Análisis del genoma arroja luz sobre el origen de la gripe porcina y la ciencia de alta velocidad
Un aspecto sin precedentes de la reacción de la comunidad científica a la actual amenaza de pandemia es la gran rapidez con la que los investigadores están haciendo la información públicamente disponible. A pocas horas de haber sido analizados los genomas de las cepas aisladas del virus, los investigadores de todos los rincones del mundo han podido cargar sus secuencias a la base de datos de la gripe GISAID o Genbank, para que cualquier persona pueda trabajar con ellas.
Mientras tanto, algunos diarios se han movido a sorprendente velocidad para obtener documentos revisados por expertos y publicado en días en lugar de meses. El grupo de Neil Ferguson del Imperial College de Londres, por ejemplo, publicó un informe inicial sobre la epidemiología del brote en Science, el 11 de mayo (ver ‘Swine flu spread matches previous flu pandemics”). Se utilizaron algunos modelos sofisticados para describir la evolución del brote, aunque los datos epidemiológicos disponibles en ese momento para la alimentación de los modelos era tan escasa que un blogger líder en salud pública describe el documento como “lectura de hoja-de-té asistida por ordenador”,”computer-aided tea-leaf reading.
Fuente: The Great Beyond: Genome analysis sheds light on swine flu origins – and high-speed science. Disponible en: http://blogs.nature.com/news/thegreatbeyond/2009/05/genome_analysis_sheds_light_on.html [Accedido Mayo 26, 2009]
The New England Journal of Medicine (NEJM) also published a somewhat meatier paper on 7 May by scientists at the US Disease Control and Prevention (CDC) providing a useful summary of the clinical symptons and age distributions of the earliest cases (see ‘US swine flu cases dissected’But another group of leading evolutionary biologists, including Oliver Pybus at the University of Oxford, and Andrew Rambaut at the University of Edinburgh, have taken a completely different tack. While preparing papers for peer-reviewed publication, they have put online on a public Wiki sophisticated analyses of the flu genome, including detailed phylogenetic trees, as soon as they got their results. They argue that it is in the interest of the public and the scientific community to make data relevant to the pandemic threat publicly available as fast as possible.
And now, Science has just published a paper by another group covering much of the same ground. The paper has some 60 authors including scientists at CDC and from the World Health Organization’s lab network.
Like the open Wiki (which the paper doesn’t cite), the research retraces the genetic origins of the virus, showing that the virus originated from a mix of a North American and Eurasian strains of swine flu, which themselves contain avian and human flu genes. It includes some preliminary antigenic analyses of the virus, showing that they so far they seem homogeneous – that should simplify vaccine strain selection. It also shows that antibodies raised in ferrets to seasonal influenza
A(H1N1) did not cross-react with the new virus, so indicating that the existing seasonal flu vaccine would not protect people from the new virus.
The Science paper is “very useful” in that it collates all the available information, says Robert Webster, a flu virologist at St Jude Children’s Research Hospital in Memphis, Tennessee, adding however that he doesn’t feel it adds much new to what everyone in the field already has learnt from multiple sources over the past few weeks. Although he feels that it’s sad that the paper didn’t cite the public wiki, he points out that scientists are in an unusual and unfamiliar situation. It certainly raises issues of how best to align fast track open web publication with the peer review process during exceptional circumstances.
Derek Smith, a researcher who carried out the antigenicity part of the Science paper, says: “There is nothing special in the [phylogenetic] trees in the just published paper, some of the paper is getting the basic data out there, peer-reviewed.” As to his colleagues’ public wiki efforts, Smith has nothing but praise: ” I think it is really great that Oli, Eddie, Andrew, Gavin, et al have been posting [to the public wiki]. It’s also great that CDC have been publishing sequences, and much other information, on the day they are generated so everyone can see immediately what is happening, and do specialist analyses.”
Indeed much of the information now appearing i peer reviewed journals, or at least parts of it, has often been in the public domain beforehand, aired at the CDC and WHO’s daily press briefings, or published as Dispatches in the CDC’s Morbidity and Mortality Weekly Report. That latter venerable if abstract publication, usually read mainly by hardened public health nerds, has become required reading for anyone with a serious interest in following the latest developments of H1N1 swine flu.
