Archive for May, 2009

H1N1’s Billion Dollar Start

Wednesday, May 27th, 2009

$1 Billion has been released from funds set aside for pandemic influenza by the HHS to begin the process of manufacturing the H1N1 influenza vaccine.  The money will fund the efforts of vaccine makers (such as Novartis and Sanofi Pasteur) to make bulk vaccine that can be held in a federal stockpile.  The bulk vaccine could then be used if the decision is made to move forward with wide-scale vaccination against the H1N1 flu virus.

What precisely will the billion pay for?  Presumably the production of pilot lots of H1N1 vaccine that can be used in human clinical trials to establish both immunogenicity and the dosing regimen most likely to offer protection against the currently circulating H1N1 strain.  This process occurs every year for the seasonal vaccine.  Just look at the package insert for a U.S. FDA approved seasonal trivalent influenza vaccine (TIV), and you will see that pilot lots of the vaccine are tested, and seroconversion, geometric mean hemagglutinin inhibition antibody titers (HAI), and adverse events (AE) are reported for these lots.  Based on this data FDA approves the company’s supplement to the Biologics License Application (BLA) for Influenza Vaccine.  The vaccine is then available for public use.

Regulatory expectations for the pandemic vaccine are the same.  Perhaps fueled by the Avian Flu scare, in May 2007 FDA issued a guidance on the ‘Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines’.  They stated that approval of a pandemic influenza vaccine for manufacturers of a U.S. licensed seasonal inactivated influenza vaccine, where the process for manufacturing the pandemic influenza vaccine is the same as for the licensed seasonal product, will require clinical immunogenicity trials to determine the appropriate dose and regimen of the pandemic influenza vaccine candidate.  FDA also requires these trials to include an assessment of safety.

It should be noted that the 2007 FDA guidance also outlines a pathway to approval for Adjuvanted Influenza Vaccines, which were discussed on this blog on 18th May 2009. This raises the question: will manufacturers take the bold but risky regulatory path of adding adjuvants to the pilot lots of H1N1 vaccine to be tested in the human clinical trials? Recall from my 18th May 2009 blog entry that these non-alum adjuvants remain unapproved by FDA despite reams of safety and manufacturing data collected over decades. I believe a piece of the billion-dollar pie should be used to evalute these adjuvants in the pilot pandemic vaccine. Adjuvanting the H1N1 strain could spare valuable doses and maximize the effectiveness of the limited amount of material that is likely to be produced to accomodate both the seasonal and pandemic flu. I hope that the new leadership at FDA recognizes the potential public health emergency and acts with a sense of urgency and pragmatism to encourage the use and approval of these adjuvants in the H1N1 pandemic flu vaccine.
 
Will FDA rise to the occasion? That is the billion dollar question

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The Egg of the Chicken

Wednesday, May 20th, 2009

In the biopharmaceutical timescale the influenza vaccine manufacturing process is back there in the Devonian period; pretty old.  The influenza virus was successfully propagated in eggs back in 1937, paving the way for the first influenza vaccines in 1945.  The vast majority of flu vaccine doses are still produced from virus propagated in embryonated eggs, making egg supply a critical link in the supply chain.   Manufacturers estimate vaccine demand and contract with farmers to provide the embryonic eggs for vaccine production.  The egg producing chickens are usually hatched in the summer so as to reach maturity and begin laying eggs by December/January when seasonal production begins.  Eggs from new laying hens are most suited to vaccine production based on size, shell thickness, bioburden and embryonic viability.  Aged flocks are sacrificed at the end of production in the summer, however the lifespan of the flock can be extended if additional vaccine production is warranted

 

A rule of thumb is that one egg can produce sufficient virus for a 15mcg hemagglutinin (HA) dose of that flu strain.  A pandemic vaccine such as H1N1 will include only one strain; however it is unclear at this time how much  H1N1HA will be required in a dose, and how many immunizations will be required to seroprotect an individual.  H5N1 studies suggest the HA content could need to be as high as 90mcg and two immunizations may be required. 

