VRBPAC Meeting on H1N1 Vaccine

July 22nd, 2009

In anticipation of the Vaccines and Related Biological Products Advisory Committee (VBRPAC) meeting scheduled for July 23rd, FDA’s Office of Vaccines Research and Review has issued a briefing document covering the ‘regulatory considerations regarding the use of novel influenza A (H1N1) virus vaccines’.  The document reduces the speculation around the performance of the seed strain virus, H1N1 vaccine timing, clinical studies, and the use of adjuvants.

On May 26th 2009 WHO recommended that novel influenza A (H1N1) vaccines should contain A/California/7/2009 (H1N1)v-like virus.  Five reassortants of this virus (X179A, IVR-153, IDCDC-RG15, NIBRG-121, CBER-RG2) were made available to vaccine manufacturers to prepare seed virus for vaccine production.  The FDA briefing document reveals that initial growth studies suggest the virus yield from the H1N1 reassortants are lower relative to the yields for seasonal influenza vaccines.  Novartis and Baxter have confirmed this.  Novartis has observed the yield for the H1N1 vaccine to be 30% to 50% of that for the company’s seasonal vaccine.  Baxter’s CEO Robert Parkinson has noted that ‘yield optimization’ will be a challenge.  

Since virus yield is directly proportional to the number of H1N1 vaccine doses, a 50% decrease in yield will result in it taking twice as long to manufacture the projected 600 million doses of H1N1 vaccine required to immunize the U.S. population.  Going back to the assumption of the WHO working group on H1N1 vaccines, it is evident that the yield assumption has not been met and hence the total global capacity for vaccine production of 4.9 billion doses over a 12 month period has dropped accordingly.

In addition to yield issues, the briefing document addresses how the availability of potency reagents affects the timing of vaccine availability.  Potency reagents consist of laboratory derived standard antiserum and positive control antigens, and are used in a method called the SRID assay, a somewhat archaic immonodiffusion technique for establishing potency discussed in this blog on May 17th. 

CBER is targeting mid-late July for availability of the reference antiserum and antigen, which would lead to an early August date for the availability of formulated inactivated vaccine for clinical trial material.  Live attenuated viruses, such as that produced by Medimmune, do not require the SRID for formulation and are not subject to the same limitations.  Interestingly, FDA notes that if reagents are not available to formulate the vaccine in time for clinical studies, alternate methods may be considered.  It is not obvious what these other methods are, although the EPAR for Celvapan does describe an HPLC method for hemagglutinin (HA) quantification that was deemed acceptable by CHMP during a  Scientific Advice process.

The clinical studies considerations put forward by FDA are fairly straightforward, although it is noted that if clinical trials cannot be completed in time to inform policy decisions regarding use of the H1N1 vaccine, then FDA will be flexible thus decisions on H1N1 vaccine formulation and use may have to be made based on results from smaller or incomplete clinical studies.

Day 0 and 21 immunizations have been recommended for evaluation in adult and pediatric populations.   Recommended study doses are as expected:  7.5 micrograms and 15 micrograms of HA in the pediatric and adult populations, with an additional 30 microgram dose in the adult population.  The University of Maryland Baltimore Medical School’s Centre for Vaccine Development , part of the Vaccine and Treartment Evaluation Unit (VTEU) will be one of the first sites to lead these studies.  CSL of Australia, who produce a U.S. licensed seasonal inactivated influenza vaccine, announced today that they initiated a trial of their H1N1 vaccine in Adelaide, and expect the vaccine to be proven safe and immunogenic by the end of September.  HHS has ordered $180 million of H1N1 vaccine from CSL.

FDA notes in the briefing document  that there are currently no U.S. licensed influenza vaccines containing an adjuvant, but acknowledges that in the light of both limited global capacity for production of an H1N1 vaccine, and the real possibility that a single dose of unadjuvanted vaccine may not yield an adequate immune response, adjuvants are being considered.  Novartis and GSK will evaluate their oil-in-water emulsion adjuvants for enhanced immunogenicity and dose sparing in separate arms of the adult and pediatric studies.  A dose of 3.8 micrograms of HA in place of the 30 microgram dose is recommended for the adjuvant groups.  HHS recently purchased $344 million of Novartis’ MF-59 adjuvant and $71 million of GSK’s AS03 adjuvant for pandemic use.

