A QUANTUM OF SCIENCE
When vaccines fail, antiviral drugs might make the difference between life and death
The seasonal flu vaccine is already being administered and a special vaccine targeting H1N1 will soon follow, but for some people a vaccine may not be enough. Children, the elderly and immunocompromised individuals are at high risk for complications from influenza. For those already infected a vaccine does no good, but fortunately, antiviral medications are available when the flu turns life-threatening.
The most well-known anti-influenza drug is TamiFlu (its official name is Oseltamivir). TamiFlu is taken orally, usually for a five-day course of treatment. Approved in 1999, it has been used to treat 50 million people to date. Currently, TamiFlu is usually reserved for serious, potentially life-threatening cases in an attempt to prevent the flu virus from mutating into a form resistant to the drug. Indeed, five cases of TamiFlu-resistant H1N1 have already been reported but overall the rate of resistance flu cases remains low (around 1.2%).
Recently, a drug called Peramivir has been developed and is on the fast track to approval by the FDA. This is not a new drug – it was abandoned in 2001 by Johnson and Johnson due to low oral availability – but in 2005 concerns over Avian flu caused drug-makers to reexamine the compound and begin testing it as an intravenous medication. Recent studies show a single intravenous dose of Peramivir is as effective as the full five-day course of oral treatment with TamiFlu. Additionally, adverse drug reactions were less common with Peramivir.
Both TamiFlu and Peramivir act by inhibiting the same viral enzyme, neuraminidase. This enzyme allows viral particles to escape infected cells and go out in the bloodstream where they can find new cells to infect. When TamiFlu or Peramivir inhibit the viral neuraminidase, viral particles remain trapped inside infected cells until the body’s immune system can respond, usually with macrophages (literally "big eaters") that engulf the infected cell and digest it, destroying the viral particles along with the cell.
Additional advantages of Peramivir include its single-dose effectiveness. There have been reports of individuals hoarding TamiFlu pills and threatening the supply of the drug, but that cannot happen with a drug which can only be administered intravenously.
For more information:
Study: New Drug Fights Flu as Well as TamiFlu
TamiFlu (Wikipedia article)
TamiFlu-resistant H1N1 cases reported
© AQOS / P. Smalley (2009)
Reproduction with attribution is appreciation
Showing posts with label H5N1. Show all posts
Showing posts with label H5N1. Show all posts
Tuesday, September 15, 2009
Thursday, May 21, 2009
A single amino acid
A QUANTUM OF SCIENCE
Why does the more lethal H5N1 Avian flu not infect humans more readily?
Several references have been made now to the "nightmare scenario" in which genes from the more lethal Avian flu (H5N1) reassort with the less dangerous but more infective Swine flu (H1N1), generating a hybrid that is both lethal and infective. We have yet to talk much about why the H5N1 strain is harder for people to catch – so hard that in some years there are only a single-digit number of cases.
Certainly, the lethality of H5N1 inhibits its spread. In epidemiological terms, the virus kills faster than it spreads, leading to a reproduction number at or below one. In a recent paper, researchers show that a single amino acid change in the sequence of the viral polymerase gene (PB2) results in a dramatic difference in both temperature tolerance and infectivity.
Scientists at University of North Carolina at Chapel Hill found that the H5N1 virus required the higher temperatures found in its bird hosts (around 40 degrees Celsius) in order to be highly infective. At 32 degrees Celsius - the temperature of the cells found in human nasal passages called HAE, or human airway epithelium – the H5N1 virus became sticky and did not effectively infect those cells. The reason for this? A single amino acid at position 627 of the polymerase protein of the H5N1 virus was changed, allowing it to be glycosylated - chemically modified to bear a particular sugar residue. Researchers were able to prove this by genetically altering a human influenza virus (which infected cells optimally at 32 degrees Celsius) at position 627, changing just that one amino acid to one that could be glycosylated. The resulting human virus was not capable of creating an infection in human airway epithelial cells, demonstrating an attenuation of the formerly infective human influenza virus. Further modification of viral coat proteins fully attained an "avian" level of temperature sensitivity.
This research is important because it significantly adds to our understanding of the molecular process by which the influenza virus mounts a successful infection in either of its principal hosts (birds or humans). Scientists who sequence previously unknown strains of influenza isolated from patients can now rapidly assess the polymerase gene (PB2) and determine quickly whether it is an avian strain or one more evolved for humans. Not only the treatments recommended but also the course of a widespread epidemiological event could be affected by this. Further, scientists searching for the molecular keys to understanding the mutations of various influenza strains can now look more effectively for such alterations, granting insight into the process of interspecies spread of the virus.
