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  • On the future of flu vaccine and anti-viral usage

    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.
    Last edited by JJackson; May 10th, 2014, 01:02 PM. Reason: added link

  • #2
    Re: On the future of flu vaccine and anti-viral usage

    JJackson,
    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.
    I'm not familiar with this; could you please briefly explain what that is?
    The salvage of human life ought to be placed above barter and exchange ~ Louis Harris, 1918

    Comment


    • #3
      Re: On the future of flu vaccine and anti-viral usage

      Originally posted by mixin View Post
      JJackson,


      I'm not familiar with this; could you please briefly explain what that is?
      Have a look at this thread from post #20.

      Comment


      • #4
        Re: On the future of flu vaccine and anti-viral usage

        Thanks, I'll check it out.

        A while back, we were discussing the different methods of passage in this thread http://www.flutrackers.com/forum/sho...d.php?t=137282 where you said:
        As I recently read this on MCDK-SIAT1 I will provide the link here for reference.
        MDCK is alpha 2,3 rich and 2,6 poor which applies selection pressure during passaging. They engineer a additional gene into the MDCK genome which doubled the number of a2,6 receptors.
        I've seen it said on the net that mutations at positions 154 and 156 of the HA were associated with low reactors. But then I read the Feb 2011 Mill Hill interim report to the WHO and saw this:
        Viruses that show differences in reactivity to post-infection ferret antiseraraised against the vaccine virus A/California/7/2009 and against the prototype virus A/California/4/2009 have been detected. The majority of these viruses 25/29 showed good reactivity with sera raised against viruses that have substitutions between 154 and 156 of the HA (A/Bayern/69/2009 and A/Lviv/N6/2009) and it is known that many of the 25 showed similar changes that were not present in the clinical sample and were therefore associated with the substrate for isolation (MDCK-SIAT cells).
        As I looked at most of the low reactor sequences, I noticed that those mutations often only showed up with that method of passage. However, I assumed MDCK-SIAT was used because it was more sensitive and picked up those mutations.

        If I'm understanding the Mill Hill report, my assumption is incorrect.
        The salvage of human life ought to be placed above barter and exchange ~ Louis Harris, 1918

        Comment


        • #5
          Re: On the future of flu vaccine and anti-viral usage

          Mixin we definitely need the help of someone who actually knows what they are talking about.
          That said I would interpret this as meaning that Mill Hill suspect the low reactor is occurring due to changes in the sequence during passage in the SIAT cell line. SIAT1 is a better approximation than strait MDCK but even with the increased alpha 2,6 provided by the gene insertion it is still 2,3 heavy – relative to human URT epithelial cells. This will apply selection pressure during passage favouring any mutations which are better optimised for alpha 2,3 binding.
          You look at more sequences than I these days but I did look at Lviv/N6(HA) at the time of its release because of its ‘low reactor’ note and found Lviv/N2, which was sequenced and released in the same batch, was identical at the AA level (there were minor changes in the RNA but they were all 3 position and silent) but did not ‘fail’ the HI test.
          The positions you, and Mill Hill, have highlighted are in antigenic site B adjacent to the receptor binding site (RBS) and presumably cause a conformational change in that area which ups alpha 2,3 affinity.


          The diagram taken from Structure and Receptor binding properties of a pandemic H1N1 virus hemagglutinin shows the RBS and some key sites including 156 & 222 on either side of it in A and in C 159 is labelled nestling among the primary HA antigenic sites.
          Click image for larger version

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          Last edited by JJackson; May 26th, 2015, 06:04 PM.

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          • #6
            Re: On the future of flu vaccine and anti-viral usage

            we definitely need the help of someone who actually knows what they are talking about.
            That certainly bears repeating!!

            I made a list of all the low reactors listed in last year's spring Mill Hill report and searched GISAID records. Many were there but a fair number had other methods of passage.

            Many did not have the mutation or the low reactor designation, even though they appeared to be from the same person. That led me to speculate they used MDCK-SIAT if they were looking for low reactors.

            I stay confused about how the method of passage affects the sequence and how it all shakes out with the vaccine. If the low reactor status is just a result of passage, is it really even important?
            The salvage of human life ought to be placed above barter and exchange ~ Louis Harris, 1918

            Comment


            • #7
              Re: On the future of flu vaccine and anti-viral usage

              Originally posted by mixin View Post
              I stay confused about how the method of passage affects the sequence and how it all shakes out with the vaccine. If the low reactor status is just a result of passage, is it really even important?
              It is important in understanding the trends in the sequences while they may drift during passage there will be limits to how far.