Both licensure and Emergency Use Authorization (EUA) are discussed as regulatory pathways for making the H1N1 vaccine available.  Licensure would require the H1N1 vaccine to be manufactured using the same process as a U.S. licensed seasonal inactivated influenza vaccine or a seasonal live attenuated influenza vaccine, and would require the generation of the clinical data described above. The EUA option is more likely for H1N1 vaccines containing the MF-59 or AS03 adjuvants, since no U.S. licensed vaccine contains these adjuvants.

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H1N1 Vaccine for UK – Redux

July 17th, 2009

On July 13th this blog discussed in detail a letter sent by David Salisbury, the UK’s minister for immunisation, declaring that an H1N1 vaccine will be available in the UK in August.  The letter described immunization schedules and who would be providing the vaccine, leading one to conclude that clinical trials to show the vaccine was safe and immunogenic had been completed.

In an interview with the UK’s Guardian newspaper  Dr. Margaret Chan, the WHO Director General, clarified the H1N1 vaccine situation.  She confirmed that WHO expects an H1N1 vaccine to be available in August, but pointed out that vaccine availability is not the same as having a vaccine that has been proven to be safe.  Her projection was that clinical trial data would not be available for two to three more months from now. 

Baxter Healthcare, one of the two Pharma companies contracted to provide H1N1 vaccine to the UK, has said that it should be ready to ship vaccine by the end of July or early August.  It now appears that clinical trials began in early July, which means clinical data would not be available for submission to regulatory agencies until September at the earliest.

So, late September or early October seems a more realistic time-frame for the first immunizations in the UK.

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UK’s H1N1 Vaccine in August

July 13th, 2009

Dr. David Salisbury, the Head of Immunisation for the UK’s Department of Health has just issued a ‘Dear Colleague’ letter.  The letter describes the UK’s decisions on use of the H1N1 vaccine, and is directed to local health authority immunisation coordinators and leads.

The Department of Health is recommending vaccines from both Baxter Healthcare and GlaxoSmithKline, and expects to have the first doses available in August, with the supply continuing for about 12 months.  A two-dose schedule (0 and 21 days) is recommended, suggesting the clinical studies of these two vaccines have been completed and that two doses of vaccine are indeed required for seroprotection. 

Regulatory approval will be required for both the Baxter and GSK vaccines prior to distribution, but this should be straightforward since both companies have received European Medicines Agency (EMEA) approval for their respective mock-up pandemic vaccines.  In January of 2009 the EMEA established a fast-track assessment procedure for pandemic influenza vaccines, as described in the Guideline on Submission of Marketing Authorization Applications for Pandemic Influenza Vaccines through the Centralized Procedure.  The guideline outlines a process for building a core MAA dossier to support approval of a mock-up vaccine during an interpandemic period; when a pandemic then arrives, the marketing authorization holder (MAH) need only submit a variation to the MAA for fast-track approval of the final pandemic strain influenza vaccine.  Baxter’s mock up vaccine is Celvapan.  GSK has received approval for two mock-up vaccines, Pandemrix and Daronrix.  All three mock-up vaccines were approved with antigens from various H5N1 flu strains, the contents of which are now being changed to the H1N1 pandemic strain for the expected August distribution

Although there is no mention of the recommended dose of pandemic vaccine in Salisbury’s letter, the European Public Assessment Reports (EPARS) for the mock-up pandemic vaccines that were submitted to the dossier reveal the Celvapan dose is 7.5 micrograms, the Pandemrix dose is 3.75 micrograms, and the Daronrix dose is 15 micrograms.  There is no evidence that the recently developed H1N1 vaccine will have comparable immunogenicity to the H5N1mock-up vaccine, so it remains to be seen what dose will recommended for the H1N1 vaccine.

The three mock-up vaccines described in the EPARS  differ fundamentally from each other in several ways.

