I'm hanging out at the Googleplex this weekend, attending SciFoo, and I see there is a new outbreak of FMD in Britain. Here is the NYT coverage. Here is the CNN coverage. Earlier today Oliver Morton showed me a story that claimed the outbreak might be an isolated escape from a lab in the English countryside. We'll have to wait and see how widespread the virus actually is.
News in the last couple of days that Indonesia has decided not to forward homegrown strains of H5N1 to the WHO and instead is dealing directly with Baxter Healthcare for production of vaccines. The worst bit of this, of course, is that there does not appear to be much cross reactivity elicited by the Vietnamese and Indonesian isolates, where the international reference vaccine is derived from a strain isolated in Vietnam. Moreover, while Baxter is supposedly making progress in producing influenza vaccines in cell culture (Baxter's Press Releases, CIDRAP's version), this technology is not yet approved for human use; only research contracts, rather than production contracts, have been let by the U.S. Government for cell culture production. Finally, despite much noise that cell culture is faster/better/cheaper than eggs for producing vaccines, it appears cell culture only beats eggs by a month or two. (Baxter does have a very comendably decent Influenza information web page, which is here.)
Here are a few paragraphs from an AP story, "Experts say Indonesian deal on H5N1 virus jeopardizes race for pandemic vaccine", via the IHT:
Indonesia Wednesday signed a memorandum of understanding with U.S. drug manufacturer Baxter Healthcare Corp. to develop a human bird flu vaccine.
Under the agreement, Indonesia will provide H5N1 virus samples in exchange for Baxter's expertise in vaccine production. Other organizations would have access to Indonesian samples provided they agree not to use the viruses for "commercial" purposes, said Siti Fadilah Supari, Indonesia's health minister.
But that is a major departure from the World Health Organization's existing virus-sharing system, where bird flu viruses are freely shared with the global community for public health purposes, including vaccine and antiviral development. Indonesia has not shared any viruses since the beginning of 2007.
Indonesia defended its decision, arguing the system works against poor countries. "The specimens we send to WHO...are then used by vaccine makers who then sell to us (at a profit)," Supari told reporters Wednesday. "This is unfair, we have the virus, we are getting sick, and then they take the virus from WHO — 'with WHO's permission' they say — and make it themselves," said Supari.
There seems to be a bit of confusion among reporters about whether Indonesia now has an official policy of withholding samples from the WHO, but Baxter is making it clear they don't have anything to do with the decision. From The New York Times' coverage: "A Baxter spokeswoman said the company had not asked Indonesia to stop cooperating with the W.H.O. She added that the agreement under negotiation would not give it exclusive access to Indonesian strains."
In any event, Indonesians feel bent out of shape that they have previously provided strains to the international community, only to be charged for the vaccine when it becomes available. News reports portray this as something of an IP spat, akin to controversy over biomining. From the Reuters coverage:
"The specimens we sent to the WHO have been forwarded to their collaborating center. There it has been used for various reasons such as vaccine development ... or research," Supari said.
"Later they sold the discovery to us. This is not fair. We are the ones who got sick. They took the sample through WHO and with WHO consent and they tried to produce it for their own use," she said at a news conference after the signing of the pact with Baxter.
Supari said Australia was producing a human bird flu vaccine using the Indonesian virus strain, but did not give details.
"I was shocked because I never gave permits to Australia to produce a vaccine using our strain," she said.
"We have been working with Baxter since the beginning and are processing intellectual property rights with them. Baxter protects our intellectual property rights," she said.
...Under the memorandum of understanding, Indonesia would have the right to produce and market the bird flu vaccine domestically. It is negotiating to export it to a number of countries.
Production would be carried out by makers appointed by the Health Ministry.
So, in conclusion, the deal appears to put Indonesian isolates of H5N1 out of the reach of governments and firms with other vaccine technologies, at least for the time being. Finally, in an interesting twist on the distribution of biological technologies, the deal also appears to put Indonesia in a position to become a leader in cell culture production of vaccines, potentially jumping to the head of the pack in the international vaccine market.