Posted by Mark Peplow on May 22, 2009
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Tighter Surveillance Of Swine Flu In Pigs Needed Worldwide Says CDC
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The US Centers for Disease Control and Prevention (CDC) said that there is a “global need for more systemic surveillance of influenza viruses in pigs”, during a press briefing where they explained the findings of a recent study on the genetic and antigenetic properties of the new 2009 H1N1 swine flu virus.
The CDC led study was published online in the journal Science on 22 May and was the work of human and animal health scientists from the US, Mexico, the UK and the Netherlands.
According to the CDC, the study is the first to explain the history and evolution of the human and swine influenza viruses in North America and other areas of the world, as deduced from the detailed analysis of the antigenic and genetic characteristics of the new H1N1 viruses.
In a press briefing on Friday, senior author Dr Nancy Cox, who is director of the CDC’s influenza division said that the study reinforced the fact that:
“Swine are an important reservoir of influenza viruses with the potential to cause significant respiratory outbreaks or even a possible pandemic in humans.”
Cox praised the “excellent collaboration” that went into the study, and stressed the importance of the global co-operation that will be needed to fight the new H1N1 strain, for example by rapidly collecting and sharing specimens, without which it is not possible to understand the origin of the virus and how to stop it spreading and re-emerging.
For the study, the researchers sequenced the genomes of more than 70 samples of the new H1N1 taken from human patients diagnosed with the infection in the recent outbreaks, including 17 viruses isolated in Mexico and 59 viruses from 12 states in the United States.
The analysis showed that the new H1N1 virus likely originated in pigs because each of its genetic components closely corresponds to genes found in swine flu viruses, said Cox, who then highlighted the study’s main findings:
• The new H1N1 viruses are very alike in the way they react to antibodies, that is their antigenetic properties are similar. However, in this respect they are very different to human H1N1 viruses (like the seasonal flu virus), so this indicates that the seasonal flu vaccine will probably not protect against the new virus, a fact that the CDC announced last week.
• The fact the new H1N1 strains are very similar means that it will be much easier to come up with a new candidate virus for vaccine development (there are already reports that a lab has sent a sample candidate virus to the CDC). Cox said as far as they could tell, the new H1N1 swine flu viruses varied much less among themselves than say the typical seasonal flu viruses do.
• From their resistance patterns it appears that the new H1N1 viruses are sensitive to the neuraminidase inhibitors, but resistant to the M2 blockers or rimantidine (Flumadine) and amantadine (Symmetrel). This is important information for the development and use of antivirals.
• As revealed in previous press briefings, the new virus also contained clusters of gene segments that had not been seen in swine or human flu viruses before. A noticeable new feature was that two gene segments, one from a matrix protein and the other from a nerve gene, seemed to have come from Eurasian swine viruses not seen outside of Eurasia before.
• While the analysis shows that all gene segments came from swine flu viruses, it was not possible to say if the virus then went straight into humans or via an intermediate host, and if it did go via a host, then which animal that would be.
• Animal scientists all over the world, including colleagues from the US Department of Agriculture (USDA) are testing samples they have kept frozen for years to see if they can provide any missing links to this part of the puzzle. For instance, there might be intermediate versions of the virus that could help narrow down the time and place where the new virus emerged.
When asked if these findings mean that pig surveillance will now be as important as avian surveillance as far as flu virus monitoring was concerned, Dr Anne Schuchat, director of CDC’s national center for immunization and respiratory diseases, said:
“This really hits home how important it is for animal and human health to cooperate and collaborate.”
She said she and her colleagues at the CDC were very pleased at how the collaboration between animal and human health has improved, implying it was vital to continue this because as the past few decades have shown, “the animal-human interface is very important”.
“Antigenic and Genetic Characteristics of Swine-Origin 2009 A(H1N1) Influenza Viruses Circulating in Humans.”
