Influenza epidemics are the cause of three to five million cases of severe illness every year and approximately 250,000 to 500,000 of these cases are fatal. Epidemics occur during autumn and winter in regions with a temperate climate, while in some tropical countries influenza viruses circulate throughout the year with one or two peaks during the rainy seasons. Mainly the young, elderly and subjects with chronical medical conditions are at risk for developing severe disease after seasonal influenza virus infection. Therefore, the World Health Organization (WHO) recommends annual vaccination of these subjects, which is an effective measure to protect them against influenza and its complications.
The genome of influenza viruses consists of eight gene segments of negative sense RNA and since these viruses lack proofreading activity during their replication, they can accumulate mutations under selective pressure. This way, influenza viruses can escape from recognition by virus-neutralizing antibodies that are induced by previous infections or vaccinations. Indeed, the highest degree of variations is observed in the antigenic sites of the hemagglutinin against which virus neutralizing antibodies are directed. As a result of this antigenic variation, the influenza vaccine that contains components of three currently circulating influenza viruses (A/H1N1, A/H3N2 and B viruses) has to be updated almost every year to match the circulating strains. Since the selection of the vaccine strains and vaccine production has to be carried out before the start of the influenza season, there is some uncertainty in this prediction and mismatches do occur occasionally. In addition to the small gradual antigenic changes of currently circulating influenza virus strains (antigenic drift), occasionally new influenza viruses of novel subtypes are introduced into the human population. The subtypes of these viruses are defined by the envelope glycoproteins of these viruses, the hemagglutinin (HA) and the neuraminidase (NA). Wild aquatic birds are the natural reservoir of all subtypes of influenza from which there is spillover to other (domestic) birds and mammalian species, like pigs, horses and men.
Because antibodies against these viruses are virtually absent in the human population, these viruses may cause pandemic outbreaks of influenza affecting a substantial proportion of the human population. In the last century, three pandemics occurred, which were caused by influenza A viruses of the H1N1, H2N2 and H3N2 subtypes. Recently, influenza A viruses of swine origin have caused the first pandemic of the 21st century. These new pandemic viruses are the result of the exchange of gene segments originating from human, classical swine and avian-like influenza viruses and have emerged and spread worldwide within a few months. As of 30 December 2009 at least 12220 people have been killed due to infection with the influenza A/H1N1(2009) virus. Since not all fatal cases are reported, the real number of fatal cases is most likely much higher.
The current pandemic caused by the new influenza A(H1N1) virus and the current pandemic threat caused by the highly pathogenic avian influenza A viruses of the H5N1 subtype have renewed the interest in the development of vaccines that can induce broad protective immunity. Preferably, vaccines not only provide protection against the homologous strains, but also against heterologous strains, even of another subtype. This paper describes viral targets and the arms of the immune response involved in protection against influenza virus infections such as antibodies directed against the hemagglutinin, neuraminidase and the M2 protein and cellular immune responses directed against the internal viral proteins.
Targets for the Induction of Protective Immunity Against Influenza A Viruses. Viruses 2010, 2(1), 166-188; doi:10.3390/v2010166
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Although cardiovascular disease is the second most frequently targeted indication in clinical trials of gene therapy, with 137 studies having received approval by the early part of 2009, this is a distant second to studies of cancer-related pathologies, which account for almost 65% of gene therapy clinical trials with close to 1,000 trials initiated or approved at the time of writing. However cardiovascular disease is the most common cause of mortality in the developed world. But despite two decades of promising pre-clinical research and numerous clinical trials, cardiovascular gene transfer has so far failed to demonstrate convincing benefits in the clinic.
