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High-dose bird flu vaccine trial fails



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By Julie Robotham

February 18, 2006



AUSTRALIA'S highly anticipated bird flu vaccine trial has produced immune protection against the virus in only a small minority of the 400 volunteers who received it, disappointing experts and throwing out estimates of how long it would take to vaccinate citizens in the event of pandemic.


Andrew Cuthbertson, the chief scientific officer of manufacturer CSL Ltd, said about half of those who received the highest dose in the trial - two 15-microgram shots with a booster substance added - had an immune response comparable to that for regular human flu shots.


But those who received single or smaller doses of the H5N1 bird flu antigen, and those whose shots did not contain the immune-boosting adjuvant, had a lesser response that was below the threshold for licensing human flu vaccines.


Dr Cuthbertson conceded the result was disappointing, but said it was positive that the company had produced a safe vaccine with no adverse reactions beyond soreness at the injection site.


He also emphasised the comparison with ordinary human flu shots was "conservative", and if H5N1 mutated to readily infect humans the required dose might be quite different. "No one on earth now knows the relationship between [test] results and protection," he said. "Does a certain antibody level stop you dying, or getting sick, or have any effect at all?"


CSL will now begin a larger trial that will include children and the elderly and will focus on higher doses still: double shots of 30 and 45 micrograms each.


Experts believe there is a one in 10 chance H5N1, which has swept across bird populations in Asia and caused 91 human deaths, could evolve to spread directly between people and trigger a pandemic. Concern has mounted in recent weeks as the virus has been isolated in birds in Africa, which is poorly equipped to cull infected birds.


Worldwide hopes had been pinned on the CSL trial, because more people could be protected more quickly if a low dose had worked. The lowest dose previously confirmed effective was two 30-microgram injections, in research by CSL's rival, the French company Sanofi-Pasteur.


CSL previously estimated it could produce enough vaccine to immunise all Australians within six months, but that was based on two injections, each containing 7.5 micrograms of antigen.


The new findings mean more than double that dose might be required to achieve robust protection against any human strain of H5N1 - potentially blowing out production time to more than a year based on factory capacity.


Alternatively, the Government could choose to distribute a lower dose vaccine while recognising it might afford only partial protection, Dr Cuthbertson said. He said the results opened the way for the Government to stockpile antigen ahead of time, but a spokeswoman for the federal Health Department, Kay McNiece, said yesterday it was too early to consider placing a contract based on the preliminary research.


The co-director of the National Centre for Immunisation Research and Surveillance, Robert Booy, said the results indicated "it's going to take longer than the best-case estimates without a doubt," to produce enough vaccine to immunise all Australians.


That meant other tactics such as border protection, quarantine and the use of protective clothing would need to come to the fore in national pandemic planning, Professor Booy said.


He welcomed the plan to test the vaccine in children, saying they were a potentially significant source of infection in the community. As well, it was possible children might receive good levels of protection at lower vaccine doses because of their more responsive immune systems.

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Govt promises to aid speedy release of bird flu vaccine


AM - Monday, 20 February , 2006 08:20:00

Reporter: David Mark


TONY EASTLEY: The Federal Government says it will provide a legal indemnity to the vaccine company CSL if it has to fast-track production on a human vaccine for bird flu before clinical trials can be completed.


CSL says it will ask for legal protection against adverse reactions if the drug is rushed onto the market.


It's a position that has been supported by Professor Ian Gust, a member of Australia's Influenza Pandemic Planning Committee - the group that will oversee the nation's response to any pandemic.


Professor Gust says that while bird flu is spreading globally, the chances of the virus mutating to humans is now being reassessed.


David Mark reports.


DAVID MARK: H5N1 now appears to be a global disease, with the bird flu virus endemic in Asia and now reaching Africa, the Middle East and spreading throughout Europe.


One week ago the World Health Organisation reported that there'd been 91 confirmed deaths from Avian Influenza in seven countries.