Rebecca J. Garten, C. Todd Davis, Colin A. Russell, Bo Shu, Stephen Lindstrom, Amanda Balish, Wendy M. Sessions, Xiyan Xu, Eugene Skepner, Varough Deyde, Margaret Okomo-Adhiambo, Larisa Gubareva, John Barnes, Catherine B. Smith, Shannon L. Emery, Michael J. Hillman, Pierre Rivailler, James Smagala, Miranda de Graaf, David F. Burke, Ron A. M. Fouchier, Claudia Pappas, Celia M. Alpuche-Aranda, Hugo López-Gatell, Hiram Olivera, Irma López, Christopher A. Myers, Dennis Faix, Patrick J. Blair, Cindy Yu, Kimberly M. Keene, P. David Dotson, Jr., David Boxrud, Anthony R. Sambol, Syed H. Abid, Kirsten St. George, Tammy Bannerman, Amanda L. Moore, David J. Stringer, Patricia Blevins, Gail J. Demmler- Harrison, Michele Ginsberg, Paula Kriner, Steve Waterman, Sandra Smole, Hugo F. Guevara, Edward A. Belongia, Patricia A. Clark, Sara T. Beatrice, Ruben Donis, Jacqueline Katz, Lyn Finelli, Carolyn B. Bridges, Michael Shaw, Daniel B. Jernigan, Timothy M. Uyeki, Derek J. Smith, Alexander I. Klimov, and Nancy J. Cox.
Published Online May 22, 2009
Science DOI: 10.1126/science.1176225
Additional sources: CDC.
Written by: Catharine Paddock, PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today
http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(09)70130-6/fulltext
The Lancet Infectious Diseases, Volume 9, Issue 6, Pages 339 – 340, June 2009
doi:10.1016/S1473-3099(09)70130-6 Cite or Link Using DOI
Preparation for a pandemic: influenza A H1N1
Priya Shetty
Influenza A H1N1 (swine flu) has spread around the world with what has, at times, felt like horrifying speed, but there is a feeling that many of us have dodged a bullet. Of the 2384 laboratory-confirmed cases reported in 24 countries, as TLID went to press, there had been 44 deaths, 42 of which were in Mexico. These numbers are far lower than the annual toll from seasonal influenza, which kills hundreds of people every day in the peak season.
But epidemiologists are still largely in the dark about how the virus will continue to spread and, ultimately, how severe the disease it causes will be. Since the first cases were identified in Mexico in late April, WHO has upped its pandemic alert level from three to five, and seems to be on the brink of moving to level six—the highest possible—which would mean the virus had reached pandemic status. But have countries prepared effective strategies to cope with this?
The threats of severe acute respiratory syndrome (SARS) and H5N1 a few years ago prompted the world to set up plans to deal with the possibility that these viruses would, by developing sustained human-to-human transmission, trigger a pandemic. The chaos caused by the outbreaks revealed just how badly countries around the world—increasingly linked by frequent international travel and growing globalisation—were prepared to deal with a worldwide infectious disease pandemic. Pandemic preparedness has come a long way since those two viruses caused worldwide alarm, says Sandra Mounier-Jack (London School of Hygiene and Tropical Medicine, London, UK) but there are holes in many countries’ plans.
In 2006, with her colleague Richard Coker, Mounier-Jack compared the strategies of Asia-Pacific countries with those in Europe. Many of the Asia-Pacific plans, had a stronger focus on early containment of disease and “social distancing”. Developing countries are likely to need this strategy more than developed ones, Mounier-Jack told TLID, because of chronic shortages of antiviral drugs and vaccines. But the problem with focusing on surveillance and monitoring, she says, is that poor countries, especially those in Asia, “don’t have a plan B if the virus becomes pandemic”.
Coker agrees. He told TLID that developing countries are “severely underprepared” for a pandemic. Furthermore, many existing plans focus, somewhat short-sightedly, “on avian influenza in poultry”.