The headlines are today loudly announcing the return of H5N1 to the United Kingdom (CNN, New York Times) at a Turkey farm near Lowestoft. Though nobody can say for sure, the virus probably arrived via migrating birds. It appears that the likelihood of transmission by migrating bird or smuggled poultry has a geopolitical dependence.
Last month, Kilpatrick, et al., published a paper in PNAS ("Predicting the global spread of H5N1 influenza") that looked at a variety of factors to classify historical outbreaks and predict new ones. The abstract does a decent job of summarizing the paper, so here it is:
The spread of highly pathogenic H5N1 avian influenza into Asia, Europe, and Africa has resulted in enormous impacts on the poultry industry and presents an important threat to human health. The pathways by which the virus has and will spread between countries have been debated extensively, but have yet to be analyzed comprehensively and quantitatively. We integrated data on phylogenetic relationships of virus isolates, migratory bird movements, and trade in poultry and wild birds to determine the pathway for 52 individual introduction events into countries and predict future spread. We show that 9 of 21 of H5N1 introductions to countries in Asia were most likely through poultry, and 3 of 21 were most likely through migrating birds. In contrast, spread to most (20/23) countries in Europe was most likely through migratory birds. Spread in Africa was likely partly by poultry (2/8 introductions) and partly by migrating birds (3/8). Our analyses predict that H5N1 is more likely to be introduced into the Western Hemisphere through infected poultry and into the mainland United States by subsequent movement of migrating birds from neighboring countries, rather than from eastern Siberia. These results highlight the potential synergism between trade and wild animal movement in the emergence and pandemic spread of pathogens and demonstrate the value of predictive models for disease control.
Of course, the only way to know if the model really works is, alas, to wait for more outbreaks. Anyway, it seems the U.S. is safe from poultry smuggling, which we have a chance of intercepting, but susceptible to migrating birds, a pathway that almost certainly resists any defensive measures.
There is an excellent news piece in last week's Science, where here the definition of excellent is both "informative" and "highly unsettling". Dennis Normile and Martin Enserink write:
An upsurge in H5N1 bird flu outbreaks in poultry across Asia is driving home the message that even countries that have eliminated the virus once shouldn't become complacent. The continuing high death toll in humans, including two recently detected cases of infection with a Tamiflu-resistant strain in Egypt, is also a grim reminder of how devastating the virus might be if it acquires the ability to spread easily among humans.
...Over the past 3 weeks, Thailand and Vietnam reported their first H5N1 outbreaks among poultry in 6 months. Japan, which seemed to have dodged the bullet since its cluster of outbreaks in 2004, confirmed that the virus hit one farm on 11 January and probably a second farm on the 23rd. South Korea, which last November suffered its first outbreak since containing the virus in 2004, reported that the virus had turned up on a fifth poultry farm. Several wild birds found dead in Hong Kong tested positive for H5N1. And Indonesia on 20 January reported its fifth human death from the virus in just 10 days, bringing its death toll to 62, by far the most of any country.
The increase in outbreaks in the Northern Hemisphere follows what has become an established pattern. The reason for the seasonality is still not well understood, says Les Sims, a veterinarian based in Manunda, Australia, who advises the U.N.'s Food and Agriculture Organization (FAO). It is likely to be some complex interaction among several factors, including cooler temperatures enabling the virus to survive longer in the environment, greater poultry trade in preparation for winter festivals, and movements of wild birds.
The recurrence of the virus in South Korea and Japan is particularly notable. In both the winter of 2003-'04 and this year, outbreaks in South Korea were followed 4 to 6 weeks later by outbreaks in Japan. "The outbreaks in Japan and South Korea suggest to me free-flying birds as the most likely origin," says Sims. Both countries are trying to determine how the virus was reintroduced.
So it seems unlikely we will be rid of the virus through culling programs, the primary mechanism thus far employed for biosecurity. That the virus seems to be spread by wild birds in these cases is interesting, but this isn't the only pathway for reintroduction into poultry or people.
