So: thank you, anyone who clicked in, and regular visitors. You make it worthwhile!!
The WordPress.com stats helper monkeys prepared a 2012 annual report for this blog.
Here’s an excerpt:
4,329 films were submitted to the 2012 Cannes Film Festival. This blog had 33,000 views in 2012. If each view were a film, this blog would power 8 Film Festivals
I am TRYING to write an eBook on influenza, which stubbornly refuses to be finished – as part of a sabbatical project, which finished in December 2010. So, like my History of Virology, I am trialling the material on you, the Web community. Enjoy / comment / be enlightened / whatever!
NEW NOTE: The ebook is finished, and is available here on the iBooks Store: please try it out (you can read it on any Mac / iPad / iPhone using the free iBooks app)
A useful online history in pictorial form can be accessed here.
While they were not recognised as such at the time, major or pandemic outbreaks of influenza disease have occurred throughout recorded history. Medical historians have used contemporary reports to identify probable influenza epidemics and pandemics from as early as 412 BCE – and the term “influenza” was first used in 1357 CE, describing the supposed “influence” of the stars on the disease. The first convincing report of an epidemic of the disease was from 1694, and reports of epidemics and pandemics in the 18th century increased in quality and quantity.
The first pandemic that historians agree on was in 1580: this started in Asia, and spread to Africa, took in the whole of Europe in 6 months, and even got to the Americas. Subsequent pandemics with significant death rates occurred in 1729 and 1781-2; there was a major pandemic in 1880-1883 that attacked up to 25% of affected populations, and another in 1898-1900 that was probably H2N2. There is an excellent account here of the first “modern” pandemic, in 1890 – or at least, the first one to be followed essentially in real time via newspapers.
Influenza A pandemics in modern times. * = probably reintroduced from a laboratory from the H1N1 circulating from 1918 until 1957.
While the first reports of this pandemic were from Spain, this was largely because theirs was possibly the only uncensored press in Europe at the time because of the 1914-1918 War. In fact, it seems generally accepted that the virus originated in the United States, possibly in a military camp, and was then taken via infected personnel travelling by troop transport, to France by April 1918. The virus spread quickly across Europe, and via troop transports again to northern Russia, north Africa and India. Further spread then occurred, to China, New Zealand and The Philippines, all by June 1918.
Initially, there was nothing unusual: infections spread quickly for a while and then declined, and death rates were not higher than in previous pandemics. However, from August 1918 – marked by a ship-borne outbreak in Sierra Leone in west Africa – the virus seemed to have become markedly more virulent, and the death rate is supposed to have increased 10-fold. The virus quickly spread through Europe, to the USA, to India by October 1918, and to Australia by January 1919, all the while spreading through and around Africa.
Some countries had second and even third waves of infection, in 1918-1919 and 1919-1920. The pandemic was initially calculated as having killed some 20 million people: however, later estimates which took into account in particular the African, Indian and Chinese death tolls have increased the death toll to at least 50 million, and possibly up to 100 million.
The virus probably infected over one third of the humans alive at the time, with a case mortality rate of up to 5%. Some regions, like Alaska and parts of Oceania, had death rates of up to 25% of the total population. By contrast, the normal mortality rate for seasonal flu is 0.1 – 0.3% of those infected.
The pandemic was unusual in that it seemed to affect mainly young adults: The graph shows case mortality rates in percent for pneumonia and influenza combined for 1918-1919, and for seasonal influenza for 1928-1929, for different age groups. The “W” shape for the 1918-1919 figures is most unusual; the later seasonal data show a far more usual “U” curve. The green line shows what could have happened if – as is suspected – people over 30 had not had some immunity to the virus, due to prior exposure to the H1 and/or N1 – possibly during the 1880 or 1893 pandemics.
Although secondary bacterial infections of the lungs were common in fatal cases in 1918, and contributed significantly to mortality, there were also many cases of rapid death where bacterial infection could not be demonstrated – so these were due to a so-called “abacterial pneumonia”. Incidentally, the archiving of pathology specimens from especially military cases in the USA proved invaluable in “viral archeology” studies as late as 1997.
