Progress with human H5N1 vaccines: a perspective from industry.

With the ongoing widespread circulation of avian H5N1 influenza viruses and the threat of pandemic influenza an ever-present reality, it is essential that those charged with protecting public health continue to focus intently on this urgent issue. As part of the response to this pandemic threat, research-based influenza vaccine manufacturers have made rapid progress with the research, development and testing of new vaccines and have greatly expanded their capacity to manufacture these products in the last few years. With the research and development phase now reaching completion, regulators have approved several prototype 'mock-up' pandemic vaccines and a number of 'prepandemic' H5N1 vaccines. As a consequence, the world is better prepared than it has ever been to counter an influenza pandemic. However, despite these advances, many policy, logistical and practical issues must be resolved for the population to benefit from these breakthroughs. In particular, the global community must establish the infrastructure required for population-wide immunization, secure appropriate vaccine supplies and undertake sufficient vaccine stockpiling to protect against the first wave of a pandemic.

New vaccine approaches for seasonal and pandemic influenza.

Inactivated influenza vaccines have been available since the late 1940s for the prevention of influenza disease. Based on the available scientific evidence, many public health authorities, including the World Health Organization, recommend annual use of these vaccines for specific populations, including the elderly. Despite these recommendations, actual vaccination uptake rates are very limited in many countries. Influenza vaccine research is confounded by the variable nature of the influenza viruses and annual influenza epidemics and by non-specific clinical diagnostic criteria. These confounding factors complicate evaluation not only of overall vaccine effectiveness, but also of the relative efficacy and effectiveness of different vaccine formulations. This paper summarizes recent advances in the development of seasonal and (pre-)pandemic vaccines, discusses the methodologic constraints on influenza vaccine research, and proposes measures to reduce the level of potential bias and confounding in influenza vaccine research.

Influenza vaccine supply: building long-term sustainability.

Influenza represents a public health paradox. The virus is responsible for significant death, disease and economic loss. However, despite the availability of safe and efficacious vaccines, uptake is poor. While policy makers increasingly recognize the value of annual immunization, and vaccine supply is increasing, further efforts are required to implement existing vaccination recommendations and drive the long-term demand that supports supply sustainability. This is equally important for pandemic vaccine supply, which will rely on the same production plants and manufacturing approaches. Technological advances and capacity expansions now offer the prospect of billions of doses of vaccine in the event of a pandemic, and the availability of pre-pandemic vaccines for stockpiling and pre-emptive use. As a result, vaccination strategies utilizing pre-pandemic vaccines, combined with vaccines matched to a pandemic strain once available, offer for the first time a viable approach for mitigating an influenza pandemic.

Antibody induction by virosomal, MF59-adjuvanted, or conventional influenza vaccines in the elderly.

In a randomized, observer-blind, three-arm, parallel group, multi-centre trial including 386 elderly subjects in four countries, the immunogenicity and safety was studied of three different trivalent inactivated surface antigen (subunit) influenza vaccine types: a conventional subunit influenza vaccine (SIV, brand: Influvac and two newer vaccines: a MF59-adjuvanted subunit influenza vaccine (adSIV, brand: Fluad and a virosomal subunit influenza vaccine (vSIV, brand: Invivac. All vaccines were trivalent containing 15 microg hemagglutinin of each virus strain as recommended by the World Health Organization for the 2004-2005 season. The study was designed to demonstrate the serological non-inferiority of vSIV to both adSIV and SIV in elderly persons. The secondary objective was to investigate whether vSIV is superior to adSIV with respect to local reactogenicity. For all three vaccine strains, the post-vaccination geometric mean titres were comparable between SIV and adSIV and between vSIV and SIV. Seroprotection rates (i.e. percentages of subjects with a post-vaccination titre >or=40) varied between 84.1-100% indicating that the three vaccines all induced a strong antibody response. Local and systemic reactions were more frequently associated with adSIV (46 and 32%, respectively) than with vSIV or SIV ( approximately 20%). Vaccinations caused only little inconvenience as measured by questionnaire. In general, all vaccines were safe and well tolerated. In this trial, virosomal vaccine had similar immunogenicity to MF59-adjuvanted and conventional subunit vaccine and was considerably less reactogenic than the MF59-adjuvanted vaccine in the elderly.

Establishing the health and economic impact of influenza vaccination within the European Union 25 countries.

BACKGROUND: In 2003, the World Health Assembly (WHA) issued a resolution for prevention and control of influenza pandemics and annual epidemics, which urges the European Union 25 (EU-25) Member States to (1) establish and implement strategies to increase vaccination coverage of all people at high risk, including the elderly and people with underlying disease, with the goal of attaining vaccination coverage of the elderly population of at least 50% by 2006 and 75% by 2010; (2) to assess the disease burden and economic impact of annual influenza epidemics as a basis for framing and implementing influenza prevention policies. This resolution was reinforced by the European Union (EU), where Member States agreed to make additional efforts to improve uptake on their territory in accordance with their own recommendations and to achieve the World Health Organisation (WHO) target of 75% in high risk groups before 2010. It was also noted that the changing demographic profile of the EU population would result in an increasing number of elderly people falling within the current target groups. OBJECTIVES: To establish the number of people who may be eligible for influenza vaccination in the EU, and estimate the costs and consequences of not vaccinating this population for five EU Member States, France, Germany, Italy, Spain, and the UK. METHODS: A mathematical model has previously been developed, in which vaccine distribution data are combined with demographic and health economics data to model the public health consequences of influenza and possible intervention strategies. We have extended that model using specific EU-25 demographic data on populations at risk of influenza during the inter-pandemic period. For each country, the total population and age breakdown was calculated to estimate the percentage of the population that falls under the WHA recommendations. Other target groups for influenza vaccination were identified by analysing estimating the proportion of the population with respiratory or cardiovascular related diseases, diabetes, AIDS or transplantation, as well as health care professionals. Target population size and possible vaccination coverage rates across the EU-25 Member States, along with the potential cost and health consequence impact is estimated. RESULTS: For the EU-25, it was estimated that up to 49.1% of the population (or 223.4 million people) should be vaccinated against influenza. This ranged from 41.6% in Cyprus to 56.4% in the UK. There were, on average, 174 vaccine doses distributed per 1000 population within the EU-25, which leads to an average vaccination rate of the target population of 35.4% based on current supply constraints. As a consequence, up to 144.4 million people who could be considered "at risk" may not currently be vaccinated. Implementing a 100% vaccination rate programme for all risk groups across the EU-25 would lead to an estimated reduction of number of influenza cases of 7.22 million, 1.96 million reduced PCP visits for influenza treatment, 796,743 less hospital admissions and 68,537 fewer influenza related deaths for all EU-25 countries. The implementation of a 100% vaccination rate programme for all risk groups in France, Germany, Italy, Spain and UK would require an additional 1.52 billion Euro. This would result in estimated savings of 39.45 million Euro of reduced primary care visits and further savings of 1.59 billion Euro in reduced hospitalisations respectively in these countries. CONCLUSIONS: There is a gap between current vaccination coverage and the EU recommendations. The public health consequences of low vaccination coverage include increased morbidity, hospitalisations and mortality associated with influenza-related complications. This model is a powerful tool to: (1) support EU public health officials in implementing recommendations; (2) to visualize the need for increased vaccination rates for better influenza control; (3) the consequences of low vaccine coverage.