A Step Closer to Meeting the Threat of Avian Influenza

I n recent years, highly pathogenic avian infl uenza A viruses of the H5N1 subtype have crossed the species barrier and infected humans in many parts of the world. These strains continue to evolve and expand their host range, and have been associated with greater than 50 percent mortality [1]. No vaccines directed against H5N1 strains are commercially available for humans, and the development of effective H5N1 vaccines poses a number of challenges on both the basic science and manufacturing levels [2]. Several strategies have been explored to produce effective H5 vaccines. These include: preparation of an inactivated vaccine using a heterotypic (see Glossary), low-pathogenicity avian infl uenza virus that is antigenically related to the H5N1 circulating strains [3]; use of a recombinant H5 hemagglutinin (HA) expressed in baculovirus [4]; an inactivated subvirion vaccine [5]; or the production of attenuated seed viruses with the H5 HA modifi ed through reverse genetics [6–8]. Unfortunately, many of these approaches have been found to be poorly immunogenic, require high doses of antigen, or require the use of an adjuvant [1,9]. An alternative approach under development is the use of live attenuated cold-adapted H5 vaccines. Live attenuated cold-adapted vaccines are attractive for the prevention of pandemic infl uenza due to the stimulation of an immune response following a single dose of vaccine, an excellent safety profi le, induction of cross-reactive immune responses, and effi cacy in children [10]. Although the cold-adapted virus is live, it does not replicate to high titers and fails to readily infect naïve people [11]. Through the use of reverse genetics, a cold-adapted H9 infl uenza virus–specifi c seed virus has already been produced and is available for clinical evaluation and use should the need arise [12]. A new study in PLoS Medicine now describes the generation of live, attenuated H5N1 infl uenza viruses that may be suitable candidates for use in humans [13]. In the current work, the authors used reverse genetics to construct high-yield 6:2 seed viruses by mixing the six internal genes from a cold-adapted (ca) donor virus with the H5 HA and N1 neuraminidase (NA) from representative H5N1 infl uenza strains. An important safety feature used in these studies was the modifi cation of the multi-basic amino acid motif at the cleavage site of the H5 HA gene to a sequence seen in avian infl uenza viruses that are not highly pathogenic in chickens [6]. This …