As early as 1901, investigators had shown that the agent of fowl plague was a “filterable virus”: however, this was not linked to human disease, as it was only shown to be an influenza virus in 1955.
Charles Nicolle and Charles Lebailly in France proposed in 1918 that the causative agent of the Spanish Flu was a virus, based on properties of infectious extracts from diseased patients. Specifically, they found that the infectious agent was filterable, not present in the blood of an infected monkey, and caused disease in human volunteers. However, many scientists still doubted that influenza was a viral disease.
A paper presented in 1918 to the Academie Francaise, describing the influenza agent as a filterable virus
In 1931, Robert Shope in the USA managed to recreate swine influenza by intranasal administration of filtered secretions from infected pigs. Moreover, he showed that the classic severe disease required co-inoculation with a bacterium – Haemophilus influenza suis – originally thought to be the only agent. He also pointed out the similarities between the swine disease and the Spanish Flu, where most patients died of secondary infections.
Pigs in the USA and elsewhere probably caught the H1N1 “Spanish Flu” from people – and it has circulated in them continuously until the present day
Patrick Laidlaw and others, working in the UK at the National Institute for Medical Research (NIMR), reported in 1933 that they had isolated a virus from humans infected with influenza from an epidemic then raging. They had done this by infecting ferrets with filtered extracts from infected humans – after an observation that ferrets could catch canine distemper – and then found that ferrets could transmit influenza to investigators by sneezing on them! The “ferret model” was very valuable, as strains and serotypes of influenza virus could be clinically distinguished from one another. Their serotype was named “influenza A”, and it was later typed as H1N1: this virus was a direct descendant of the Spanish flu virus, and had circulated in humans since 1918. It was the same subtype, incidentally, as that isolated by Shope from pigs.
Frank Macfarlane Burnet from Australia in 1936 showed that it was possible to do “pock assays” for influenza virus on the chorioallantoic membranes of fertilised chicken eggs, and subsequently said that:
“It can probably be claimed that, excluding the bacteriophages, egg passage influenza virus can be titrated with greater accuracy than any other virus.”
Historic picture on the wall in the routine influenza isolation laboratory at the National Institute of Communicable Diseases, Johannesburg.
This finding led directly to the development of the first influenza A vaccine – a killed virus preparation made in eggs – by Thomas Francis in the USAin late 1943. He had earlier, in 1940, isolated the first influenza B, which was made into a vaccine by 1945. It was then clear that seasonal influenza was caused by two viruses: the A H1N1 type, and influenza B.
After the influenza pandemic of 1918-1920, influenza went back to its usual seasonal pattern – until the pandemic of 1957. This started with the news that an epidemic in Hong Kong had involved 250 000 people in a short period. This was a unique event in the history of influenza, as for the first time the rapid global spread of the virus could be studied by laboratory investigation. The virus was quickly identified as an H2N2 subtype.
Except for people over 70, who had possibly been exposed to an influenza pandemic in 1898 – also probably a H2N2 pandemic – the human population was again confronted by a virus that was new to it – and again, the virus alone could cause lethal pneumonia. However, better medical investigation showed that chronic heart or lung disease was found in most of these patients, and women in the third trimester of pregnancy were also vulnerable.
The 1957 pandemic was the first opportunity for medical people to observe the vaccination response in the many people who had not previously been exposed to the novel virus. This was very different to the 1918 virus that had been circulating ever since, meaning that most people had no immunity to it at all. More vaccine was initially needed to give protective immunity than with the earlier type A vaccines. However, by 1960 as the virus recurred as a seasonal infection, immunity levels in the general population increased and vaccine responses were better, due to “priming” of the response by natural infection or first immunisation.
The death toll for this pandemic was around two million people – even though a vaccine was available by late 1957. Infections were most common among school children, young adults, and pregnant women in the early pandemic. Elderly people had the highest death rates, even though this was the only group that had any prior immunity, and there was a second wave in this group in 1958.