Perhaps most importantly, these findings help to partially allay fears that H5N1 is likely to reassort with H1N1 – since avian flu infects HAE cells poorly due to their intolerance for colder temperatures, we are less likely to endure that kind of hybrid virus.
For more information:
Avian Influenza Virus Glycoproteins Restrict Virus Replication and Spread through Human Airway Epithelium at Temperatures of the Proximal Airways.
© A Quantum of Science / Peter Smalley (2009)
Reproduction with attribution is appreciation
Why does the more lethal H5N1 Avian flu not infect humans more readily?
Several references have been made now to the "nightmare scenario" in which genes from the more lethal Avian flu (H5N1) reassort with the less dangerous but more infective Swine flu (H1N1), generating a hybrid that is both lethal and infective. We have yet to talk much about why the H5N1 strain is harder for people to catch – so hard that in some years there are only a single-digit number of cases.
Certainly, the lethality of H5N1 inhibits its spread. In epidemiological terms, the virus kills faster than it spreads, leading to a reproduction number at or below one. In a recent paper, researchers show that a single amino acid change in the sequence of the viral polymerase gene (PB2) results in a dramatic difference in both temperature tolerance and infectivity.
Scientists at University of North Carolina at Chapel Hill found that the H5N1 virus required the higher temperatures found in its bird hosts (around 40 degrees Celsius) in order to be highly infective. At 32 degrees Celsius - the temperature of the cells found in human nasal passages called HAE, or human airway epithelium – the H5N1 virus became sticky and did not effectively infect those cells. The reason for this? A single amino acid at position 627 of the polymerase protein of the H5N1 virus was changed, allowing it to be glycosylated - chemically modified to bear a particular sugar residue. Researchers were able to prove this by genetically altering a human influenza virus (which infected cells optimally at 32 degrees Celsius) at position 627, changing just that one amino acid to one that could be glycosylated. The resulting human virus was not capable of creating an infection in human airway epithelial cells, demonstrating an attenuation of the formerly infective human influenza virus. Further modification of viral coat proteins fully attained an "avian" level of temperature sensitivity.
This research is important because it significantly adds to our understanding of the molecular process by which the influenza virus mounts a successful infection in either of its principal hosts (birds or humans). Scientists who sequence previously unknown strains of influenza isolated from patients can now rapidly assess the polymerase gene (PB2) and determine quickly whether it is an avian strain or one more evolved for humans. Not only the treatments recommended but also the course of a widespread epidemiological event could be affected by this. Further, scientists searching for the molecular keys to understanding the mutations of various influenza strains can now look more effectively for such alterations, granting insight into the process of interspecies spread of the virus.
Perhaps most importantly, these findings help to partially allay fears that H5N1 is likely to reassort with H1N1 – since avian flu infects HAE cells poorly due to their intolerance for colder temperatures, we are less likely to endure that kind of hybrid virus.
For more information:
Avian Influenza Virus Glycoproteins Restrict Virus Replication and Spread through Human Airway Epithelium at Temperatures of the Proximal Airways.
© A Quantum of Science / Peter Smalley (2009)
Reproduction with attribution is appreciation
Wednesday, May 20, 2009
Mapping H1N1
A QUANTUM OF SCIENCE
Where in the world is H1N1?
The spread of H1N1 around the world has significant implications for the etiology and epidemiology of the disease, as well as the global health infrastructure’s response to it. Raw numbers alone do not tell the story as well as this single image, taken from the WHO pandemic alert and response website.
This map is current: as of today there are a global total of 10,243 laboratory-confirmed cases of H1N1 influenza that have been reported to the WHO, including 80 deaths (making the global mortality rate one death out of every 128 cases). While the actual number of total cases is inevitably somewhat higher due to the lagging nature of lab confirmations and reporting, what is more interesting is the distribution of the cases – and deaths – and what this might tell us about the past and future of H1N1.