The duo’s analyses showed that countries, including those in Europe, “did not adequately address organisational responsibility at the local level”. Even now, these plans have only really been tested through desk-based exercises, says Mounier-Jack. Whether strategic plans are operational is the key question, says Coker. In southeast Asia, for example, only Thailand has evaluated its preparedness. “Despite being a relatively affluent country in the region, it would have substantial resource shortages if a pandemic is anything but mild”, he says. “Without this sort of analysis”, Coker adds, “policy makers risk making knee-jerk decisions in their allocation of resources that may be ineffective, inefficient, and inequitable”.
A 2007 survey of 30 countries by the European Centre for Disease Prevention and Control revealed that European preparedness was patchy too. Many plans included only half of the WHO recommendations for dealing with pandemics.
The challenges Mounier-Jack foresees are implementational—how responsibility is divided between primary and secondary care, for example—rather than in technical or medical problems. She also advocates a cohesive multisectoral approach between the food industry, the health-care sector, and government.
Quarantine and travel bans might seem an intuitive way to curb the spread, but the reality is more complicated. For one thing, health officials have been at odds over the advice the public should follow. In late April, the European Union’s health commissioner Androulla Vassiliou said Europeans “should avoid travelling to Mexico or the USA unless it’s very urgent”. Almost immediately, Richard Besser, the acting director for the US Centers for Disease Control and Prevention, and Michael Bloomberg, New York City’s mayor, disagreed.
Apart from the fact that “travel restrictions would have very little effect on stopping the virus from spreading”, says Alessandro Vespignani (Indiana University, Bloomington, IN, USA), “it would be highly disruptive to the global community”. Vespignani is modelling the spread of H1N1 with travel data, high-definition geographical population data, and disease dynamics, including the number of people each infected person passes it on to (reproductive rate). Estimates for H1N1’s reproductive rates are 1•0—1•4, which is fairly low given that seasonal influenza has a rate of 1•5—3•0.
Vespignani’s predictions for the rest of May “point to a steady increase in the number of observed cases”. More worryingly, he told TLID that “just in the USA, we could hit several thousand cases”. He hopes, however, that he will soon see discrepancies between his model and the reality on the ground. Although this is not a scenario scientists usually wish for, in this case it would mean that containment and mitigation measures had been successful.
Full-size image (96K) Claudio Cruz/AP/Press Association Images
A stadium worker watches a football match from which the public have been excluded in Mexico City
H1N1’s seemingly low reproductive rate does not mean we should be complacent: a 2006 study of the rate of the 1918 pandemic influenza suggests that the rate of the first wave of the virus was about 1•5, but that of the second wave was 3•5. Coker points out that H5N1 is still present in many countries and is endemic in southeast Asia. One concern at the back of many virologists’ minds is the prospect, however remote, that the H1N1 might recombine with the virulent H5N1 to form a so-called Armageddon virus. If that happened, says Coker, antivirals would need to be rapidly distributed; the problem is that those drugs are currently being allocated to deal with the existing H1N1 virus.
For now, though, the northern hemisphere is out of its annual influenza season and there is a window for H1N1 vaccine production. An initial idea to incorporate this strain into the vaccine against regular seasonal influenza has been dismissed, and WHO is due to talk with vaccine manufacturers about switching to production of a pandemic H1N1 vaccine. On May 6, Marie-Paule Kieny, director of WHO’s vaccine research initiative, said WHO estimated that the world’s vaccine production capacity could make 1 billion to 2 billion doses of H1N1 vaccine. During the H5N1 outbreaks, tests indicated that, unlike seasonal influenza, people needed two doses for a vaccine to be effective. Whether people would need two doses of H1N1 vaccine is too early to say, said Kieny.
Full-size image (51K) kanonn
Influenza A H1N1 is susceptible to oseltamivir—but for how long?
For developing countries, these issues are less pressing than the question of whether they can get their hands on the vaccine at all. So, on May 19, WHO’s Director General Margaret Chan and UN Secretary General Ban Ki-Moon are meeting in Geneva with vaccine manufacturers to appeal to “corporate responsibility” and discuss “avenues to ensure equitable access for developing countries to this vaccine”.