              Flu is famous for its ability to mutate so if you have a swab and grow it in X – where X is one of MDCK, SIAT, egg or some other cell line – you are going to get a whole range of variations around what ever was in the swab. All of the virions produced will then have to find a new cell to infect in the growth medium but which of this generation succeed will depend, at least in part, on how well adapted the RBS of their HA is to what ever X we happened to choose. The reason we have to passage the virus at all is the swab sample size is too small. Each generation is termed a passage and each passage produces more virus but it also increases the chance that the virus will drift away from the sequence we would have got if we had been able to exactly clone the original sample (I am ignoring the whole quasi species aspect of flu to keep it simple – think of it as adding an extra passage).

              From the above we can see that what comes out is not necessarily identical to what went in. The question is how different is it? That depends on two main variables how many passages were performed and how strong the selection pressure was. To minimise the drift we can reduce the number of passages – for which we either need a bigger initial sample or we can increase the diagnostic sensitivity (needs less product) – and/or we can reduce the selection pressure by making sure we match, as accurately as possible, our passage cell line to the samples host species. There is no perfect match for a human flu virus sample; egg would be worse than MDCK which would not be as good as SIAT. There is a limit to the amount of drift you are likely to get so you will end up near the ideal but not exactly on target.
              Now if you use your product in an HI test then original samples which were already further away from the test antisera are more likely to have drifted over the boarder into 'low reactor' territory. Conversely on remote branches of the phylogenic tree could – which would have been low reactor – samples may passage back into the more central zone.

              If you look at the plot of H3N2’s HI tests over time from its emergence in 1968, taken from another of my posts in this work shop Hemagglutination Inhibition assays and antigenic mapping. It should make it easier to visualise. The linked post does have further links to H1N1(2009) antigenic maps but as it has not had very long in which to accumulate mutations and branch out, phylogenically, they still form a fairly tight grouping and are consequently not as useful as this rather elegant map of H3N2's erratic meander. Each square is a two fold dilution in an HI test, each little circle is a HI test, each colour denotes the area covered by a different vaccine, the TX77 is the groups representative sequence, in this case Texas 1977.
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              There were 11 vaccine changes needed in 34 years due to H3N2's natural drift, which is not untypical across serotypes.

              H1N1(2009) starts from a point at emergence (note the earlier colours form tighter knots) which will help to keep it tight but on the other hand it is in a new species which should cause higher selection pressure (for all the same reasons as our passage sample when they were grown in the 'wrong' medium)

              For anyone following this and needing more background there are several useful links in the linked post above and Prof. Vincent Racaniello's Influenza 101 is a brilliant source and his index page links to post on HI testing, Quasi species, RBS and everything else flu related.

              One more graphic from Structure of the Uncleaved Human H1 Hemagglutinin from the Extinct 1918 Influenza Virus which again shows the RBS with some AAs labeled inc. 153. As always beware differences in serotype numbering systems which cause some papers to talk about the same position as 222 and others call it 225, I have not been clear in this post as it relates to an area not a critical SNP and is not critical to the principals involved.Name:  bd8f576e128f50ed974e323539f47aec.jpg
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              Last edited by JJackson; October 31st, 2014, 01:30 PM. Reason: In the interests of clarity - well thats the theory - and links

              Comment


              • #8
                Re: The Cochrane NAI report - An opinion

                This is a personal opinion only and I am not writing on behalf of FluTrackers or anyone else.

                First a bit of background.
                The Cochrane Collaboration are heavy-weights and and their analysis is taken very seriously in the industry. Usually if they ask for data it is forthcoming but in this case Roche were very reluctant to let them have their clinical trials data and tried to limit access and set rules. This is akin to an author submitting to Nature stipulating terms for publication. Cochrane were unimpressed and a long stream of rancorous communication, which was released into the public domain, ensued before Cochrane eventually got the data.

                The findings
                In short NAIs are not a magic bullet. What they will do is 'smooth the edges' of the symptom set a little. Tetano pasted the findings here, and I reviewed Tamiflu's action and some other problems relating to prescribing in the 'Antiviral Catch 22' section of the first post in this thread. The US CDC made, what I thought was a well balanced response, which Giuseppe Michieli posted here.

                Where does that leave us?
                If you have not already done so I would recommend reading the first post in this thread as it lays out much of the background which I will not repeat here.

