Posts Tagged ‘adjuvant’

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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GSK’s H1N1 Vaccine: A Split Personality

Thursday, 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

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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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.

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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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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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Clinical Trials of Candidate H1N1 Vaccines

Thursday, July 9th, 2009

Vaccine manufacturers will initiate small-scale clinical studies to evaluate the safety and immunogenicity of their respective candidate H1N1 vaccines prior to initiating commercial production.  CDC released the reassortant virus stock to the manufacturers back on May 27th 2009, so the H1N1 vaccine clinical studies should be starting in July.

H1N1 vaccine recipients will be immunologically naive with respect to the H1N1 virus.  This is different to the situation encountered with seasonal flu vaccines, when vaccinees are usually primed by natural exposure to flu virus or by a history of flu vaccination, and only require a single dose of vaccine to achieve seroprotection.  In addition, little is known about the immunogenicity of the H1N1 vaccine, so the H1N1 vaccine trials will differ from those routinely performed for seasonal vaccines.

Clinical studies for regulatory approval of seasonal vaccines evaluate a single 15 microgram dose of each of the three seasonal strains. Reviewing published clinical studies on H5N1 vaccines such as Focetria and Pandemrix, the H1N1 vaccine studies will probably evaluate a two-dose schedule (0 and 21 days) and several strengths of vaccine (probably 7.5, 15, and 30 micrograms).  When the manufacturer has access to an adjuvant, there likely will be an arm of the trial that evaluates the adjuvant for dose-sparing and enhanced immunogenicity effects.

CSL of Australia have now announced that they are ready to commence a clinical trial of their H1N1 vaccine candidate, with vaccinations beginning mid-July in healthy adults between 18 and 64 years of age.  They have confirmed they will evaluate a two-dose schedule of 0 and 21 days, and compare a standard dose of the vaccine with increased dosages.  The standard dose would be 15 micrograms, suggesting CSL does not expect a 7.5 microgram dose of their vaccine to be sufficiently immunogenic.  If this is so, and applies to other manufacturers vaccines, this will have significant impact on the the number of H1N1 vaccine doses that can be produced with the current manufacturing capacity

It should take about 6 weeks to complete and analyze the initial immunogenicity portion of the CSL clinical study, so information on proposed dose and regimen for the CSL H1N1 vaccines should be available by the end of August.  Novartis have also confirmed they are initiating their clinical studies in July, so there should be some comparative data available that will begin to clarify the picture with respect to vaccine availability and capacity.

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HHS Orders Around the World

Monday, June 1st, 2009

Health and Human Services (HHS) has inked deals with five flu manufacturers to supply bulk H1N1 vaccine; Australia’s CSL ($180 million), GlaxoSmithKline ($181.1million),  Sanofi Pasteur ($190.6 million), Novartis ($288.8 million), and MedImmune ($90 million).   The HHS funding comes from the $1 billion released for pandemic preparedness on May 22nd to facilitate the manufacture of bulk vaccine.  Another $150 million of this funding will go to the above companies to conduct clinical evaluation of pilot lots for dose, regimen and safety.

Sanofi Pasteur manufactures its bulk flu vaccine at the Swiftwater facilities in Pennsylvania.  CSL will manufacture bulk vaccine in Victoria Australia, GSK in Dresden Germany, MedImmune in Speke UK, and Novartis in Siena Italy or Liverpool UK.    Sanofi Pasteur will be the only manufacturer who produces vaccine on US soil.   So if the Stage 6 H1N1 pandemic comes to pass both the virus and the solution will be global.  There isn’t enough local capacity for national vaccine production, as has been seen historically for seasonal vaccine production, and was so clearly highlighted by the Chiron supply failure in 2004. 

WHO predicts the top end of global H1N1 capacity to be 4.9 billion doses over a 12 month period after full-scale production is initiated.  The two assumptions underlying this prediction are that there is a vaccine yield equivalent to that routinely obtained for seasonal vaccine, and that there is the use of the most dose-sparing formulations.

WHO must be banking on vaccine manufacturers to produce adjuvant-containing formulations for dose-sparing.   Apparently HHS has heard the call; the H1N1 orders to GSK and Novartis included an order for their proprietary adjuvants, AS03 and MF59C.1 respectively, both squalene containing oil-in-water emulsions that can significantly decrease the dose of antigen needed to produce the required immune response.  Since both can be added to the antigen at the time of administration, adjuvant production is decoupled from that of the antigen;  there is no need for coformulation.  This mitigates the risk of an untested, adjuvanted flu-vaccine being the solely produced pandemic vaccine.  FDA is likely to approve the H1N1 antigen‑alone formulation which could be distributed without the adjuvant in the case of a pandemic.

HHS’ hedge still has a silver lining.  Perhaps egged on by its parent organization, FDA will approve an H1N1 flu vaccine containing a novel, non-alum, adjuvant as discussed in this blog on 18th May 2009.  This would be a winner.

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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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Adjuvanted H1N1 Vaccine from GSK

Monday, May 18th, 2009

GlaxoSmithKline (GSK) has shed some light on the H1N1 vaccine production arena, announcing that they have received orders from governments aiming to stockpile a new candidate H1N1 vaccine. The announcement provides several data points on plans for the vaccine.

GSK expects the first doses of the vaccine to be available 4-6 months after receiving the virus seed from the WHO. I think the virus seed could be ready as early as June, putting vaccine availability in the Q4 2009 timeframe. They have noted that they plan to complete the 2009/2010 seasonal influenza vaccine campaign by the end of July. This is consistent with the proposed timeline for H1N1 vaccine production, allowing it to begin in August.

Of course all of this is subject to regulatory approval. However the pandemic vaccine will be produced by a similar process to the seasonal vaccine and in the same facilities, so it seems improbable that there would be any significant regulatory delays. GSK already received a European license for a pandemic vaccine based on a ‘mock-up’ dossier, and expects this to facilitate a faster registration of the new A (H1N1) vaccine. This is currently being discussed with EU regulatory authorities.

A notable aspect of the GSK pandemic vaccine is the proposed inclusion of GSK’s proprietary ASO3 adjuvant. ASO3 is an alpha-tocopherol based oil-in-water emulsion, similar to Novartis’s MF59. Adjuvants typically stimulate 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 formulation. This effect can decrease the amount of antigen required in a dose and hence increase the number of vaccine doses that can be produced. In addition an adjuvanted flu vaccine has the potential to provide protection even if the strain drifts, a distinct possibility with the current H1N1.

This is of such interest because, to the best of my knowledge, no non-alum adjuvanted vaccine has been approved by the US FDA. A recent NIAID/NIH sponsored workshop was held to discuss adjuvants, including their inclusion in pandemic flu vaccines. The emergence of H1N1 could accelerate the resolution of the adjuvant debate as the US Department of Health & Human Services grapples with the potential public health emergency.

The seasonal influenza vaccine contains a 15mcg dose of each of three antigens, and no adjuvant. If prepared as a pandemic vaccine, the H1N1 vaccine will contain only the single antigen. It is unknown at this time how much unadjuvanted antigen will have to be included in the vaccine formulation to elicit seroprotection, but for the H5N1 vaccine as much as 90mcg per dose has been required. The adjuvanted dose could be as low as 3-10mcg, realising a significant increase in the available doses. The H5N1 pandemic vaccine requires two doses to seroprotect, so it is also possible that the H1N1 vaccine will be similar, requiring 2 doses. This will place additional strain on the available manufacturing capacity. An adjuvant may become mandatory for translating the available manufacturing capacity into sufficient doses to meet global demand, and GSK clearly intend on travelling down that pathway. It will be fascinating to see how FDA reacts.

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