Posts Tagged ‘bird flu’

Bird flu vaccine now? More than a shot in the dark | Reuters

11 July, 2012

See on Scoop.itVirology News

“LONDON (Reuters) – Culls of hundreds of thousands of chickens, turkeys and ducks to stem bird flu outbreaks rarely make international headlines these days, but they are a worryingly common event as the deadly virus continues its march across the globe.

As scientists delve deeper into H5N1 avian influenza, they have discovered it is only three steps way from mutating into a potentially lethal human pandemic form, adding new urgency to a debate over how to protect humans.

In 2009, during the H1N1 swine flu pandemic, vaccines only became available months after the virus had spread around the world – and even then there was only enough for one in five of the world’s 7 billion people.

Next time, experts say, we need another approach.

Talk is centred on “pre-pandemic vaccination” – immunising people years in advance against a flu pandemic that has yet to happen, and may never come, rather than rushing to create vaccines once a new pandemic starts.”


Yes, well: regulars of this blog will recognise that I have been rattling on about this topic for some time now; nice to see serious heavyweights are starting to do the same thing.


Seriously, pre-emptive vaccination could almost certainly not hurt, would probably help a LOT – and would amp up production capacity for H5 and other potential pandemic influenza viruses [see Mexico H7N3 outbreak] as well, for pandemic vaccine production readiness.


And of course, you could do it all in plants.  Just saying.


See on

Setting up a platform for plant-based influenza virus vaccine production in South Africa

5 May, 2012

A virus-like particle formed by influenza virus haemagglutinin budding out of plant cells. By Russell Kightley Media

See it also on Scoop.itVirology News

Our (very) recently-published article on plant-made flu vaccines in BMC Biotechnology:

Setting up a platform for plant-based influenza virus vaccine production in South Africa

Elizabeth Mortimer, James M Maclean, Sandiswa Mbewana, Amelia Buys, Anna-Lise Williamson, Inga I Hitzeroth and Edward P Rybicki

During a global influenza pandemic, the vaccine requirements of developing countries can surpass their supply capabilities, if these exist at all, compelling them to rely on developed countries for stocks that may not be available in time. There is thus a need for developing countries in general to produce their own pandemic and possibly seasonal influenza vaccines. Here we describe the development of a plant-based platform for producing influenza vaccines locally, in South Africa. Plant-produced influenza vaccine candidates are quicker to develop and potentially cheaper than egg-produced influenza vaccines, and their production can be rapidly upscaled. In this study, we investigated the feasibility of producing a vaccine to the highly pathogenic avian influenza A subtype H5N1 virus, the most generally virulent influenza virus identified to date. Two variants of the haemagglutinin (HA) surface glycoprotein gene were synthesised for optimum expression in plants: these were the full-length HA gene (H5) and a truncated form lacking the transmembrane domain (H5tr). The genes were cloned into a panel of Agrobacterium tumefaciens binary plant expression vectors in order to test HA accumulation in different cell compartments. The constructs were transiently expressed in tobacco by means of agroinfiltration. Stable transgenic tobacco plants were also generated to provide seed for stable storage of the material as a pre-pandemic strategy.

For both transient and transgenic expression systems the highest accumulation of full-length H5 protein occurred in the apoplastic spaces, while the highest accumulation of H5tr was in the endoplasmic reticulum. The H5 proteins were produced at relatively high concentrations in both systems. Following partial purification, haemagglutination and haemagglutination inhibition tests indicated that the conformation of the plant-produced HA variants was correct and the proteins were functional. The immunisation of chickens and mice with the candidate vaccines elicited HA-specific antibody responses.

We managed, after synthesis of two versions of a single gene, to produce by transient and transgenic expression in plants, two variants of a highly pathogenic avian influenza virus HA protein which could have vaccine potential. This is a proof of principle of the potential of plant-produced influenza vaccines as a feasible pandemic response strategy for South Africa and other developing countries.”

I have mentioned time and again that going green is the sensible thing to do: here is a concrete example of how my research group is trying to go about it.  This is a very sensible technology for rapid-response vaccine production, and especially for emerging or orphan or pandemic virus threats.  We got really good expresion levels of H5N1 HA protein via transient expression in plants, and have already started on pandemic H1N1 HA expression.  Let’s hope some governmental types in SA take some notice!

I thank Russell Kightley Media for the specially-commissioned graphic of budded HA-only VLPs.


Engineered H5N1: the wheels grind on, and on, and on….

19 April, 2012

The Scientist has a nice collection of articles on this topic, which I have commented on all over the place, so I though I might consolidate some of it in one place.

In response to the article entitled “Deliberating Over Danger“, I wrote the following:

The point I and others have made before is that H5N1 and other influenza viruses are not waiting for us to let engineered versions loose, before they cause pandemics: all of the mutations noted by the Fouchier and Kawaoka groups are almost certainly present in the several environments where H5N1 viruses are now endemic – and all it takes for all of them to be present together is a little more mixing.

