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NBSB Pandemic Influenza Working Group Detailed Report If a potency reagent is available in early August, the product could be ready for clinical trials in early September, and the first data would be available in November. Pilot data from GSK's smaller trials in Europe, including interim analyses after administration of dose 1 (in a 2-dose schedule), could be available somewhat earlier, in October. Novartis Vaccines and Diagnostic—Rino Rappuoli, Ph.D. Dr. Rappuoli said Novartis has been working on pandemic influenza since 1999. The company plans to begin trials of an H1N1 vaccine with and without adjuvant in late July or early August. Studies will include about 4,000 children and adults ranging in age from six months to over 65 years. Data analysis should be completed by October or November, but preliminary data may be available sooner. Data from influenza cell culture trials in Europe may be available in September. Novartis’ adjuvant, Mf59, has been licensed for use in Europe since 1997 as part of a seasonal influenza vaccine, and 45 million commercial doses have been distributed. It provides protection against drifted strains. Data comes from 120 studies involving more than 200,000 subjects, including a database of pediatric patients. After one dose, Mf59 stimulates strong response from helper B cells and T cells. Boosting with Mf59 induces a protective immune response against all H5N1 isolates in seven days. H5N1-plus-Mf59 prepandemic vaccine increases antibody production when compared to unadjuvanted vaccine and so reduces the amount of antigen needed. It also demonstrates cross-reactivity against most H5N1 subclades that have caused human disease, and Novartis has seen cross-coverage when Mf59 is combined with seasonal influenza vaccine. After a primary vaccine is administered, a booster dose can be given 6-8 years later and demonstrate protection in 7 days. The prepandemic vaccine has a favorable safety profile and a growing clinical database that includes children as young as six months. The combined safety data for Mf59 provided to FDA include 25,000 cases compared with normal influenza vaccine. Adverse events are all local reactions that resolve quickly. Novartis is currently conducting a 3-year trial in Italy of 150,000 elderly people. The pharmacovigilance database from that study includes spontaneous reports after 40 million doses and has revealed no safety signals for selected adverse events. Novartis is producing a cell-culture based H1N1 vaccine at its facility in Germany and is working with HHS to build a plant in North Carolina. With the addition of the North Carolina plant, Novartis will have the capacity to produce 150 million doses. Novartis is planning to have commercial production of prepandemic vaccine, adjuvant, and seasonal influenza vaccine in 2012. Novartis’ influenza cell culture (Optaflu) demonstrated efficacy of 84% against vaccinelike virus strains when compared with placebo. Adjuvanted influenza cell culture H5N1 20
NBSB Pandemic Influenza Working Group Detailed Report vaccine is both antigen- and adjuvant-dose-sparing. Novartis has limited capacity to produce this product, but it can still be available quickly. Dr. Rappuoli concluded that Novartis has had an ongoing partnership with HHS to develop an H5N1 vaccine. It is working to develop a novel H1N1 vaccine for current pandemic in adjuvanted and unadjuvanted formulations, with potential use of Mf59 potential for dose sparing and cross-protection. MedImmune, LLC—Raburn Mallory, Ph.D. Dr. Mallory explained that the FluMist A (H1N1) is a monovalent live attenuated 6:2 reassortant vaccine. It will be delivered intranasally via a unit-dose AccuSpray device at 0.2 mL per dose (0.1 mL in each nostril). It contains no preservative or adjuvants. The vaccine dose is fixed on the basis of clinical efficacy studies conducted with MedImmune’s trivalent seasonal influenza vaccine, FluMist, at 10 6.5-7.5 FFU (fluorescent focus units). Lower doses resulted in lower efficacy in one study, and higher doses are constrained by sporadic fever rates and the manufacturing process. While no correlate of protection (e.g., seroprotective hemagglutination inhibition assay [HAI] titers) has been identified, vaccination generates a broad immune response including cellular, humoral and mucosal responses. MedImmune conducts an annual study to incorporate new influenza strains into FluMist and the FluMist A (H1N1) studies are based on this design. Two concurrent, placebocontrolled, clinical studies are planned to evaluate the attenuation of the new influenza A (H1N1) vaccine; one in adults ages 18–49 years (n = 300 subjects) and one in children ages 2–17 years (n = 300 subjects). The subjects in the studies will receive two doses approximately one month apart. Investigators will evaluate fever rates and serum immune responses after each dose and also look at solicited symptoms and adverse events. Initiating the studies depends on selection of the final master virus seed, which Dr. Mallory expected to occur shortly. The clinical studies will begin in August and initial safety data will be available about 1 month after the first patients are enrolled. The annual strain change procedure that MedImmune usually follows with CBER would allow for vaccine approval based on this safety data. Immunology data could be available beginning in October, which may be late in terms of the planned distribution of the vaccine. Sanofi Pasteur—James Matthews, Ph.D. Dr. Matthews said Sanofi Pasteur is doing parallel work on H1N1 vaccine in Europe and the United States. The company has been working on a clinical development plan for the United States since the end of April. It is currently negotiating with CBER on proposed trial designs. CBER has asked the company to expand the number of subjects in the clinical trials (from 1,500 to 3,100 children and adults), limit the number of formulations tested, and place less emphasis on the adjuvanted formulations. Sanofi Pasteur’s proposed protocol would have provided some data by mid-October, but accommodating CBER’s requests will affect the timeline of studies and availability of data. The company has proposed to drop one of its non-adjuvanted formulas from its studies; also, it may not 21
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