 

For the 2008-2009 flu season the six manufacturers estimated 146 million doses of vaccine would be available.  Sanofi Pasteur have just brought on line capacity for another 100 million doses, putting US FDA approved capacity at about 250 million doses of seasonal vaccine.  So if all of the capacity is dedicated to H1N1, 750 million doses could be produced at 15mcg, or 180 million doses at 90mcg – 90 million doses if a two dose regimen is required.  Going back to the rule of thumb, whatever the final dose and regimen, nearly a billion eggs will be required to produce sufficient virus to utilise the available capacity.

 

In 2005 the Department of Health and Human Services had the foresight to recognize the criticality of the egg supply and awarded a contract to Sanofi Aventis to ensure there are enough eggs on hand to manufacture flu vaccines in the event of a pandemic flu outbreak or future vaccine shortages.  I assume this means that Sanofi Pasteur now has the egg supply to go straight into H1N1 manufacturing on the back of the 2009-2010 seasonal vaccine campaign.  It is not clear to me, given the nature of supply chains, especially for critical raw materials, that sufficient eggs would be available to all manufacturers in time to initiate H1N1 manufacturing in the summer of 2009.  Maybe this will become clearer as the manufacturer’s and WHO’s plans unfold and become public. As described above the manufacturers may decide not to sacrifice the old flocks in order to meet the egg demand.

Flu vaccine manufacturing has always been challenging; this is partly because of the dependence on eggs.  Fortunately several manufacturers have now developed cell culture techniques for producing the virus, ridding the process of eggs.  Unfortunately the cell culture-based capacity will be relatively insignificant for H1N1 production, at least in the 2009-2010 timeframe.  So lay chicken lay.

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Adjuvanted H1N1 Vaccine from GSK

Monday, May 18th, 2009

GlaxoSmithKline (GSK) has shed some light on the H1N1 vaccine production arena, announcing that they have received orders from governments aiming to stockpile a new candidate H1N1 vaccine. The announcement provides several data points on plans for the vaccine.

GSK expects the first doses of the vaccine to be available 4-6 months after receiving the virus seed from the WHO. I think the virus seed could be ready as early as June, putting vaccine availability in the Q4 2009 timeframe. They have noted that they plan to complete the 2009/2010 seasonal influenza vaccine campaign by the end of July. This is consistent with the proposed timeline for H1N1 vaccine production, allowing it to begin in August.

Of course all of this is subject to regulatory approval. However the pandemic vaccine will be produced by a similar process to the seasonal vaccine and in the same facilities, so it seems improbable that there would be any significant regulatory delays. GSK already received a European license for a pandemic vaccine based on a ‘mock-up’ dossier, and expects this to facilitate a faster registration of the new A (H1N1) vaccine. This is currently being discussed with EU regulatory authorities.

A notable aspect of the GSK pandemic vaccine is the proposed inclusion of GSK’s proprietary ASO3 adjuvant. ASO3 is an alpha-tocopherol based oil-in-water emulsion, similar to Novartis’s MF59. Adjuvants typically stimulate immune responses to the antigen components of the vaccine, and can generate a higher immune response with lower amounts of antigen when compared to the unadjuvanted formulation. This effect can decrease the amount of antigen required in a dose and hence increase the number of vaccine doses that can be produced. In addition an adjuvanted flu vaccine has the potential to provide protection even if the strain drifts, a distinct possibility with the current H1N1.

This is of such interest because, to the best of my knowledge, no non-alum adjuvanted vaccine has been approved by the US FDA. A recent NIAID/NIH sponsored workshop was held to discuss adjuvants, including their inclusion in pandemic flu vaccines. The emergence of H1N1 could accelerate the resolution of the adjuvant debate as the US Department of Health & Human Services grapples with the potential public health emergency.

The seasonal influenza vaccine contains a 15mcg dose of each of three antigens, and no adjuvant. If prepared as a pandemic vaccine, the H1N1 vaccine will contain only the single antigen. It is unknown at this time how much unadjuvanted antigen will have to be included in the vaccine formulation to elicit seroprotection, but for the H5N1 vaccine as much as 90mcg per dose has been required. The adjuvanted dose could be as low as 3-10mcg, realising a significant increase in the available doses. The H5N1 pandemic vaccine requires two doses to seroprotect, so it is also possible that the H1N1 vaccine will be similar, requiring 2 doses. This will place additional strain on the available manufacturing capacity. An adjuvant may become mandatory for translating the available manufacturing capacity into sufficient doses to meet global demand, and GSK clearly intend on travelling down that pathway. It will be fascinating to see how FDA reacts.