Last week the Australian company, CSL, reported on a trial for a human vaccine against bird flu, which showed about half the volunteers in the trial had produced an immune response.


Now CSL has told AM the company is calling for immunity from lawsuits if it has to ramp-up production for a pandemic.


A spokeswoman for the Federal Health Minister Tony Abbott says CSL was indemnified for previous trials, and added the Government would do whatever was necessary to get the vaccine into production if it was in the national interest.


That position is supported by Professor Ian Gust, the Director of the World Health Organisation Collaborating Centre for Influenza in Melbourne, and a member of the National Influenza Pandemic Planning Committee.


IAN GUST: And if you look worldwide you'll find that the same situation applies in Europe and the United States.


When a manufacturer's called on to produce, at short notice, very large quantities of vaccine, which haven't been tested in large numbers of people beforehand, and to produce that for public health purposes, I think it's reasonable that they should be indemnified against any untoward complications that might occur.


DAVID MARK: With the bird flu virus spreading, Australia is gearing up for a possible pandemic.


The spokeswoman for the Health Minister says 44 per cent of the population will have access to the prophylactic drugs Tamiflu and Relenza within a year, in the case of a human pandemic.


Professor Gust says Australia is as well prepared as any country.


IAN GUST: Well, I think we all have to be aware that no matter how much preparation one does, that if a pandemic were to occur there'd be very significant disruption. But saying that, I think Australia is at least as well prepared as any other country in the world, probably better prepared.


We've got a larger stockpile of antivirals per head of population, we've got a national manufacturer that's capable of making vaccine for every person in the country. We've got a good functioning public health infrastructure. I think we're in pretty good shape.


DAVID MARK: Many experts have predicted the chances of bird flu mutating to a from that could be transmitted from human to human are about 10 per cent in any given year, but Professor Gust thinks the figure may actually be lower.


IAN GUST: My own view is that as the spread of the disease has occurred in birds and more and more and more people become exposed to infected birds, the probability of a pandemic occurring in man has probably diminished rather than increased.


DAVID MARK: Why's that?


IAN GUST: Well, I think that what we're seeing is that the probability of the feared mutation occurring seems to be lower than people originally estimated.


DAVID MARK: Do you believe that there will be a time where we'll be able to say actually this danger has passed, from this particular virus at least?


IAN GUST: It depends I think on whether the H5 virus, in its current highly pathogenic form, becomes endemic in bird populations around the world. If it remains endemic and produces a reservoir of infection, then it will remain a threat.


However, if it were to burn itself out over the next year or so, then I think we would say look, the threat from this particular virus has evaporated. But the threat of a pandemic is always there.


TONY EASTLEY: Professor Ian Gust ending David Mark's report.





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CSL Ltd ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â‚¬Å¡Ã‚¬Ãƒâ€¦Ã‚¡ÃƒÆ’‚¬Ãƒâ€Â¦ÃƒÆ’¢Ã¢Ã¢â‚¬Å¡Ã‚¬Ãƒâ€¦Ã¢â‚¬Å“ Stockpiling makes the bird flu vaccine trials material


CSL's initial two dose clinical trial (400 patients) using a 15 microgram (ÃÆâ€â„¢ÃƒÆ’ƒÂ¢Ãƒ¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡ÃƒÆ’â€Å¡Ãƒƒâہ¡ÃƒÆ’‚µg) antigen vaccine to the H5N1 avian virus produced an adequate immune response. Further trials (800 patients) will refine dose.


The Australian government has now placed a $16.6m / 5m dose stockpile order that is likely to be filled 2HFY06. Vaccine manufacturers are ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’â€Â¹Ãƒƒâ€Â¦ÃƒÆ’¢Ã¢Ã¢â‚¬Å¡Ã‚¬Ãƒâ€¦Ã¢â‚¬Å“scarceÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¾Ãƒâہ¡ÃƒÆ’‚¢ and other nations are seeking access. CSL has given priority to Australia; this may force AustraliaÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¾Ãƒâہ¡ÃƒÆ’‚¢s hand to place a more significant stockpile order.


