Posts Tagged ‘AS03’

FDA Approves Four H1N1 Vaccine Products

Monday, September 21st, 2009

Five months after the first reported US case of H1N1 influenza, and 4 months after the declaration of a Phase 6 Pandemic by WHO, FDA has approved four Influenza A (H1N1) 2009 monovalent vaccines.  Three of the vaccines, manufactured by CSL, Novartis, and Sanofi Pasteur, are injectible inactivated vaccines containing 15 mcg of antigen in a 0.5ml dose. They are approved for use as a single intramuscular injection, except in children 4-9 years old (Novartis), and 3-9 years old (Sanofi Pasteur), who require two 0.5 ml intramuscular injections approximately 1 month apart. 

Children 6-35 months old require two 0.25 ml doses of the Sanofi vaccine approximately 1 month apart. Sanofi has gone as far as to produce the vaccine in four different presentations, one of which, the prefilled 0.25ml syringe for 6-36 month olds, is distinguished by a pink plunger rod.  The CSL vaccine is not approved for people under 18 years of age.

The fourth approved vaccine, manufactured by MedImmune, is an intranasal live attenuated virus vaccine containing 10 million FFUs in a single 0.2 ml dose.  A single intranasal dose is recommended for children, adolescents, and adults 10 to 49 years old.  As with the inactivated virus vaccines, children 2-9 years old require two doses approximately 1 month apart.  The MedImmune vaccine is discussed in detail in the August 10th blog posting.

Clinical results that supported the single 15 mcg dose were finally generated by the NIAID’s Vaccine and Treatment Evaluation Units (VTEUs) at the same time as companies began to publish their independently sponsored clinical trial results.  NIAID Director Anthony Fauci reported that, after 8-10 days, a single dose of 15 mcg of the Sanofi Pasteur vaccine generated a robust immune response in 96% of adults aged 18 to 64 and in 56% of adults aged 65 and older.  Similarly, among healthy adults who received a single 15 mcg dose of the CSL Limited vaccine, a robust immune response was measured in 80% of adults aged 18 to 64 and in 60% of adults aged 65 and older.  CSL independently reported similar results from a trial they sponsored in Australia.

The government has ordered 195 million doses of the vaccine, of which about 45 million doses are expected to be available in mid-October.  Of those 45 million doses, it looks like the first available H1N1 vaccine will be MedImmune’s inhaled product.   Approximately 3.4 million doses of the inhalable MedImmune vaccine will be shipped and available in the first week of October. 

The somewhat surprising (yet replicable) outcome that a single 15 mcg dose of the H1N1 vaccine produces a robust immune response in healthy adults ends a lot of speculation on how many doses will be available for the 2009-2010 flu season.  As discussed many times on this blog, the need to go to a higher dose or two shots would have dramatically reduced the already tight vaccine supply; the single 15 mcg dose allows the supply to be stretched further.  Only addition of an adjuvant could further stretch the vaccine supply.

Results from a clinical trial sponsored in Germany by GSK show that a single injection of a 5.25 mcg dose combined with their ASO3 adjuvant  gave a robust immune response 12 days after immunization in 98% of the healthy volunteers aged 18 to 60 years old.  Given the limited global production capacity for the H1N1 vaccine, approval of an adjuvanted H1N1 vaccine, which is likely to occur in Europe, could further boost the global vaccine supply.

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VRBPAC Meeting on H1N1 Vaccine

Wednesday, 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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UK’s H1N1 Vaccine in August

Monday, 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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HHS Orders Around the World

Monday, 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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