Influenza Drugs Both for Prophylactic and Therapeutic Use

Journal of Antivirals & Antiretrovirals - Open Access JAA/Vol.1 Issue.1 fections in humans who were in contact with the pigs (Dawood ers in bridging the complex interplay between innate (germline et al., 2009; Shinde et al., 2009; Trifonov et al., 2009). How- encoded) and adaptive (antigen specific) immunity. These sig- ever, the widespread and effective transmission to humans did nature molecules of host defence are present in virtually all spe- not start until May 2009. cies of life and carry a broad spectrum of activities, i.e. direct antibacterial, antifungal, antiviral and antiparasitic activities A looming influenza pandemic has always been feared prior (Jenssen et al., 2006b) as well as modulation of host cell im- to the H1N1 "swine flu". Previously, subtypes H5N1, H7N3, mune responses (Hancock and Sahl, 2006; Oppenheim and Yang, H7N7 and H9N2 of avian origin were feared as potential hu- 2005; Hancock, 2001; Zasloff, 2002). They are generally short man pandemic strains since they were all endemic in birds. (12 to 50 residues), with a net positive charge (+ 2 to 9) due to (Cauthen et al., 2000; Fouchier et al., 2004; Hirst et al., 2004; an excess of basic arginine/lysine residues, and contain up to Lin et al., 2000) The H9N2 strain was considered to be low 50% hydrophobic amino acids. Structurally they are sorted into pathogenic in birds, but has sporadically been transmitted to four classes based on their amphiphilic conformations (i.e., β- humans, (Cameron et al., 2000; Hossain et al., 2008) resulting structures with two to four β-strands, amphipathic α-helices, in disease development and influenza-like symptoms, though loop and extended structures). Consequently, due to their broad no deaths have been reported (Uyeki et al., 2002). The H7N7 spectrum of activities, several of the novel drug candidates that and H5N1 strains differ from H9N2 in that they are highly patho- are currently passing through clinical trials are tailored around genic in birds (Horimoto and Kawaoka, 2005). In humans, H7 host defence peptides. avian influenza A commonly manifests as conjunctivitis and/or respiratory symptoms (Belser et al., 2009). In contrast, H5N1 Influenza Virus Evasion of the Immune System can produce respiratory symptoms, encephalopathy and/or di- Despite the measures taken by the body to fight off an influ- arrhea, and in severe cases, multi-organ failure (Beigel et al., enza infection, the virus has its own mechanism for subverting 2005; Cheung et al., 2002). There have been multiple reported the host immune system. Three different studies of clinical pa- cases of bird to human transmission of H5N1 and H7N7 in re- tients infected with influenza A H5N1 observed that infected cent years and human to human transmission has been suggested patients had higher serum levels of proinflammatory cytokines in some households (Beigel et al., 2005; Horimoto and Kawaoka, and chemokines in their plasma compared to healthy controls 2005). Fortunately, these viruses have not attained the efficiency (Beigel et al., 2005; Horimoto and Kawaoka, 2005; Seo et al., of human to human transmission that the "swine flu" has at- 2002). This has also been observed in vitro when macrophages tained. Although it is feared that eventual mutations could lead from healthy blood donors were infected with H5N1. In com- to improved transmission of these viruses between humans, thus parison to the cells infected with influenza H3N2 or H1N1, it leading to a pandemic strain. was found that H5N1 infected cells had greater up-regulation Host Antiviral Response to Influenza Infections of proinflammatory cytokines and chemokines in response to the infection (Cheung et al., 2002). Hypercytokinemia and the Typically, influenza infects the epithelial cells of the upper subsequent reactive hemophagocytic syndrome have also been respiratory tract, but it is also capable of infecting monocytes/ implicated as the cause of death of many H5N1 infected pa- macrophages and other leukocytes, though immune cell infec- tients as it results in the observed sepsis syndrome, acute respi- tions are less productive for the virus, as only a few viruses are ratory distress syndrome and multi-organ failure (Beigel et al., produced prior to the virus-induced apoptosis of these cells 2005; Cheung et al., 2002). Therefore, the exaggerated immune (Julkunen et al., 2000; Julkunen et al., 2001; Kaufmann et al., response is suspected of causing the severity that is observed in 2001). Humans are equipped with the necessary mechanisms these infections (Cheung et al., 2002). Despite the surge of for clearance of the virus during influenza infections. Primarily, proinflammatory cytokines, H5N1 is able to avoid clearance as the innate immune system participates in this process by pro- its non-structural protein 1 is able to interfere with maturation viding a strong T 1 response induced by type 1 interferons h of the immune response by inhibiting dendritic cell maturation (Fernandez-Sesma et al., 2006). This response would require and interferon-α/β