Posts Tagged ‘MF59C.1’

European H1N1 Vaccine Latecomers Herald the Regulatory Acceptance of Innovation

Sunday, December 20th, 2009

By the end of October, three H1N1 vaccines,  Celvapan,  Focetria, and Pandemrix, had been granted marketing authorisation by the European Commission through the centralized procedure.  Under this procedure the decision by the commission is binding on all EU Member States to authorise the product, effectively resulting in a marketing authorisation for all 27 countries.  As discussed in earlier blog entries the vaccines were all granted authorizations  under strain change variances to their original marketing authorizations.  In the couple of months since then two additional H1N1 vaccines have appeared,  Novartis’s Celtura and Sanofi Pasteur’s Panenza, but supported by dossiers submitted in EU countries under the decentralized procedure.

Panenza, a non-adjuvanted influenza A (H1N1) 2009 monovalent vaccine produced by Sanofi Pasteur at its facility in Val de Reuil, France, containing 15 mcg of hemagglutinin per dose and indicated for immunisation of adults and children 6 months of age and older, has been granted a marketing authorisation in France by Afssaps (Agence francais de securite sanitaire des produits de sante).  Sanofi Pastuer filed a decentralized marketing authorisation application for Panenza in Belgium, France (Reference Member State), Germany, Italy, Luxembourg, and Spain.  Sanofi Pasteur does not have an adjuvant that is ready to be included in its H1N1 vaccine so it has come to the table late with an unadjuvanted vaccine, and is hoping to fill the space created by those who are skeptical of adjuvants, or for reasons of age or health may be better served by an unadjuvanted vaccine.   Sanofi itself statedthat it produced Panenza in response to recommendations by authorities to make a non-adjuvanted H1N1 vaccine available

Celtura is an MF59-adjuvanted influenza A (H1N1) 2009 monovalent vaccine produced at Novartis’s facility in Marburg, Germany.  It contains  3.75 mcg of hemagglutinin and 0.125 ml of MF59 adjuvant  per 0.25 ml dose and is indicated for immunisation of children 3 years of age and older and adults up to 50 years of age, a narrower indication than that approved for Panenza.

Celtura has been granted marketing authorisations in Germany and Switzerland, where Focetria and Pandemrix, the two other adjuvanted H1N1 vaccines are already available.  However Celtura is differentiated from Focetria and Pandemrix through its cell-culture based production technology.  As described previously in this blog, Novartis has a validated cell-culture process for production of influenza virus antigens which have traditionally been produced in embryonated hens’ eggs. The cell-culture technology has already been licensed in Europe for the production of the Novartis’s seasonal flu vaccine, Optaflu.

Given the late arrival of Celtura into an already crowded H1N1marketplace, the H1N1 pandemic has created an unprecedented opportunity for vaccine companies to achieve marketing authorisations for their more niche, or technologically innovative products, such as those containing adjuvants or made by the cell-culture process.  Availability of these innovative 2nd generation vaccines should speed up their acceptance in the general marketplace and broaden regulatory agencies ‘comfort zones’ given the significant amount of post-marketing data that will now be available to these agencies to review. 

It is unfortunate, but ultimately inevitable, that it takes a health crisis to catalyse broad acceptance of innovation.  The state of available vaccine technology will be stronger in 2010 as a result of the H1N1 pandemic.

Tags: , , , , , , ,
Posted in H1N1 Flu, Uncategorized | 1 Comment »

EMEA Approves Adjuvanted H1N1 Vaccines

Wednesday, October 7th, 2009

Close on the heels of the FDA’s approval of four H1N1 vaccines, the European Medicines Agency (EMEA) has recommended to the European Commission that two H1N1 vaccines be granted marketing authorisation.  The EMEA’s Committee for Medicinal Products for Human Use (CHMP) expedited its assessment ofthe two vaccines. The data that allowed replacement of the strain in the mock-up vaccine with the H1N1strain was reviewed as a variation to the previously issued Marketing Authorisation (MA).  The core pandemic dossiers had already been evaluated by the EMEA and the associated mock-up vaccine had been granted Marketing Authorisations, although the final vaccine could only be used during an officially declared pandemic. 