The shelf life is uncertain, but could be 2 years, implying repeat orders. The USA has a US$150m stockpile order with Sanofi.


There is some suggestion that the vaccine be provided to the Australian population as a intermediate protective measure (would require 40m doses); this might ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’â€Â¹Ãƒƒâ€Â¦ÃƒÆ’¢Ã¢Ã¢â‚¬Å¡Ã‚¬Ãƒâ€¦Ã¢â‚¬Å“buy some timeÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¾Ãƒâہ¡ÃƒÆ’‚¢ if a pandemic were to occur, as then a specific virus strain would be identified and specific vaccine produced.


With stockpiling, the announcement is material. Citigroup Investment Research upgrade FY06 EPS by 0.7% and FY07 by 3.1% relying upon conservative and broad assumptions, ie. 15 ÃÆâ€â„¢ÃƒÆ’ƒÂ¢Ãƒ¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡ÃƒÆ’â€Å¡Ãƒƒâہ¡ÃƒÆ’‚µg of antigen per dose would imply 60m doses produced per six months, but yields are lower and plant utilisation priorities will need to be made. Further stockpiling or overseas supply would represent further upside. Citigroup Investment Research assume this is a 2 year phenomenon only, ie. they assume no production after CY07.


Including H5N1 flu vaccine, their revised target price is $57.89 (was $57.64ps). Citigroup Investment Research maintains their recommendation of Buy / Medium Risk.





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Vaccine in the works


March 2, 2006


Genetics hold the key for scientists working on protection against avian flu, writes Christopher Jay.


In Britain's Tower of London are six ravens, with their wings clipped. King Charles II decreed that there must always be at least six ravens in the Tower, reinforcing a legend that should they ever leave, the fortress will crumble and the British monarchy disintegrate.


A week or so ago it was decided that Thor, Munin, Branwen, Hugine, Gwyllum and Baldrick would have to be brought indoors, for fear they contract the deadly bird flu virus from a migrating wild bird dropping in to the tower courtyards. The ravens were a bit put out, but Thor eventually resumed saying "Good morning" to raven master Derrick Coyle when he brings in the 5am breakfast of meat and biscuits.


This little vignette underlines the depths of the concern sweeping health authorities throughout the world because of their inability to eradicate a stubborn and deadly strain of bird flu, H5N1, which has been entrenched in Asia for almost 20 years, and started killing people (in Hong Kong) in 1997.


The death toll is now approaching 100, if unreported casualties haven't already taken it past that figure.


For more than a year, health officials have been warning of a possible worldwide pandemic should the virus, so far affecting only humans in close contact with birds, become readily transmissible human to human. A human cough can propel a human flu virus as far as 300 metres.


In 1918, a mutated bird flu which became human transmissible, the Spanish Flu, killed at least 50 million people worldwide in the aftermath of the privations and food shortages of World War I.


That same Spanish Flu, recently reconstituted after several years of brilliant biotechnology work at a US Army laboratory, has proven 100 per cent fatal on unvaccinated test animals.


So what is being done in Australia to prepare for a possible pandemic? Flu vaccines are normally made from fertilised chicken eggs ("embryonated eggs"). Virus particles are introduced, vaccine serum develops and the eggs are then carefully broken by hand and the contents harvested.


The chickens are not factory chickens. They are kept in comfortable barns to ensure they don't catch bird flu themselves.


Australia's only manufacturer of flu vaccine, CSL, in Melbourne, is pushing ahead with tests on an experimental vaccine derived from a master strain of the bird flu virus distributed by the World Health Organisation.


One problem of working on a virulent strain such as this is that in its raw form H5N1 kills the chicken eggs. In the case of CSL, the H5N1 master strain is rendered harmless through a process called reverse genetics, to produce a vaccine with broken-up pieces of inactivated virus.


This is no longer able to do active damage, either to the chicken eggs or later to humans, but still contains major antigens (proteins) that the human immune system can recognise and develop defences against.