The new H2N2 virus completely replaced the previous H1N1 type, and became the new seasonal influenza type.
This pandemic started in mid-1968 in Hong Kong, and rapidly spread in a few months to India, the Philippines, Australia, Europe and the USA. By 1969, it had reached Japan, Africa and South America. Worldwide, the death toll peaked in December – January. However, although around one million people died, the death rate was lower than in 1957 – 1958 for a number of reasons, including the following:
The virus was similar in some respects to the Asian Flu variant – it was an H3N2 isolate, similar to the pre-1918 seasonal type, sharing N2 – meaning people infected then had partial immunity
The better availability of antibiotics meant secondary bacterial infections were less of a problem.
A vaccine to the new virus became available a month after the epidemic peaked in the USA – following a trend which had started with the 1958 pandemic, of vaccines becoming available only after the peak of the pandemic had passed.
An interesting development soon after this was the finding that waterfowl are the natural hosts of all influenza A viruses – and that there was a greater diversity of viruses in birds than in humans.
Between May and November of 1977, an epidemic of influenza spread out of north-eastern China and the former Soviet Union – hence the name “Red Flu”. The disease was, however, limited to people under the age of 25 – and was generally mild. It was soon found that virus responsible was effectively identical to the H1N1 that had circulated from 1918 through to 1958, and which had been replaced by the Asian flu, which was in turn supplanted by the Hong Kong flu. This was a most unlikely scenario, given that it was already known that influenza A viruses mutated rapidly as they multiplied – and it had been twenty years since the Spanish or H1N1 flu had been seen in humans. It also explained why infections were limited to young people: anyone who had caught the seasonal flu prior to 1958 was protected.
There has been speculation that the pandemic was due to an inadequately-inactivated or attenuated vaccine released in a trial; there has even been mention of escape from a freezer in a biological warfare lab. There is no firm evidence for either possibility; however, the result is that the virus that had reappeared then co-circulated with the H3N2 as a seasonal virus, continuously until the next pandemic. This was unusual, as a pandemic virus usually becomes the next seasonal strain.
The next major pandemic to follow on from the 1968 outbreak was again a type A H1N1 virus – which this time, originated in Mexico or the south-western USA, and probably came directly from intensively-farmed pigs. This had been an unusually long interval between pandemics, and warnings of the coming plague had been issued regularly for years: however, it had been expected that the next pandemic would involve the highly pathogenic avian influenza virus H5N1, which had been popping up since 1997, and had been established as an endemic virus in farmed chickens since 2004. This was therefore rather a surprise – but a reasonably welcome one, as the virus turned out to be relatively mild in its effects.
Intensive research on the origin of the virus threw up some very interesting results: it was effectively a direct descendant of the original Spanish flu H1N1 virus, but which had been circulating in pigs ever since 1918 – and had had contributions of genetic material from swine, humans and birds (see Chapter 3, here).
By June 2009 the World Health Organisation had raised the pandemic alert level to Phase 6 – the highest level, indicating that the virus had spread worldwide and that there were infected people in most countries. The “swine flu” pandemic was not as serious as had been feared, however: symptoms of infection were similar to seasonal influenza, albeit with a greater incidence of diarrhoea and vomiting. The virus was also found to preferentially bind to cells deeper in the lungs than seasonal viruses: this explained both why it was generally mild – it did not often get that far down – but also why it could be fatal, as it could cause severe and sudden pneumonia if it did penetrate deep enough, similar to the 1918 influenza. Binding to cells in the intestines also explained the unusual nausea and vomiting. It was also found that there were distinct high-risk groups, including pregnant women and obese individuals. In these respects it was similar to the 1918 flu, as this also predominantly affected young people, and pregnant mothers.
