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ISIS Report 16/09/09

Swine Flu Virus Created from Pig Vaccine?

The swine flu virus had three parents from two continents and appeared suddenly without warning, evading all routine flu surveillance and quarantine; sequence data suggest it may have been created from a faulty vaccine given to pigs in North America Prof. Adrian Gibbs and Dr. Jean Downie

This report has been submitted to the US FDA and CDC, and to Sir Liam Donaldson, UK’s Chief Medical Officer

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Background

Several papers reporting phylogenetic analyses of the gene sequences of the new pandemic swine-origin H1N1 virus (S-OIV) have been published.  All show that S-OIV inherited its genes from parents that came from two well-known groups of swine flus.  Flu viruses have 8 different genes and in mixed infections sometimes shuffle those genes to form ‘reassortants’ with new combinations of the 8 genes chosen from those of the parents.  Several reports have shown that six of the genes of S-OIV came from a ‘triple-reassortant’ influenza virus (or viruses).  These viruses have been common in North American pigs for more than a decade, and have never been found in Europe.  The other two genes (NA and MP) came from Eurasian ‘avian-like’ viruses common in Europe for longer, but never found in North America.  Both groups of viruses have however been found recently in pigs in SE Asia.

The analyses reveal an unusual feature of the S-OIV genes, which is that none of the genes have been found recently in swine influenzas collected during routine flu surveillance.  The NA gene had not been sampled (identified in samples) for 17 years before it reappeared in S-OIV, and the others, including the MP gene, for around 11 years.  Thus the NA and MP genes were most likely acquired by S-OIV from Eurasian ‘avian-like’ viruses on separate occasions, and therefore S-OIV probably had at least three parents.

We have done further specific analyses to find out which isolates contain the genes that are closest to those of S-OIV.  We find that all are viruses of pigs.  The NA gene of S-OIV is closest to that of European ‘avian-like’ H1N1 influenza viruses sampled in 1991/1993, its MP gene closest to that of H3N2 Asian ‘avian-like’ viruses sampled in 1999, and its other six genes are closest to those of North American H1N2 ‘triple-reassortant’ viruses sampled in 1999/2000.  Note that the dates those isolates were collected agree with the calculated ‘time-line’ leading to S-OIV; NA 17 years ago, all the others 11 years.

In summary, S-OIV is a reassortant with at least three parents.  The parents were sampled over a decade ago, all found in pigs, and in three very distant parts of the world; North America, Europe and SE Asia!!!

The Questions

Where were S-OIV’s genes between the time that they were last sampled and 2008 when they all reappeared in S-OIV?  In which virus or viruses, which host, and when and how did they get together?  It is important for us to try to answer these questions as it might help us avoid similar pandemics in future.

The Theories

There are two theories regarding the origin of S-OIV, as described below.

The “unsampled pig theory”, was published by Gavin Smith and his colleagues in Nature [1]. They suggest that “the progenitor of the S-OIV epidemic originated in pigs”.  The “long unsampled history observed for every segment” of the S-OIV genome “suggests that the reassortment of Eurasian and North American swine lineages may not have occurred recently, and it is possible that this single reassortant lineage has been cryptically circulating rather than two distinct lineages of swine flu”, and that “Movement of live pigs between Eurasia and North America seems to have facilitated the mixing of diverse swine influenzas, leading to the multiple reassortment events associated with the genesis of the S-OIV strain.”  Note that Smith and his colleagues had not realized that their results showed that S-OIV had at least three, not two, parents. 

Their theory has three parts. First, S-OIV’s parents reassorted to produce S-OIV at least a decade ago; second, the reassortant has been circulating in untested pigs since then, and third, it entered North America in the live pig trade from Eurasia.

The sequence databases show that during the past decade only the swine influenzas of Europe, North America and SE Asia were collected (and gene sequenced), so Smith and colleagues are correct in concluding that S-OIV, or its parents, could have been circulating undetected in, for example, South America or Africa or much of Asia.  However the parent(s) of S-OIV would require at least two trans-continental trips to get together in one place, and hence this theory requires at least two quarantine failures, probably three.  Is this likely? Given that quarantine has kept the widespread Eurasian avian-like swine viruses out of North America, and the ‘triple reassortant’ swine viruses of North America out of Europe.  Furthermore S-OIV is very infectious for both human beings and pigs, a characteristic that is probably an ‘emergent property’ of the reassortant, not of its parents, therefore it is more likely that the reassortment event producing S-OIV occurred immediately before it first appeared in humans in late 2008, than over a decade ago.  If S-OIV had originated earlier then most likely it would have spread to the human and/or pig populations earlier, and would probably have been found.