Last week's issue of New Scientist revisits the notion that "Deadly H5N1 may be brewing in cats". (Most of the relevant text is available here at ProMed.) Felines may be serving as a mammalian host that might enable the virus to adapt to mammalian biology and thereby become more dangerous to humans. This is something I started wondering about after cats started dying in Europe so soon after the virus arrived there last year. The New Scientist provides corroborating evidence that cats are important in the dynamics of the virus in Indonesia. The story reports some surprise on the part of scientists doing the field work with regard to the prevalence of the virus in cats in Indonesia:
In the first survey of its kind, an Indonesian scientist has found that in areas where there have been outbreaks of H5N1 in poultry and humans, 1 in 5 cats have been infected with the virus, and survived. This suggests that as outbreaks continue to flare across Asia and Africa, H5N1 will have vastly more opportunities to adapt to mammals than had been supposed.
Chairul Anwar Nidom of Airlangga University in Surabaya, Indonesia, told journalists last week that he had taken blood samples from 500 stray cats near poultry markets in four areas of Java, including the capital, Jakarta, and one area in Sumatra, all of which have recently had outbreaks of H5N1 in poultry and people.
Of these cats, 20 per cent carried antibodies to H5N1. This does not mean that they were still carrying the virus, only that they had been infected - probably through eating birds that had H5N1. Many other cats that were infected are likely to have died from the resulting illness, so many more than 20 per cent of the original cat populations may have acquired H5N1.
This is a much higher rate of infection than has been found in surveys of apparently healthy birds in Asia. "I am quite taken aback by the results," says Nidom, who also found the virus in Indonesian pigs in 2005. He plans further tests of the samples at the University of Tokyo in February.
The data explicitly contradicts prior statements from the WHO downplaying the role of cats in harboring or spreading the virus, which I wrote about here. I continue to be fascinated by the extent to which the behavior of the virus in the wild contradicts the expectations and public statements of "officials" in various organizations around the world. H5N1 is clearly evolving in ways that are both surprising and worrying.
The New Scientist and Science stories both note that two people in Egypt who recently died from H5N1 infections were carrying strains of the virus evidently resistant to Tamiflu. It is unclear whether the virus carried the relevant mutations before it infected these patients, or whether it evolved during their illness because they were treated with Tamiflu in the hospital. Either way, it seems that many people infected with H5N1 are diagnosed after the window in which antivirals are most effective, in part because diagnosis is both difficult and slow. This phenomenon is described in two articles and a commentary in the 26 November, 2006, issue of The New England Journal of Medicine that report disturbing analyses of human H5N1 outbreaks in Indonesia and Turkey last year.
In a New York Times article about the NEJM papers, Donald Mcneil, reports the following:
Rapid tests on nose and throat swabs failed every time, and in Turkey, so did all follow-up tests known as Elisas. The only tests that consistently worked were polymerase chain reaction tests, or PCRs, which can be done only in advanced laboratories and take several hours.
''It'll be a disaster if we have to use PCRs for everybody,'' said Dr. Anne Moscona, a professor of pediatrics and immunology at Weill Cornell Medical College. ''It just isn't available at a whole lot of places.''
If the A(H5N1) flu mutates into a pandemic strain, rapid tests ''will be really key,'' she said.
What the NYT didn't report is that the patients were infected on average 5 days prior to the appearance of symptoms, outside the window recognized for effective use of antiviral drugs. Robert Webster and Elena Govorkova have an excellent Perspective piece accompanying the NEJM articles, and they note that in the Indonesian cases, "...Treatment [with oseltamivir] began 5 to 7 days after initial infection. Such delayed administration of the drug limits its value in decreasing the viral load and might lead to the selection of resistant strains." It isn't clear from the paper describing the Turkey outbreak when oseltamivir was administered, but those patients did not experience symptoms for an average of 5 days after exposure to the virus, and then received antibiotics for the first 3-7 days of hospitalization before transfer to a unit that treated them for influenza. In summary, it appears the virus is often being exposed to oseltamivir after the period when the drug is expected to be effective, enhancing the probability of selecting for resistant mutants.