Vaccine manufacture was initiated in June 2009 by the WHO and manufacturers: while there was some concern over the slower-than-normal growth rate of the vaccine strains of the virus, this was rectified in a few months. However, as also happened with the other pandemics, there was not enough vaccine made soon enough to deal effectively with the pandemic – even though similarities between the pandemic virus and the 1977 outbreak virus meant that most middle-aged people had pre-existing immunity to it, which either prevented infection, or reduced the severity of infections. This also meant a single dose was sufficient in adults, similar to the seasonal vaccine.
While the disease may have been mild in most cases, and initially the death toll was thought to be low, by 2012 it was calculated that 300 000 or more people probably died, mainly in Africa and Southeast Asia. A sobering quote: “since the people who died were much younger than is normally the case from influenza, in terms of years of life lost the H1N1 pandemic was significantly more lethal than the raw numbers suggest”. The virus has now become a normal seasonal strain, replacing the previously-circulating H1N1, but interestingly, has not replaced the H3N2 that has circulated since 1968.
All material Copyright EP Rybicki, except for the Camp Funston image, which is in the public domain.
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
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!!
…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!
Students of HIV history may know that I have picked a number of public fights with our ex-President, Thabo Mbeki: chief among these was when two colleagues and I took him to task in Nature for being an unashamed AIDS denialist (see Retroid Raving link).
Now it appears that he has found more things to deny: it appears that as of six days ago, he does not believe in:
These disbeliefs are part of an argument he developed at a prestigious “Knowledge Management Conference” in Stellenbosch, South Africa, on January 16th 2012: he used them as examples of “false knowledge”, propagated by everyone from the Western Powers (Libya) to the pharmaceutical industry (flu pandemic),
“…which illustrate the grave challenge all humanity faces to confront the critical issues that are the subject of this important Conference, of the management of knowledge in the interests of genuine human advancement”.
His comment on the H1N1 pandemic was as follows:
The Council of Europe has asserted that false ‘knowledge’ was propagated during 2009, which resulted in billions of tax-payer dollars being spent in many countries to respond to a fictional ‘swine flu epidemic’, which benefited the globally dominant and highly profitable pharmaceutical companies.
How. Breathtakingly. STUPID!! a comment. Right up there with how he knew no-one who had died of AIDS, or how a virus could not cause a syndrome. Amazing thing, that being ready for something can mean you can forestall it – like the Y2K problem, Crazy Muammar’s intended genocide – and flu pandemics.
As I have done before, then, an open letter to the ex-President.
Dear Mr Mbeki;
It appears that, once again, you rush in where angels fear to tread – and disbelieve the existence of a major human disease. This time, it is not quite as serious as not believing in AIDS – however, calling into question the existence of a pandemic which killed a significant number of people, simply to further a laboured and rather contrived argument about “false knowledge”, not only betrays your profound ignorance about ANYTHING to do with viruses and disease, it also illustrates a profound and invincible antipathy to conventional medical and pharmaceutical science.
I refer, of course, to your disbelieving in the 2009 H1N1 influenza pandemic – which according to you, was a “fictional swine flu pandemic, which benefited the globally dominant and highly profitable pharmaceutical companies”.
Really? A fictional pandemic? So the WHO was completely incorrect in its repeated assessments of the global spread of a novel virus? And the following statement from a reputable source must obviously be false?
“In the United States, there were 2,117 laboratory-confirmed deaths, yet the Centers for Disease Control estimate actual deaths in the US alone at between 8,870 and 18,300. Applying similar multiples to laboratory-confirmed cases around the world would yield 72,000 to 162,000 deaths. But that number, since it is still based on confirmed cases, still understates the deaths by a wide margin”
So are the folk who died not actually dead – or not dead of pandemic flu? The fact is, Mr Mbeki, that we were lucky with that pandemic: it turns out the virus was actually reasonably similar to the one which was circulating prior to 1958, meaning anyone born prior to that who had that flu, was probably protected – meaning far fewer older people died than normally do in a flu pandemic. Which, if you consider that more than 250 000 people die in any NORMAL year of influenza, means a disproportionately larger number of YOUNG people died.
