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Current research on drugs and vaccines for fighting bird flu
Transactions of the Royal Society of Tropical Medicine and Hygiene (2007) 101, 1171—1172
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
MINI-REVIEW
Current research on drugs and vaccines for fighting bird flu Viroj Wiwanitkit ∗ Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand Available online 25 July 2007
KEYWORDS H5N1; Bird flu; Disease transmission; Drugs; Vaccines; Research
Summary Bird flu, or avian flu, caused by the H5N1 virus, is of concern worldwide. The antiviral drugs oseltamivir and zanamivir have been used to treat human cases, and resistance has been reported. Studies on the molecular mechanisms of antiviral resistance are needed to understand the problem and to aid future drug development. Control of a major outbreak would require a vaccine, but current manufacturing technology is not adequate to support influenza vaccine production in the event of an avian influenza outbreak. © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
Bird flu, or avian flu, caused by the H5N1 virus, is a new infectious disease. WHO considers the avian influenza A/H5N1 virus a public health risk with pandemic potential. Outbreaks in poultry have been associated with human transmission. The WHO has documented 272 confirmed human infections since 2003, with 166 deaths. To fight a possible pandemic, effective drugs and vaccines are needed. Several preventive and therapeutic strategies have been proposed for bird flu, including new antiviral drugs: in particular the neuraminidase inhibitors (NIs), such as oseltamivir and zanamivir. In crucial areas where an epidemic strain might emerge, such as Thailand, most suspected patients with influenza-like illness are investigated with rapid diagnostic tests and, if positive, treated with an NI. However, resistance does occur. Resistance to NIs can be seen for influenza virus carrying the H274Y NA enzyme. When selected in vivo, these strains have reduced sensitivity to oseltamivir carboxylate (Ives et al., 2002). However, this resistance has never been reported when used to treat H5N1 infections. Study of the molecular
∗
Tel.: +66 2 2564136. E-mail address: [email protected].
mechanism of the antiviral resistance and surveillance for mutated viruses may guide the search for further drugs. Salomon et al. (2006) suggested that adaptive changes in polymerase genes are required for high virulence in mammalian species of an avian H5N1 virus (VN1203) with a cleavable hemagglutinin. This change helped to overcome the species barrier. They found that exchanging hemagglutinin and neuraminidase genes did not alter pathogenicity, but substituting CH58 polymerase genes completely attenuated VN1203 and reduced viral polymerase activity (Salomon et al., 2006). Thus, antivirals targeting polymerase proteins are needed. Advanced computational chemical technology is helpful for molecular docking research to study the drug—virus interaction. Current influenza vaccine development technology is not adequate in the event of an avian influenza outbreak. The current system is based on dissection of the pathogen using biochemical, immunological and microbiological methods, and entails a long development period. Whole genome analysis for epitope prediction, protein localization and major histocompatibility complex binding prediction, represents the most effective technology to rapidly produce a pandemic influenza vaccine. A worldwide search for an inactivated vaccine based on reverse genetics
0035-9203/$ — see front matter © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2007.06.010
1172 forms the basis of WHO recommendations. Reverse genetics seeks to find the possible phenotypes that may derive from a specific genetic sequence found by DNA sequencing. Epitope discovery is the present focus of H5N1 vaccine development. Using immunoinformatics, new T-cell epitope candidates can be predicted (Wiwanitkit, 2006). Additional in vitro studies to confirm the epitope can be done to confirm the value for vaccine development (Wang et al., 2007). At present in Thailand there is discussion about the use of avian vaccine for prevention of bird flu infection in fowls. Such vaccination is not permitted because carrier status could result. However, this should be reconsidered, as there is no scientific evidence and systematic evaluation to help decision-making. Vaccination of fowls with the available avian vaccines might be a cost-effective strategy for the control of emerging infection. It should be noted that, although there are several suggestions regarding mutations that would enable H5N1 to move from birds to humans, there has been no report on any such mutation in infected human cases. It is not known whether human cases have some underlying genetic cellular defects that result in susceptibility to H5N1 virus. The clarification of the detailed pathobiology of human infection is needed. Using advanced bioinformatics techniques to study homologs and to find the H5N1 cellular receptor in humans could resolve the issue. Such investigations might challenge the present direction of drug and vaccine search.
V. Wiwanitkit Funding: None. Conflicts of interest: None declared. Ethical approval: Not required.
References Ives, J.A., Carr, J.A., Mendel, D.B., Tai, C.Y., Lambkin, R., Kelly, L., Oxford, J.S., Hayden, F.G., Roberts, N.A., 2002. The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res. 55, 307—317. Salomon, R., Franks, J., Govorkova, E.A., Ilyushina, N.A., Yen, H.L., Hulse-Post, D.J., Humberd, J., Trichet, M., Rehg, J.E., Webby, R.J., Webster, R.G., Hoffmann, E., 2006. The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J. Exp. Med. 203, 689—697. Wang, M., Lamberth, K., Harndahl, M., Roder, G., Stryhn, A., Larsen, M.V., Nielsen, M., Lundegaard, C., Tang, S.T., Dziegiel, M.H., Rosenkvist, J., Pedersen, A.E., Buus, S., Claesson, M.H., Lund, O., 2007. CTL epitopes for influenza A including the H5N1 bird flu; genome-, pathogen-, and HLA-wide screening. Vaccine 25, 2823—2831. Wiwanitkit, V., 2006. Predicted epitopes of H5N1 bird flu virus by bioinformatics method: a clue for further vaccine development. Chin. Med. J. (Engl.) 119, 1760.