The “vaccine theory” was contrasted with the “unsampled pig theory” in a paper we submitted for publication in an academic journal.  We note that influenza viruses survive well in virus laboratories, that laboratories are not subject to routine surveillance, and that there are probably many laboratories in the world where a range of swine influenzas from different sources and continents are kept.  These viruses are used for research, diagnostic tests and for making vaccines.  Thus if laboratory activity was involved in the genesis of S-OIV, this would explain most simply why S-OIV’s genes had escaped surveillance for over a decade, and how viruses last sampled in North America, Europe and Asia could have got together.  Note too that there have been several reports, especially by Deborah Mackenzie in the ‘New Scientist’, about swine influenzas in agribusiness piggeries, and the uncontrolled production of veterinary vaccines, mostly “multivalent” (i.e. containing several different viruses).  

So how could a laboratory mistake produce S-OIV?  The simplest scenario is that a multivalent vaccine was not fully sterilized.  Multivalent ‘killed’ vaccines are mixtures of virus particles that have been grown in hen’s eggs and then chemically sterilized.  Such vaccines are widely used in North American piggeries to control influenzas.  Thus S-OIV might have been produced if insufficient sterilant, usually formaldehyde or propiolactone, had been added to the particle mixture.  The live mixture would then infect pigs ‘vaccinated’ with it, and the growing viruses could then reassort to produce S-OIV. 

It is significant that one of the North American H1N2 ‘triple reassortants’ closest to S-OIV is probably used in commercial multivalent pig vaccines in North America [2].  This may be the reason why, as the S-OIV pandemic started, there has been no report of an outbreak of S-OIV in a pig farm in the USA, whereas it has been reported from unvaccinated pig herds in other parts of the world; two each in Canada and Australia, and one in Argentina.  It is also relevant that the three likely parents of S-OIV are those one would choose if one were designing a multivalent swine influenza vaccine for international use.

There are historical precedents for laboratories being involved in virus outbreaks, not just foot-and-mouth disease and polio, but also influenza.  For example there was the H1N1 influenza lineage that circulated in the human population for four decades after the 1918 Spanish influenza epidemic but disappeared during the 1957 Asian influenza pandemic and reappeared in 1977.  The H1N1 that reappeared was found to be genetically very close to an H1N1 isolate collected in 1950, indicating that it had probably been held in a laboratory freezer between 1950 and 1977.  There is also the recent incident of a commercial human test vaccine being found to contain live H5N1 virus.

Action plan

So what can be done to distinguish between these two theories, and any others that are proposed?  The phylogenetic patterns in the present gene sequence data do not distinguish between them – more data are needed. 

First, samples of all isolates of influenza used in swine vaccines in North America in 2008 must be collected, and their gene sequences determined.  This would immediately check the vaccine theory.  Second, the refrigerators of vets throughout the world, especially those of South and Central America, Asia and Africa, should be checked for samples of swine influenzas collected over the past decade, and the gene sequences of the isolates viruses determined.  Third, the quarantine authorities of North America should discuss, if they have not already done so, whether it is likely that pigs infected with S-OIV or its parents could evade quarantine measures when coming from other parts of the world.

It is important for the relevant authorities to obtain this evidence while the ‘scent’ is still warm – the search for the source of S-OIV must not be relegated to the ‘too hard’ basket, some possibilities can still be checked.  Influenza is a significant and very costly cause of mortality and morbidity in the human population.  If we wish to avoid new outbreaks rather than just minimizing the damage they cause, we must better understand what conditions produce them.

Jean Downie and Adrian Gibbs are viologists, they study the evolution of viruses using their gene sequences

References

1.Smith GJD, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 2009, 459, 1123-6.

2.H1N1 Influenza Veterinary Talking Points – 5/5/09, http://www.aasp.org/public/H1N1InfluenzaVeterinaryTalkingPoints-05-05-09.doc