If doomsayers are right, and H1N1 does become pandemic, the biggest guns in the drug arsenal are oseltamivir and zanamivir. However, monotherapy is vulnerable to resistance. “N1 genes are more prone to mutations, and oseltamivir-resistance occurrence in N1 genes is not uncommon”, says Alan McNally (Nottingham Trent University, Nottingham, UK). “Indeed the vast majority of seasonal H1N1 isolates this past autumn—winter were oseltamivir resistant. This undoubtedly poses a threat, and is something that reference labs will be monitoring extremely closely”, says McNally.
WHO is at pains to stress that raising the alert to level six would not relate to the severity of the infection. If anything, initial indications are that the virus is no more harmful than seasonal influenza. H1N1 is a hybrid of virus genes originating in viruses of pigs, birds, and human beings. Wendy Barclay (Imperial College, London, UK) has analysed H1N1’s genes and says that it has “no genetic features of a highly pathogenic virus at all”. She told TLID that “it looks as though this virus should target the upper respiratory tract and not the lung”. This is important because viruses that bind in the lower respiratory tract, such as H5N1, cause more severe illness. Barclay adds that the virus’s NS1 protein “looks normal, so we would not expect a cytokine storm”.
Epidemiologists are also scrabbling to collect as much information as they can about which groups of people are the hardest hit, and to find out why some people develop more severe symptoms than others. On May 5, WHO’s assistant director-general for health security and environment, Keiji Fukuda, told reporters that the average age of infection was the mid-20s. But he pointed out that the infections tend to be seen in travellers, so does the age reflect a characteristic of the virus or the fact that young people are most likely to travel? Older people might have an immunity if they have been exposed to components of the virus before.
Countries worldwide will now be figuring out how to prepare for a relatively unknown quantity. Did scientists and health officials take their eye off the ball after the initial fears of a bird flu or SARS pandemic faded? It is understandable that pandemic fatigue set in, says Mounier-Jack, since countries have a range of health-care concerns to deal with. But should scientists have seen this coming? In 2004, Richard Webby and Robert Webster (St Jude Children’s Research Hospital, TN, USA) raised a note of concern that in 1998 swine H1N1 had recombined with human and bird viruses. They warned that “the growing complexity of influenza at this animal—human interface and the presence of viruses with a seemingly high affinity for reassortment makes the US swine population an increasingly important reservoir of viruses with human pandemic potential”. Knowing this potential is one thing, but it is not clear “how one would prevent that from happening”, says Barclay.
As Fukuda told reporters on May 4, “there is no timetable for how the virus will spread”. For now, it is going to be a matter of watching and waiting to see what H1N1 does next.
Published 21 May 2009, doi:10.1136/bmj.b2065
Cite this as: BMJ 2009;338:b2065
http://www.bmj.com/cgi/content/full/338/may21_3/b2065
Feature
Pandemic Flu
The problem with flu vaccines
Andrew Jack, pharmaceuticals correspondent
1 Financial Times, London
Andrew.Jack@ft.com
Observations: doi:10.1136/bmj.b2019
With the number of cases of swine flu continuing to rise, Andrew Jack assesses our capability to produce enough vaccine to cope with a pandemic
As the H1N1 swine flu virus spreads swiftly from Mexico around the world, public health specialists and flu vaccine manufacturers are scrambling to catch up. This week, they are meeting in Geneva, on the margins of the World Health Assembly, to discuss how best to respond.
They face scientific uncertainties and technical problems alike. The first decision is whether to switch to production to a new vaccine tailored to provide protection against the virus. A second question is how to maximise production if they do. A third is how to distribute and make affordable the still scarce stocks likely to result.
At best, the different commercial manufacturers can produce a total of about 480 million doses of trivalent seasonal flu vaccine this year. That figure—a small fraction of the world’s population—reflects a history of modest demand that has kept manufacturing relatively small.
In Europe, vaccination rates remain modest, with wide variations between countries. Where programmes take place, they are concentrated among children, elderly people, and other risk groups with weak immune systems. In the developing world, where most of the estimated annual 500 000 seasonal flu deaths occur, coverage is still more scant.
The scarcity of vaccine even in normal times was highlighted in 2004, when quality problems halted production in Chiron’s Speke factory near Liverpool. The resulting shortage in meeting US orders for seasonal flu vaccine left Americans struggling to find alternative supplies.