A trial of the experimental vaccine, starting on October 5 last year, was held at the Murdoch Children's Research Institute in conjunction with Melbourne University and the Royal Adelaide Hospital. Some 400 healthy volunteers got two doses, three weeks apart, with results checked after each injection.


Half of them had their vaccine laced with a booster preparation called an adjuvant, which enhances the immune response; the others got straight vaccine.


In each set of 200, a normal dose of 15 micrograms went to 100 volunteers, dropping to a half-dose of 7.5 micrograms for the other 100. The researchers' idea was that if they could get away with a half dose minus the adjuvant, they could make a lot more individual doses from each batch of bulk vaccine. But it was not to be.


It took two injections of the full dose, plus an adjuvant, to produce a workable immune response in some of the volunteers. Basically, about 50 per cent achieved an acceptable level of protection.


The normal trivalent annual flu vaccine for existing strains achieves a protection level of about 70 per cent. For CSL, the next task is to get its new bird flu vaccine up to the 70 per cent protection level, or possibly even better.


That means another set of tests, this time on 800 volunteers starting this month, with results by about August this year.


Dosage levels will be higher, some possibly going to 45 micrograms, to refine the exact dosage which will give immunity to most people receiving the vaccine.


A pandemic flu version, when and if it appears, will have some mutations. But this preliminary work means that once CSL obtains a master strain of any truly lethal new virus, the new vaccine could be coming off the production line six weeks later.






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CSL Ltd ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â‚¬Å¡Ã‚¬Ãƒâ€¦Ã‚¡ÃƒÆ’‚¬Ãƒâ€Â¦ÃƒÆ’¢Ã¢Ã¢â‚¬Å¡Ã‚¬Ãƒâ€¦Ã¢â‚¬Å“ Plasma survey for March quarter


In Citigroup Investment Research Mar-06 quarterly pricing survey, IVIG prices are up by a weighted average of 9% over Dec 05 qtr; part due to Jan-06 pricing increases and change in sales mix. CSL had a 4.5% price gain if we take the midpoint of headline prices for CSLÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¾Ãƒâہ¡ÃƒÆ’‚¢s Carimune IVIG at ~US$46/g. The magnitude of the change is the key, as realised price can be lower.


European prices are harder to 'pin-down' but we hear reports of some manufacturer's passing thru a EUR10/g increase in IVIG prices (off average base of ~EUR35/g) in the Mar-06 qtr.


Albumin continues its run with headline prices in the USA now ~US$20 per 12.5 gram vial (up >15% from the Dec-05 quarter).


All coagulation product prices/volumes stable, but CSL's Von Willibrand disease indicated pdFVIII is a 'cash-cow' realising perhaps 7% demand growth - CSL are a net buyer of 'cryo' to keep up.


IVIG supply-demand in the US market remains a key issue; we understand that all manufacturers are ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’â€Â¹Ãƒƒâ€Â¦ÃƒÆ’¢Ã¢Ã¢â‚¬Å¡Ã‚¬Ãƒâ€¦Ã¢â‚¬Å“fully committedÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¾Ãƒâہ¡ÃƒÆ’‚¢ for all product for CY06. The US Office of Inspector General will examine the industry over the next 24mths or so.


By end CY07 new collection centre openings might add ~12% in new industry supply, but the bulk of that impacts FY08e and will do little to alter the balance with demand growing ~7%pa.


Citigroup Investment Research remain 'happy' to be at 'top end' of FY06e guidance. They maintain a target price of $62.39ps and recommend Buy / Medium Risk (1M).





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New blood keeps CSL pumping


Matthew Stevens

March 11, 2006


CSL is an Australian-born corporate success story which deserves a much broader local currency. In little more than a decade, chief executive Brian McNamee and his unusually enduring executive have turned a withering state-owned animal medicines business worth $22 million into a $10 billion home-grown multinational.