Celvapan is a whole virion inactivated vaccine.  Whole virion vaccines contain a complete virus that has been purified from the production matrix by centrifugation.  The virus is inactivated with formaldehyde and UV irradiation.  Inactivation makes the virus incapable of replication and infection, rendering it safe for use as a vaccine.  Probably the most unique element of Celvapan is that it is produced using cell-culture technology, the wave of the future for flu vaccine manufacturing.  Specifically, the virus is grown in Vero cells, a mammalian cell-line derived from the kidney epithelial cells of African green monkeys.  As described in this Blog on June 12th, only about 5% of the worlds current manufacturing capacity is cell-culture based.  Baxter produces Celvapan in Bohumil, Czech Republic. 

GSK’s Pandemrix is a split-virion inactivated vaccine, produced in embryonated hens eggs.  Split-virion vaccines contain virus that has been disrupted with detergent, and purified by centrifugation and diafiltration. The virus is inactivated with formaldehyde and sodium deoxycholate.  In contrast to Celvapan, which contains no adjuvant, Pandemrix contains the adjuvant AS03, a squalene based oil-in-water emulsion. The vaccine is supplied in a two-vial format, one containing the antigen, the other the adjuvant.  The adjuvant is added to the antigen vial at the time of dispensing for immunisation.  The vaccine antigen is produced in Dresden, Germany.

GSK’s second mock-up pandemic vaccine, Daronrix, is a whole virion inactivated vaccine like Baxter’s Celvapan, but it is produced by conventional methods in eggs.  Alum is used as an adjuvant.  The antigen is adsorbed to the alum prior to the final fill, so this vaccine is supplied in a single-vial format.  GSK also produces the Daronrix antigen in Dresden, Germany.

In a June 6th 2009 press release GSK described their candidate H1N1 vaccine as being adjuvanted with AS03, so I am assuming that alum-adjuvanted Daronrix is not being pursued by GSK and the UK Department of Health will be purchasing the H1N1 strain of Pandemrix.  If so, and vaccine production remains on schedule, then August may mark the first use of the H1N1 vaccine and immunisation with the first commercial dose of the AS03 adjuvant.

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Clinical Trials of Candidate H1N1 Vaccines

July 9th, 2009

Vaccine manufacturers will initiate small-scale clinical studies to evaluate the safety and immunogenicity of their respective candidate H1N1 vaccines prior to initiating commercial production.  CDC released the reassortant virus stock to the manufacturers back on May 27th 2009, so the H1N1 vaccine clinical studies should be starting in July.

H1N1 vaccine recipients will be immunologically naive with respect to the H1N1 virus.  This is different to the situation encountered with seasonal flu vaccines, when vaccinees are usually primed by natural exposure to flu virus or by a history of flu vaccination, and only require a single dose of vaccine to achieve seroprotection.  In addition, little is known about the immunogenicity of the H1N1 vaccine, so the H1N1 vaccine trials will differ from those routinely performed for seasonal vaccines.

Clinical studies for regulatory approval of seasonal vaccines evaluate a single 15 microgram dose of each of the three seasonal strains. Reviewing published clinical studies on H5N1 vaccines such as Focetria and Pandemrix, the H1N1 vaccine studies will probably evaluate a two-dose schedule (0 and 21 days) and several strengths of vaccine (probably 7.5, 15, and 30 micrograms).  When the manufacturer has access to an adjuvant, there likely will be an arm of the trial that evaluates the adjuvant for dose-sparing and enhanced immunogenicity effects.

CSL of Australia have now announced that they are ready to commence a clinical trial of their H1N1 vaccine candidate, with vaccinations beginning mid-July in healthy adults between 18 and 64 years of age.  They have confirmed they will evaluate a two-dose schedule of 0 and 21 days, and compare a standard dose of the vaccine with increased dosages.  The standard dose would be 15 micrograms, suggesting CSL does not expect a 7.5 microgram dose of their vaccine to be sufficiently immunogenic.  If this is so, and applies to other manufacturers vaccines, this will have significant impact on the the number of H1N1 vaccine doses that can be produced with the current manufacturing capacity

It should take about 6 weeks to complete and analyze the initial immunogenicity portion of the CSL clinical study, so information on proposed dose and regimen for the CSL H1N1 vaccines should be available by the end of August.  Novartis have also confirmed they are initiating their clinical studies in July, so there should be some comparative data available that will begin to clarify the picture with respect to vaccine availability and capacity.