The CHMP have provided details of the scientific rationale they used in order to reach the conclusions on the benefit-risk balance for the two H1N1 vaccines that led to the positive opinion.  Simply put, they employed the “proof of principle” approach by which safety and immunogenicitydata were generated with the mock-up vaccine containing subtypes of influenza A (H5N1) to which the majority of the population is naive.  These data were then extrapolated to the current vaccine containing the A(H1N1) pandemic strain.

The two EMEA-approved vaccines are Focetria (Novartis) and Pandemrix (GSK).  The CHMP is currently recommending a two-dose vaccination schedule at an interval of three weeks for adults, pregnant women, and children over 6 months old.

Focetria is an inactivated purified subunit vaccine composed of 7.5 mcg of hemagglutinin and the MF59C.1 adjuvant.  MF59C.1 is a submicron oil-in-water emulsion, comprising  squalene, sorbitan trioleate, and polysorbate80.  Stay tuned for a future entry with more details on MF59C.1.

Pandemrix is an inactivated purified subunit vaccine composed of 3.75 mcg of hemagglutinin and the ASO3 adjuvant.  AS03 is also a submicron oil-in-water emulsion, comprising squalene, alpha-tocopherol (Vitamin E), and polysorbate 80.

The differences between the EMEA innoculation recommendations for the H1N1 vaccines and those approved by FDA are quite dramatic.  Most strikingly, FDA recommended a single dose of the inactivated H1N1 influenza vaccines while EMEA recommended a two-dose vaccination schedule, 21 days apart, for adults, pregnant women, and children over six months of age.  The EMEA did note that future data from ongoing clinical trials may result in these recommendations being updated.

FDA approved a single 15 mcgdose of H1N1 vaccine;  EMEA recommended both a 7.5 mcg and 3.75 mcg dose.  The effectiveness of the lower dose is probably due to the use of the adjuvantwhich typically stimulates the 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 vaccine formulation.

This adjuvant effect can decrease the amount of antigen required in a dose and hence potentially increase the number of vaccine doses that can be produced.  Obviously the current recommendation for two doses of Focetria at 7.5 mcg of viral antigen per dose dose not save antigen when compared to a single unadjuvanted 15 mcg dose, but if, as Novartis have indicated, just one dose of this vaccine can protect healthy adults, the number of people that can be immunised with Focetria significantly increases.  The same reasoning applies to Pandemrix. 

GSK has received and agreed to orders from governments and health authorities around the world for 440 million doses of their H1N1 vaccines, which include Pandemrix and an unnamed vaccine produced by ID Biomedical (owned by GSK) in Quebec.  GSK is planing to fill these orders through the first half of 2010.

The capacity advantages of a 3.75 mcg Pandemrix dose can but put into clear perspective.  The GSK Dresden manufacturing facility, which produces the antigen for Pandemrix, is advertised as having a capacity of approximately 60 million doses of seasonal flu vaccine, which contains 45 mcg of antigen per dose.  Therefore, at 3.75 mcg per dose, the available GSK Pandemrix capacity translates to 720 million doses.  If the yield of the H1N1 strain is approximately 30-50% of that routinely obtained for a seasonal strain then the number of doses drops to 240-360 million, a significant proportion of the doses ordered from GSK.  In contrast, if Pandemrix contained a 15 mcg dose, the capacity of the Dresden facility would decrease to 60-90 million doses.

As discussed on this blog back on May 18th, an adjuvant may become mandatory for translating the available flu vaccine manufacturing capacity into sufficient doses to meet global demand.  GSK and Novartis have clearly travelled down this pathway and have been able to produce H1N1 vaccines that look like they will be effective and safe at one half to one quarter of the antigen dose required for a single strain in a seasonal flu vaccine.

Tags: , , , ,
Posted in Adjuvants, H1N1 Flu | 2 Comments »

Offshore H1N1 Vaccine Data – Single Shot

Thursday, September 10th, 2009

In early June, Novartis produced the first batch of monovalent bulk H1N1 vaccine.  As discussed in this blog on June 12th, Novartis used cell-culture manufacturing technology instead of the traditional egg-based technology to produce the prototype vaccine, avoiding the delays normally incurred during adaption of the wild-type (WT) virus to grow in eggs.

