European H1N1 Vaccine Latecomers Herald the Regulatory Acceptance of Innovation

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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Recombinant Seasonal Flu Vaccine

December 14th, 2009

The  2009 H1N1 pandemic has highlighted that  however well a nation prepares for the emergence of a new influenza virus strain,  the mechanics of producing the vaccine remain perhaps the greatest obstacle to a successful immunization program. 

The manufacturing process approved in the US for both the seasonal and 2009 H1N1 pandemic vaccine is a lengthy one.  The seasonal vaccine, with its three strains can take at least 8 months from strain identification to becoming available.  The single strain pandemic H1N1 vaccine took 5 months from strain identification to distribution.

The egg-based manufacturing process  requires generation of a seed virus, growth of the virus in eggs, isolation of the hemagglutinin antigen from virus, QC testing of the monovalent bulk antigen, formulation, fill, and finally QC testing of the finished vaccine.  Difficulties that can occur during the process, such as slow virus growth and low yields, both increase the time to vaccine availability and decrease the amount of vaccine available — undesirable outcomes, especially in a pandemic scenario. 

Sure enough, the worst came true for the 2009 H1N1 pandemic vaccine.  Manufacturers encountered both slow virus growth and low yields of hemagglutinin.  During Novartis’s October 22nd third quarter earnings call,  CEO David Vasella stated that the H1N1 strain had yields of about 23% of a normal influenza yield.

The difficulties associated with producing a vaccine from an egg-adapted virus leads to the obvious question of why there is not a recombinant flu vaccine production technology.  Recombinant proteins, which can be produced in weeks rather than months, have been around since the commercial production of insulin by Eli Lilly in 1982. 

To date there are no approved recombinant influenza vaccines, although several are in development.  Protein Sciences’ Flublok, an investigational seasonal recombinant influenza vaccine, which has been discussed before on this blog, is the nearest thing to an approved recombinant vaccine in the US.  It is produced in insect cells using the baculovirus expression system, the same technology used to produce Cervarix, GSK’s HPV vaccine.  Protein Sciences estimates that the cloning,  expression, and manufacture of Flublok can be accomplished in under 2 months. 

Protein Sciences began development of Flublok in the mid ’90s under three different INDs held by the NIH/NIAID, only sponsoring the last five clinical trials themselves.  They finally  submitted their BLA over 10 years later,  in April 2008.   The VRBPAC met on November 19th to review the safety and effectiveness of Flublok.  The committee was asked to answer three specific questions.

  1. Do the available clinical data support an indication in the prevention of flu caused by subtypes A & B included in the vaccine in adults 18 – 49 years of age, 50-64 years of age, and 65 years and older?       
  2. Do the available data support the safety in adults 18 years and older?     
  3. Please comment on what additional studies, if any, should be requested post-licensure 

In summary, the committee was less than impressed.  Members voted in favor of the vaccine for only the 18-49 age group in answer to Question 1, and they voted against the vaccine in answer to Question 2.  Several suggestions were made in response to Question 3, including additional safety studies in subjects over 65 years of age, and properly powered efficacy studies, especially in the over 65 population.

However the committee did recognise the benefit of the potentially faster egg-free production, especially in the context of a pandemic, but these theoretical benefits did not sway the committee in favor of the vaccine.

Given Flublok’s lukewarm debut at the advisory committee it will still be a while before a recombinant seasonal flu vaccine is approved, with the indication likely limited to the the less at-risk 18-49 year old population.  Insurmountable though it seems approval of a recombinant seasonal flu vaccine is not the finish line — people can’t get vaccinated until there is adequate manufacturing capacity to produce the vaccine.

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GSK’s H1N1 Vaccine: A Split Personality

November 12th, 2009

Tuesday’s  FDA approval of  GSK’s H1N1 vaccine means all five of the manufacturers  approved to manufacture and distribute the 2009-10 seasonal influenza vaccine (CSL, GSK, MedImmune, Sanofi-Pasteur, and Novartis) are now approved to manufacture and distribute H1N1 vaccines .

