Tweet
Tetano posted
The Lancet: Influenza protection?natural immunity and new vaccines
Abstract - I have not read the whole article as it is behind a pay firewall - but it, and the WHO pandemic review process, has prompted me to write more generally about flu vaccine.
While I would be delighted by a miracle cure vaccine I have too much respect for this virus to believe we are on the verge of producing one. I am however very concerned that this longer term goal may detract from the current imperative which is to move from egg based to one of the available alternatives. The litmus test is how quickly it can produce vaccine in the quantities required in the event of influenza pandemic.
If you have read any of my many postings on the need for a complete reappraisal of our flu vaccine production systems ? which are now lost somewhere in the 300,000+ posts in this forum ? you need not bother with the rest of this post as precious little has changed. For the rest of you the argument goes like this.
Pandemic flu has the potential to kill far more people in your country than anything short of full scale nuclear war. The 1914-18 war is infamous for the senseless slaughters of Ypres & Passchendaele and yet the whole four year war killed less than a few weeks of H1N1(1918).
All the pandemic plans, which helped with the H1N1(2009) pandemic, were in place due to the fear of HP H5N1 going pandemic with its extreme virulence even partly intact ? none of the plans even attempted to account for its virulence remaining largely intact. My first question is why when we are willing to ?dig deep? to put in place defences to threats to National Security do we limit it to human threats which are largely imaginary? As I sit and type in the North of England there are no existential threats to my nation (from other Nation States) and that applies to all the nations developed enough to have flu vaccine plants. An unseen viral revolution somewhere in a pig farm or chicken shed could however set in motion a very real threat to all I love and my government has NO defence. The plan(s) as devised and implemented in 2009 could not protect against infection only a reasonably effective vaccine can. Anti-virals also are not a solution for reasons I will expand on later.
Cursed by vaccine capacity.
Last year?s unused pandemic vaccine was taken out of mothballs this year, in the UK, and used to supplement dwindling seasonal vaccine supplies. The point being that the end products of pandemic, and seasonal, vaccine production technologies are indistinguishable. The temptation ? and mistake ? then is to use seasonal flu production capacity and techniques to produce pandemic vaccine. What we need to do is scrap the egg based production capacity and replace it with a pandemic flu vaccine production system which can then be used to produce seasonal vaccine. The two do not commute; you can produce seasonal vaccine (smaller quantities and longer lead times) in a pandemic facility but not vice versa.
The problem then is financial. Vaccine manufacture is currently a commercial operation and there is no incentive system which would make the manufactures rip up perfectly good vax plants to replace them with a different system which will only be need in pandemic years which, currently, seem to occur a few times a century and, quite possibly, not at all within the life time of the plant. So to recap we can declare vaccine production a matter of National Security and either nationalise it or pay the industry to retool and maintain surge capacity. The alternative is to go with the status quo and accept that pandemic influenza will perform a cull of our species intermittently and we will have no control over the depth of the cuts it will make. When making that choice it should be borne in mind an unattenuated HP H5N1 could kill half the world?s population and, with only a handful of pandemic influenzas to guide us, we have no idea if that is even a worst case scenario.
Killing some sacred cows
In anticipation of some of the arguments I anticipate, and have met before, regarding scaremongering about high virulence I will address a couple of the most common ? and look forward to any others readers may post.
Very high virulence is not in the virus? best interest. Granted but with some caveats. This is in relation to an equilibrium state achieved between the virus and its host species. H5N1 in a mallard (a representative host species) cause a low virulence infection but the same virus in a human tends to be fatal in most cases. As the virus is not generally going on to cause further human to human (h2h) infections there is no selection pressure to attenuate until efficient h2h replication is achieved and a pandemic is underway. At this point selection pressure will tend to select against high virulence if it is impeding transmission. Darwin has nothing to say about the starting virulence or how much damage is done to the new host species on the road to equilibrium.
The general argument is if a respiratory illness takes you out of circulation before you have a chance to pass it on then its reproductive number (Ro) drops and it is at a disadvantage relative to milder mutations that keep their host up and infecting. The converse is that if the virus is too mild it is not trying hard enough and a mutation that is highjacking more of the host?s cells to make virus (which must have an impact on the host) should out perform it. A balance is then reached which is going to be dependant on frequency of infectious interactions for which we can use population density as a proxy.