Originally dubbed as Swine Flu, the official name for this strain of H1N1 is North American influenza, and indeed the overwhelming majority of the cases are in North America (93.8%). What is interesting to note is that 79 of the 80 confirmed deaths are also in North America (98.75%). Digging a little deeper into the distribution of deaths, we find that this is due to the large contribution of deaths from H1N1 in Mexico, where the mortality rate is one death for every 50.6 cases. That is two and a half times the global mortality rate, and eighteen times the mortality rate in the adjacent United States. With the sequencing of the H1N1 genome in Canada that was announced yesterday, no significant differences were found in strains isolated in Mexico versus those in the United States or Canada. While this is somewhat reassuring because it means there is not a more virulent strain on the loose in Mexico, it requires a different explanation. Some authorities have suggested Mexico has deficiencies in its health infrastructure, but others cite a cultural inhibition that may play a more pervasive role in preventing infected persons from seeking help until it is too late. In either case, however, countries with similar health infrastructures and cultures would be expected to have a similar mortality rate, and this has not yet been borne out (as the map’s number for Central and South America show).
Another point of interest brought out by the map of H1N1 cases to date are the non-North American hot spots. Japan is the leader of these, with 210 cases, followed almost evenly by Spain (107) and the United Kingdom (102). What is interesting about this is the far-flung locations of the hotspots outside North America. Nothing like the close distribution of cases in Mexico-US-Canada have been seen in these Asian and European hotspots. This could mean that there is something particular to North America that supports the infectivity of the viral strain; or it could mean that it is simply too soon, and the neighbors of these hotspots will soon show a commensurate rise in cases. It is worth noting that strains of influenza are known to show a strong geographical preference; the deadly Bird flu (H5N1) is almost unknown outside of the Far East, for reasons that scientists are still trying to elucidate. This also brings up the potential for reassortment of viral genes between H1N1 and H5N1, now that the former has entered the latter’s territory. Still, Japan has been aggressive about treating flu cases and currently Roche (the maker of Tamiflu) estimates that 35 million of the 50 million people who have been treated with Tamiflu are in Japan. It can be hoped that this aggressive treatment schedule will be effective in containing the possible hybridization of H1N1 with H5N1.
For more information:
WHO Epidemic and Pandemic Alert and Response
WHO H1N1 map (20-May-2009 version)
Tamiflu (Oseltamivir) information, including use in Japan
© A Quantum of Science / Peter Smalley (2009)
Reproduction with attribution is appreciation
Where in the world is H1N1?
The spread of H1N1 around the world has significant implications for the etiology and epidemiology of the disease, as well as the global health infrastructure’s response to it. Raw numbers alone do not tell the story as well as this single image, taken from the WHO pandemic alert and response website.
This map is current: as of today there are a global total of 10,243 laboratory-confirmed cases of H1N1 influenza that have been reported to the WHO, including 80 deaths (making the global mortality rate one death out of every 128 cases). While the actual number of total cases is inevitably somewhat higher due to the lagging nature of lab confirmations and reporting, what is more interesting is the distribution of the cases – and deaths – and what this might tell us about the past and future of H1N1.
Originally dubbed as Swine Flu, the official name for this strain of H1N1 is North American influenza, and indeed the overwhelming majority of the cases are in North America (93.8%). What is interesting to note is that 79 of the 80 confirmed deaths are also in North America (98.75%). Digging a little deeper into the distribution of deaths, we find that this is due to the large contribution of deaths from H1N1 in Mexico, where the mortality rate is one death for every 50.6 cases. That is two and a half times the global mortality rate, and eighteen times the mortality rate in the adjacent United States. With the sequencing of the H1N1 genome in Canada that was announced yesterday, no significant differences were found in strains isolated in Mexico versus those in the United States or Canada. While this is somewhat reassuring because it means there is not a more virulent strain on the loose in Mexico, it requires a different explanation. Some authorities have suggested Mexico has deficiencies in its health infrastructure, but others cite a cultural inhibition that may play a more pervasive role in preventing infected persons from seeking help until it is too late. In either case, however, countries with similar health infrastructures and cultures would be expected to have a similar mortality rate, and this has not yet been borne out (as the map’s number for Central and South America show).
