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.
