and vaccination, supported by evidence-based information. The role of international organizations, the media, and the industry in the implementation of communication strategies was discussed and the impact of litigation issues on vaccination was evaluated. The Viral Hepatitis Prevention Board confirms its commitment to current recommendations for universal and risk group hepatitis B vaccination and further encourages the conduct of vaccine safety studies and the dissemination of their results.

Ensuring vaccine safety in immunization programmes : a WHO perspective

Ever since vaccines were firstly used against smallpox, adverse events following immunization have been reported. As immunization programmes expand to reach even the most remote communities in the poorest countries, it is likely that many more events will be temporally linked with vaccine administration. Furthermore, the profound shift in the general public and media interest in adverse events may lead to undue concerns and allegations which may ultimately jeopardize immunization programmes world-wide. While the health professional has understood this issue for some time, the public and the media have now also become all too aware of the significance of vaccine-related adverse events. The familiar vaccines, well-tested over decades, have not changed--but the perception regarding their safety has shifted. Claims outrageous or reasonable are being made against both the old and the newly-introduced vaccines. At the same time, the immunological and genetic revolution of the last decade may well bring to our notice some hypothetical risks that need to be addressed at pre-clinical level. WHO has been at the leading edge to guarantee vaccine safety for the last 30 years and will continue to do so. The Organizations plans for the next decade and beyond include the Safe Injection Global Network (SIGN), the development and introduction of safer technologies, and the prevention, early detection and management of AEFIs. The new technologies include needle-containing injection devices such as the autodisable syringe, as well as mucosal and transcutaneous immunization. Training will continue to be at the centre of WHOs efforts, limiting human error to a minimum. Mechanisms have been set in place to detect and respond to new and unforeseen events occurring. Above all, there is a willingness to respond to new climates and new technologies so that the Organization is in the best position to ensure safe immunization for all the worlds children.

Measles vaccines: A review of adverse events

A great deal of controversy has recently been generated over the publication of several articles implicating measles vaccine in the induction of Crohn’s disease and autism. The publication of this work has already had a negative impact on measles vaccine acceptance in the UK. These allegations are particularly troubling because they arise in the context of increased use of measles vaccine as global control of measles nears and the international community considers strategies for a drive towards eradication.In 1994, the US Institute of Medicine reviewed the world literature and published a comprehensive review of adverse events associated with measles-containing vaccines. Reviewing the literature published between 1994 and the present day, reveals that there is considerable new data suggesting that modified gelatin rather than egg proteins is responsible for most episodes of anaphylaxis following measles vaccination. New work weakens the possible links between measles vaccine and subacute sclerosing panencephalitis and Guillain-Barré syndrome, but strengthens the rare association of measles-containing vaccines with post infectious encephalomyelitis. The alleged associations between measles vaccination and Crohn’s disease and autism are based upon weak science and have largely been refuted by a large volume of stronger work.A review of the data generated in the last 4 years amply demonstrates the continued efforts of the scientific community to monitor and understand true measles vaccine-associated adverse events. The rapidity and clarity of this same community’s debunking of the spurious associations with Crohn’s disease and autism suggests that those charged with vaccination programmes have learned from past mistakes.During 30 years of worldwide use, measles vaccination has proven to be one of the safest and most successful health interventions in the history of mankind. It is not a ‘perfect’ vaccine, but the benefits of measles vaccination far outweigh the risks even in countries with low incidence of measles and high rates of measles vaccine coverage.

The future of immunisation policy, implementation, and financing

Vaccines have already saved many lives and they have the potential to save many more as increasingly elaborate technologies deliver new and effective vaccines against both infectious diseases--for which there are currently no effective licensed vaccines--such as malaria, tuberculosis, and HIV and non-infectious diseases such as hypertension and diabetes. However, these new vaccines are likely to be more complex and expensive than those that have been used so effectively in the past, and they could have a multifaceted effect on the disease that they are designed to prevent, as has already been seen with pneumococcal conjugate vaccines. Deciding which new vaccines a country should invest in requires not only sound advice from international organisations such as WHO but also a well informed national immunisation advisory committee with access to appropriate data for local disease burden. Introduction of vaccines might need modification of immunisation schedules and delivery procedures. Novel methods are needed to finance the increasing number of new vaccines that have the potential to save lives in countries that are too poor to afford them. Here, we discuss some options.

Safety of immunisation and adverse events following vaccination against hepatitis B.

Hepatitis B vaccines (HBVs) are composed of highly purified preparations of hepatitis B virus surface antigen (HBsAg). An adjuvant, either aluminium phosphate or aluminium hydroxide, is added to the vaccines, which are sometimes preserved with thiomersal. In placebo-controlled studies, common side effects other than local reactions were reported no more frequently among vaccine recipients than among individuals receiving a placebo. A number of controversial adverse events have, however, been purported to be associated with HBVs, including rheumatoid arthritis (RA), diabetes, demyelinating diseases (e.g., multiple sclerosis [MS]), chronic fatigue syndrome, and more recently, lymphoblastic leukaemia. In addition, the safety of the thiomersal and aluminium contained in the vaccine has also been under close scrutiny. These issues have been reviewed by a number of country-specific or international independent review committees such as that of the US Institute of Medicine (IOM) and the World Health Organization’s (WHO) Global Advisory Committee on Vaccine Safety (GACVS). Upon review of the scientific evidence, none of the serious allegations have so far been confirmed. On the contrary, scientific evidence has accumulated to disprove many of the allegations. In particular, the IOM committee has concluded that the evidence favoured rejection of a causal relationship between HBV administered to adults and incident MS or MS relapse. Whilst it is important to continue monitoring some of the safety issues, there is no evidence to suggest that the WHO should consider altering its recommendation that all countries should have universal infant and/or adolescent immunisation programmes. The risks of hepatitis B vaccination are only theoretical in comparison with clear benefits in terms of cirrhosis and cancer prevention, and the HBV remains one with an excellent safety profile.