Archive for July, 2009

ACIP Recommendations for H1N1 Vaccine

Wednesday, 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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VRBPAC Meeting on H1N1 Vaccine

Wednesday, July 22nd, 2009

In anticipation of the Vaccines and Related Biological Products Advisory Committee (VBRPAC) meeting scheduled for July 23rd, FDA’s Office of Vaccines Research and Review has issued a briefing document covering the ‘regulatory considerations regarding the use of novel influenza A (H1N1) virus vaccines’.  The document reduces the speculation around the performance of the seed strain virus, H1N1 vaccine timing, clinical studies, and the use of adjuvants.

On May 26th 2009 WHO recommended that novel influenza A (H1N1) vaccines should contain A/California/7/2009 (H1N1)v-like virus.  Five reassortants of this virus (X179A, IVR-153, IDCDC-RG15, NIBRG-121, CBER-RG2) were made available to vaccine manufacturers to prepare seed virus for vaccine production.  The FDA briefing document reveals that initial growth studies suggest the virus yield from the H1N1 reassortants are lower relative to the yields for seasonal influenza vaccines.  Novartis and Baxter have confirmed this.  Novartis has observed the yield for the H1N1 vaccine to be 30% to 50% of that for the company’s seasonal vaccine.  Baxter’s CEO Robert Parkinson has noted that ‘yield optimization’ will be a challenge.  

Since virus yield is directly proportional to the number of H1N1 vaccine doses, a 50% decrease in yield will result in it taking twice as long to manufacture the projected 600 million doses of H1N1 vaccine required to immunize the U.S. population.  Going back to the assumption of the WHO working group on H1N1 vaccines, it is evident that the yield assumption has not been met and hence the total global capacity for vaccine production of 4.9 billion doses over a 12 month period has dropped accordingly.

In addition to yield issues, the briefing document addresses how the availability of potency reagents affects the timing of vaccine availability.  Potency reagents consist of laboratory derived standard antiserum and positive control antigens, and are used in a method called the SRID assay, a somewhat archaic immonodiffusion technique for establishing potency discussed in this blog on May 17th. 

CBER is targeting mid-late July for availability of the reference antiserum and antigen, which would lead to an early August date for the availability of formulated inactivated vaccine for clinical trial material.  Live attenuated viruses, such as that produced by Medimmune, do not require the SRID for formulation and are not subject to the same limitations.  Interestingly, FDA notes that if reagents are not available to formulate the vaccine in time for clinical studies, alternate methods may be considered.  It is not obvious what these other methods are, although the EPAR for Celvapan does describe an HPLC method for hemagglutinin (HA) quantification that was deemed acceptable by CHMP during a  Scientific Advice process.

The clinical studies considerations put forward by FDA are fairly straightforward, although it is noted that if clinical trials cannot be completed in time to inform policy decisions regarding use of the H1N1 vaccine, then FDA will be flexible thus decisions on H1N1 vaccine formulation and use may have to be made based on results from smaller or incomplete clinical studies.

Day 0 and 21 immunizations have been recommended for evaluation in adult and pediatric populations.   Recommended study doses are as expected:  7.5 micrograms and 15 micrograms of HA in the pediatric and adult populations, with an additional 30 microgram dose in the adult population.  The University of Maryland Baltimore Medical School’s Centre for Vaccine Development , part of the Vaccine and Treartment Evaluation Unit (VTEU) will be one of the first sites to lead these studies.  CSL of Australia, who produce a U.S. licensed seasonal inactivated influenza vaccine, announced today that they initiated a trial of their H1N1 vaccine in Adelaide, and expect the vaccine to be proven safe and immunogenic by the end of September.  HHS has ordered $180 million of H1N1 vaccine from CSL.

FDA notes in the briefing document  that there are currently no U.S. licensed influenza vaccines containing an adjuvant, but acknowledges that in the light of both limited global capacity for production of an H1N1 vaccine, and the real possibility that a single dose of unadjuvanted vaccine may not yield an adequate immune response, adjuvants are being considered.  Novartis and GSK will evaluate their oil-in-water emulsion adjuvants for enhanced immunogenicity and dose sparing in separate arms of the adult and pediatric studies.  A dose of 3.8 micrograms of HA in place of the 30 microgram dose is recommended for the adjuvant groups.  HHS recently purchased $344 million of Novartis’ MF-59 adjuvant and $71 million of GSK’s AS03 adjuvant for pandemic use.

Both licensure and Emergency Use Authorization (EUA) are discussed as regulatory pathways for making the H1N1 vaccine available.  Licensure would require the H1N1 vaccine to be manufactured using the same process as a U.S. licensed seasonal inactivated influenza vaccine or a seasonal live attenuated influenza vaccine, and would require the generation of the clinical data described above. The EUA option is more likely for H1N1 vaccines containing the MF-59 or AS03 adjuvants, since no U.S. licensed vaccine contains these adjuvants.

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H1N1 Vaccine for UK – Redux

Friday, July 17th, 2009

On July 13th this blog discussed in detail a letter sent by David Salisbury, the UK’s minister for immunisation, declaring that an H1N1 vaccine will be available in the UK in August.  The letter described immunization schedules and who would be providing the vaccine, leading one to conclude that clinical trials to show the vaccine was safe and immunogenic had been completed.

In an interview with the UK’s Guardian newspaper  Dr. Margaret Chan, the WHO Director General, clarified the H1N1 vaccine situation.  She confirmed that WHO expects an H1N1 vaccine to be available in August, but pointed out that vaccine availability is not the same as having a vaccine that has been proven to be safe.  Her projection was that clinical trial data would not be available for two to three more months from now. 

Baxter Healthcare, one of the two Pharma companies contracted to provide H1N1 vaccine to the UK, has said that it should be ready to ship vaccine by the end of July or early August.  It now appears that clinical trials began in early July, which means clinical data would not be available for submission to regulatory agencies until September at the earliest.

So, late September or early October seems a more realistic time-frame for the first immunizations in the UK.

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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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