Novartis have now released top-line information on the performance of this vaccine, called Celtura, in clinical testing.  As speculated, they evaluated the prototype vaccine in conjunction with MF59, their oil-in-water emulsion adjuvant, to see if a dose sparing effect or a shortened regimen could be achieved.  The trial was run at the UK’s University of Leicester and University Hospitals of Leicester in 100 healthy volunteers, aged between 18 and 50.  The vaccine schedule comprised one or two doses of 7.5 mcg MF59 adjuvanted surface-antigen A/California/2009 vaccine.

The pilot trial demonstrated that the MF59 adjuvanted cell culture-based H1N1 vaccine elicited a strong, potentially protective, immune response to Influenza A (H1N1) in 80%  of the subjects after one dose, and in more than 90% after two doses.  Hemagglutination-inhibition titres reached 1:40 or greater in 80 percent of those receiving one dose and more than 90 percent in those receiving two doses. These response rates would satisfy the immunogenicity criteria set by the European and US regulators. Importantly, the vaccine was well tolerated, with pain at the injection site being the most frequent adverse event.

In the same timeframe, Sinovac Biotech, a Chinese Biopharmaceutical company, also began egg-based production of Panflu.1, it’s unadjuvanted H1N1 vaccine, initiating clinical trials in late July.  Again, the top-line results showed good safety and immunogenicity after a single dose.  China’s State Food and Drug Administration (SFDA) organized an Expert Evaluation Conference, and the experts unanimously agreed that the vaccine is suitable for  people 3-60 years old.  SFDA subsequently approved the registration application and issued Sinovac a production license for Panflu.1. The recommended dose is a single shot of 15 mcg in 0.5ml.  The Chinese Central Government has now issued an initial order to Sinovac to purchase Panflu.1 for the national stockpiling plan; 3.3 million doses are required to be delivered by September 15th, 2009.

These company-sponsored clinical trials have demonstrated that an H1N1 vaccine can illicit a potentially protective immune response with a single dose containing 7.5 mcg of an adjuvanted antigen or 15mcg of an unadjuvanted antigen. Similar results should be obtained from the NIAID sponsored trials that are being performed at the VTEUs in the United States.  As luck would have it, the industry-sponsored clinical trial results of a single 15 mcg unadjuvanted dose being immunoprotective ended up being in line with FDA’s recommendations for licensure as described at the July 21st VRBPAC meeting to discuss clinical trials to support the use of vaccines against the 2009 H1N1 virus.

The transcript of the VRBPAC meeting quotes Norman Baylor, the Director of the Office of Vaccines Research and Review, CBER, as stating that FDA has determined that a monovalent unadjuvanted vaccine against influenza A (H1N1) can be licensed as a strain change supplement to existing BLAs, consistent with the approach for seasonal influenza vaccines.  For inactivated vaccines this only requires a submission under the existing license, accompanied by CMC data for the new strain.  Wellington Sun, also of the FDA’s Office of Vaccine Research and Review, goes on to suggest that the H1N1vaccines will initially be unadjuvanted and formulated at 15 mcg per dose.  The complete data from clinical trials of inactivated H1N1 vaccines would be submitted to the BLA post-licensure, with modifications then being made to the product if indicated by the clinical data.  Sun considered this approach to allow for the earliest availability of licensed H1N1vaccine.

A few days after the VRBPAC meeting the Advisory Committee for Immunization Practices (ACIP) met to discuss recommendations for the use of the H1N1 vaccine.  The report has just been issued, outlining the priority group recommended to be the first to receive the influenza A (H1N1) 2009 monovalent vaccine, as it is officially called.  The target group includes 159 million Americans such as pregnant women, health-care and emergency workers and children and young adults aged 6 months to 24 years.

By all indications it appears that sufficient doses will be available for that priority group 45 million, of whom could be vaccinated in mid-October when the 45 million doses are distributed.  The additional 20 million doses expected to be available on a weekly basis after October 15th would allow the ACIP target group to be immunized by the end of the year.

Tags: , , , , , ,
Posted in H1N1 Flu | No Comments »

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.

Tags: , , , , , , ,
Posted in H1N1 Flu | 1 Comment »

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.

Tags: , , , , , , ,
Posted in H1N1 Flu | No Comments »