From a flu pandemic which, according to you, did not happen.
You were probably lucky, Mr Mbeki: you were born prior to 1958, and so were probably immune. You may well not be so lucky the next time – and there WILL be a next time; flu is like that. It is not, and never has been, an invention of pharmaceutical companies – and in any case, the WHO raised the alarm, not Big Pharma. They just made the vaccines they were asked to.
I am reminded of a famous graffito from London, sometime in the 1960s – that you may even have seen. It went something like “God is dead – Nietzche. Nietzche is dead – God”.
My version would be “Flu pandemic is fake – Mbeki”.
You can fill in the rest.
Regards,
Ed Rybicki
Depiction of virus mixing in a pig http://www.rkm.com.au
In an issue of Virus Research devoted to commemorating the career of Brian Mahy, who retired recently from the CDC and now as Editor-in-Chief of Virus Research, there is a paper by Taubenberger and Kash on the 1918 H1N1 flu – wherein they say the following:
“In a recent set of experiments, it was shown that mice vaccinated with the monovalent 2009 pandemic H1N1 vaccine were completely protected in a lethal challenge model with the 1918 influenza virus…”
Because the modern pandemic “swine flu” H1N1 HA protein descends directly from the 1918 virus, but in pigs rather than in humans. Remember all the hype around THAT work – resurrecting the legendary Spanish Flu, and how it would kill us all? And here we already have a vaccine, that will completely protect us.
We have vaccine candidates against H5 as well. Time for a universal flu vaccination campaign and pre-emptive strike, people!
Seeing as it’s officially over – well, the odd people still dying might dispute this, but the WHO Has Spoken – I thought I would share this with you, seeing as I agree 100% with the sentiments (I wanted it called Mexico Flu). Arvind Varsani, my one-time PhD student now in The Land of the Long Black White Cloud, sent me this link today – thanks Arv! You win a free ViroBlogy article! I expect it within a month.
The WHO recently declared the H1N1 “swine flu” pandemic to be over – on August 10th, 2010. From the AFP article:
“The world is no longer in phase six of the pandemic alert. We are now moving into the post-pandemic period,” WHO Director General Margaret Chan said
….
Swine flu has killed more than 18,449 people and affected some 214 countries and territories since it was uncovered in Mexico and the United States in April 2009, according to WHO data.
The new virus spread swiftly worldwide despite drastic measures including a week long shutdown in Mexico, prompting the UN health agency to scale up its alerts and declare a pandemic on June 11, 2009, banishing kisses and frowning on handshakes.
Fears about the impact of swine flu on unprotected populations and a harmful mutation sparked a rush for hundreds of millions of dollars worth of specially-developed vaccines and a flurry of public health precautions.
However, those concerns dwindled in late 2009 to be replaced by recriminations in Western nations about the cost of unused vaccines and what some European critics regarded as an unjustified scare.
Amazing, that: the world authorities get it right, help mitigate what could have been a nasty pandemic – then get it in the neck for being alarmist, and helping drug companies make a profit.
Further from the article:
After petering out in Europe and the United States before their winter flu season was over, in recent months swine flu has affected parts of South Asia and “limited areas” of tropical South and Central America, as well as Africa for their second season.
But unlike 2009, when A(H1N1) ousted most other types of flu viruses around the world, known seasonal viruses now are prevalent and even dominant in countries such as South Africa.
Yeeessssss…and that’s all very well, because do you know what happened in South Africa? They’ve only just released H1N1 vaccine stockpiled for health workers for the duration of the Soccer World Cup, is what – late in the flu season, and almost too late to do any good. Meaning exactly what was predicted at the beginning of the pandemic, came to pass: there was not enough vaccine for developing countries, and even a year after its emergence, it was still not being distributed evenly.
Not a very good practice run for the Big One, if you ask me: still not enough vaccine being made quickly enough; vaccine not being distributed to at-risk countries; too much fussing over the welcome news that it was not as bad as it could have been.
I’m going to put my faith in plants….