Dr.Greger<sup>1</sup> has been banging this drum in relation to high density animal production and its ability to sustain much more virulent stains. Influenza further complicates this model by having an infectious period prior to symptom onset.
The other caveat is that attenuation is not required if efficient zoonotic infection is achieved without, or with only limited, h2h as is probably the case with Nipah (here bats may be feeding on palms the juice from which is then being drunk by humans) or Hanta (where the natural hosts droppings are swept up and the dust inhaled). At present humans do not easily catch flu from birds or pigs but if a strain were to develop that was mild for one species, but fatal for another, and very infectious across species then the second species would just be collateral damage and the usual breaking effect of reduced Ro due to thinning of the species? density never applies and species extinctions can occur - for an example see http://en.wikipedia.org/wiki/Chytridiomycosis.
The Anti-viral catch 22
There is the non-specific, to flu, problem that all anti-biotics and anti-virals face in they create selection pressure against themselves.
When it comes to flu there are the two classes of antiviral action, interruption of the M2 ion pump mechanism (very susceptible to resistance emergence) and inhibition of sialic acid cleavage by the Neuraminidase glycoprotein (NA). Of the Neuraminidase inhibitors there are two slightly different actions employed by Zanamivir (Relenza) and Oseltamivir (Tamiflu). Relenza is an inhaled powder and has not been adopted as widely as the tablet form of Oseltamivir marketed as Tamiflu. Of the two Relenza is mechanistically less susceptible to resistance emergence. Tamiflu has been known to fairly readily form resistant mutations but, fortunately in most cases, these have had an attendant fitness penalty and, once competing with the wild type away from Tamiflu treatment, they are quickly out performed and become extinct. Unfortunately in, or around, 2006/7 the seasonal H1N1 achieved a genetic background on which the H275Y(NA) mutation no longer came with a fitness penalty and with in about a year almost all H1N1 was effectively resistant.
The H1N1(2009) pandemic seems to have almost completely killed off the old resistant seasonal strain and returned us to the position we were in prior to 2006/7 namely Oseltamivir susceptible (new) seasonal H1N1. As we do not really understand the conformational changes that lead to the loss of fitness penalty in the old H1N1 we can not tell how likely the emergence of a no-penalty background is in the new H1N1.
As Tamiflu is ?the? de facto flu anti-viral we need to be aware of a problem in its mode of action which makes it very difficult to use, especially with H1N1(2009). When flu takes over a host cell it creates new virus particles which are then released by a process called budding. The new virus has a problem in that one of its surface proteins (Haemagglutinin HA) binds to sialic acid residues on the cells surface as part of the infection process however at this point, viral release, the virus is in search of new prey and binding to the already infected cell is not helpful. Enter the other main viral surface protein (Neuraminidase) which snips off sialic acid residues so preventing clumping and aiding release.
The released virus can then float off and find new cells to infect in the same host or, extremely rarely, in a new host. Remember from a single infected cell millions of other cells are likely to be infected in the same host before the infection jumps ship to a new host. Flu infects single cells which just happen to be part of a multi-cellular organism.
Neuraminidase inhibitors (NI) bind to the Neuraminidase preventing it from cleaving the residues. If we consider this modus operandi we will see it can not prevent infection of a cell what it can do is help slow up the spread to new cells if there is enough NI, for binding to NA, at the point of cell release. The slowing of spread aids the host?s immune response to clear the infection.
This MO makes it an effective prophylactic, as relatively low doses would prevent early spread and greatly aid in viral clearance. The prescribing advice says ?to be taken within 48hrs of symptom onset? which makes sense given that the patient would be asymptomatic until viral levels, and immune response, made them feel unwell. Two days after this point the virus is going to be rampant and so many cells are going to be producing virus failing to block even a few will still leave plenty to re-infect. The drug is not useless it is just progressively less useful the later it is taken. The corollary is the earlier you start treatment the better and 48hrs is already very late in the infection as for that matter is symptom onset.