The unadjuvanted GSK H1N1 vaccine is actually manufactured in Canada by ID Biomedical Corporation of Quebec, which is owned by GSK.  The process used to produce the hemaggluttinin antigen (HA) is the same as that used for production of the antigen in the seasonal influenza vaccine Fluviral, which has been approved in Canada since 1992 and in the US as Flulaval since October of 2006.

The United States Department of Health and Human Services has placed an order to fill 7.6 million doses of  H1N1 pandemic vaccine from GSK, which will contribute to the approximately 250 million doses secured by the US government.  The vaccine will be produced in multi-dose vials from bulk vaccine manufactured at GSK’s facility in Quebec, Canada.  GSK expects to begin shipping vaccine in December and to provide all 7.6 million doses by the end of the year.

The  HHS order was for $38 million of vaccine, suggesting a cost of $5 for each of the 7.6 million doses.  As discussed in this blog on September 21st, this is in line with the $5.30 per dose paid for the 75.3 million doses contracted from Sanofi, but still a considerable discount to the price of  $10.65 a dose for the 42 million doses contracted from MedImmune.

The GSK H1N1 vaccine is an inactivated split virus influenza vaccine that will be administered as a single 0.5 ml dose containing 15 mcg of antigen.  The multi-dose format of the vaccine packaging necessitates the inclusion of the preservative thimerosal, which is an organo mercury compound with antibacterial properties, included to allow multiple withdrawals to be made from the vial up to a prespecified period of time after the first entry.

In contrast to the unadjuvanted GSK H1N1 vaccine approved in the US,  Canadians will get an oil-in-water AS03 adjuvanted version of the same vaccine,  called Arepanrix.  

After review of the available data on quality, safety, and immunogenicity, Health Canada have concluded that the benefit/risk profile of the Arepanrix H1N1 vaccine is favourable for active immunization against the H1N1 2009 influenza strain and issued a Notice of Decision for the vaccine.  The Minister of Health authorized the sale of Arepanrix on October 21st, 2009 based on the limited clinical testing in humans under the provision of an interim order issued by request of the Public Health Agency of Canada on October 13th.

As described here in earlier blogs about the European pandemic vaccine approval process, Canada employed the mock vaccine approach, developing an H5N1 vaccine in the pre-pandemic period.  Health Canadainspected the antigen  manufacturing facilities, evaluated data from the process, and reviewed both animal and human data from studies performed with the mock vaccine.  Safety and effectiveness of the AS03 adjuvant was also evaluated and deemed acceptable.

Arepanrix H1N1 vaccine is given as a single 0.5 ml intramuscular dose containing 3.75 mcg of hemagglutinin (HA) in the AS03 adjuvant.  As noted above, the HA antigen is manufactured in Quebec by ID Biomedical Corporation of Quebec.

Arepanrix is provided as a two-component vaccine.  One multidose vial contains the antigen and a second multidose vial contains the AS03 adjuvant.   The 10 ml H1N1 antigen vial contains 2.5ml of antigen.  The 3 ml AS03 adjuvant vial contains 2.5 ml of adjuvant.  Prior to injection the entire content of the AS03 vial is withdrawn, added to the H1N1 antigen vial, and mixed.  The mixed final product for injection is an emulsion containing enough vaccine for 10 doses, and contains 50 mcg of thimerosal, which is the equivalent of 2.5 mcg of organic mercury per 0.5ml dose.  This is ten fold less mercury as found in other multidose flu vaccines, probably because the final vaccine vial must be discarded within 24 hours of addition of the adjuvant.  Non adjuvanted multi-dose influenza vaccine vials, such as Flulaval, can be used for up to 28 days after the first entry, therefore typically include 25mcg of mercury per dose.

Now that the  H1N1 vaccines produced by the major manufacturers have all been approved, it’s a good time to survey the regulatory landscape.  As highlighted in this Blog entry, Health Canada has approved an adjuvanted H1N1 vaccine (Arepanrix).  Europe’s EMEA has approved both adjuvanted (Focetria and Pandemrix) and unadjuvanted (Celvapan) H1N1 vaccines.    Finally, FDA has only approved unadjuvanted H1N1 vaccines (GSK, Novartis, CSL, Sanofi, MedImmune), despite the fact that it’s parent organization, HHS purchased nearly $700 million worth of AS03 adjuvant from GSK and MF59 adjuvant from Novartis.

