Abstract
Since the Second European Influenza Conference in 2005, the field of influenza research has advanced immensely. The main topics discussed were the possible mandatory vaccination of healthcare workers against seasonal influenza, the oseltamivir resistance, the pandemic and prepandemic vaccination strategies and the mathematical modeling of a pandemic. A key discussion was on the efficacy of seasonal vaccination of the elderly. Young scientists presented promising work on influenza transmission in the guinea pig model, the pathogenicity of the re-engineered 1918 Spanish Flu influenza virus and the global migration routes of influenza viruses.
The Third European Influenza Conference, organized by the European Scientific Working Group on Influenza, was held in Villamoura, Portugal, on the 14–17 September 2008. The 1362 attendees came from 55 countries (66% from the EU and 34% from the rest of the world). The scientific program consisted of 82 oral presentations and 278 posters on 11 different subjects. More than 50 young-scientist grants made it possible to present promising scientific results. In a parallel track, ‘science in practice’ for government representatives and opinion leaders in healthcare, interaction with scientists was enhanced. Only the highlights will be presented here.
Influenza vaccination of healthcare workers
Influenza vaccine has been shown to be both effective and cost–effective in preventing influenza amongst healthcare workers (HCWs) and, additionally, is effective in reducing mortality among their patients. Rachel Jordan from the University of Birmingham, UK, provided evidence from a meta-analysis on the effectiveness and cost–effectiveness of vaccinating HCWs, along with an evaluation of the evidence concerning the best methods for improving uptake Citation[1]. From Germany, Dieter Walter (Robert Koch Institute) gave some examples of best practices in German hospitals. The ethicist Hans van Delden (University Medical Center Utrecht, The Netherlands) presented a study into the ethics of mandatory vaccination against influenza for healthcare workers Citation[2]. A group of European ethicists argued that institutions caring for the frail elderly have the responsibility to implement voluntary programs for vaccination against influenza of HCWs. When the uptake falls short, a mandatory program may be justified.
Mechanisms of oseltamivir resistance
Influenza A H1N1 viruses resistant to the neuraminidase inhibitor oseltamivir emerged globally during the winter of 2007–2008. Maria Zambon (HPA Centre for Infection, London, UK) argued that a mutation in the neuraminidase protein at position 275 (H275Y) was responsible for the antiviral resistant phenotype Citation[3]. Isolation of this variant did not correlate with drug treatment or transmission from a treated individual. She demonstrated that the 2007–2008 circulating resistant strains do not appear to have a growth disadvantage, in contrast to previous strains with this mutation and are, therefore, able to compete for transmission in humans.
Pandemic & vaccination strategies
During the Second European Influenza Conference in 2005, much discussion was made about the impossibility of preparing for a next pandemic, because of the time lag in producing the right pandemic vaccine. Now, in 2008, the field has advanced immensely. The stockpiling and use of prepandemic and pandemic vaccines has been the subject of intense debate between scientists and policymakers. In the late breaker session, the newly developed adjuvanted H5N1 vaccines were discussed Citation[4]. They allow a highly flexible prime–boost vaccination strategy. Next to that, the adjuvanted vaccines give the possibility for antigen sparing, which is good news because of the restricted production facilities of today. Furthermore, intradermal vaccination may improve the immunogenicity of the seasonal influenza vaccine in the elderly.
Mathematical modeling of the pandemic
Since the conducting of trials is not possible as long as the pandemic is pending, mathematic modeling presents the only possibility of studying the impact of interventions. Ira Longini (University of Washington, DC, USA) described the recent use of mathematical models for the detection, transmission and control of pandemic influenza, in clusters of households and wider geographical regions. Containment with antiviral agents, prepandemic influenza vaccines and social distancing measures can be effective. Cécile Viboud (US NIH, Bethesda, MD, USA) used data from the 1918–1920 pandemic in 13 countries. The conclusion was that the most likely biological explanation for the observed mortality patterns of the Spanish Flu is a composite one, involving a protection effect against mortality in adolescents, combined with partial immunity in older individuals due to antigenic recycling. Neil Ferguson (Imperial College, London, UK) discussed what the rapid spread of the transmission-fit oseltamivir-resistant H1N1 strain across Europe implies for the possible emergence of antiviral resistance in a pandemic.
Assessing vaccine efficacy
The benefits of influenza vaccination are widely accepted by healthcare policymakers and members of the scientific community, particularly as a means of reducing mortality among seniors. Yet, questions remain as to precisely how effective vaccination is, and questions have emerged regarding the methods used to evaluate vaccine efficacy. Recent excess mortality studies, surprisingly, could not confirm a decline in influenza-related mortality in several countries, even as senior vaccination coverage rose greatly. On the other hand, a large number of observational studies have consistently reported that vaccination reduces the risk of dying in winter from any cause by some 50%. This estimate far exceeds the assessments from excess mortality studies that less than 10% of all winter deaths are attributable to influenza. In observational studies, the very selection of patients for influenza vaccination may introduce a confounding bias and, hence, vaccine effects may be over- or underestimated.