Now for the catch 22. The reality is most people do not see a doctor at symptom onset for seasonal flu, or for the next 48hrs. If their immune system is not getting the better of the virus after a few days they then go to the doctor for help, by which time the efficient prescribing window has closed. H1N1(2009) has further complicated the picture by causing mild illness in most and severe illness in a few. Of the few many are in identifiable at risk groups ? for who prescription at symptom onset seems a wise precaution ? but a significant proportion appear to be fit young adults with nothing to indicate they are going to have a problem. This group are also not likely to have been targeted for vaccination and present too late to get the full benefit from antivirals. This is a relative unusual phenomenon for wealthier nations which have grown accustomed to not loosing their children to communicable diseases. The population at large is certainly unused to mass casualties to communicable disease and has a very poor grasp of the realities of a fast spreading, virulent pandemic, be it flu or some other novel infectious agent, and our inability to magically produce a new drug in the timescales allowed. HIV/AIDS is a classical pandemic but in slow-motion and we are having difficulty in pharmasutically keeping up with its evolution despite its timescales being in decades rather than weeks for flu or SARS.
On the future of vaccine
I am writing this at this time partly in response to another article on a vaccine for all flu strains, which I have my doubts about. Looking further ahead if Dr. Greger is right and we are in for a period of much higher emergence of novel diseases in humans from animal reservoirs then applying surge capacity for flu is inadequate and we should be looking for a more generic solution. I discussed with Mingus many years ago air-lift fermentation of monoclonal antibodies as a longer term solution. The advantage being it is aiding our immune response by the production of mAbs which can be selected for any disease and would not be used singly. By varying the cocktail regularly you make it very difficult for the disease to achieve resistance. If several antibodies are produced and only a random subset included in each flu shot then even multiple simultaneous resistances against one vaccine does not help the virus in its new host. The technology, if it can be made to work cost effectively, can be switched from anti-bodies for flu to those for SARS or anything else as needed.
1] Dr.Greger This link is to his lecture on his book of the same name Bird Flu: A Virus of Our Own Hatching
or this later one called Flu Factories which covers much the same ground
Edit:
This link is to A Review of the Antiviral Susceptibility of Human and Avian Influenza Viruses over the Last Decade which has an excellent history of resistance emergence with all the know SNP markers. Another
to Tetano for his ever useful postings in the Scientific Library forum.
The Lancet: Influenza protection?natural immunity and new vaccines
Abstract - I have not read the whole article as it is behind a pay firewall - but it, and the WHO pandemic review process, has prompted me to write more generally about flu vaccine.
While I would be delighted by a miracle cure vaccine I have too much respect for this virus to believe we are on the verge of producing one. I am however very concerned that this longer term goal may detract from the current imperative which is to move from egg based to one of the available alternatives. The litmus test is how quickly it can produce vaccine in the quantities required in the event of influenza pandemic.
If you have read any of my many postings on the need for a complete reappraisal of our flu vaccine production systems ? which are now lost somewhere in the 300,000+ posts in this forum ? you need not bother with the rest of this post as precious little has changed. For the rest of you the argument goes like this.
Pandemic flu has the potential to kill far more people in your country than anything short of full scale nuclear war. The 1914-18 war is infamous for the senseless slaughters of Ypres & Passchendaele and yet the whole four year war killed less than a few weeks of H1N1(1918).
All the pandemic plans, which helped with the H1N1(2009) pandemic, were in place due to the fear of HP H5N1 going pandemic with its extreme virulence even partly intact ? none of the plans even attempted to account for its virulence remaining largely intact. My first question is why when we are willing to ?dig deep? to put in place defences to threats to National Security do we limit it to human threats which are largely imaginary? As I sit and type in the North of England there are no existential threats to my nation (from other Nation States) and that applies to all the nations developed enough to have flu vaccine plants. An unseen viral revolution somewhere in a pig farm or chicken shed could however set in motion a very real threat to all I love and my government has NO defence. The plan(s) as devised and implemented in 2009 could not protect against infection only a reasonably effective vaccine can. Anti-virals also are not a solution for reasons I will expand on later.
Cursed by vaccine capacity.
Last year?s unused pandemic vaccine was taken out of mothballs this year, in the UK, and used to supplement dwindling seasonal vaccine supplies. The point being that the end products of pandemic, and seasonal, vaccine production technologies are indistinguishable. The temptation ? and mistake ? then is to use seasonal flu production capacity and techniques to produce pandemic vaccine. What we need to do is scrap the egg based production capacity and replace it with a pandemic flu vaccine production system which can then be used to produce seasonal vaccine. The two do not commute; you can produce seasonal vaccine (smaller quantities and longer lead times) in a pandemic facility but not vice versa.
