Posts Tagged ‘pandemic’

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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HHS Purchases More MedImmune H1N1 Vaccine

Monday, September 21st, 2009

Back on August 10th I discussed MedImmune’s intranasallive attenuated H1N1 influenza vaccine and the potential for a dose surplus.  HHS had contracted for 12.8 million doses of the vaccine at a cost of $151 million, with MedImmune having the production capacity to make up to 200 million doses by March 2010. However, MedImmune had only sufficient Accusprays to fill approximately 40 million of these doses in the same timeframe.

The U.S. Department of Health and Human Services (HHS) has now ordered an additional 29 million doses of MedImmune’s H1N1 vaccine, which when added to the original 13 million dose order, accounts for all of the Accuspray delivery devices.

The total contract value is now about $447 million for the 42 million doses, or $10.65 a dose.  HHS also ordered an additional 27.3 million doses of injectible inactivated vaccine from Sanofi Pastuer at a cost of $143.5 million.  The Sanofi contract is now at $396 million for 75.3 million doses, or $5.30 per dose, a condsiderable discount to the MedImmune price.

MedImmune began developing the vaccine at the end of April, and about 3.4 million doses have been released by the FDA. They are expected to be shipped to states the first week in October.

MedImmune was in discussions with FDA to define a path for an alternative delivery device, possibly a dropper, to optimize utilization of the additional bulk vaccine capacity, which appears to be about 150 million doses.  This entails working with FDA’s CBER to gain the regulatory approvals needed for an alternative delivery device.  Since HHS only purchased the amount of H1N1 vaccine for which there are sufficient Accusprays, the fate of the excess capacity remains unknown.

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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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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 Backs A Recombinant Baculovirus H1N1 Vaccine

Wednesday, 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

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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H1N1’s Billion Dollar Start

Wednesday, May 27th, 2009

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

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

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

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

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