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HHS Backs A Recombinant Baculovirus H1N1 Vaccine

June 24th, 2009

Virtually all flu vaccines are produced from influenza virus grown in embryonated eggs.  The technology is slow and dependent on a supply of suitable eggs, so in recent years a cell-culture technology has been developed that is egg-free and faster than the egg- based method.  Cell-culture technology still requires live influenza virus as the seed stock for the manufacturing process, but does not require adaption of the virus for growth in eggs.

A third production technology is now in late-stage development; recombinant influenza vaccine produced in baculovirus-infected insect cells.  Health and Human Services (HHS) has awarded a $35 million contract to Protein Sciences Corporation , a US-based pioneer of baculovirus technology that has been developing such a recombinant influenza vaccine.  The award is under the National Strategy for Pandemic Influenza Implementation Plan, which calls on HHS to develop and procure medical countermeasures for pandemic influenza or for potentially pandemic strains, such as the recent H1N1 flu virus.  The thinking behind the HHS award is that recombinant technology  will help meet surges in demand for U.S.-based vaccine, such as is being seen for the H1N1 flu vaccine. 

Because there is no requirement for live influenza virus in the production of the Protein Sciences recombinant vaccine, the vaccine could more quickly progress through the prototype vaccine, clinical investigational lots, and commercial-scale production steps in comparison to the traditional egg-based vaccine.  In addition, the insect cells can be frozen for ‘on demand’ use, simplifying the supply chain and decreasing  the start-up time for production

Simply put, once the sequence of the flu virus strain is available, a strain-matched hemagglutinin gene encoding recombinant baculovirus seed lot is generated.  This is the time-saving step.  An  S. frugiperda insect cell line is then infected with the recombinant baculovirus and grown to a high cell density.  Finally the hemagglutinin (HA) antigen is purified from the disrupted cells and formulated to produce the finished vaccine. 

Interestingly, the Protein Sciences’ FlubloK seasonal influenza vaccine made by the recombinant process, and for which a Biologics License Application (BLA) is currently under review at FDA, is formulated to contain 45 micrograms of each HA strain.  This is three times the amount found in all other manufacturers’ seasonal flu vaccines, which contain 15 micrograms of each HA strain.  This suggests recombinant HA produced using the baculovirus expression system is less potent than the live virus-derived HA.

FDA has not yet approved a flu vaccine produced by recombinant technology; in fact FDA has yet to approve a product produced using the baculovirus expression system.  Only one baculovirus expression system-produced vaccine has ever been approved for human use, and that is Cervarix, manufactured by GlaxoSmithKline Biologicals.  EMEA granted marketing authorisation by on the 20th September 2007 for the prevention of premalignant cervical lesions and cervical cancer causally related to Human Papillomavirus (HPV) types 16 and 18.

If and when FDA approves this recombinant technology, the HHS contract requires Protein Sciences to establish domestic manufacturing capability to provide a finished vaccine within 12 weeks of the onset of a pandemic and to produce at least 50 million doses of pandemic flu vaccine within six months of pandemic onset.  With a U.S. population of over 300 million and and a very limited domestic flu vaccine capacity, the $35 million Protein Sciences award is a significant step forward in building a domestic vaccine supply chain.  Getting a baculovirus-derived product approved by FDA, and increasing the portfolio of proven production technologies, is a big bonus.

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Phase 6 Influenza Pandemic Announced and a Prototype H1N1 Vaccine Arrives on Schedule

June 12th, 2009

The H1N1 influenza strain has spread from person to person and country to country and, as expected, the scientific criteria for an influenza pandemic have been met.  The WHO has raised the influenza pandemic alert from phase 5 to phase 6, signaling the start of the 2009 influenza pandemic -  the first in 40 years.

In apparent lock step with the announcement of Phase 6, and weeks ahead of expectations, Novartis has produced the first ten litre batch of monovalent bulk vaccine.  It is derived from the wild-type H1N1 virus that the CDC supplied back in early May.  Novartis used cell-culture manufacturing technology instead of the traditional egg-based technology to produce the prototype vaccine , avoiding the delay incurred while having to adapt the wild-type (WT) virus to grow in eggs. 