Finally, in a slight change of direction, in the 21 December issue of Nature, John Oxford has a review of a new book on influenza, "Bird Flu: A Virus of Our Own Hatching", by Michael Greger. You may recall that Oxford is primarily responsible for the hypothesis that the 1918 flu emerged at a British army camp near Etaples, a tale I wrote about a couple of years ago (The Spanish Flu Story). Oxford notes that:
I am often kicked around by American authors in books about influenza. How dare a Limey suggest that the Spanish influenza A H1N1 virus arose in a gas-infected, pig-ridden and bird-infected army camp of 100,000 people in France in 1916, when the whole world knows it started in Dorothy's home state, Kansas? But I felt less bruised than usual. Perhaps I am getting used to it.
I still find Oxford's version of the origin of the Spanish Flu to be the most compelling, in part because it describes a situation of close contact between animals and people, where those animals were killed and prepared as food by soldiers on a daily basis in conditions not so dissimilar to those in many developing countries where H5N1 is present today.
There has been serious progress recently in developing DNA vaccines for pandemic influenza. First, Vical just announced (again by press release and conference presentation, rather than peer reviewed publication) single dose protection of mice and ferrets against a lethal challenge with H5N1 using a trivalent DNA vaccine. Ferrets are seen by many as the best model for rapid testing of vaccines destined for use in humans. According to the press release:
"We are excited by the recent advances in our pandemic flu vaccine development program," said Vijay B. Samant, President and Chief Executive Officer of Vical. "Earlier this week, we presented data from mouse studies demonstrating the dose-sparing ability of our Vaxfectin(TM) adjuvant when used with conventional flu vaccines. Today we presented data from ferret studies demonstrating the ability to provide complete protection with a single dose of our Vaxfectin(TM)-formulated avian flu DNA vaccine. Our goal is to advance into human testing with this program as quickly as possible, both to provide a potential defense against a pandemic outbreak and to explore the potential for a seasonal flu vaccine using a similar approach."
Mr. Samant will be attending the bio-era H5N1 Executive Round table in Cambridge in a few weeks, along with Dr. David Nabarro, the Senior UN System Coordinator for Avian and Human Influenza. I'm looking forward to finally meeting these gentlemen in person.
Powdermed is in early human clinical trials for its annual and pandemic flu DNA vaccines in the U.K. and the U.S., and has recently been acquired by Pfizer. This should provide needed cash for trials, technical development, and perhaps even for building a manufacturing facility for large scale production of their proprietary needle free injection system. I think it is interesting that a large pharmaceutical company -- a specialty chemicals company, in essence -- has acquired technology that is essentially a chemical vaccine. I wonder if Pfizer can lend expertise to packaging and DNA synthesis.
Despite progress in the lab and greater funding, there are still significant challenges in getting these vaccines into the clinic. Here is the DNA Vaccine Development: Practical Regulatory Aspects slide presentation from the NAIAD. Obviously, lots of work to do there. And as I have written about previously, it doesn't appear that the FDA is really interested in allowing new technologies to fairly compete, even if they are the best option for rapid manufacture and deployment as countermeasures for pandemic flu.
In other DNA vaccine news, a recent paper in PNAS demonstrated, "Protective immunity to lethal challenge of the 1918 pandemic influenza virus by vaccination." Kong, et al., showed that, "Immunization with plasmid expression vectors encoding hemagglutinin (HA) elicited potent CD4 and CD8 cellular responses as well as neutralizing antibodies." Here is more coverage from Effect Measure, which notes that the paper is primarily interesting as a study of the mechanism of DNA immunization in mice against the 1918 virus.
However, if I understand the paper correctly, the authors developed a means to directly correlate the effect of immunization with antibody production and thereby, "define [the vaccine's] mechanism of action". This appears to be a significant step forward in understanding how DNA vaccines work. I interviewed Vijay Samant of Vical by phone a few months ago, and he noted that because animal studies demonstrate complete protection even though traditional measures of immunity do not predict that result, he has a hunch that “tools for measuring immunogenicity for DNA will need to be different than for measuring protein immunogenicity.” Perhaps the results of Kong, et al., point the way to just such a new tool.