                We are faced by a very dangerous, and variable, disease for which we have some not very effective tools.

                Testing & Diagnosis.
                While RT-PCR lab analysis is excellent and, apart from the limitation discussed in this thread and some concerns over where sampling is concentrated, is doing a good job and building increasingly useful sequence databases. The problem is more with the absence of a reliable field rapid test kit, these have abysmal reliability.

                Treatment Options (again please see first post for vaccine production limitations and resistance concerns.)
                We have Vaccines, Antivirals and Other potential treatments.

                Vaccines
                The problem here is they are not very effective and hardly work at all in the group that needs them the most. The first problem is there are three types of flu - A, B & C - and we need to cover A & B. Then there are two main linages of B and two seasonal subtypes of A. The type A subtypes are further divided into myriad of clades, sub-clades and strains. As there is no single vaccine for all of these circulating seasonal flus the compromise is to produce 3 vaccines incorporating a best guess as to the probable dominating strains from each of (A)H3N2, (A)H1N1(2009) & B for the following season which are combined to produce a trivalent flu shot. This is done twice a year once each for the Northern and Southern Hemisphere seasons. Assuming the guess is correct then in the adult (but not elderly) population the vaccine is about 60%; effective. Unfortunately the fatalities from flu fall very heavily on the elderly with H3N2 particularly prominent and the over 65s recording about 95% of all flu deaths. The vaccine produces such a poor immune response by this group that it is difficult to be statistically sure it has any benefit despite this being the largest group targeted for vaccination.

                AntiVirals.
                On the NAIs as the Cochrane analysis - and previous studies - show once again the benefit is marginal.
                Consider a vaguely 'Normal Distribution' curve with the number of cases plotted on the Y axis and the X axis depicting increasing symptom severity so you go from asymptomatic & mild near the Origin and ICU & fatal cases at the other extreme. In the hump in the middle you would get the bulk of cases with a standard ILI symptom set. The data would suggest applying Tamiflu to these patients would shift the whole plot very slightly toward the origin. If the graph basically retained its shape then the area of interest is at the extreme severity end of the graph > 3 standard deviations above the mean. These are the fraction of a fraction of a percent who are on the boarder line between ICU & death and for whom any, however minor, help could be critical. There is also all the others who benefit by a slightly quicker recovery or are nudged the right side of the 'self treatment'/hospitalisation & general ward/ICU boundaries.
                If all of the above is basically correct then the question becomes was it worth the investment in NAI's or could the money have been better used on something else?

                Other treatments
                For the bulk of the population seasonal flu is generally a very unpleasant but not existential experience. The principle exception are those with poor immune systems, either due to age or some co-morbidity, or - as this is a respiratory disease - impaired cardiovascular function. The exception to this rule is a small group of healthy young people with robust immune systems who, for reasons that are unclear (at least to me), badly over react to the infection and end up causing severe Lower Respiratory tract damage. This form of immune dysfunction (AKA a cytokine storm) is more prevalent with certain Type A strains and radically skewed the age distribution in the 1918 H1N1 pandemic and has - to a much lesser extent - reappeared with H1N1(2009) although was not so common with pre 2009 H1N1, H3N2 or the Type B linages. This aspect of flu's behaviour is probably the most promising area for alternative treatments.
                In 1918 the new wonder drug Asprin was widely used but, with the benefit of hindsight, may not have been such a wise choice as the LRT damage caused primary pneumonia and would have been exacerbated by Asprin's blood thinning properties counteracting the benefits of fever reduction. Statins (which are cheap - out of patent - and widely available globally not just in the rich countries) have been proposed by Dr. Fedson and others (inc. Dr. Susan Chu who like Dr. Fedson are member here at FluTrackers) as a better solution and eloquently made their case in a letter in the Times (Thread link - the original is now behind a pay firewall). I also note that Tetano posted an abstract today for a paper looking at PGE2 and its roll in macrophage recruitment to the site of infection (Macrophages are a primary cause of the LRT collateral damage) which also looks promising. Given the marginal efficacy of our primary weapons - vaccine and anti-virals - I think there is a strong case for further work in this area given the Statins strong showing in the clinical trials but there seems to be little appetite for pursuing the work necessary to move an out of patent class of drugs from off-label to on-label use as an immune dysfunction regulator.

                All-in-all I think we need to continue with Tamiflu as, while not very effective, it is the best tool available at present but all of the above hopefully emphasises the urgent need to work harder on our vaccine, antiviral and other weapons.
                As I said up front this is my personal view of the situation and I look forward to your comments and thoughts.