Don’t discount other flu subtypes, either: while everyone is obsessing about H5N1, H3N2 is busy popping out of pigs in the USA; H9N2 in birds in Bangladesh; H5N2 in ostriches in South Africa – and all it would take is one or a couple of fortuitous reassortments, and a whole new flu virus could be unleashed.

While the “deadly” H5N1s are being worked on in lockdown facilities.

If we don’t know what the virus does, we won’t know what it can do. If we don’t know what to look for, we may be taken unawares, when the next 1918-type pandemic strikes.

I want to have universal flu vaccines by then – so we won’t HAVE to worry about a new flu


There are also three newer articles covering the controversy: these are

  • H5N1 Researcher to Defy Dutch Gov’t?
  • (with my comment – “Export permit to publish something?  Really?  A complete misapplication of laws to material that should not be subject to them.”)
  • White House Weighs in on H5N1
  • Flu Review Criticized
  • (with my comment – “So after a full and frank hearing did not go his way, after changes had been made to the paper in question (Fouchier’s), Osterholm complains.  Such is life….”

There is the slightly older article – “Bird Flu Papers to Publish” - describing the reversal of the NSABB’s decision to ask for redaction of the two papers describing mammal-to-mammal aerosol-transmissible H5N1.

An interesting article also describes Yoshihiro Kawaoka’s results:

“First, he introduced two mutations—N224K and Q226L—into the haemagglutinin (HA) protein of H5N1 that made the virus capable of sticking to receptors on human tracheal cells. Then he created a chimeric virus by combining the mutated HA protein with genes from the H1N1 virus, which sparked a pandemic in 2009. Kawaoka identified another HA mutation, called N158D, that allowed the virus to spread between ferrets that were not in direct physical contact. A fourth mutation, T318I, also showed up in the H5N1 strain, but its role in making the virus more transmissible among mammals is less clear.”

So there you are: an actual recipe for aerosol-transmissible H5N1.  It was always going to come out somehow, and now these two papers will probably the most cited flu papers ever.  Nothing like a little hype!  Meanwhile, H5 and its brothers and sisters are out there mutating away, with no help needed from anyone.  Roll on universal flu vaccines!!

And while they were arguing about killer H5N1…

8 February, 2012

…Elsevier’s Virology was calmly publishing another paper on a “mutant” H5N1….

The abstract:

Acquisition of α2-6 sialoside receptor specificity by α2-3 specific highly-pathogenic avian influenza viruses (H5N1) is thought to be a prerequisite for efficient transmission in humans. By in vitro selection for binding α2-6 sialosides, we identified four variant viruses with amino acid substitutions in the hemagglutinin (S227N, D187G, E190G, and Q196R) that revealed modestly increased α2-6 and minimally decreased α2-3 binding by glycan array analysis. However, a mutant virus combining Q196R with mutations from previous pandemic viruses (Q226L and G228S) revealed predominantly α2-6 binding. Unlike the wild type H5N1, this mutant virus was transmitted by direct contact in the ferret model although not by airborne respiratory droplets. However, a reassortant virus with the mutant hemagglutinin, a human N2 neuraminidase and internal genes from an H5N1 virus was partially transmitted via respiratory droplets. The complex changes required for airborne transmissibility in ferrets suggest that extensive evolution is needed for H5N1 transmissibility in humans. [my emphasis - Ed]

I have covered the use of glycan arrays to characterise influenza viruses’ binding specificity previously; I thought then, and do now, that it is a very cool technology – and one that has shown in this case that H5N1 variants can be selected from an originally “wild” population, that preferentially bind the human-type receptor.

And they did it like this:

To examine the functional evolution of H5 HA receptor specificity in the laboratory, we implemented an in vitro receptor-binding virus enrichment approach that recapitulates in vivo selection. Synthetic 6′-sialyl (N-acetyl-lactosamine) (6′ SLN) was used as the affinity ligand mimicking the human receptor to capture spontaneous viral receptor variants on the surface of magnetic beads. Starting with a pool of 108 EID50 of A/Vietnam/1203/2004 (VN04 virus), we performed four consecutive rounds of in vitro binding and elution followed by isolation of 150 individual virus clones by plaque purification and characterization by sequence analysis.

No “genetic engineering” here – or furore over “killer viruses escaping the lab!”  Possibly because (a) “mutant virus was transmitted by direct contact in the ferret model although not by airborne respiratory droplets”, and (b) “a reassortant virus with the mutant hemagglutinin, a human N2 neuraminidase and internal genes from an H5N1 virus was partially transmitted via respiratory droplets” [my emphasis].