Influenza A viruses mixing in susceptible hosts
I have been waiting with great interest to see what would happen in the wrong northern hemisphere 2009-2010 winter season with the Mexican – sorry; politically incorrect, aka pandemic H1N1 – flu – and it has pretty much happened, and it wasn’t nearly as bad as it could have been.
From ProMED:
INFLUENZA PANDEMIC (H1N1) (05): VACCINE UPDATE
**********************************************
A ProMED-mail post
Date: Mon 11 Jan 2010
Source: Reuters News [edited]Countries re-think swine flu vaccine orders
– ——————————————-
The United States said on Monday [11 Jan 2010] it had cut in half its order for influenza pandemic (H1N1) 2009 virus vaccine from Australia’s CSL Ltd, but said it is not certain how far orders from other suppliers will be trimmed. While U.S. officials are still calculating how much swine flu vaccine they will need, it is becoming increasingly clear that the United States will not need all 251 million doses it ordered from 5 companies. …
Several other governments have started to cut orders for [pandemic] H1N1 vaccines because the pandemic has not turned out to be as deadly as originally feared and most people need only one dose, not 2, to be fully protected.
…Germany’s Bild newspaper reported that the German government had agreed to cut its vaccine order with GlaxoSmithKline Plc by one-3rd. The newspaper said the agreement would save states about 133 million euros (USD 193 million). On Friday [8 Jan 2010], Britain said it was in talks with Glaxo about reducing supplies. ….
…While the pandemic is slowing down in North America, the World Health Organization said on Monday [11 Jan 2010] the virus was still active in parts of central, eastern and southeastern Europe, North Africa and South Asia. Governments are torn between trying to encourage companies to make influenza vaccine and wasting money on doses that are never given. But bulk antigen — the vaccine before it is put into a syringe – — can be stored and might be used in next year’s seasonal vaccine.
The U.S. government was still promoting vaccination, reminding people that influenza is unpredictable and that [pandemic] H1N1 could come back in a 3rd wave. One potentially large market for the vaccine is children. Children under 10 need 2 doses of vaccine to be fully protected and some U.S. school districts were planning more vaccination clinics this week to get children a 2nd dose. …
[Byline: Maggie Fox]– —
Communicated by:
ProMED-mail Rapporteur Mary MarshallCommunicated by:
ProMED-mail
Flu virus life cycle. Copyright Russell Kightley Media
The September 2009 issue of Nature Biotechnology has a letter concerning the receptor specificity of AH1N1 2009 pandemic influenza virus – which accounts pretty well for why it CAN be pretty nasty, and for why it may get nastier yet.
Childs et al., in a letter entitled “Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray“, describe what amounts to a tour de force analysis of the receptor binding of a number of influenza viruses, which concludes with the statement that:
“The differences in receptor binding between the 2009 pandemic and seasonal H1N1 viruses may therefore account, at least in part, for the higher virus replication and greater pathology reported in the lungs of ferrets, mice and nonhuman primates infected with pandemic viruses, than observed with contemporary seasonal viruses.”
Which would help explain why some otherwise healthy young people are dying of the virus, while others are getting only mildly ill. But we get ahead of ourselves: in January last year I wrote in MicrobiologyBytes about recpetor specificities of A-type influenza viruses, in the context of how H5N1 was less likely to mutate to easy human-to-human transmissibility than had origianlly been thought.
I wrote at the time:
According to a letter in the January 2008 issue of Nature Biotechnology, it is a characteristic structural topology, and not just the α2,6 linkage, that enables specific binding of HA to α2,6 sialylated glycans. The authors state:
…recognition of this topology may be critical for adaptation of HA to bind glycans in the upper respiratory tract of humans. An integrated biochemical, analytical and data mining approach demonstrates that HAs from the human-adapted H1N1 and H3N2 viruses, but not H5N1 (bird flu) viruses, specifically bind to long α2-6 sialylated glycans with this topology. This could explain why H5N1 viruses have not yet gained a foothold in the human population.