An upcoming Nature paper by Micheal Katze, just down the hill here in the UW Medical School, elucidates some of the mechanisms behind the extraordinary lethality of the 1918 virus in mice. Writing in Nature, Kash, et al., show that:
...In a comprehensive analysis of the global host response induced by the 1918 influenza virus, that mice infected with the reconstructed 1918 influenza virus displayed an increased and accelerated activation of host immune response genes associated with severe pulmonary pathology. We found that mice infected with a virus containing all eight genes from the pandemic virus showed marked activation of pro-inflammatory and cell-death pathways by 24 h after infection that remained unabated until death on day 5.
In other words, the immune response to infection with the 1918 virus contributed to mortality. Moreover, "These results indicated a cooperative interaction between the 1918 influenza genes and show that study of the virulence of the 1918 influenza requires the use of the fully reconstructed virus." That is, you have to be able to play with the entire reconstructed bug in order to figure out why it is so deadly. And this result gives an interesting context to the recent paper of Maines, et al., demonstrating that reassortant viruses of the present H5N1 and lesser strains are not as fearsome as the complete H5N1 genome (which I wrote about a few weeks ago). This latter observation has been interpreted in the press as evidence that H5N1 is "not set for pandemic", even though H5N1 is demonstrably changing in nature primarily by mutation rather than by swapping genes. H5N1 is quite deadly, and it may simply be that the particular combination of evolving genes in H5N1 gives it that special something.
Finally, an upcoming paper in J. Virology demonstrates an entirely new antiviral strategy based on peptides that bind to HA proteins in vivo and thereby prevent viral binding to host cells. "Inhibition of influenza virus infection by a novel antiviral peptide," by Jones, et al., at the University of Wisconsin, appears to still be in pre-press.
In the abstract the authors state:
A 20-amino acid peptide (EB) derived from the signal sequence of fibroblast growth factor-4 exhibits broad-spectrum antiviral activity against influenza viruses including the H5N1 subtype in vitro. The EB peptide was protective in vivo even when administered post-infection. Mechanistically, the EB peptide inhibits the attachment to the cellular receptor preventing infection. Further studies demonstrated that the EB peptide specifically binds to the viral hemagglutinin (HA) protein. This novel peptide has potential value as a reagent to study virus attachment and as a future therapeutic.
This is just an initial demonstration, but it is extremely interesting nonetheless. However, because it is a protein based drug, it risks generating an immune response against the drug itself. It will have to be administered in a way that preserves function in vivo in humans and doesn't spook the immune system. The last thing you want to do is generate antibodies against a protein vital for human health.
Yet, precisely because it is a fragment of a human protein, it might mean there is a lower risk of generating that immune response, especially if it can be produced in a way that has all the right post-translational modifications (glycosylation, etc). Though I wonder about variation in the population: various alleles and SNPs. What if you are given a version of the peptide that differs in sequence from the one you are carrying around? Would this generate an immune response against the drug even though it is closely related to something you carry naturally, and if so would those antibodies also pick out your allele? Definitely the potential for bad juju there. Another example of where personalized medicine, and having your genome sequence in your file, might be handy. Alternatively, I suppose you could just use your own sequence for the peptide, and have the thing synthesized in vitro for use as a personalized drug. Sequence --> DNA synthesis --> in vitro expression --> injection. Hmmm...you could probably already stuff all that technology in a single box...
However it is used, this advance is probably a very long way from the clinic. It might go faster if they use the peptide as inspiration for a non-protein drug, which, incidentally, the authors suggest near the end of the paper. Definitely a high-tech solution, either way, but probably the wave of the future.
A few days ago, Wired News carried a story by Sean Captain about the Healthmap project, a mash-up of Google Maps and various disease reporting services:
The new Healthmap website digests information from a variety of sources ranging from the World Health Organization to Google News and plots the spread of about 50 diseases on a continually updated global map. It was developed as a side project by two staffers at the Children's Hospital Informatics Program in Boston -- physician John Brownstein and software developer Clark Freifeld.
