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NBSB Pandemic Influenza Working Group Detailed Report with a thimerosal preservative and is mixed before injection with AS03, a tocopherol based emulsion adjuvant system also presented a 10-dose vial. The adjuvant is manufactured in Belgium and the United States; the antigen is manufactured in Dresden (D) and Quebec (Q); the processes differ depending on the location. GSK’s Dresden-manufactured H5N1 vaccine is approved in the European Union (EU), Australia, Singapore, Malaysia, and Hong Kong. GSK plans to submit the Q H5N1/AS03 vaccine for approval in Canada and the United States in 2009. The company has clinical data from 3,500 adults, ages 18–93 years, and a safety summary from approximately 9,900 adults, including completed studies with the Dresden vaccine. GSK believes the data are sufficient to support use of the H1N1/AS03 vaccine under an EUA and eventually licensure. Clinical data suggest that the Dresden- and Quebec-manufactured H5N1 antigens plus adjuvant have equivalent immunogenicity. Current plans permit GSK to initiate clinical trials of a Dresden-produced H1N1 pandemic vaccine several weeks before trials of the Quebec product. Dr. Innis noted that early data from the Dresden vaccine can guide emergency use of the Quebec product. The H5N1 vaccine is highly immunogenic in children and adults and even in the elderly, despite prior TIV vaccination. These responses greatly exceed the thresholds for seroconversion mandated by CBER in its guidance. The correlates of immunity against pandemic influenza A are unknown. Therefore, GSK has investigated the effect of its adjuvant on cell-mediated as well as humoral immunity. The company’s evidence shows that the adjuvanted H5N1 vaccine generates better T and B cell memory than unadjuvanted vaccine. Immunization with the H5N1 vaccine is protective. In ferrets administered a range of doses of adjuvanted vaccine or control vaccine on days 0 and 21 and challenged 4 weeks later, all the controls died, and 22/23 animals receiving the adjuvanted vaccine survived. Moreover, the adjuvanted vaccine reduced the amount of virus in the subjects’ lung tissue by at least 3.5 logs compared with controls. Immunity elicited by the H5N1 vaccine protects against severe disease and is likely to reduce virus shedding, potentially reducing virus transmission. Although two doses of vaccine are required, the GSK H5N1/AS03 vaccine can be administered as two injections in separate extremities at a single visit and still achieve protection. This approach saves both time and antigen. Vaccine with the AS03 adjuvant is a new product, and GSK has made unparalleled efforts prelicensure to evaluate its safety. The company has compiled safety data from adults in eight completed trials of H5N1/AS03 vaccine manufactured in Quebec or Dresden. Subjects were followed for 6 months after vaccination. Rates of medically attended and serious adverse events were comparable between the vaccine and controls. The total number of adverse events with adjuvanted vaccine is slightly higher than the total for controls because of increased reports of reactogenicity during the days 18
NBSB Pandemic Influenza Working Group Detailed Report immediately following vaccination. These events were predominantly mild and transient. There was no escalation with the second dose, and compliance in receiving the second dose was above 95%. GSK agreed with CBER to query the data for a list of 120 immune-mediated diseases, called adverse events of special interest (AESIs). There were 16 AESIs in the H5 group and one among the controls (p > 0.2). GSK ran the same query on a pooled database of 11,721 subjects enrolled in five clinical trials of TIV conducted by GSK since 2004. Comparing the data demonstrates that the events reported more than once in the H5 group also appear in the TIV control group. These data provide no evidence for an association of any single event or of this class of events with the H5N1/AS03 vaccine. GSK’s safety summary supports a favorable risk-benefit profile for AS03-adjuvanted influenza vaccines and additional trial data are forthcoming. GSK has investigated two reports of asymptomatic autoimmune hepatitis. In case 1 (a child) the condition existed before vaccination and is in remission following treatment. In case 2 (an adult), the condition resolved spontaneously, and experts have cast doubt on the diagnosis. Since September 2008, GSK has been following a cohort of 43,000 elderly subjects vaccinated with TIV/AS03 or control, and their safety data are being reviewed by an Independent Data Monitoring Committee. GSK recently expanded the pooling of safety data to include recipients of any influenza vaccine with AS03. Results from this analysis of 20,500 adults exposed to AS03 will become available in July. The planned clinical development of H1N1 vaccine with AS03 includes at least 13 trials of D- or Q-H1N1 vaccine in the United States and Canada or in Europe, with over 5,000 children and adults exposed to adjuvanted vaccine. The trials performed under an investigational new drug application (IND) are all randomized, blinded trials using antigen-only vaccine as a control. The adjuvanted vaccine will be evaluated simultaneously in children and adults. The trials will evaluate the benefit of the adjuvant in terms of dose-sparing, efficacy, and immunogenicity compared with antigen-only vaccine, and the two-dose, one-visit schedule. The possibility of interference between TIV and the pandemic vaccine will be evaluated when these products are coadministered or given sequentially. GSK will assess whether AS03 can overcome interference and will also confirm the equivalent immunogenicity between D and Q products. GSK will rapidly expand the safety database for this new vaccine. By December, the Company anticipates that 4,340 subjects will have been exposed to H1N1/AS03 in a GSK trial. Because the use of a novel adjuvant raises questions that can be addressed best by longterm follow up, GSK is discussing with HHS the need for a large, simple safety study involving, for instance, 40,000 persons who would be followed for up to two years after vaccination. 19
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