Since then, a growing realisation of the burden of seasonal flu and fresh concern over a future pandemic have helped stimulate expanding demand. The rise of more lucrative patented vaccines—led by Wyeth’s Prevnar for pneumococcal disease, the first vaccine to generate more than $1bn in annual sales—has also helped stimulate fresh corporate investment.
Alongside the well established players of GlaxoSmithKline, Merck, and Sanofi-Aventis, other large drug companies have entered the market, with Novartis acquiring Chiron, AstraZeneca taking over MedImmune, and, most recently, Pfizer buying Wyeth.
New developments
Yet influenza vaccine is a relatively low priced, commoditised vaccine, which has meant there has been far less innovation in manufacturing than for other vaccines. Most producers still rely on the cumbersome cultivation of antigen in eggs as part of an uncertain process that typically takes six months from identification of each year’s changing seasonal viruses, through production, to final delivery. No manufacturer has yet finalised technology that would overcome the need to make specific vaccines each year in order to tackle the constantly mutating flu viruses, although several biotechnology companies are researching such approaches.
Two important evolutions are currently taking place, however. Firstly, companies such as Baxter have invested in cell based manufacturing techniques, which offer the prospect of trimming a month or more off the current egg dependent production cycle.
Secondly, vaccines are being revolutionised by adjuvants—chemicals that boost the human immune response, offering both the potential to use a smaller volume of antigens in each dose to achieve the same result, and greater “cross protection” against flu viruses other than the one for which a vaccine was specifically developed.
Traditionally limited to aluminium, a new generation of proprietary adjuvants has been developed in recent years that could be added to flu vaccines. Novartis’s MF59 is already included in one relatively expensive flu vaccine it sells in small volumes in Europe for people with weak immune systems. GlaxoSmithKline has also added its own adjuvants to some vaccines, including Cervarix, the human papillomavirus vaccine, and Mosquirix, currently in late stage clinical trials in Africa for malaria.
Vaccine choices
Rising concern triggered by H5N1 bird flu in 2005 mobilised a number of countries to express interest in stockpiling “pre-pandemic” vaccines. Several companies have already produced supplies based on variants of this strain for distribution in the event that it turns into a pandemic. Although regulators have approved these products in principle, the vaccines still require final authorisation in the event of a pandemic being declared. However, the prospect that the pandemic could come from an H1N1 strain makes production of H5N1 vaccines all but irrelevant, with there being too much genetic difference between the strains to allow cross protection.
WHO experts are trying to understand whether existing H1N1 seasonal flu vaccinations could offer limited protection from the new Mexican H1N1 virus. Novartis says in vitro tests with its adjuvant containing flu vaccine suggest some cross protection may exist. But the consensus from the WHO’s ad hoc advisory working group on A (H1N1) vaccines, published in mid-May, was sceptical of any effect.1
Nevertheless, if the new virus is judged a big public health threat, a new pandemic vaccine will be required. In the coming weeks specialists will need to decide whether to recommend that a vaccine should be produced. That depends on analysing more data on H1N1’s spread and impact on mortality and morbidity, compared with that of the three strains for which the current seasonal vaccine is targeted.
So far, although WHO’s pandemic alert is at its highest ever level (5), it remains one below full pandemic status. However, even this ranking system takes no account of the severity of infection, on which the data remain unclear.
If the scientific advisers consider the new virus presents a greater threat than seasonal flu, which seems increasingly likely given current assessment of its infectivity, they have two choices. One is to incorporate Mexican H1N1 into the seasonal vaccine, either by swapping with one of the current antigens, most likely that for Brisbane H1N1 strain, or by adding a fourth antigen. The alternative is to abandon the next production cycle of trivalent seasonal vaccine entirely and switch all manufacturing to a monovalent H1N1 pandemic strain instead. The advantage of this more radical approach would be higher productivity (as all resources could be concentrated on the one antigen) offering a way to increase total vaccine output. The downside is the loss of the existing seasonal flu vaccines, resulting in an increase in health effects from these infections, which will continue to circulate.
