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Prof. Michael Bohm
Dr. Nicolas Werner
The recently described influenza A H1N1 2009 virus (2009H1N1), with its global spread, has resulted, in June 2009, with the first declaration by the World Health Organization (WHO) of an influenza pandemia in 41 years. Influenza and its prevention and treatment has been a major focus in preventive and cardiovascular medicine since 2005, when the influenza virus subtype H5N1 was spread in Europe. In contrast to the H5N1 virus, which is pathogenic primarily for poultry and only rarely causes human infections and deaths, the human influenza A virus infection (subtypes H1N1, H1N2, and H3N2) leads to thousands of deaths each year. Vaccination with seasonal trivalent inactivated influenza vaccines has been associated with a 50% reduction in all-cause mortality in healthy elderly persons (1). A meta-analysis of 20 cohort studies confirmed a reduction in death rates of 68% (2). Interestingly, in patients with cardiovascular disease, vaccination against influenza was associated with a decreased rate in new onset acute myocardial infarction within the 1997/1998 (3) influenza season. In further studies evaluating 280,000 patients, vaccination against influenza was associated with a risk reduction for hospitalisation due to cardiovascular disease, cerebrovascular disease, and all-cause mortality (4).
The underlying pathophysiological explanations include prevention of systemic inflammation that involve the release of inflammatory cytokines, development of endothelial dysfunction, changes in plasma viscosity, as well as endogenous catecholamines, dehydration, and induction of pro-coagulative activity of infected endothelial cells which may contribute to the development of instable plaques and plaque rupture (5).
Data now available derived from the influenza season of the southern hemisphere clearly demonstrate that 2009 H1N1 infections will likely be a public health burden in Europe with substantial increases in the incidence of 2009 H1N1 infection. Between April and August 2009 the proportion of the new influenza reached 60-70%. While recent influenza A virus infections affected mostly the elderly, the 2009 H1N1 virus seems to preferably affect younger people. The mean age in Germany of infected patients is 22.8 years and about 75% of infected patients are between 10 and 29 years of age. Risk factors for a severe form of the influenza are pregnancy and chronic disease e.g. pulmonary and cardiovascular diseases. About 90% of deceased patients due to 2009 H1N1 infection had a previous history of chronic disease (6).
A recently published article in the New England Journal of Medicine related the information demonstrating that vaccination with recent seasonal nonadjuvanted or adjuvanted influenza vaccines induced little or no cross-reactive antibody response to 2009 H1N1(7). Interestingly, only 4% of persons who were born after 1980 had pre-existing cross-reactive antibody titers of 1:40 or more against 2009 H1N1, whereas 34% of persons born before 1950 had titers of 1:80 or more. These observations underline the importance of a specific immunisation against the 2009 H1N1 virus.
Meanwhile, two preliminary studies have been published showing promising results concerning the efficacy and safety of monovalent Influenza A H1N1 2009 Vaccine(8;9). The first study comes from Australia and has investigated a monovalent vaccine developed by CSL in a total of 240 healthy subjects. In order to study the different susceptibility against the 2009 H1N1 virus according to age groups, the cohort was divided into two age groups (<50 years and =50 years). Subjects were randomised to receive either a single shot of 15 µg or 30 µg of hemagglutinin antigen by intramuscular injection. The primary endpoints were antibody titers using hemagglutination-inhibition and microneutralisation assays at baseline and 21 days after vaccination. Antibody titers of 1:40 or more were observed in 96.7% of subjects who received the 15-µg dose and in 93.3% of patients who received the 30-µg dose. Adverse events of the vaccination were comparable to other influenza vaccinations with mild to moderate local discomfort at the injection site (mainly pain and tenderness) in 46.3% and systemic events (mainly headache, malaise, myalgia) in 45%. No deaths, serious adverse events, or unexpected adverse events were observed suggesting an acceptable safety profile of the vaccine. The second available study is a single-center study from the UK evaluating the effect of a monovalent influenza A/California/2009 (H1N1) surface-antigen vaccine developed by Novartis in 175 adult subjects in the age of 18 to 50 years. In contrast to the CSL vaccine, an adjuvant as well as a non-adjuvanted form was investigated. The addition of adjuvant is known to enhance immunogenicity and may further induce cross-reactive antibodies against antigenically drifted variants. In order to study dose effects and efficacy of multiple dosing, subjects were randomised to receive either
Antibody responses were measured by means of hemagglutination-inhibition assay and a microneutralization assay on days 0, 14, 21, and 42 after injection of the first dose.
The interim analysis published only compromises group 1 treated with the 7.5-µg dose of MF59-adjuvanted vaccine by days 0, 7, and 14. Here it was shown that antibody titers were significantly higher at day 14 in subjects who had received two 7.5-µg doses of the MF59-adjuvanted vaccine than among those who had received only one by day 14 (Group 1d with a scheduled second dose on day 21). By 21 days after vaccination, the rates of seroconversion were 76% and 92% dependant on the assay used in subjects treated with only one dose (Group 1c) and 88, 92, 88% and 92, 96, 96% in subjects who had already received both doses (Group 1 a-c, respectively). Again, the safety profile of the vaccine was acceptable with frequent local and systemic reactions in 70% and 42% of subjects, respectively.
1. Nichol KL, Wuorenma J, von Sternberg T. Benefits of influenza vaccination for low-, intermediate-, and high-risk senior citizens. Arch Intern Med. 1998;158:1769-1776. 2. Gross PA, Hermogenes AW, Sacks HS, Lau J, Levandowski RA. The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature. Ann Intern Med. 1995;123:518-527. 3. Naghavi M, Barlas Z, Siadaty S, Naguib S, Madjid M, Casscells W. Association of influenza vaccination and reduced risk of recurrent myocardial infarction. Circulation. 2000;102:3039-3045. 4. Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med. 2003;348:1322-1332. 5. Madjid M, Naghavi M, Litovsky S, Casscells SW. Influenza and cardiovascular disease: a new opportunity for prevention and the need for further studies. Circulation. 2003;108:2730-2736. 6. Vaillant L, La Ruche G, Tarantola A, Barboza P. Epidemiology of fatal cases associated with pandemic H1N1 influenza 2009. Euro Surveill. 2009;14. 7. Hancock K, Veguilla V, Lu X, Zhong W, Butler EN, Sun H, Liu F, Dong L, Devos JR, Gargiullo PM, Brammer TL, Cox NJ, Tumpey TM, Katz JM. Cross-Reactive Antibody Responses to the 2009 Pandemic H1N1 Influenza Virus. N Engl J Med. 2009. 8. Clark TW, Pareek M, Hoschler K, Dillon H, Nicholson KG, Groth N, Stephenson I. Trial of Influenza A (H1N1) 2009 Monovalent MF59-Adjuvanted Vaccine -- Preliminary Report. N Engl J Med. 2009. 9. Greenberg ME, Lai MH, Hartel GF, Wichems CH, Gittleson C, Bennet J, Dawson G, Hu W, Leggio C, Washington D, Basser RL. Response after One Dose of a Monovalent Influenza A (H1N1) 2009 Vaccine -- Preliminary Report. N Engl J Med. 2009.
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