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
MINI-REVIEW
Current research on drugs and vaccines for fighting bird flu Viroj Wiwanitkit ∗ Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand Available online 25 July 2007
KEYWORDS H5N1; Bird flu; Disease transmission; Drugs; Vaccines; Research
Summary Bird flu, or avian flu, caused by the H5N1 virus, is of concern worldwide. The antiviral drugs oseltamivir and zanamivir have been used to treat human cases, and resistance has been reported. Studies on the molecular mechanisms of antiviral resistance are needed to understand the problem and to aid future drug development. Control of a major outbreak would require a vaccine, but current manufacturing technology is not adequate to support influenza vaccine production in the event of an avian influenza outbreak. © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
Bird flu, or avian flu, caused by the H5N1 virus, is a new infectious disease. WHO considers the avian influenza A/H5N1 virus a public health risk with pandemic potential. Outbreaks in poultry have been associated with human transmission. The WHO has documented 272 confirmed human infections since 2003, with 166 deaths. To fight a possible pandemic, effective drugs and vaccines are needed. Several preventive and therapeutic strategies have been proposed for bird flu, including new antiviral drugs: in particular the neuraminidase inhibitors (NIs), such as oseltamivir and zanamivir. In crucial areas where an epidemic strain might emerge, such as Thailand, most suspected patients with influenza-like illness are investigated with rapid diagnostic tests and, if positive, treated with an NI. However, resistance does occur. Resistance to NIs can be seen for influenza virus carrying the H274Y NA enzyme. When selected in vivo, these strains have reduced sensitivity to oseltamivir carboxylate (Ives et al., 2002). However, this resistance has never been reported when used to treat H5N1 infections. Study of the molecular
∗
Tel.: +66 2 2564136. E-mail address: [email protected].
mechanism of the antiviral resistance and surveillance for mutated viruses may guide the search for further drugs. Salomon et al. (2006) suggested that adaptive changes in polymerase genes are required for high virulence in mammalian species of an avian H5N1 virus (VN1203) with a cleavable hemagglutinin. This change helped to overcome the species barrier. They found that exchanging hemagglutinin and neuraminidase genes did not alter pathogenicity, but substituting CH58 polymerase genes completely attenuated VN1203 and reduced viral polymerase activity (Salomon et al., 2006). Thus, antivirals targeting polymerase proteins are needed. Advanced computational chemical technology is helpful for molecular docking research to study the drug—virus interaction. Current influenza vaccine development technology is not adequate in the event of an avian influenza outbreak. The current system is based on dissection of the pathogen using biochemical, immunological and microbiological methods, and entails a long development period. Whole genome analysis for epitope prediction, protein localization and major histocompatibility complex binding prediction, represents the most effective technology to rapidly produce a pandemic influenza vaccine. A worldwide search for an inactivated vaccine based on reverse genetics
0035-9203/$ — see front matter © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2007.06.010
1172 forms the basis of WHO recommendations. Reverse genetics seeks to find the possible phenotypes that may derive from a specific genetic sequence found by DNA sequencing. Epitope discovery is the present focus of H5N1 vaccine development. Using immunoinformatics, new T-cell epitope candidates can be predicted (Wiwanitkit, 2006). Additional in vitro studies to confirm the epitope can be done to confirm the value for vaccine development (Wang et al., 2007). At present in Thailand there is discussion about the use of avian vaccine for prevention of bird flu infection in fowls. Such vaccination is not permitted because carrier status could result. However, this should be reconsidered, as there is no scientific evidence and systematic evaluation to help decision-making. Vaccination of fowls with the available avian vaccines might be a cost-effective strategy for the control of emerging infection. It should be noted that, although there are several suggestions regarding mutations that would enable H5N1 to move from birds to humans, there has been no report on any such mutation in infected human cases. It is not known whether human cases have some underlying genetic cellular defects that result in susceptibility to H5N1 virus. The clarification of the detailed pathobiology of human infection is needed. Using advanced bioinformatics techniques to study homologs and to find the H5N1 cellular receptor in humans could resolve the issue. Such investigations might challenge the present direction of drug and vaccine search.
V. Wiwanitkit Funding: None. Conflicts of interest: None declared. Ethical approval: Not required.
References Ives, J.A., Carr, J.A., Mendel, D.B., Tai, C.Y., Lambkin, R., Kelly, L., Oxford, J.S., Hayden, F.G., Roberts, N.A., 2002. The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res. 55, 307—317. Salomon, R., Franks, J., Govorkova, E.A., Ilyushina, N.A., Yen, H.L., Hulse-Post, D.J., Humberd, J., Trichet, M., Rehg, J.E., Webby, R.J., Webster, R.G., Hoffmann, E., 2006. The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J. Exp. Med. 203, 689—697. Wang, M., Lamberth, K., Harndahl, M., Roder, G., Stryhn, A., Larsen, M.V., Nielsen, M., Lundegaard, C., Tang, S.T., Dziegiel, M.H., Rosenkvist, J., Pedersen, A.E., Buus, S., Claesson, M.H., Lund, O., 2007. CTL epitopes for influenza A including the H5N1 bird flu; genome-, pathogen-, and HLA-wide screening. Vaccine 25, 2823—2831. Wiwanitkit, V., 2006. Predicted epitopes of H5N1 bird flu virus by bioinformatics method: a clue for further vaccine development. Chin. Med. J. (Engl.) 119, 1760.