This follows on Declan Butler's Avian Flu Mashup. Both efforts encountered significant issues with data formats and parsing the trustworthiness of various data sources.
The Wired News story starts out with this lead: "Web-based maps are handy for keeping tabs on weather and traffic, so why not for disease outbreaks, too?" And the title is "Get Your Daily Plague Forecast," which. because it is a tad trite, I find rather ironic because a recent PNAS paper demonstrates that, "Plague dynamics are driven by climate variation."
Stenseth, et al., studied the prevalence of Yersinia pestis in the primary host animal, gerbils, as a function of average temperature over 45 years in Central Asia. They find that ,"A 1°C increase in spring is predicted to lead to a >50% increase in prevalence." The virus causes bubonic plague in humans, and transmission from rodents to humans is thought to be the main route into the human population. The authors note in the abstract that:
Climatic conditions favoring plague apparently existed in this region at the onset of the Black Death as well as when the most recent plague pandemic arose in the same region, and they are expected to continue or become more favorable as a result of climate change. Threats of outbreaks may thus be increasing where humans live in close contact with rodents and fleas (or other wildlife) harboring endemic plague.
And as a cheery final note, they conclude that:
Our analyses are in agreement with the hypothesis that the Medieval Black Death and the mid-19th-century plague pandemic might have been triggered by favorable climatic conditions in Central Asia. Such climatic conditions have recently become more common and whereas regional scenarios suggest a decrease in annual precipitation but with increasing variance, mean spring temperatures are predicted to continue increasing. Indeed, during the period from the 1940s, plague prevalence has been high in its host-reservoir in Kazakhstan. Effective surveillance and control during the Soviet period resulted in few human cases. But recent changes in the public health systems, linked to a period of political transition in Central Asia, combined with increased plague prevalence in its natural reservoir in the region, forewarn a future of increased risk of human infections.
The combination of climate influences on the prevalence of infectious disease, documented climate change over the last few decades, and the rise of megacities is something we definitely need to watch.
And all this time I was so worried about the flu...
Here are some comments about the GSK adjuvant announcement, the expansion of vaccine candidates by the WHO, H5N1 evolution in the lab and in the wild, and sequence data sharing.
GlaxoSmithKline announced recently that through the use of a proprietary adjuvant they have dramatically reduced the amount of egg-grown vaccine required to produce a decent antibody response in humans.
A news story at CIDRAP explains that, "The GSK vaccine was made from an inactivated H5N1 virus collected in Vietnam in 2004, according to Jennifer Armstrong, a GSK spokeswoman in Philadelphia," and then notes that, "It is uncertain, however, how effective the vaccine would be against H5N1 strains other than the one it was made from. [Albert Osterhaus of Erasmus Unversity in the Netherlands] told the AP, "This vaccine will only give protection against this particular H5N1 strain and possibly other strains.""
This last statement may be true, but in my view it may also give false hope. Aside from criticisms others have raised about GSK announcing science by press release, instead of waiting until a publication is ready, or alternatively just releasing the data, we already know that there are H5N1 variants in the wild that kill humans but don't cross prime immune systems.
In response to this development, the WHO recently advised work begin on vaccines based on clade 2 isolates from Indonesia. (Here is CIDRAP's take, and here is the original WHO announcement.) Note that this does not mean we will immediately have vaccines in production against these isolates; as far as I know the reference vaccine is still solely based on the original Vietnamese isolate.
As is fairly widely understood at this point, it is not at all clear that vaccines made from either the Vietnamese or Indonesian isolates will protect humans against potential pandemic strains that arise in nature. Some effort at discerning the threat from certain potential strains was reported in PNAS in early August. A news story in Nature describes the results with the headline, "Bird flu not set for pandemic, says US team" (subscription req.).
I find that headline very confusing, because the work in question has very little to do with whether H5N1 is "set for [a] pandemic." Instead, the research explored the effects on ferrets of a exposure to a small number of recombinant viruses consisting of components from H5N1 and H3N2. The text following the headline is clearer: "The scientists who conducted the work, at the [CDC], say it suggests that the H5N1 virus will require a complex series of genetic changes to evolve into a pandemic strain... The study [does not] address whether H5N1 could evolve into a pandemic strain by accumulating mutations."