production in myeloid dendritic cells activation of at least nuclear factor kappa B, interferon regula- (Fernandez-Sesma et al., 2006). tory factor and signal transducers and activators of transcrip- tion pathways (Julkunen et al., 2000; Julkunen et al., 2001). Similarly, in some cases of H1N1 "swine flu" infected indi- The following pathways would then allow the affected cells to viduals, the symptoms, unlike seasonal influenza, are similar to produce the chemokines and cytokines involved in the desired those found in H5N1 infected patients (Peiris et al., 2009). The antiviral immune response. Influenza A virus infected macroph- specific inflammatory responses to the virus have yet to be de- ages/monocytes secrete macrophage inflammatory protein-1α/ termined but hypercytokinemia and reactive hemophagocytic β and -3α, chemokine C-C motif ligand 5, monocyte chemotac- syndrome may also be suspected as the cause of death in these tic protein-1/3, interferon-inducible protein-10, interferon-α/β, individuals. This outlines the crucial role the immune system interleukin-1 and -6, and tumor necrosis factor-α while epithe- plays in the pathogenesis of influenza and thus, must be ad- lial cells infected with influenza secrete chemokine C-C motif dressed to be able to alleviate the symptoms or eliminate infec- ligand 5, monocyte chemotactic protein-1, interleukin-8 and tions. interferon-α/β (Julkunen et al., 2000; Julkunen et al., 2001). In Influenza Vaccination addition to this proinflammatory response, the human body also expresses numerous host defence peptides, both constitutively The technique of vaccination dates back more than two hun- and in response to stimuli. dred years to when Edward Jenner successfully vaccinated his patients against smallpox virus through exposure to cowpox Host defence peptides have been demonstrated to be key play- virus. Vaccination has since proven a very effective public health J Antivir Antiretrovir Volume 1(1): 001-010 (2009) - 002 ISSN:1948-5964 JAA, an open access journal Journal of Antivirals & Antiretrovirals - Open Access JAA/Vol.1 Issue.1 initiative, preventing the severity and magnitude of several in- lored around. To illustrate this; in 1996 the first devastating re- fectious diseases. In principle vaccination is done through ad- ports came on the highly pathogenic avian flu (H5N1), and vari- ministration of an attenuated micro-organism or important com- ants of this have since circulated in domestic and wild birds ponents of a micro-organism (e.g. surface proteins) able to trig- resulting in an imminent threat of a pandemic onset (de Jong et ger an immune reaction in the host. The efficacy of a vaccine al., 1997; Yen and Webster, 2009). Despite several reported cases relies completely on the Th cell regulated development of high of avian to human transmission, the influenza strain has so far affinity B cell memory and the consolidation of the response not been able to adopted the ability to efficiently spread amongst through antigen re-challenge. Resultant B cell memory is the humans, and has not per definition caused a pandemic. How- key feature yielding immunity after vaccination. Influenza vac- ever, in this same time period, investors and granting agencies cines have been available since the 1940s and are without doubt have enabled initiation of more than 60 prepandemic clinical the most important strategy to prevent influenza virus epidem- vaccine trials against the strain. Then, almost out of the blue ics. Since the circulating influenza strains are constantly chang- came reports on an influenza strain (H1N1) from porcine origin ing U.S. Food and Drug Administration annually recommend that started to cause severe influenza-like respiratory illnesses two of the influenza A strains (currently a wild type of H3N2 in Mexico in Fraser et al., (2009) and by early May 2009 the and H1N1) and one B strain most responsible for human infec- World Health Organization classified this as an influenza pan- tions to be included in the following seasons vaccine. There are demic (Neumann et al., 2009). several licensed manufacturers world wide, and all of them produce their vaccines in eggs, either formulated as a trivalent in- Although there is no doubt that vaccination has proven ex- activated influenza vaccine for intramuscular injection or as a tremely efficient in the control of influenza, the protection is live attenuated influenza vaccine administered as an intranasal never a hundred percent, hence supporting the need for good spray. Comparative studies of the two vaccine types have indi- influenza drugs both for prophylactic and therapeutic use. Drug cated that the live attenuated influenza vaccines offers a signifi- development could also be encouraged as an international prepa- cantly better protections against both well matched influenza ration strategy for the next influenza pandemic, as these strains and against strains that have undergone antigenic drift pandemics are caused by novel strains of influenza where hu- (Belshe et al., 2007).

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