Three authors discussed this subject. Lone Simonson (NIH), discovered the cause of the inflated 50% figure Citation[5]. She calls it ‘frailty selection bias’: many physicians were not vaccinating frail seniors, while healthier seniors were being vaccinated. The death of the unvaccinated seniors skewed the figures. Simonson advocates conducting detailed chart reviews to eliminate this bias. Kristin Nichol (University of Minnesota, MN, USA) sees the problem as more fundamental. She thinks that the actual number of influenza deaths is under-reported because patients may die from other complications. Nichol believes that mortality rates during the influenza season are inflated because we fail to account for heterogeneity.
Eelko Hak (University Medical Center Utrecht, The Netherlands) reported a study that confirmed the benefits of vaccination among the elderly, even taking into account the potential for residual confounding Citation[6]. He used the national mortality statistics to determine change in excess mortality among elderly persons during periods of increased influenza and respiratory syncytial virus activity before and after the start of the Dutch National Influenza Campaign in 1995/1996. After the campaign began, the average annual influenza-associated mortality declined from 131 to 105 per 100,000 people. No decline was observed in respiratory syncytial virus-associated mortality.
In short, the approaches of all indicated that influenza vaccination was associated with considerable mortality reduction and that the potential for confounding bias was relatively small. The available evidence, therefore, favors annual immunization of the elderly against influenza.
The best guinea pigs are … guinea pigs?
The new generation of scientists presented themselves in a special plenary session for young scientists. Anice Lowen (Mount Sinai School of Medicine, NY, USA) characterized the guinea pig as a model host for influenza Citation[7]. Guinea pigs are highly susceptible to infection with human influenza isolates and transit these viruses efficiently, both via aerosol and contact routes.
Julie McAuley (St Jude Children’s Research Hospital, TN, USA) sought to better understand virus pathogenicity by re-engineering the 1918 influenza virus Citation[8]. The researchers zeroed in on the proapoptotic protein PB1-F2. This virus, constructed by reversed genetics, was more virulent in mice, induced a heightened cellular and inflammatory cytokine response, caused more-severe pulmonary immunopathology and potentially made individuals more susceptible to secondary bacterial pneumonia. These and other findings implicate PB1-F2 as an important virulence factor.
Colin Russell and colleagues (University of Cambridge, UK) studied the global migration routes of influenza viruses Citation[9]. They analyzed the hemagglutinin of some 13,000 human influenza A (H3N2) viruses from six continents during 2002–2007. They discovered that, each year, epidemics in the temperate regions were seeded by viruses from East and South East Asia. The researchers concluded that the antigenic characteristics of influenza A (H3N1) viruses outside East and South East Asia may be forecast each year based on surveillance within East and South East Asia, with implications for the vaccine strain selection.
Summary & conclusion
Since the Second European Influenza Conference in 2005, the field has advanced immensely. Main topics in this Third European Influenza Conference were the possible mandatory vaccination for seasonal influenza of healthcare workers, oseltamivir resistance of the H1N1 virus, the pandemic and prepandemic vaccination strategies and the mathematical modeling of a pandemic. A discussion was held on the efficacy of seasonal vaccination of the elderly. Young scientists presented promising work on influenza transmission in the guinea pig model, the pathogenicity of the reengineered 1918 Spanish Flu influenza virus and the global migration routes of influenza viruses.
Financial & competing interests disclosure
GA van Essen is a member of the European Scientific Working group on Influenza (ESWI) and a member of the organising committee and scientific program committee of the Third European Influenza Conference. ESWI is equally financed by all European influenza vaccine and antiviral manufacturers. GA van Essen was also a member of the editorial board of the daily conference newspaper, which was a source for this article. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
- Burls A, Jordan R, Barton P et al. Vaccinating healthcare workers against influenza to protect the vulnerable – is it a good use of healthcare resources? A systematic review of the evidence and an economic evaluation. Vaccine24(19), 4212–4221 (2006).
- van Delden JJ, Ashcroft R, Dawson A, Marckmann G, Upshur R, Verweij MF. The ethics of mandatory vaccination against influenza for health care workers. Vaccine26(44), 5562–5566 (2008).
- Lackenby A, Hungnes O, Dudman SG et al. Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Euro Surveill.13(5), 8026 (2008).
- Rumke HC, Bayas JM, de Juanes JR et al. Safety and reactogenicity profile of an adjuvanted H5N1 pandemic candidate vaccine in adults within a Phase III safety trial. Vaccine26(19), 2378–2388 (2008).
- Simonson L, Taylor RJ, Viboud C et al. Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infect. Dis.7(10), 658–666 (2008).
- Jansen AG, Sanders EA, Nichol KL et al. Decline in influenza-associated mortality among Dutch elderly following the introduction of a nationwide vaccination program. Vaccine26(44), 5567–5574 (2008).
- Lowen AC, Mubareka S, Tumpey TM et al. The guinea pig as a transmission model for human influenza viruses. Proc. Natl Acad. Sci. USA103(26), 9988–9992 (2006).
- McAuley JL, Hornung F, Boyd KL et al. Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia. Cell Host Microbe2(4), 240–249 (2007).
- Russell CA, Jones TC, Barr IG et al. The global circulation of seasonal influenza A (H3N2) viruses. Science320(5874), 340–346 (2008).