In fact, only very limited conclusions can be drawn from the paper in question, "Lack of transmission of H5N1 avian–human reassortant influenza viruses in a ferret model" (Mains, et al., PNAS, vol 103, no 32). The first and last paragraphs of the discussion section show the authors are relatively circumspect in interpreting the data:
If H5N1 viruses acquire the ability to undergo efficient and sustained transmission among humans, a pandemic would be inevitable. An understanding of the molecular and biologic requirements for efficient transmissibility is critical for the early identification of a potential H5N1 pandemic virus and the application of optimal control measures. The results of this study demonstrate, that unlike human H3N2 viruses, avian H5N1 viruses isolated from humans in 1997, 2003, or 2005 lack the ability to transmit efficiently in the ferret model. Furthermore, reassortant viruses bearing 1997 avian H5N1 surface glycoproteins with four or six human virus internal protein genes do not transmit efficiently in ferrets and thus lack the key property that predicts pandemic spread.
Although these findings do not identify the precise genetic determinants responsible for influenza virus transmissibility, they provide an assessment of the risk of an H5N1 pandemic strain emerging through reassortment with a human influenza virus. Our results indicate that, within the context of the viruses used in this study, H5N1 avian–human reassortant viruses did not exhibit properties that would initiate a pandemic. Nevertheless, H5N1 viruses continue to spread geographically, infect a variety of mammals, and evolve rapidly. Therefore, further evaluation of the efficiency of replication and transmissibility of reassortants between contemporary H5N1 viruses and circulating human influenza viruses is an ongoing public health need. The ferret transmission model serves as a valuable tool for this purpose and the identification of molecular and biologic correlates of efficient transmissibility that may be used for early detection of a novel virus with pandemic capability.
It is certainly true that this sort of work is vital for figuring out how influenza works, and in particular vital for trying to sort out how reassortant viruses arise, how they change during passage between animals, and how they kill mammals. Reassortment was historically important in some flu pandemics. However, the genetic changes seen in nature in the present H5N1 outbreak appear to be solely due to mutation. In particular, a cluster of cases in Indonesia in April and May -- the first clear example of human-to-human transmission of H5N1, according to the WHO -- allows tracking sequence changes between viruses that infected eight family members.
In "Family tragedy spotlights flu mutations" (subscription req.), Declan Butler writes that;
Viruses from five of the cases had between one and four mutations each compared with the sequence shared by most of the strains. In the case of the father who is thought to have caught the virus from his son — a second-generation spread — there were twenty-one mutations across seven of the eight flu genes. This suggests that the virus was evolving rapidly as it spread from person to person.
[While] many of the genetic changes did not result in the use of different amino acids by the virus...experts say they cannot conclude that the changes aren't significant. "It is interesting that we saw all these mutations in viruses that had gone human-to-human," says one scientist who was present at the Jakarta meeting but did not wish to be named because he was commenting on confidential data. "But I don't think anyone knows enough about the H5N1 genome to say how significant that is."
So there is considerable mutation occurring, even between viruses present in different family members, and we don't yet know enough about H5N1 in humans to say whether this is significant with respect to evolving into a pandemic strain. But even more interesting, there are so many differences between the viruses that they look like different clades. Again, from Dr. Butler:
Elodie Ghedin, a genome scientist at the University of Pittsburgh School of Medicine in Pennsylvania, says she's surprised that the virus from the father had so many mutations compared with others in the cluster, apparently arising in just a few days. "I have a hard time believing that the father acquired the virus from his son," she says, adding that the nine mutations in one gene in the father's virus are almost identical to those in viruses isolated from human cases in Thailand and Vietnam in 2004.
One possibility is that the father simply caught a different strain of virus from birds, although other mutations in his virus are similar to those in the strain isolated from his son. Or perhaps the virus from the son reassorted with another flu strain circulating in his father at the time, Ghedin says.