                If I could also make a RFI. I noted how rapidly the pre 2009 H1N1 went from Tamifu susceptible to resistant in the first post in this thread but would be grateful for a link if anyone knows of a good paper covering the changes to the genetic background and why they permitted the SNP to not only remain fit but dramatically outperform its parent strain contrary to the received wisdom that 'this SNP change carries with it a fitness penalty'.
                Last edited by JJackson; May 11th, 2018, 11:11 AM.

                Comment


                • #9
                  Re: On the future of flu vaccine and anti-viral usage

                  The issue concerns also the lack in the Cochrane analysis of the observational studies regarding at risk people, hospitalized patients and on the ground experience with avian influenza cluster of cases (ie the so-called 'tamiflu-blanket' in several part of Eurasia, like the H5N1 Sumatera human-to-human transmission event. What would be the scenario if the drug would not be prophylactically administered to all village dwellers?).

                  This is a critical issue: outpatients effectiveness may be negligible (and economically unsustainable if the drug is provided through public health insurance), for otherwise healthy patient with uncomplicated influenza virus infection, that is - for the seasonal strain - almost universally a self-limiting condition.

                  Clearly, if a drug is administered to a patient that is recovering well, the effect will be unnoticeable.

                  But the discussion should be focused on hospitalized patient with severe influenza A of animal origin, with virological response, duration of viral shedding, impact on cytokine inductions, etc.

                  Without NAIs there are not other viable pharmaceutical option to reduce the impact on first instance at the start of a pandemic.

                  As other researchers pointed out in the past, clinical management of influenza is far for being perfect, because the lack of effective intervention in host inflammatory response and immune modulation.

                  We need with extremely urgency a detailed plan to address these issue because another pandemic will materialize at a certain point in the future and we cannot afford to fight it with witchcraft, sorcerers, magics or other Middle Age instruments.

                  gm

                  Comment


                  • #10
                    Re: On the future of flu vaccine and anti-viral usage

                    Giuseppe I agree but the scope set for the Cochrane report limited it to an analysis of the placebo controlled clinical trials data and, as they pointed out, it would be unethical to give placebos to ICU patients to find out if it worked in that environment. As explained in the opening post in this thread the way the NAIs work requires an early start to treatment for them to be effective so if the patient is already in ICU either it was used too late to prevent a foothold or just was not working very well. Looking at the drugs MO it is very unlikely to be much use in late stage illness although - as I argued in my last post - for these patients even a very slight edge could be enough to make a life or death difference.

                    Regarding the 'Tamiflu blanket' prophylactic use as means of stopping a pandemic emergence I have severe doubts. The action of the drug makes it well suited to this use however the problem is the lack of a reliable rapid test kit. Having watched the birth of the 2009 pandemic and the progress of H5N1, H7N9 et al it seems likely it would be well 'out of the box' long before the blanket descended. In addition to which a truly novel flu, without either an H or N from a seasonal strain, would be wholly reliant on an innate immune response with no adaptive component which would probably greatly outweigh NI effect.

                    Comment


                    • #11
                      Re: On the future of flu vaccine and anti-viral usage

                      I think we've seen many other incidents where tamiflu blankets may have avoided a H5N1 with enhanced transmissibility to spread Beyond its first cluster: in Pakistan, in Turkey, in Azerbaijan, etc.

                      The Cochrane review was not designed to include observation studies and took into consideration mostly non-hospitalized patients, with self-limiting disease.

                      I think that R. Webster Group had a great amount of research into these drugs and their effect on pathogensis of influenza infection.

                      The overuse of NAIs for out-patients is clearly not warranted, as the widespread antibiotics use for minor conditions is also of no benefit for patients.

                      The main issue with antivirals stockpile to anticipate a pandemic first line of defense is the cost: many of the countries in Europe are not longer interested in these preparedness activities because the austerity policy is drying universal health care expenditures at level never seen in the continent since the end of WWII.

                      If you want I will be completely honest, then I have to say that the major purpose of the review is to support the new policy of savage cuts in all hazards preparedness.

                      If one considers that some EU MS are very vulnerable to extreme climate events, in seismologically active regions, with dilapidated infrastructures, then it will be possible to understand better the impact of such policies into the preparedness activities.

                      If a M8 quake will hit Tomorrow Florence or Rome, how many people do you think will die? 1,000, 10,000, 100,000+? Because of the complete lack of prevention.