The Novartis produced vaccine is only a prototype because the CDC’s reassortant virus seed (not WT) must be used for routine production of flu vaccine.  The reverse genetics reassortant is carefully screened and selected for quality and safety using  controlled and documented methods .  The wild-type prototype vaccine can however be used for preclinical evaluation’ which may lead to early information on the dose and regimen needed for an H1N1 vaccine.  The wild-type prototype vaccine will probably also be tested with an adjuvant to see if a dose sparing effect or a shortened regimen can be achieved.  CDC’s Anne Suchart has already stated that they are aware that an H1N1vaccine will require “a lot of antigen to get the response”. 

Novartis received the  reverse genetics reassortant seed virus from CDC on May 27th, and expects to enter human clinical trials with the resulting vaccine in July, receiving WHO licensure in the fall of 2009.  The studies could be completed within 2 months, and licensure could be granted by October, assuming that one and two dose immunization schedules are evaluated and immunogenicity is measured approximately three weeks post second immunization.

Only about 5% of the worldwide flu vaccine capacity employs cell culture technology so Novartis’ early competitive advantage will quickly dissipate as the egg technology vaccines begin to emerge from the likes of  Sanofi Pasteur and GSK.  Even the majority of Novartis’ capacity is egg technology, based in Siena Italy and Liverpool UK.  Their cell-culture facility is in Marburg Germany, while a second facility is under construction in Holly Springs North Carolina.  By approximately 2012 the HHS funded Holly Springs facility is anticipated to be capable of producing 150 million doses of pandemic vaccine within six months of the declaration of an influenza pandemic.

Novartis’ cell-culture H1N1 vaccine is a taste of the future.  The vast majority of the H1N1 vaccine will be produced in eggs this time around, as discussed in this blog on May 20th.  It took 40 years for this pandemic to arrive; cell-culture based flu vaccines should be ubiquitous next time around.

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HHS Orders Around the World

June 1st, 2009

Health and Human Services (HHS) has inked deals with five flu manufacturers to supply bulk H1N1 vaccine; Australia’s CSL ($180 million), GlaxoSmithKline ($181.1million),  Sanofi Pasteur ($190.6 million), Novartis ($288.8 million), and MedImmune ($90 million).   The HHS funding comes from the $1 billion released for pandemic preparedness on May 22nd to facilitate the manufacture of bulk vaccine.  Another $150 million of this funding will go to the above companies to conduct clinical evaluation of pilot lots for dose, regimen and safety.

Sanofi Pasteur manufactures its bulk flu vaccine at the Swiftwater facilities in Pennsylvania.  CSL will manufacture bulk vaccine in Victoria Australia, GSK in Dresden Germany, MedImmune in Speke UK, and Novartis in Siena Italy or Liverpool UK.    Sanofi Pasteur will be the only manufacturer who produces vaccine on US soil.   So if the Stage 6 H1N1 pandemic comes to pass both the virus and the solution will be global.  There isn’t enough local capacity for national vaccine production, as has been seen historically for seasonal vaccine production, and was so clearly highlighted by the Chiron supply failure in 2004. 

WHO predicts the top end of global H1N1 capacity to be 4.9 billion doses over a 12 month period after full-scale production is initiated.  The two assumptions underlying this prediction are that there is a vaccine yield equivalent to that routinely obtained for seasonal vaccine, and that there is the use of the most dose-sparing formulations.

WHO must be banking on vaccine manufacturers to produce adjuvant-containing formulations for dose-sparing.   Apparently HHS has heard the call; the H1N1 orders to GSK and Novartis included an order for their proprietary adjuvants, AS03 and MF59C.1 respectively, both squalene containing oil-in-water emulsions that can significantly decrease the dose of antigen needed to produce the required immune response.  Since both can be added to the antigen at the time of administration, adjuvant production is decoupled from that of the antigen;  there is no need for coformulation.  This mitigates the risk of an untested, adjuvanted flu-vaccine being the solely produced pandemic vaccine.  FDA is likely to approve the H1N1 antigen‑alone formulation which could be distributed without the adjuvant in the case of a pandemic.

HHS’ hedge still has a silver lining.  Perhaps egged on by its parent organization, FDA will approve an H1N1 flu vaccine containing a novel, non-alum, adjuvant as discussed in this blog on 18th May 2009.  This would be a winner.

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H1N1’s Billion Dollar Start

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

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

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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