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H1N1 Vaccine Development

Sunday, May 17th, 2009

The process of developing a candidate vaccine virus is underway, coordinated by the WHO. Two parallel technologies are being employed, reverse genetics and classical reassortment. Several isolates are being evaluated, the majority of the effort going into A/California/4/2009(H1N1) and A/California/7/2009(H1N1), although other isolates as diverse as A/England/195/2009(H1N1) and A/New York/20/2009(H1N1) are being investigated.

CDC, CBER, St Judes Children’s Research Hospital in the US, NIBSC in the UK, NIID in Japan, and CSL Limited in Australia are all developing candidate viruses, reflecting the global nature of the effort. These organizations routinely do this work for seasonal vaccines. Success will entail a candidate virus being succesfully adapted for growth in eggs, a subsequent pilot vaccine being produced from the seed, and then criteria such as potency and yield being acheived.

In order to evaluate the potency of the vaccine candidate there need to be potency reagents, which include laboratory derived standard antiserum and positive control antigens. These reagents are used in a method called the SRID assay, a somewhat archaic immonodiffusion technique for establishing potency. NIBSC UK, CBER USA, TGA Australia, and NIID Japan are all slated to work on these reagents. To put the SRID assay into perspective it will be used to guide the development of the vaccine manufacturing process and to test the final vaccine prior to release to the public, so development of these reagents is a critical early step in the vaccine process.

Wild type H1N1 viruses are also being distributed to manufacturers (Baxter, CSL, GSK, MedImune, to name a few) so they can initiate their own development efforts.

The challenge for the WHO, one they face on an annual basis with seasonal flu, will be to predict whether one of the viruses currently being developed will be adequate for use in the vaccine or whether a further mutation will occur during the Southern Hemisphere season rendering the vaccine suboptimal. Given the 6-9 month lead time required to produce significant quantities of the vaccine my guess is that they will have to bet on one of the current isolates and initiate a full blown manufacturing effort by July, when some of the seasonal vaccine capacity will be freed up. If manufacturing were to occur in this timeframe significant quantities of vaccine could be available for distribution in the late 2009 – early 2010 timeframe.

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Algie Flu (aka H1N1)

Friday, May 15th, 2009

My Thursday 24th 2009 news headlines had a minor link to a story in the Arizona Daily Star describing two US cases of human infection with the swine influenza virus. Apparently the people had not been in contact with pigs, and CDC was investigating. Next day the top headline broadcast that a potential swine flu pandemic was underway in Mexico and the virus was passing person-to-person. Over the next two days, the virus spread to several regions of the US, Canada, and Europe. The US announced a Health Emergency on Sunday 27th April 2009, and freed up 25% of the antiviral stockpile. In less than a week a potential flu pandemic had materialized, stockpiles were being released and the first sequences of the virus were being published. Technology has come a long way since the 1968-69 ‘Hong Kong Flu’ pandemic—and the virus keeps pace thanks to daily global travel.

On April 29th 2009 the World Health Organization (WHO) elevated the global pandemic alert level to Phase 5, indicating sustained human-to-human transmission of a novel influenza strain (H1N1) of animal origin in one WHO region of the world, and exported cases detected in other regions. There has been no recommendation by the WHO or CDC for manufacturers to begin production of a pandemic vaccine, however if and when this comes it will put the biopharmaceutical and vaccine industries to the test. Can they quickly produce large quantities of vaccine, a vaccine being the most sure-fired way of managing a pandemic? Anti-virals (Tamiflu™ and Relenza™) are effective treatments if administered within 48 hours of the first signs of infection, but only a vaccine will prevent infection.

Scientists are working on developing a reassortant of the H1N1 virus that can be grown up in eggs and become the seed for the vaccine. Only time will tell as to how many egg produced doses can be made and how quickly, but all of the big players will be in there (Novartis, GSK, sanofi pasteur).

There are also cell-culture based flu vaccines. A lot of government money has gone into developing this type of manufacturing technology but it has not come fully on line in time for H1N1 and will probably only make a small contribution to the total number of doses available. And then there are the novel technologies that are still in development (e.g. Protein Sciences Corp’s BEVS technology) that will probably not play a meaningful role this time around. Big Pharma will do the heavy lifting if and when the call is made.

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