There are 16 comments on this article so far. Add your comment
Volker Hampe Comment left 2nd November 2009 21:09:42
Sorry, I think I posted a wrong link here is the link to the original patent application http://www.wipo.int/pctdb/en/wads.jsp?IA=US2005019382&LANGUAGE=EN&ID=id00000004184887&VOL=60&DOC=0131cd&WO=06/083286&WEEK=32/2006&TYPE=A2&DOC_TYPE=PAMPH&PAGE=1 Volker Hampe, Germany
Volker Hampe Comment left 2nd November 2009 21:09:36
I just want to provide a link to an original filing for a swine vaccine dated 2006. http://www.wipo.int/pctdb/en/wo.jsp?WO=WO/2006/083286&IA=US2005019382&DISPLAY=DOCS (maybe you have to first open the first part of the web address http://www.wipo.int/pctdb/en/wo.jsp?WO=WO and than copy and paste the rest of the link.) Some Claims in the actual version are cancelled. http://www.patentstorm.us/applications/20090010962/claims.html Most of the cancelled claims in the original patent application deal with an alternative bioengineered swine flu virus, which was a hybrid with another kind of virus. A chicken egg, which was inoculated with this chimeric virus was provided as a prototype. Two of the 6 inventors (Palese and García-Sastre)were also involved in the ressurrection of the Spanish flu. Robert Webster, another inventor, heads the World Health Organisation (WHO) collaborating laboratory on animal influenza. The WHO has been scaring the public with inflated swine flu propaganda. Volker Hampe, Germany
Prince Pieray C. Peter Odor Comment left 18th September 2009 17:05:14
In the place of “avoid” used in the last statement of the report, let us say: BAN, most strictly and inviolably, all tampering with the DNAs and genes of organisms—not ban the study of the DNA or genes, as this is different from tampering—which are carried out now and promoted with lofty promises and claims of successes until we get a “pregnancy” such as S-OIV that make “virginity” no more a claim, makes a “hood” no more a symbol of humanitarianism, and reveals the anti-God attitudes so far projected as innovation. In addition to a ban, ALL bio-scientists and governments must be compelled to promote and protect life and not create and commercialise life or the progeny of life. Thirdly, a new rule must be created for global governments which must punish the interference with or violation of the DNA or gene by any bio-scientist or government without any government exempted, as is the case now—I mean the exemption of the government of the USA the greatest culprit. Prince Pieray C. P Odor Lagos, Nigeria
gsgs Comment left 16th September 2009 13:01:55
how could they have a vax from a distant virus which did escape detection by all the experts ? Why would they not just use HA ? Why should they make a vax against a virus that is so rare ? The "is this likely" part from theory 1 does still apply.
uppity layman Comment left 23rd September 2009 08:08:16
"serious" scientists can't mention the possibility it was deliberately created, a bioweapon ... how childish, how pathetic. as if bioweapons programs didn't exist, the possibility someone with ill intent might gain access to the necessary tools without organization sanction is not possible. as if a biological research facility itself might intentionally create the virus is impossible.
Rabbit Comment left 23rd September 2009 10:10:29
The only ducks involved are the woodducks who don't even consider the likelihood this was deliberately produced in laboratories.
Ernes Wiebe of Canada Comment left 23rd September 2009 17:05:27
What about the four people who have their names on the patent of this virus? They have had a few years to work on the vacine and why it is ready now.
Dan Eden Comment left 23rd September 2009 20:08:09
Re: "ducks to pigs"... if one drives from the border of Vietnam through to Phnom Penh one sees a pattern of duck ponds near the road, then pig pens on the bank, then the family dwelling. There are literally millions of such configurations and I suspect the same is true for other developing countries.
DocVan Comment left 23rd September 2009 20:08:38
I'm hoping this is not off-subject. I've seen no one mention it, but would taking the "Swine Flu" vaccine be in violation of religious laws against pork/pigs/swine for the Jews, Muslims, and such? Would they be able to refuse it, and thus avoid the vaccine on religious grounds?
WhatWeAllNeedToKnow Comment left 25th September 2009 07:07:54
What this article by Prof. Adrian Gibbs fails to address, is the particular genetic behavior this virus exhibited, when his team investigated it, upon release of the DNA databases that occurred in early May 2009. This was a particular feature of his findings, which he reported in a live interview on Bloomberg on May 13, 2009. In Dr. Gibbs own words, from the interview, “But each one of those 8 genes, instead of just evolving at roughly the same sort of rate as all the genes related to it, they had actually speeded up before we got them. The ones that are in the new flu have been going along at about three times the rate of those in influenza. And its not just one of them, its all 8 of those genes, including the two from Eurasia.” So it seems a full discussion about this virus overlaps the 2 questions (1) – its particular genetic blueprint (2) its