Meaning they didn’t actually make anything that could immediately elicit such scare-mongering as the more notorious studies I and many others have reported on previously.

However, the grim NSABB folk were quick to decry the publication, saying “”I think it is fair to say that we would have liked to have seen it before it was published,” [Paul Keim, chairman of the National Science Advisory Board for Biosecurity], and the “…altered bird flu virus could mutate in dangerous ways if unleashed in nature”.

I am more worried, to be perfectly honest, over the dangerous ways the the wild type virus could mutate IN nature, given that mutants can be selected so apparently easily!

Influenza virus migrations – a lesson from 1961

13 January, 2012

Influenza A viruses carried by birds

I have been doing quite a lot of digging into virus history recently, and it was interesting to pick up – while checking on who had published what from our University on viruses – a paper from 1966 describing “The isolation and classification of Tern virus: Influenza Virus A/Tern/South Africa/1961″ by WB Becker of the Virus Research Unit here at UCT.  It is interesting because it was isolated from sick migratory Common Terns along the south coast of South Africa, which were infected as part of an “explosive epizootic” which resulted in many deaths.  It became more interesting when it was shown in 1967 to cause few or no symptoms in Swift Terns but was shed in large amounts, to be highly pathogenic in chickens, and was subsequently typed as H5N3.

The discussion of the original paper was not only highly prescient, but may be completely valid today: a significant quote follows.

The isolation of Tern virus raises interesting epidemiological possibilities. The outbreak in chickens in Scotland caused by Chicken/Scot. virus preceded the Tern epizootic by about 17 months and occurred during stormy weather which drove sea-birds a little inland to take shelter. Large numbers ofHerring Gulls (Larus argentatus) were at that time working thef arm at which the out break in chickens occurred in November 1959 (J. E. Wilson, personal communication). The chickens might have contracted the infection from sea-birds, a viewpoint possibly supported by the preceding mass mortality in Kittiwakes (Rissa tridactyla) and Fulmars (Fulmaris glacialis) from February to August 1959 (Joensen, 1959) off the coast of Britain and Scandinavia. Unfortunately the aetiology of the last-mentioned outbreak was not investigated, but it is tempting to think it was caused by the Tern virus which was isolated at Cape Town some 18 months later in 1961, from migrant European Common Terns.

One might postulate: that certain sea-birds suffer latent or sporadic infection with avian influenza; that epizootics may be precipitated in them by conditions of stress, e.g. poor feeding under unfavourable weather conditions such as pre- ceded the Tern epizootic; and that spread to other sea-birds or domestic poultry may occur. [my emphases - Ed]

The 1967 tern infection paper continues this theme:

The outbreak in chickens in Scotland in 1959 (Dr J. E. Wilson, personal communication) and the Tern epizootic in 1961 were caused by influenza A viruses with closely related strain specific antigens which were unrelated to those of any previously known influenza A viruses. Recently strains of influenza A related to the Tern and Scottish viruses were isolated from turkeys in Canada (Dr G.Lang, personal communication). This lends further support to the hypothesis that migrating sea-birds such as the Common Tern may transmit avian influenza A viruses to domestic poultry.

This was followed up more recently (2002) by a paper describing transmission of the tern virus to laughing gulls:

This investigation detailed the clinical disease, gross and histologic lesions, and distribution of viral antigen in juvenile laughing gulls (Larus atricilla) intranasally inoculated with either the A/tern/South Africa/61 (H5N3) (tern/SA) influenza virus or the A/chicken/Hong Kong/220/97 (H5N1) (chicken/HK) influenza virus, which are both highly pathogenic for chickens. Neither morbidity nor mortality was observed in gulls inoculated with either virus within the 14-day investigative period. Gross lesions resultant from infection with either virus were only mild…. Antibodies to influenza viruses …at 14 DPI were detected only in the two tern/SA-inoculated gulls and not in the two chicken/HK-inoculated gulls.

Their conclusions, too, were rather disturbing:

The positive isolation of the tern/SA and chicken/HK viruses from the OP and cloacal swabs suggests that, with adequate exposure, gulls could serve as hosts for these and possibly other HPAI viruses. Isolation of the A/gull/Germany/79 (H7N7) virus during a HPAI outbreak in Eastern Europe provides further evidence to support the potential for pelagic birds to serve as biological vectors for (HP)AI viruses (D. J. Alexander, pers. comm., originally referenced in 29). This is a significant finding in terms of the epidemiology of AI viruses, especially considering the fact that the chicken/HK virus was a zoonosis (26,27). Moreover, pelagic birds have been implicated as the source for other AI viruses that transmitted to and may have caused disease in mammals (8,13).

Everybody is obsessed with H5N1: maybe we should be a little more concerned with what may be raining down from above, as seabirds carry recombinant / reassortant viruses from areas of high H5N1 endemicity around the world.



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