Apparently the critical shape in humans is umbrella-like, whereas the avian receptor is characteristically cone-like. Again from the paper:
The topology of α2-3 and α2-6 is governed by the glycosidic torsion angles of the trisaccharide motifs-Neu5Aca2-3Galb1-3/4GlcNAc and Neu5Aca2-6Galb1-4GlcNAc, respectively (Supplementary Fig. 3 online).
Ram Sasisekharan and colleagues showed that human-adapted viruses with mixed α2,3/α2,6 binding ability that bound the umbrella-type receptor were efficiently transmitted, whereas viruses with the same basic specificity that did not have HA binding specificity to “long” α2,6, were not.
The present paper reports the following investigation:
“We have compared directly, by carbohydrate microarray analysis, the receptor-binding characteristics of two isolates of the novel pandemic H1N1 virus, Cal/09 and A/Hamburg/5/2009 (Ham/09), with those of a seasonal human H1N1 virus, A/Memphis/14/96-M (Mem/96), as representative of a virus well adapted to humans [and a reassortant human H3N2 virus A/Aichi/2/68 x PR8 (X31)]. As the HA of the novel H1N1 pandemic virus originated from a virus similar to triple reassortant swine H1N1 viruses, we compared one such example, A/Iowa/1/2006 (Iowa/06), isolated from a human infection, and an older close relative of classical swine H1N1 viruses, A/New Jersey/76 (NJ/76), the human isolate that initiated the concern of a pandemic threat in 1976.”
This is a really comprehensive analysis – for such a short communication – which throws up a number of interesting points. First, I was not aware it was possible to do “carbohydrate microarrays”! Second, the paper shows quite conclusively that the swine-derived AH1N1 viruses have a significantly wider range of receptor specificities than a standard seasonal AH1N1 virus, and – but to a lesser extent – than the reassortant H3N2 virus X31.
Carbohydrate microarray analyses of the six viruses investigated.
From the following article (with permission from NBT):
Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray.
Robert A Childs, Angelina S Palma, Steve Wharton, Tatyana Matrosovich, Yan Liu, Wengang Chai, Maria A Campanero-Rhodes, Yibing Zhang, Markus Eickmann, Makoto Kiso, Alan Hay, Mikhail Matrosovich & Ten Feizi.
Nature Biotechnology 27, 797 – 799 (2009).
doi:10.1038/nbt0909-797
Legend:
Numerical scores for the binding signals are shown as means of duplicate spots at 5 fmol per spot (with error bars). The microarrays consisted of eighty sialylated and six neutral lipid-linked oligosaccharide probes, printed on nitrocellulose-coated glass slides. These are listed in Supplementary Table 1 and arranged according to sialic acid linkage, oligosaccharide backbone chain length and sequence. The various types of terminal sialic acid linkage are indicated by the colored panels as defined at the bottom of the figure.
And what does all this mean, exactly? The authors sum it up well:
These results indicate that no major change in receptor-binding specificity of the HA was required for the emergent pandemic virus to acquire human-like characteristics and become established in the human population. …
The broader specificity, namely, the ability to bind to 2-3- in addition to 2-6-linked receptors is also pertinent to the greater virulence of the pandemic virus than seasonal influenza viruses observed in animal models, and its capacity to cause severe and fatal disease in humans, despite the generally mild nature of most infections. Binding to 2-3-linked receptors is thought to be associated with the ability of influenza viruses to infect the lower respiratory tract where there is a greater proportion of 2-3- relative to 2-6-linked sialyl glycans, although long chain 2-3-linked sialyl (poly-N-acetyllactosamine) sequences are present in ciliated bronchial epithelial cells in humans where they are the receptors for another human pathogen, Mycoplasma pneumoniae.
So there you have it: the viruses can get deeper in to your lungs than the standard flu – which, if it happens, can make you seriously ill.
So what happens if it gets better at binding the 2,3-type receptors in humans? Well, we’re only in the middle of the pandemic. We may yet find out the hard way.
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