The problem then is financial. Vaccine manufacture is currently a commercial operation and there is no incentive system which would make the manufactures rip up perfectly good vax plants to replace them with a different system which will only be need in pandemic years which, currently, seem to occur a few times a century and, quite possibly, not at all within the life time of the plant. So to recap we can declare vaccine production a matter of National Security and either nationalise it or pay the industry to retool and maintain surge capacity. The alternative is to go with the status quo and accept that pandemic influenza will perform a cull of our species intermittently and we will have no control over the depth of the cuts it will make. When making that choice it should be borne in mind an unattenuated HP H5N1 could kill half the world?s population and, with only a handful of pandemic influenzas to guide us, we have no idea if that is even a worst case scenario.
Killing some sacred cows
In anticipation of some of the arguments I anticipate, and have met before, regarding scaremongering about high virulence I will address a couple of the most common ? and look forward to any others readers may post.
Very high virulence is not in the virus? best interest. Granted but with some caveats. This is in relation to an equilibrium state achieved between the virus and its host species. H5N1 in a mallard (a representative host species) cause a low virulence infection but the same virus in a human tends to be fatal in most cases. As the virus is not generally going on to cause further human to human (h2h) infections there is no selection pressure to attenuate until efficient h2h replication is achieved and a pandemic is underway. At this point selection pressure will tend to select against high virulence if it is impeding transmission. Darwin has nothing to say about the starting virulence or how much damage is done to the new host species on the road to equilibrium.
The general argument is if a respiratory illness takes you out of circulation before you have a chance to pass it on then its reproductive number (Ro) drops and it is at a disadvantage relative to milder mutations that keep their host up and infecting. The converse is that if the virus is too mild it is not trying hard enough and a mutation that is highjacking more of the host?s cells to make virus (which must have an impact on the host) should out perform it. A balance is then reached which is going to be dependant on frequency of infectious interactions for which we can use population density as a proxy.
Dr.Greger<sup>1</sup> has been banging this drum in relation to high density animal production and its ability to sustain much more virulent stains. Influenza further complicates this model by having an infectious period prior to symptom onset.
The other caveat is that attenuation is not required if efficient zoonotic infection is achieved without, or with only limited, h2h as is probably the case with Nipah (here bats may be feeding on palms the juice from which is then being drunk by humans) or Hanta (where the natural hosts droppings are swept up and the dust inhaled). At present humans do not easily catch flu from birds or pigs but if a strain were to develop that was mild for one species, but fatal for another, and very infectious across species then the second species would just be collateral damage and the usual breaking effect of reduced Ro due to thinning of the species? density never applies and species extinctions can occur - for an example see http://en.wikipedia.org/wiki/Chytridiomycosis.
The Anti-viral catch 22
There is the non-specific, to flu, problem that all anti-biotics and anti-virals face in they create selection pressure against themselves.
When it comes to flu there are the two classes of antiviral action, interruption of the M2 ion pump mechanism (very susceptible to resistance emergence) and inhibition of sialic acid cleavage by the Neuraminidase glycoprotein (NA). Of the Neuraminidase inhibitors there are two slightly different actions employed by Zanamivir (Relenza) and Oseltamivir (Tamiflu). Relenza is an inhaled powder and has not been adopted as widely as the tablet form of Oseltamivir marketed as Tamiflu. Of the two Relenza is mechanistically less susceptible to resistance emergence. Tamiflu has been known to fairly readily form resistant mutations but, fortunately in most cases, these have had an attendant fitness penalty and, once competing with the wild type away from Tamiflu treatment, they are quickly out performed and become extinct. Unfortunately in, or around, 2006/7 the seasonal H1N1 achieved a genetic background on which the H275Y(NA) mutation no longer came with a fitness penalty and with in about a year almost all H1N1 was effectively resistant.
