Publication of papers concerning laboratory modified A(H5N1) viruses that transmit naturally between and animal model for human influenzaArchived
Influenza pandemics occur when new influenza viruses appear that transmit efficiently between humans and to which a substantial proportion of the population is susceptible. Their severity depends on a combination of the new viruses’ transmissibility, the proportions of the population that are susceptible, attacks rates and pathogenicity in humans. The last four pandemics have arisen from animal influenza viruses and this has led scientists to try to understand which of the many naturally occurring animal influenzas most represent a threat either alone following natural mutation, or following recombination with other flu viruses. This is sometimes called Virological Risk Assessment and the rationale is thatthis process will guide decisions on the viruses for which diagnostics and seed vaccines should be prepared.
Imai M, et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets Nature 2012 485 (3 May) doi:10.1038/nature10831
Herfst S, Schrauwen EJA, Linster M, Chutinimitkul S, de Wit E, Munster VJ et al. Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets Science 212; 336: 1534-1541.
Russell CA, Fonville JM, Brown AEX, Burke DF, Smith DL James SL et al The Potential for Respiratory Droplet–Transmissible A/H5N1 Influenza Virus to Evolve in a Mammalian Host Science 2012 (22 June): 1541-1547.
Influenza pandemics occur when new influenza viruses appear that transmit efficiently between humans and to which a substantial proportion of the population is susceptible. Their severity depends on a combination of the new viruses’ transmissibility, the proportions of the population that are susceptible, attacks rates and pathogenicity in humans. The last four pandemics have arisen from animal influenza viruses and this has led scientists to try to understand which of the many naturally occurring animal influenzas most represent a threat either alone following natural mutation, or following recombination with other flu viruses. This is sometimes called Virological Risk Assessment and the rationale is thatthis process will guide decisions on the viruses for which diagnostics and seed vaccines should be prepared.(1)
Uniquely among avian influenzas the A(H5N1) viruses make public health scientists and policy developers nervous. This is for three reasons. They are entrenched in domestic poultry in a number of poor and moderate resource countries with no prospect of elimination. Hence they are constantly coming into contact with humans, other domestic animals such as pigs and presumably therefore with other animal and human influenza viruses. Secondly they keep evolving and exchanging genetic material with other influenzas. Thirdly for the few humans they infect they are very pathogenic with an observed case fatality ratio of around 60% in confirmed cases. The latter statistic must be an overestimate, but not much of one.(2) Hence the question of whether A(H5N1) is enough of a pandemic threat to prepare A(H5) human vaccines and even to pre-emptively vaccinate groups was a strong policy consideration before 2009 and so-called prepandemic A(H5N1) vaccines (better called human A(H5N1) vaccines) were developed and licensed, and then stockpiled by some European countries.(3)
Then came the relatively benign 2009 A(H1N1) pandemic, suggesting that an exclusive focus on severe 1918 or A(H5N1)-like pandemics was misguided.(4) Also the fact that an A(H5N1) pandemic has not happened led some to question whether these viruses are either inherently incapable of acquiring transmissibility in humans and other mammals or that considerable further viral evolution was necessary.(5,6) Such consideration have made European policy makers question whether to replace expiring stockpiles of human A(H5N1) vaccines.