Relative anonymity, though, does not seem to rankle CSL's boss. Performance will ever be more important than publicity. It is, however, sort of typical that McNamee's flashy interim result release a couple of weeks ago somehow seemed to slip beneath the market's radar. The interim, which featured a thumping 54 per cent increase in profit earned from an 8 per cent increase in sales, represent more than just a solid set of financials.


For McNamee, the figures marked the delivery of a promise made in 2003 when CSL spent $956 million on a US blood products business, Aventis Behring. After two years of muscular management, CSL has absorbed the US acquisition and its share price seems to have found a new support level beyond $50 (closing last night at $53.70).


The Aventis deal, which instantly delivered global leadership in the plasma market to CSL, was the second time McNamee had bet his executive future, if not his company, on a company-transforming takeover. For the past five years McNamee has worked on a theory that the global plasma market, like many mature industries, was a sector "in end-game consolidation".


McNamee's first big deal came in 2000 when, ill and anaemic from a third round of chemotherapy in his fight against testicular cancer and a collection of secondary tumours, McNamee flew to Bern to win an international bidding war for Switzerland's ZLB Bioplasma. In stumping up $890 million for the Swiss company, CSL was became a global name in plasma. While the personal challenge in winning ZLB was clearly extraordinary, the Aventis deal was probably more commercially daunting.


CSL hit a growth wall in 2003 and its share price was under pressure for much of the year. For the first time since the company floated in 1994, McNamee's right to his executive chair became an issue. While the market dwelt on weakness, McNamee prepared to jump again and this time the target would be in the US -- not a happy hunting ground for Australian companies.


McNamee did not allow Aventis to draw breath before merging it with ZLB to create the world's biggest plasma business. ZLB Behring has endured deep consolidation of its administration and operations, a reduction of throughput and inventories and a sharpening of its sales force. The result: a 43 per cent jump in basic earnings to $262 million on first-half sales growth of just 13 per cent.


Two times then McNamee has rolled the takeover dice and both times, discipline ("don't pay too much") and diligence ("when you sign the cheque, that is when the work really starts") ensured he walked away a winner. But he reckons it will be a while before CSL again makes a major acquisition as there are no obvious "end-game consolidations" left to tackle.


CSL is entering a new stage of its corporate life. Its future will be innovation in the area of medical science it knows best: vaccines. Its big research plays are influenza and cervical cancer and the portents are exciting. McNamee recently announced a charge at the US flu vaccine market with the investment of $80 million in Australian vaccine production lines to double output to 40 million doses per season. Half will be sent to the US. Even more exciting is the Gardasil project. In 1991, Dr Ian Frazer made a break-through in his research into a vaccine for cervical cancer. CSL struck a deal with Frazer and the University of Queensland to continue with collaborative research. The result is the Gardasil, which research shows "prevents 100 per cent of high-grade cervical pre-cancers and non-invasive cervical cancers" and "70 per cent of all cervical cancers".


Gardasil has been licensed to US pharmaceutical giant Merck and in December it took the vaccine to the US FDA, and various European authorities, for registration. The global market for Gardasil is clearly the astounding. CSL will share in a royalty from international sales but retains the Australian commercial rights. Any earnings from Gardasil will be booked to the Australian business. And that is important for CSL shareholders, who receive no franking credits because Australian-sourced earnings have remained much as they were when CSL floated. The plan is that the big expansion of the flu business and the Gardasil revenue stream provide the company with an Australian tax base and rebuild CSL's franking credits.


The other good news for CSL shareholders is that McNamee, who will be 50 in November, has no plans to move on yet. His enduring incumbency reflects one of the distinctive strengths of CSL. While the evolution of CSL's business has been relentless and rapid since its quietly contentious listing in 1994, the faces of the executive and the board of directors have not changed.


"The thing is, when you are managing a company that revolves around quality and technology, you really need intelligence," he says. "The bigger we get, the more we are going to be in the innovation business. And it is people that innovate. In the end, money ain't smart. What it can do, though, is help you get and keep the right people."





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