Posts Tagged ‘cell culture’

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.

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Posted in H1N1 Flu, Uncategorized | 1 Comment »

Celvapan: Cell-Culture H1N1 Vaccine Approved

Monday, October 19th, 2009

After a ‘positive opinion’ by EMEA’s CHMP, the European Commission (EC) has granted marketing authorization for Baxter’s  Celvapan H1N1 pandemic vaccine.  Celvapan H1N1 is the first cell culture-based, non-adjuvanted, pandemic influenza vaccine to receive marketing authorization in the European Union.  The other two approved H1N1 vaccines are Pandemrix and Focetria, both of which are produced  in eggs and contain oil-in-water emulsion adjuvants. GSK’s Daronrix is the remaining vaccine that has been authorised as a ‘mock up’ vaccine for potential use during an influenza pandemic, but has not yet been approved in the EU for use in the current H1N1 pandemic. 

Celvapan H1N1 is an inactivated whole virion  vaccine that contains 7.5 mcg of antigen in a 0.5 ml dose.  Whole virion vaccines contain a complete virus that has been purified from the production matrix by centrifugation.  For Celvapan, 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.   Pandemrix and Focetria differ from Celvapan in that they have had the viral surface antigens dissociated and purified from the virus by detergent treatment and centrifugation, so they are termed split virus vaccines.

A careful reading of the EPAR for Celvapan H1N1 reveals that a major objection was raised during the review process.  Baxter had not provided validation  data from commercial-scale production batches for virus inactivation by formaldehyde.  This objection was finally resolved after Baxter provided a scientific justification that supported the high capacity of the process to effectively inactivate H1N1 virus within a short time frame.  CHMP concluded that a sufficient safety margin existed for vaccine production at an industrial scale.  In addition, Baxter committed to provide additional inactivation data on three industrial scale batches to confirm the existing results.

The review process also identified problematic bacterial contamination of cell culture medium; 3 out of 16 commercial fermentation batches were contaminated (through 23rd September 2009).  The three batches were consecutive and kept in quarantine.  A root cause for the contamination was ultimately identified and corrective measures were put into place to prevent future contaminations.  A product related inspection at the manufacturing site confirmed the conclusions that the root cause for the bacterial contamination during the fermentation was identified and corrective actions were effective.

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 world’s current manufacturing capacity is cell-culture based.  Baxter produces Celvapan in Bohumil, Czech Republic.

Celvapan is the first approved cell-culture-based pandemic influenza vaccine, but not the first approved cell-culture-based  influenza vaccine.  Novartis’ Optaflu is a seasonal trivalent inactivated influenza vaccine produced in cell culture and granted marketing authorisation in the European Union in June 2007.  Optaflu is also an inactivated, detergent disrupted and purified product.  It is produced in Madin Derby Canine Kidney (MDCK) cells.  The MDCK cell line was originally established from the kidney of an adult male cocker spaniel in 1958 by Madin and Derby at UC Berkeley, California.  No cell-culture based influenza vaccines have been approved to-date in the US, although capacity is currently being created by companies like Novartis and GSK through HHS funding.

Now that marketing authorisation of the pandemic vaccines Celvapan, Focetria and Pandemrix has diversified the approved technologies for influenza vaccines, it seems likely that Baxter, Novartis, and GSK will shoot for approval of lower doses, Vero cell technology, and ASO3 and MF59 adjuvants in their seasonal influenza vaccines.  I anticipate a  glimpse of this in 2010, although it seems unlikely that there will be any changes for the 2010-2011 season vaccines themselves given the timeline for manufacture.  Of course, if the decision is made to include the A/California/07/2009 (H1N1)v strain in the 2010-2011 seasonal vaccine, things could get very interesting.

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Posted in Adjuvants, H1N1 Flu | 1 Comment »

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.

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Posted in H1N1 Flu | No Comments »

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

Friday, 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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Posted in H1N1 Flu | 3 Comments »

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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Posted in H1N1 Flu | 3 Comments »