H5N1, a wealth of knowledge to improve pandemic preparedness

Abstract

Influenza infections have been recognized in humans since ancient times, associated with the belief that it was caused by a supernatural influence (Latin influentia). In 1933, the causative agent of human influenza was identified and by 1955 it was realized it shared a genomic composition similar to the “fowl plague” (avian influenza) virus (Potter, 2001). Influenza viruses belong to the family Orthomyxoridae that include the influenza viruses type B and C, the insect viruses Togotho and Dhori, and Salmon Anemia virus. However, the most notorious members of the family are the type A influenza viruses, which are responsible for annual epidemics in humans, recurrent epidemics in swine and horses, sporadic cases in minks, seals and whales, and devastating outbreaks in poultry (Webster, 1997). The terminology “highly pathogenic avian influenza” (HPAI) was officially adopted in 1981 to designate the highly virulent forms of avian influenza. It is commonly accepted that migratory waterfowl, including ducks, sea birds, or shorebirds are the natural hosts of influenza viruses and from where they jump the species barrier (Alexander, 2000). When they do so into domestic poultry, some of these viruses can become highly pathogenic. Although HPAI viruses are primarily restricted to poultry, the world has experienced an emergence of avian influenza strains within the last 15 years that can readily jump to mammalian hosts causing disease and death. This is particularly the case of the so-called H5N1 HPAI viruses, which since 1997 have been responsible for more than 600 human infections with more than 300 deaths spanning vast geographic regions of the world, from Asia, to the Middle East, to Africa (Van Kerkhove et al., 2011). The high mortality rate of these infections, added to the evidence that many pandemic viruses emerge from the avian reservoir, make H5N1 viruses a major public health threat. Luckily, H5N1 HPAI viruses are not easily transmitted among humans or other mammals. Transmission, particularly by respiratory droplets, is considered one of the conditions for the emergence of influenza strains with pandemic potential. Another condition is to have a human population with little or no immunity against the novel strain. Expansion of these viruses into new geographical regions and wild bird hosts has been accompanied by an increase in genetic diversity through antigenic drift and reassortment, producing multiple clades. Eradication efforts have generally failed and lead to the emergence of many antiviral resistant strains. Research aimed at better understanding the ecology, evolution, pathogenesis and transmission of H5N1 viruses has resulted in a wealth of knowledge, including novel antivirals, alternative vaccines, and better vaccination strategies (Banner and Kelvin, 2012; Neumann et al., 2010; Sambhara and Poland, 2010). For the past 15 years, researchers have been puzzled and challenged by a virus that can poorly jump the species barrier into humans, but when it does, the outcome is uncharacteristically fatal. Early work with animal models was crucial to demonstrate that such phenomena could be reproduced in other mammalian hosts. Initial work in mice and ferrets demonstrated the high lethality of some strains of H5N1 for these animals. There has been generally good correlation between the origin of such strain, whether it was isolated from a human or a chicken, and the outcome of disease in animal models; with those isolated from the former having higher virulence than those isolated from the latter, in either mice or ferrets or both. This early work led to the realization that the polybasic cleavage site in the HA glycoprotein of H5N1 viruses plays a major role the viral pathogenesis in mammals and that key amino acid mutations in PB2 are significant contributors to virulence, although additional mutations elsewhere in the virus are important too (Hatta et al., 2001a). Early studies in ferrets also showed that, like in humans, H5N1 infections can be fatal but exhibit poor respiratory droplet transmission among cage mates (Neumann et al., 2010). These observations prompted further studies into analyzing the sialic acid receptor specificity of H5N1 viruses and better characterizations of receptor distribution in humans and many other mammalian and avian species (Kimble et al., 2010; Shinya et al., 2006; Stevens et al., 2006; Wan and Perez, 2006). Today, it is clear that it is the distribution rather than the presence or absence of receptors which determines the ability of these viruses to replicate in the upper or lower respiratory tract of a given host. It is also clear that a change in receptor specificity alone, from the typical avian-like (α2,3-sialic acid) to the typical human-like (α2,6-sialic acid), is not sufficient to make H5N1 strains transmissible in ferrets. Likewise, reassortment between H5N1 and human seasonal viruses does not improve transmission in ferrets (Chen et al., 2012; Jackson et al., 2009; Maines et al., 2005, 2006).