Perhaps, but it would seem that if the father was also carrying a virus from Thailand or Vietnam that there should be signs in birds or other humans. I was unable to find out whether the father was in a position to pick up a virus from another clade, which would be a good check on the likelihood of reassortment.
Dr. Butler goes on to note that a simple lack of information is a significant factor in the slow progress:
Part of the reason the picture is so unclear, say virologists contacted by Nature, is that the continued withholding of genetic data is hampering study of the virus. None of the sequence data from the Indonesian cluster has been deposited in public databases — access is restricted to a small network of researchers linked to the WHO and the US Centers for Disease Control and Prevention in Atlanta, Georgia.
Fortunately, this has changed and the Global Initiative on Sharing Avian Influenza Data (GISAID) is now in place. I'll have something more later on the sharing plan after I digest all the information. It looks like a nice step forward, but, as always, we'll have to see what comes of it.
Here's a recent story from Reuters about PowederMed's vaccine.
The first-time-in-man clinical trial will be conducted at a clinical research unit in London and will examine the ability of a vaccine based upon the Vietnam H5N1 avian influenza strain to protect against a potential pandemic form of flu.
It seems there is a profusion of bad information about the present Indonesian H5N1 outbreak. Over the last week, The New York Times has reported conflicting statements from the World Health Organization about whether the cluster of cases was caused by human to human transmission. Somebody needs to make up their mind about when to talk to the press, and who to let speculate about the science when they obviously have no idea what's going on. How are we supposed to have any confidence if they keep shooting from the hip before solid evidence is in hand?
As important as whether there was confirmed human to human spread is the issue of how the sequence is varying. I wrote earlier this week about reports that changes in the human sequence appeared to put it closer to a feline sequence, but Wired News is carrying a Reuters story in which the WHO states otherwise:
"Sequencing ... found no evidence of genetic reassortment ... and no evidence of significant mutations," the United Nations health agency said in its statement.
I would note now that I'm not sure what Andrew Jeremijenko means by "the closest match we have to the human virus is from a cat virus." I was unaware there was any distinction observed in the wild between viruses afflicting humans and felines. But the point is that one agency is saying the virus is changing and may be related to something killing other mammals, while another says there are no mutations and can't make up its mind whether we already have human to human transmission.
People, get your shit together, please. Don't talk to the press until you know what's going on. This thing is scary and complicated enough as it is without having to sort through conflicting information from "official sources".
(Sitting in the Synthetic Biology 2.0 meeting, so this will be brief.)
Following up on my earlier reports and speculation (here, here and here) about the role of felines in spreading H5N1:
The Australian Broadcast Company is carrying an interview in which Andrew Jeremijenko, Project Leader of the Influenza Surveillance Studies for a US Naval Medical Research Group, suggests the outbreak in Indonesia may be directly related to infection in cats.
The article, entitled "Failed Indonesian bird flu response concerns experts", by Peter Cave, contains the following exchange:
PETER CAVE: Are you seeing mutations in the virus in Indonesia?
ANDREW JEREMIJENKO: Yes, that's a good question. We are seeing mutations in the human virus. We are not seeing that same mutation in the bird virus. And that's of great concern.
Basically, when you do an investigation of a bird flu case, you should try to find the virus from the human and match it up with the virus from the bird and find the cause.
Now, in Indonesia, the investigations have been sub-optimal, and they have not been able to match the human virus to the poultry virus, so we really do not know where that virus is coming from in most of these human cases.
PETER CAVE: Does it suggest it's going through an intermediary before it's infecting humans?
[Andrew Jeremijenko]: It's a possibility that we can't rule out. I think they really need to do a lot more investigations. So far the closest match we have to the human virus is from a cat virus. So the cat could be an intermediate. We really don't know what's happening yet.
| Sun | Mon | Tue | Wed | Thu | Fri | Sat |
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | ||
| 6 | 7 | 8 | 9 | 10 | 11 | 12 |
| 13 | 14 | 15 | 16 | 17 | 18 | 19 |
| 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| 27 | 28 | 29 | 30 | 31 |
Recent Comments