particular rate of mutation – as related to the introduction of vaccines to counteract it. Genetic Blueprint The genetic blueprint was reported to be unique by Dr. Richard Webby, who analyzed the virus’s DNA code. Webby completed his DNA database search, during the week of April 23 - 30, and failed to identify an exact match, suggesting the emergence of a new virus to which people would have little or no immunity. Rate of Mutation as Related to Vaccines Investigative Journalist Wayne Madsen (WMR) provided more information on the issue of mutation rate of this virus, as it was told to him by research scientists, and its relation to a planned rollout of vaccines on May 13, 2009. Quote: WMR has learned from an A/H1N1 researcher that the current "novel" flu strain is mutating rapidly in humans but no animals have contracted the virus. The enzyme in A/H1N1, as with all influenza A viruses, is called a polymerase. Scientists have calculated the molecular clock of A/H1N1 from the virus's polymerase rate. Because of the rapid mutation of the virus and the fact that, unlike 1918, rapid global transportation is now the norm, scientists are predicting that the molecular clock of the A/H1N1 virus, coupled with modern transportation, means that almost all the countries of the world will experience an A/H1N1 outbreak within the next few months. The fear is that once a vaccination against AH1N1 is started, the virus will re-assort itself into a hybrid H1N1/H5N1 strain or mutate into a new H5N1 strain. The current AH1N1 strain, as previously reported by WMR, contains synthetically gene-spliced strains of two forms of human flu viruses, two forms of swine flu viruses, and a single form of avian flu virus. …with vaccinations, the AH1N1 virus will, of course, be rejected by human hosts and cases around the world will decrease. However, then, the virus will begin to mutate in order to successfully infect human hosts. And when that happens, the new, newly mutated virus will become much more transmissible and more pathogenic. The nightmare scenario is that the new, mutated virus may take on the characteristics of H5N1 or the avian flu. The vaccines administered for AH1N1 will be ineffective against the new strain of H5N1 and the world may face a more deadly pandemic then the current AH1N1 outbreak. There are scientists at WHO who are aware of this scenario but their alarm has been suppressed by political and economic considerations. ****************************** Vaccine Paradox: A recent report, published in March of this year studies in relation to Bird Flu suggests that the introduction of vaccines does in fact corroborate what is mentioned above. Paradox of Vaccination: Is Vaccination Really Effective against Avian Flu Epidemics? Shingo Iwami1, Takafumi Suzuki2, Yasuhiro Takeuchi1* 1 Graduate School of Science and Technology, Shizuoka University, Shizuoka, Japan, 2 Graduate School of Engineering, Shizuoka University, Shizuoka, Japan "Although vaccination can be a useful tool for control of avian influenza epidemics, it might engender emergence of a vaccine-resistant strain. Field and experimental studies show that some avian influenza strains acquire resistance ability against vaccination. We investigated, in the context of the emergence of a vaccine-resistant strain, whether a vaccination program can prevent the spread of infectious disease. We also investigated how losses from immunization by vaccination imposed by the resistant strain affect the spread of the disease." ****************************** Lab Origin Hypothesis Gibbs and ‘Lab Origin Hypothesis’ is corroborated in a publication from the China Animal Health and Epidemiology Center: "In addition, the above inference and other information available now could not exclude the possibility that the current new A (H1N1) influenza virus came from a laboratory, as in many laboratories in multiple countries, it is not that difficult to generate such a new virus using the technique of reverse-genetics from tubes without clear manmade signs." page 2177 Origin and future distribution of the new A (H1N1) influenza virus emerging in North America in 2009, CHEN JiMing, SUN YingXue, LIU Shuo, JIANG WenMing, CHEN Jie, HOU GuangYu & LI JinPing, China Animal Health and Epidemiology Center, Qingdao 266032, China ******************************* So why the push for mandatory vaccines – as outlined by the WHO International Health Regulations (IHR) of 2005, which included passage of legislation empowering state surveillance and the monitoring of a mandatory vaccine program, as agreed to 194 member countries. www.theflucase.com
amicus curiae Comment left 6th October 2009 14:02:05
A company called Novavax was trialling this exotic combination from about Oct 08? in San Antonio. Material provided by?( NIH or CDC atlanta..??) go see their web pages. trials data. see what you all think. I just figure its Very likely people from Mexico were participants....
Gerard Ridgway Comment left 16th September 2009 12:12:07
From ducks and humans and then into pigs is one way the story of a vaccine is told. Maybe ducks are part of the story here aswell.
carol Comment left 29th October 2009 06:06:01