                      It is easy for a cash-strapped government to announce cuts but the consequences will fall directly of the life expectancy of the population at Whole.

                      The antivirals story is part of this scenario.

                      No one asks the EU government to pay a price to high for the drugs they needed. A correct policy would have suggested to impose the price for Emergency use and not to allow drugs firms to do their interests.

                      Because I am very skeptical about Cochrane review and I strongly disagree with the conclusion and the prospect to defuse one of the few countermeasure in case of Emergency.

                      Vaccine manufacturers, conversely, will be happy... gm

                      Comment


                      • #12
                        Re: On the future of flu vaccine and anti-viral usage

                        I remember several studies from 2006,2007 that examine the
                        role of antivirals and vaccines and social distancing on
                        a (severe pandemic) flu-wave

                        one optimistically calculated a 90&#37; reduction ...

                        we discussed it here and elsewhere

                        maybe I can find it and add a link later

                        --------edit--------------
                        I didn't find the studie(s) that I had in mind, which were widely discussed here and at fluwiki
                        but I searched pubmed ... here my summary

                        searching pubmed for "post exposure prophylaxis" and pandemic , 37 hits
                        http://www.ncbi.nlm.nih.gov/pubmed/23735960
                        For case-targeted interventions, such as antiviral treatment and post-exposure prophylaxis,
                        we identify the visibility and transmissibility of a pandemic as the key drivers of controllability.
                        Taking a case-study approach, we suggest that high-impact pandemics, for which control is
                        most desirable, are likely uncontrollable with case-targeted interventions. Strategies that do
                        not rely on the identification of cases may prove relatively more effective
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                        Mass oseltamivir prophylaxis halts pandemic influenza A H1N1 2009 outbreak in a secondary
                        school in Ashanti Region, Ghana.
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                        http://www.ncbi.nlm.nih.gov/pubmed/23324555
                        prophylaxis reduced median secondary infection risks (SIRs) among exposed individuals
                        from 16.6% to 2.1% From the outbreak data in Madagascar, the effectiveness of mass
                        chemoprophylaxis in reducing secondary transmissions was estimated at ~ 94%
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                        Post-exposure prophylaxis for H1N1 with oseltamivir in renal allograft recipient--safe and
                        effective without any immunosuppresive drug interaction.
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                        http://wwwnc.cdc.gov/eid/article/17/...61_article.htm
                        The effectiveness of antiviral prophylaxis in preventing infection was 92%.(2009,H1N1,UK)
                        ---------------------------------------------------------------------------
                        http://www.ncbi.nlm.nih.gov/pubmed/21094080
                        10 prophylaxis failures
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                        http://www.ncbi.nlm.nih.gov/pubmed/20537158
                        CONCLUSIONS: Post-exposure oseltamivir prophylaxis reduced the rate of infection during
                        outbreaks, and did not substantially increase subsequent infection rates upon cessation.
                        Asymptomatic infections occur during prophylaxis, which may confer protection against
                        future infection. Post-exposure prophylaxis is effective as a measure in mitigating
                        pandemic influenza outbreaks.
                        -----------------------------------------------------------------------------
                        http://www.ncbi.nlm.nih.gov/pubmed/23331352
                        Optimal constraint of epidemic growth was achieved by intensive ascertainment of
                        contacts of cases for post-exposure prophylaxis for as long as feasible
                        -----------------------------------------------------------------------------
                        http://www.ncbi.nlm.nih.gov/pubmed/20346187
                        Antiviral drug treatment of 50% of symptomatic cases reduced the attack rate from 32.5% to 26%.
                        Treatment of diagnosed individuals combined with additional household prophylaxis reduced
                        the final attack rate to 19%. Further extension of prophylaxis to close contacts (in schools
                        and workplaces) further reduced the overall attack rate to 13%
                        ------------------------------------------------------------------------------
                        Cochrane: http://www.ncbi.nlm.nih.gov/pubmed/20166059
                        In prophylaxis compared to placebo, neuraminidase inhibitors had no effect against ILI
                        Oseltamivir for post-exposure prophylaxis had an efficacy of 58% and 84% in two trials
                        for households. Zanamivir performed similarly.
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                        http://www.ncbi.nlm.nih.gov/pubmed/19954514
                        limiting prophylaxis when resistant strains are present
                        -----------------------------------------------------------------
                        We showed that post-exposure prophylaxis combined with isolation at home and school
                        closure significantly decreases the total number of cases in the community and can mitigate
                        the spread of pandemic H1N1 in Japan 2009
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                        http://www.ncbi.nlm.nih.gov/pubmed/19645639
                        Understanding Australia's influenza pandemic policy on the strategic use of the antiviral drug
                        stockpile. Targeted post-exposure prophylaxis represents a more efficient use of the stockpile
                        than treatment alone.
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                        neuraminidase inhibitors should not be considered as symptomatic treatment of influenza,
                        but as specific antiviral drugs and play an important role (especially oseltamivir) in the
                        French pandemic plan.
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                        Targeted post-exposure prophylaxis delays the onset of the pandemic and for a wide range
                        of parameter values, a delay of the order of 6-18 months may be achievable
                        ---------------------------------------------------------------------------
                        Neuraminidase inhibitors should be given not only to patients but also to their close contacts
                        (post-exposure prophylaxis). During phase 6, post-exposure prophylaxis is no longer indicated
                        and neuraminidase inhibitors are prescribed for all patients with symptoms of pandemic influenza.
                        Prophylaxis without preceding close contact with an influenza patient (primary prophylaxis) is
                        recommended only in exceptional cases. Physicians should not prescribe antiviral drugs on
                        demand to concerned citizens for stockpiling. (article in Dutch), 2007
                        -----------------------------------------------------------------------------------
                        Oxford: In PEP, both NIs effectively protect the close contacts of index cases from symptomatic influenz
                        -----------------------------------------------------------------------------------
                        Cochrane: http://www.ncbi.nlm.nih.gov/pubmed/16855962
                        (same as above ?)
                        also: http://www.ncbi.nlm.nih.gov/pubmed/16443037
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                        http://www.ncbi.nlm.nih.gov/pubmed/16605283
                        PEP with oseltamivir results in reduced morbidity (i.e. fewer influenza cases) and associated
                        reductions in complications, hospitalisations and mortality due to influenza. When comparing
                        oseltamivir PEP with no prophylaxis for contact attack rates of 8%, 12% and 30%, the mean
                        costs per QALY gained for scenario one were estimated at 29,938 pounds, 18,697 pounds
                        and 5403 pounds, respectively; the mean costs per case avoided were 467 pounds,
                        293 pounds and 84 pounds, respectively
                        -----------------------------------------------------------------------------------------------
                        Osterhaus,Fouchier 2004: http://www.ncbi.nlm.nih.gov/pubmed/14753128
                        zanamivir and oseltamivir appear to considerably reduce morbidity and mortality from influenza
                        ------------------------------------------------------------------------------------------
                        I'm interested in expert panflu damage estimates
                        my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