It is not clear why FDA has failed to join other regions in approving the adjuvanted vaccines, especially in the face of the more difficult production of the H1N1 antigen compared to the seasonal antigen.  The AS03-adjuvanted  GSK Arepanrix vaccine approved in Canada requires four-fold less antigen than the corresponding unadjuvanted GSK vaccine approved in the US.  A split personality indeed.

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Celvapan: Cell-Culture H1N1 Vaccine Approved

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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EMEA Approves Adjuvanted H1N1 Vaccines

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.

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HHS Purchases More MedImmune H1N1 Vaccine

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

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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Offshore H1N1 Vaccine Data – Single Shot

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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Low-Tech Solution to the Flumist A (H1N1) Dose Surplus

August 10th, 2009

MedImmune’s Flumist™ seasonal flu vaccine differs from the five other seasonal flu vaccines approved for use in the U.S. in two significant ways. First, it is a live attenuated influenza vaccine (LAIV), not an inactivated split or subunit vaccine. Secondly, it is administered intranasally via a special syringe that introduces large-particle aerosol droplets of the vaccine to the nasal mucosa.

The vaccine was approved by FDA in 2003 for active immunization for the prevention of disease caused by influenza A and B viruses in healthy children and adolescents, 5-17 years of age, and healthy adults, 18-49 years of age. In 2008, FDA approved expanding the population to include children between the ages of 2 and 5. 

The virus is attenuated, or weakened,  by inserting genes that confer the properties of cold adaption (ca) to efficient replication at 25°C, growth-restriction at 37°C (rt) for the Type B and 39°C for the Type A strains, and limited replication in the lungs of ferrets (att).  These genes come from the master donor virus strains ca B/Ann Arbor/1/66 and ca A/Ann Arbor/6/60.  The seed virus used for annual production of the seasonal vaccine is a 6:2 reassortant produced by reverse genetics.  There are 6 internal genes from the attenuated donor virus, and the HA and NA genes from the wild type virus.

When administered intranasally, the LAIV induces both serum and mucosal antibodies, an immune response that closely resembles the body’s natural response to influenza infection, but does not cause illness.  The syringe that delivers the intranasal dose is the BD AccuSpray, which is based on the BD Hypak SCF (sterile, clean, ready-to-fill) technology.  The total dose is 0.2 mL.  The plunger is installed with a dose-divider clip which only permits 0.1ml to be delivered to the first nostril when the plunger is depressed.  The clip is then removed so the plunger can be further depressed and deliver the remaining 0.1 mL dose to the second nostril.

In response to the H1N1 pandemic, HHS contracted with Medimmune for 12.8 million doses of the H1N1 strain of Flumist at a cost of $151 million.  Apparently Medimmune’s virus strain grew well; 20 million doses have already been produced, and the company projects they could produce up to 200 million doses by March 2010.  Unfortunately there are only sufficient Accusprays to fill approximately 40 million of these doses by March 2010.  BD has said it will run its sprayer factory around the clock to increase annual production from 20 million sprayers to 70 million.  However this would still leave a significant surplus of doses that cannot be filled.

Medimmune is working to define a path for an alternative delivery device, possibly a dropper, to optimize utilization of the additional bulk vaccine capacity.  This entails working with FDA’s CBER to gain the regulatory approvals needed for an alternative delivery device.  The dropper was used to deliver the vaccine in some of Medimmune’s earlier clinical trials.

Medimmune plans to conduct two concurrent placebo-controlled clinical studiesof the H1N1 candidate in 300 adults 18-49 and 300 children 2-17, using a two-dose schedule one month apart. They expect to have safety data from the first dose by early September and 29-day immunogenicity data by mid-October.  They expect to have safety data from the second dose by mid-October and 29-day immunogenicity data by early November. 