Boosting production
With a pandemic now imminent, much discussion is focused on other ways to boost productivity. Earlier this year the consultancy Oliver Wyman published an analysis of the world’s capability of manufacturing H5N1 vaccine in the event of a pandemic. It concluded that growing interest in flu vaccines has led to a big increase in capacity in the past two years and that in theory, output could rise to between 2.5 billion and 7.7 billion doses a year within 12 months of declaration of a pandemic, and up to 14.5 billion doses within five years.2 WHO’s latest assessment is 4.9 billion doses, with each person likely to require two doses for protection.1
One contribution to this increased output would come from simply cutting out the “down time” between current seasonal flu production cycles, making existing plants work to their current limits. A second contributor would be to adopt widespread “antigen sparing” techniques with broader use of adjuvants, either aluminium or the new patented products. GlaxoSmithKline has indicated that it would be willing to license its adjuvant to others, although it is wary that any such joint manufacturing arrangements could infringe US antitrust rules.
The US itself presents a particular challenge. The country has yet to approve the new generation adjuvants in any vaccine, including Cervarix. The country remains cautious after mass vaccination of Americans against swine flu in 1976 was halted because of claims that the vaccine caused dozens of cases of Guillain-Barré syndrome.
A final way raised by others to make existing vaccine production go further would be to use intradermal injections, although this would require specialist training for those giving vaccinations.
In the longer term, it seems likely that rising global demand for a pandemic vaccine—and perhaps a subsequent willingness to strengthen seasonal vaccination—is likely to expand manufacturing capacity. This may include the opening of new sites in developing countries by both local and multinational companies.
Nearly four fifths of global vaccines are still made within Europe, although the US has encouraged new investment in plants, and some countries in the former Soviet countries as well as India, China, Japan, South Korea, and Australia are expanding local production.
WHO has helped encourage technology transfer to ease this process. Apart from tensions over intellectual property, however, critics respond that it will take several years before any such factories could win good manufacturing practice approval and that opening new factories may prove less efficient and more costly than expanding existing plants.
In any case, the short term prospects for producing large quantities of H1N1 pandemic vaccine are limited. In the next few weeks, most manufacturers will have finished their current production cycle for trivalent seasonal flu doses to supply the southern hemisphere, which is entering its peak flu period.
That will free up capacity to begin to produce a H1N1 vaccine—with deliveries from the end of this year—to developed countries that order it now. That would be in time to help tackle a second and, judging by past pandemics, more dangerous wave of infection during the northern hemisphere’s coming winter.
The problem is very tight production constraints. GlaxoSmithKline last week agreed to produce nearly 130 million H1N1 doses for the UK, France, Belgium, and Finland. Baxter is producing another 30 million for the UK. Yet even these supplies were subject to tough negotiations, suggesting that only modest spare capacity remains during 2009.
With signs that fear of a pandemic has already sent governments rushing to protect their own citizens rather than working cooperatively with others, manufacturers need to keep an eye on ensuring that they can meet the demands of countries where their flu vaccine plants are located. GlaxoSmithKline’s factories are in Canada and Germany, neither of which has yet ordered any H1N1 stocks, for instance, while Sanofi-Aventis has plants in the US and France.
For other countries—such as the EU’s poorer members states and the developing world—that have neither funds nor domestic production capacity, the long term options may look better than ever. But the short term ones look bleak.
Cite this as: BMJ 2009;338:b2065
Observations: doi:10.1136/bmj.b2019
________________________________________
References
1. World Health Organization. Recommendations of the strategic advisory group of experts (SAGE) on influenza A (H1N1) vaccines. 2009. www.who.int/csr/resources/publications/swineflu/tc_report_2009_05_14/en/index.html.
2. Oliver Wyman. Influenza vaccine supply and demand: summary of findings. 2009. www.ifpma.org/pdf/2009_04_29_Wyman-IFPMA%20Influenza%20Vaccine%20Supply%20&%20Demand%20Stusy%20Apr%205%202009.pdf.
Publicado: may 26th, 2009.