However the fact that an A(H5N1) pandemic has not happened does not mean it cannot or will not occur. The molecular changes required for an animal influenza virus to become transmissible among humans are not understood.(7) In response to this researchers have for some years been carefully modifying wild A(H5N1) viruses to see if the viruses could become naturally transmissible between mammals. They have mostly worked with ferrets, generally considered the best animal model for influenza in humans. (8,9)The work has been carried out in secure laboratories working at BSL3+ biosafety levels with the goal of discovering if A(H5N1) viruses have pandemic potential, which specific viruses and mutations to look for in nature and which vaccines and diagnostics to prepare.(1,7) The last decade has seen many manipulations looking at various hybrids including those known to increase binding to human upper respiratory tract receptors.(6) Together such work has suggested that that mutations that increase sialic acid (Sia) Siaα2,6 receptor binding and others that that stabilize haemagglutinin (HA) structure are important markers for A(H5) viruses that can transmit between mammals.(7)
In 2011 two independent academic groups, one based in Wisconsin (USA) and the other in Rotterdam (the Netherlands) announced they made serial genetic manipulations that rendered wild A(H5N1) viruses obtained from Viet Nam and Indonesia naturally transmissible between ferrets. After a prolonged delay papers describing the findings have finally appeared in Nature and Science.(10,11) Other studies have approached this point before but these are the first demonstration of A(H5N1) viruses transmitting naturally in a mammalian model.(7,8) The numbers of mutations required for the change are small, only five, and these findings have added to the evidence that A(H5N1) viruses do at least have the potential to cause a human pandemic.(7) Both sets of researchers introduced mutations into the head of the HA molecule, where the receptor-binding domain is located. The US group produced a reassortant virus combining H5 material with gene segments from a 2009 pandemic A(H1N1) viruses and this showed binding to human-like Sia α2,6 respiratory cell receptors.(9) The group in the Netherlands assisted the process by serial passage of the viruses in ferrets (and also induced a mutation in a polymerase complex protein).(11) In parallel with this a broader research group (including the Madison and Rotterdam principle investigators) investigated virological surveillance data and modelled the likelihood of further mutations happening in nature. They found out that two of the five mutations were already in some wild A(H5N1) viruses and considered the additional changes at least possible naturally.(12)
One welcome finding was that at least in ferrets the modified viruses are not very pathogenic when they transmitted naturally through the air. No ferrets died from their infection in either setting and most experienced only mild or asymptomatic infection. Also transmission was not that efficient.(10,11) Because of the lack of natural transmission previous studies of pathogenicity of A(H5N1) viruses in ferrets has used direct injections into the bronchial tree, when it can be lethal, especially if given in large doses.(9) Because there is a moratorium on further work what is not clear yet here is whether this loss of pathogenicity comes with the mutations or simply reflects the mode of transmission.
In a commentary in Nature, Yen and Peiris argue that it is likely that different combinations of mutations may achieve the same effects, and further studies are needed to explore this possibility of convergent evolution.(7) They also point out similarities with the mutations in another recent US study where partial transmissibility was achieved in ferrets by combining the neuraminidase of a human A(H3N2) virus with HA mutations in an A(H5N1) virus.(6) These findings do not only provide further indication that such a virus may arise naturally; they also pave the way for improved influenza surveillance and pandemic preparedness. In response CDC working with others and the WHO GISRS network has produced an inventory list of the A(H5N1) viruses most worth watching for. (12)
ECDC Comment: (30 June 2012)
These findings reinforce the need for focusing even greater attention on A(H5N1) infections in birds, humans and other mammals including pigs. There are many challenges, including in Europe. Because influenza viruses in commercial pig herds are not of much economic concern there is rarely any routine surveillance in Europe or North America. What surveillance there is in Europe often exists through EU research funding from DG-RTD with projects like FLUPIG and ESNIP-3. Equally surveillance for infections in humans probably only detects a proportion of the human infections with the non-A(H5N1) animal influenzas.(13) There are also virological challenges. Because influenza viruses can be quasi-species even within a single clinical specimen important genetic variations may be missed by conventional sequencing. This will require the application of more extensive so-called ‘deep sequencing’ for these mutations, and for other mutations that confer similar functionality.(14) Only this will allow the evaluation of A(H5N1) adaptations that are taking place in domestic birds and mammals hosts. Certainly however these three papers and the establishing of the A(H5N1) genetic change inventory under CDC/WHO represents a significant scientific advance with public health implications. Working with its partners ECDC will now consider revising its influenza A(H5N1) risk assessments (last done in September 2011) in order to inform decisions in Europe by policy makers on development of diagnostics and vaccines.(1) In parallel with the above developments the two central papers generated intense debate on other issues, almost to the exclusion of the scientific and public health aspects.(8,9) It came as a surprise to many that this work was being done at all and the lack of published information on the pathogenicity of the viruses allowed considerable speculation on how dangerous the viruses were. Legitimate issues have arisen concerning biosafety (what level of laboratory safety should these experiments be carried out at , and where, and by whom) biosecurity (could the technique be used to generate bio-weapons), legal aspects (when is the international transfer of biological specimens and manuscripts allowed under EU regulations (16) ) and academic freedom to undertake research and publish.(8,10,11) Despite the pressing research needs there is currently a voluntary moratorium on further work except for obvious risk assessment purposes.(8) Indeed the issue of the journal Science where the Rotterdam group research was published contained multiple articles almost excluding the risk assessment aspects.(17) In ECDC’s view what has not received enough attention is how this work fits into the new pandemic influenza preparedness framework with its guarantee of rapid and unfettered international sharing of influenza specimens and information.(18,19) As pointed out by WHO earlier this year there are some aspects of this debate that threaten this process which is absolutely essential to global health security.(20)
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