The H1N1(2009) pandemic seems to have almost completely killed off the old resistant seasonal strain and returned us to the position we were in prior to 2006/7 namely Oseltamivir susceptible (new) seasonal H1N1. As we do not really understand the conformational changes that lead to the loss of fitness penalty in the old H1N1 we can not tell how likely the emergence of a no-penalty background is in the new H1N1.
As Tamiflu is ?the? de facto flu anti-viral we need to be aware of a problem in its mode of action which makes it very difficult to use, especially with H1N1(2009). When flu takes over a host cell it creates new virus particles which are then released by a process called budding. The new virus has a problem in that one of its surface proteins (Haemagglutinin HA) binds to sialic acid residues on the cells surface as part of the infection process however at this point, viral release, the virus is in search of new prey and binding to the already infected cell is not helpful. Enter the other main viral surface protein (Neuraminidase) which snips off sialic acid residues so preventing clumping and aiding release.
The released virus can then float off and find new cells to infect in the same host or, extremely rarely, in a new host. Remember from a single infected cell millions of other cells are likely to be infected in the same host before the infection jumps ship to a new host. Flu infects single cells which just happen to be part of a multi-cellular organism.
Neuraminidase inhibitors (NI) bind to the Neuraminidase preventing it from cleaving the residues. If we consider this modus operandi we will see it can not prevent infection of a cell what it can do is help slow up the spread to new cells if there is enough NI, for binding to NA, at the point of cell release. The slowing of spread aids the host?s immune response to clear the infection.
This MO makes it an effective prophylactic, as relatively low doses would prevent early spread and greatly aid in viral clearance. The prescribing advice says ?to be taken within 48hrs of symptom onset? which makes sense given that the patient would be asymptomatic until viral levels, and immune response, made them feel unwell. Two days after this point the virus is going to be rampant and so many cells are going to be producing virus failing to block even a few will still leave plenty to re-infect. The drug is not useless it is just progressively less useful the later it is taken. The corollary is the earlier you start treatment the better and 48hrs is already very late in the infection as for that matter is symptom onset.
Now for the catch 22. The reality is most people do not see a doctor at symptom onset for seasonal flu, or for the next 48hrs. If their immune system is not getting the better of the virus after a few days they then go to the doctor for help, by which time the efficient prescribing window has closed. H1N1(2009) has further complicated the picture by causing mild illness in most and severe illness in a few. Of the few many are in identifiable at risk groups ? for who prescription at symptom onset seems a wise precaution ? but a significant proportion appear to be fit young adults with nothing to indicate they are going to have a problem. This group are also not likely to have been targeted for vaccination and present too late to get the full benefit from antivirals. This is a relative unusual phenomenon for wealthier nations which have grown accustomed to not loosing their children to communicable diseases. The population at large is certainly unused to mass casualties to communicable disease and has a very poor grasp of the realities of a fast spreading, virulent pandemic, be it flu or some other novel infectious agent, and our inability to magically produce a new drug in the timescales allowed. HIV/AIDS is a classical pandemic but in slow-motion and we are having difficulty in pharmasutically keeping up with its evolution despite its timescales being in decades rather than weeks for flu or SARS.
On the future of vaccine
I am writing this at this time partly in response to another article on a vaccine for all flu strains, which I have my doubts about. Looking further ahead if Dr. Greger is right and we are in for a period of much higher emergence of novel diseases in humans from animal reservoirs then applying surge capacity for flu is inadequate and we should be looking for a more generic solution. I discussed with Mingus many years ago air-lift fermentation of monoclonal antibodies as a longer term solution. The advantage being it is aiding our immune response by the production of mAbs which can be selected for any disease and would not be used singly. By varying the cocktail regularly you make it very difficult for the disease to achieve resistance. If several antibodies are produced and only a random subset included in each flu shot then even multiple simultaneous resistances against one vaccine does not help the virus in its new host. The technology, if it can be made to work cost effectively, can be switched from anti-bodies for flu to those for SARS or anything else as needed.
1] Dr.Greger This link is to his lecture on his book of the same name Bird Flu: A Virus of Our Own Hatching
or this later one called Flu Factories which covers much the same ground
Edit:
This link is to A Review of the Antiviral Susceptibility of Human and Avian Influenza Viruses over the Last Decade which has an excellent history of resistance emergence with all the know SNP markers. Another
to Tetano for his ever useful postings in the Scientific Library forum.
Comment