Another point of interest brought out by the map of H1N1 cases to date are the non-North American hot spots. Japan is the leader of these, with 210 cases, followed almost evenly by Spain (107) and the United Kingdom (102). What is interesting about this is the far-flung locations of the hotspots outside North America. Nothing like the close distribution of cases in Mexico-US-Canada have been seen in these Asian and European hotspots. This could mean that there is something particular to North America that supports the infectivity of the viral strain; or it could mean that it is simply too soon, and the neighbors of these hotspots will soon show a commensurate rise in cases. It is worth noting that strains of influenza are known to show a strong geographical preference; the deadly Bird flu (H5N1) is almost unknown outside of the Far East, for reasons that scientists are still trying to elucidate. This also brings up the potential for reassortment of viral genes between H1N1 and H5N1, now that the former has entered the latter’s territory. Still, Japan has been aggressive about treating flu cases and currently Roche (the maker of Tamiflu) estimates that 35 million of the 50 million people who have been treated with Tamiflu are in Japan. It can be hoped that this aggressive treatment schedule will be effective in containing the possible hybridization of H1N1 with H5N1.
For more information:
WHO Epidemic and Pandemic Alert and Response
WHO H1N1 map (20-May-2009 version)
Tamiflu (Oseltamivir) information, including use in Japan
© A Quantum of Science / Peter Smalley (2009)
Reproduction with attribution is appreciation
Tuesday, May 19, 2009
Quantum: flu expert fears H5N1 nightmare
A QUANTUM OF SCIENCE
What happens when the lethal but less-infective H5N1 strain of influenza mingles with the relatively benign but more-infective H1N1?
Dr. Yi Guan of Hong Kong Kong University is one of the leading flu experts in the world. His claim to fame was the isolation of the SARS virus in wild civets in 2003; his recommendation to eliminate the population of captive civets may have prevented a re-emergence of SARS since then. Now he has some strong criticisms of the World Health Organization's handling of H1N1, and worries about the potential for a sharing of lethal H5N1 genes with H1N1, which has proven itself far better at spreading itself around than H5N1.
The difference between the two strains' ability to infect may be in the gene encoding hemagglutinin, the protein that helps the virus get into cells and infect them. Recently published data shows that the genetic sequence for the hemagglutinin (HA) gene is only 9.7% similar between H5N1 and H1N1, by far the largest difference between their genetic codes. Because influenza is capable of rapid reassortment - the shuffling of genes like decks of cards - it may only be a matter of time before the HA gene from H1N1 is adopted by H5N1. That could have profoundly dire effects if experts like Dr. Guan are to be believed. So far the only ray of hope that nightmare scenario will not happen is the H1N1 seems restricted to North America, while H5N1 is only found in Asia. Critics of the WHO like Dr. Guan seem to be quite justified in calling for increased attention to transcontinental spread of H1N1 and more aggressive use of TamiFlu and other treatments to curb the spread of H1N1 into Asia.
More information:
http://blogs.sciencemag.org/scienceinsider/2009/05/exclusive-meet.html
© A Quantum of Science / Peter Smalley (2009)
Reproduction with attribution is appreciation
What happens when the lethal but less-infective H5N1 strain of influenza mingles with the relatively benign but more-infective H1N1?
Dr. Yi Guan of Hong Kong Kong University is one of the leading flu experts in the world. His claim to fame was the isolation of the SARS virus in wild civets in 2003; his recommendation to eliminate the population of captive civets may have prevented a re-emergence of SARS since then. Now he has some strong criticisms of the World Health Organization's handling of H1N1, and worries about the potential for a sharing of lethal H5N1 genes with H1N1, which has proven itself far better at spreading itself around than H5N1.
The difference between the two strains' ability to infect may be in the gene encoding hemagglutinin, the protein that helps the virus get into cells and infect them. Recently published data shows that the genetic sequence for the hemagglutinin (HA) gene is only 9.7% similar between H5N1 and H1N1, by far the largest difference between their genetic codes. Because influenza is capable of rapid reassortment - the shuffling of genes like decks of cards - it may only be a matter of time before the HA gene from H1N1 is adopted by H5N1. That could have profoundly dire effects if experts like Dr. Guan are to be believed. So far the only ray of hope that nightmare scenario will not happen is the H1N1 seems restricted to North America, while H5N1 is only found in Asia. Critics of the WHO like Dr. Guan seem to be quite justified in calling for increased attention to transcontinental spread of H1N1 and more aggressive use of TamiFlu and other treatments to curb the spread of H1N1 into Asia.
More information:
http://blogs.sciencemag.org/scienceinsider/2009/05/exclusive-meet.html
© A Quantum of Science / Peter Smalley (2009)
Reproduction with attribution is appreciation
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