I have the feeling that the H1N1 could have accidentally originated in the seasonal flu vaccines that are given out every year to millions of people. The fact is that there can be viruses that go undetected in vaccines and that is exactly why one of the side effects listed for many vaccines is that you can get certain viruses like Jacob-Kruesfelt(spelling?) otherwise known as Mad cow because of course some vaccines are grown in serum from cows. They say that the fetal blood from calves is much less likely to have this virus, but when you think about it it is highly possible that viruses still unknown to us can get into vaccines. That is why so many peopla are opposed to live vaccines for their children. I don't believe that you can kill every possible virus when you are isolating a flu virus from the live medium you grow it in. I had some science background at university and have given a lot of thought to this subject.
Johan Neeskens Comment left 23rd September 2009 14:02:47
Theory 3 The virus was deliberatly created by some company which would gain $$$ from selling hundreds of million vaccines???
Steptic Comment left 16th November 2009 23:11:18
Three separate articles offer an explanation for the origin of H1N1 (Brockwell-Staats et al., 2009; Kingsford et al., 2009; Smith et al., 2009). The explanation is based on facts, including gene sequences of previously known influenza viruses. While it is possible that H1N1 was engineered, there is no direct evidence of this. The best explanation for H1N1 is a natural origin. One virologist, Adrian Gibbs, hypothesized that H1N1 escaped from a lab. He has stated that he is uncertain of this and that it is simply a plausible hypothesis. The WHO has responded that the hypothesis does not stand to scrutiny (Hitt, 2009). Brockwell-Staats C, Webster RG, Webby RJ. (2009) Diversity of Influenza Viruses in Swine and the Emergence of a Novel Human Pandemic Influenza A (H1N1). Influenza Other Respi Viruses. 3: 207 - 213. [PMID: 19768134] Hitt E. (May 14, 2009) Novel H1N1 Flu a Naturally Circulating Virus, Not From a Laboratory. Medscape Medical News. [http://www.medscape.com/viewarticle/702862] Kingsford C, Nagarajan N, Salzberg SL. (2009) 2009 Swine-origin influenza A (H1N1) resembles previous influenza isolates. PLoS One. 4: e6402. [http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0006402] Smith GJ, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, Pybus OG, Ma SK, Cheung CL, Raghwani J, Bhatt S, Peiris JS, Guan Y, Rambaut A. (2009) Origins and evolutionary genomics of 2009 swine-origin H1N1 influenza A epidemic. Nature. 459: 1122 - 1125. [http://www.nature.com/nature/journal/v459/n7250/pdf/nature08182.pdf] -------- A simple summary of the three articles offering an explanation for 2009/H1N1's natural origin follows. Influenza A virus genome consists of 8 negative sense ssRNA segments: M, NA, PB1, PB2, PA, NP, NS and HA. Influenza viruses change by reassortment, which occurs when two different influenza viruses infect one cell and RNA segments are mixed. Pigs are thought to be reassortment vessels for influenza because they can be infected by swine, avian and mammalian strains (Webster et al., 1992). Pandemic 2009/H1N1 resulted through reassortment between Eurasian swine H1N1 (ES-H1N1) and triple reassortment swine H1N2 (TRS-H1N2). The M and NA segments came from the ES-H1N1 and other 6 came from TRS-H1N2. TRS-H1N2 has been circulating in North America since 1998. It has PB1 and NA segments from human H3N2 influenza; PA and PB2 segments from avian influenza; NP, M, NS and HA segments from classical H1N1 swine influenza. When ES-H1N1 and TRS-H1N2 reassorted, the M and NA segments from H1N1 were packaged with the six other segments from H1N2. 2009/H1N1 is this new 2+6 'package' of gene segments. Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. (1992) Evolution and ecology of influenza A viruses. Microbiol Rev. 56: 152 - 179. [http://mmbr.asm.org/cgi/reprint/56/1/152.pdf] -------- Viruses are small particles of protective protein coats, sometimes enveloped by a membrane, and inside is genetic material. In the case of influenza A virus, that genetic material is RNA (instead of DNA). The RNA in the virus is made up of eight single stranded segments of negative sense RNA (contrast this with a bacterial chromosome which is a usually a large, circular piece of double stranded DNA). One way that influenza viruses are known to evolve is by reassortment. Reassortment occurs when two influenza viruses infect the same cell, during the packaging process, when the RNA is being packaged. The segments can mix and match during reassortment. Each virus has to have at least one of each segment (note they have names). So there are 2^8 = 256 different possible reassortments that can occur between two different influenza A strains. 2009/H1N1 is just one reassortment. The segments that were exchanged and their origins is what's explained in the three articles (2 segments from one influenza, 6 segments from the other).
anne-marie Comment left 23rd October 2009 18:06:38
Is vaccination safe for everyone?I've heard vaccination has different side effects,I think it needs severe monitoring.I've read about tamiflu medicine,want to learn more about it?(enter on tamiflu4rx.com)

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