The Flumist device bottleneck highlights the supply chain challenges that will occur during the response to the pandemic, one that was clearly not anticipated in the case of Flumist. As discussed in this blog on May 20th, 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. 

Fortunately, in this case, the decidedly low-tech dropper may save the day.  The potential surplus of Flumist can then be used to expand the U.S. supply or provided to other countries.

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ACIP Recommendations for H1N1 Vaccine

July 29th, 2009

The Advisory Committee on Immunization Practices (ACIP) is appointed by the Secretary, Department of Health and Human Services (HHS) to advise and guide HHS and the Centers for Disease Control and Prevention (CDC) regarding vaccines and related agents for effective control of vaccine-preventable disease in the civilian population.  There was a special meeting of the ACIP on July 29th in Atlanta to discuss the use of influenza vaccines in the prevention and control of H1N1 influenza.

The committee considered the timing and availability of H1N1 vaccine doses and available epidemiology in order to make recommendations with respect to priority groups for H1N1 vaccination.  Initial feedback from the meeting indicates that the committee recommended that the first to receive the vaccine should be health-care workers, pregnant women, people with an infant too young (under 6 months) to be vaccinated in the household,  children and young adults up to 24 years of age, and people under 64 years of age with underlying medical conditions.  After people in the broader high-priority group receive the vaccine, then it may be offered to healthy adults between ages 25 and 64. Last in line would be people age 65 and over, because they have been less affected by this virus.

At the meeting Robin Robinson of the HHS’s BARDA (Biomedical Advanced Research and Development Authority)  said that the U.S. government has taken delivery of 20 million doses of H1N1 vaccine, had ordered a total of 195 million doses, and should be ready to start immunization in October.

It is not clear how the contracts with the manufacturers define ‘a dose’.  For a seasonal influenza vaccine a dose is 15 micrograms of each of the three strains of the flu virus.  However, the safe and effective dose of an H1N1 vaccine has yet to be determined; it could be as little as 3.8 micrograms or as much as 30 micrograms.  The NIAID (National Institutes of Allergy and Infectious Diseases) will launch some of the first U.S. based clinical trials through it’s Vaccine and Treatment Evaluation Units (VTEU), which are located at such sites as Baylor College of Medicine in Houston and Group Health Cooperative in Seattle. These clinical studies will guide the dose decision. The VTEU trials, specific details of which can be obtained at  clinicaltrials.gov, will all evaluate 15 or 30 microgram doses of the H1N1 vaccine on a 0 and 21 day schedule.

If the U.S. government assumes a dose of H1N1 vaccine , akin to the seasonal influenza dose per strain, then if a 30 microgram dose is actually necessary form immunogenicity, the number of doses contracted would be halved to 97.5 million.  If the vaccine contains an adjuvant then it is possible that less than a 15 micrograms dose will be effective, increasing the number of doses in the contract.  The briefing document for last weeks VRBPAC meeting, discussed on this Blog on July 22nd, described FDA’s recommendations that clinical trials should evaluate the safety and immunogenicity of antigen doses as low as 3.8 micrograms in the presence of adjuvant.  A 3.8 microgram vaccine dose would increase the number of doses available in the contract by four-fold, to 780 million, enough to immunize the whole U.S. population with a two-dose schedule.  My guess is that a 7.5 microgram dose with an adjuvant will be both safe and immunogenic, and will be the recommended dose for an adjuvanted H1N1 vaccine.  This would result in the original U.S. government contracts for 195 million doses being closer to 390 million doses.

From an operational perspective, the H1N1 vaccine currently being produced by the vaccine manufacturers is being held at the bulk antigen stage; i.e. the virus has been inactivated and split or purified as described on July 13th, has been assigned a strength by the SRID assay, and is being held as a sterile solution in large volumes at 2-8°C.  Once a dose of the vaccine has been recommended, the bulk will be diluted to the concentration required to deliver the final dose, and filled into syringes or vials.  These syringes and vials, which are the final dosage form of the vaccine, will then be tested by the manufacturers for such attributes as potency, purity, and identity, and finally released for distribution and use by FDA.

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