                        Comment


                        • #13
                          Re: On the future of flu vaccine and anti-viral usage

                          Perhaps, it is not the case, but it may be useful to remind the story of one of the scientist that helped the world to have the first active compound against Neuraminidase sub-unit of influenza viruses, Graeme Laver: http://virologyhistory.wustl.edu/Laver.htm

                          Comment


                          • #14
                            Re: On the future of flu vaccine and anti-viral usage

                            I am sorry to return to this discussion, that I have not started firstly, but around the mainstream media are appearing some extremely disconcerting and absolutely scary stuff:

                            -- 2009 H1N1pdm09 pandemic has not happened;

                            -- H5N1 is a hoax;

                            -- H7N9 is another hoax;

                            -- both H5&H7 are fabricated stories to sell vaccines & antivirals;

                            -- vaccines are useless, as well as drugs and prevention;

                            -- health scare are all fabricated and WHO/US CDC/ECDC and other health agencies deserve no trust;

                            -- drugs cos. are the only responsible for the great fanfare about health scare;

                            -- add many other as needed...

                            These 'piece of news' appeared in almost all main media outlets around the world, from UK to US, from Brazil to Italy, without any noticeable reaction from health agencies, except from US CDC, with minor impact.

                            I urge all flublogia and FT members to activate a quick response in order to put things in their correct perspective.

                            We spent half a dozen of year here collecting all sort of stories about dying people with avian flu, pandemic flu and other.

                            Have we to see this work wasted this way?

                            gm

                            Comment


                            • #15
                              Re: On the future of flu vaccine and anti-viral usage

                              and there are no viruses in the first place, lol

                              http://www.spiegel.de/gesundheit/dia...-a-963772.html
                              I'm interested in expert panflu damage estimates
                              my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

                              Comment

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