The goal of this project is for Crucell to manufacture clinical-grade master virus seed stocksand trivalent, clinical-grade rAd26 and rAd5HVR48 vaccine products for the clinical trials describedin Project 2. Crucell Holland BV is a medium-sized biotechnology company that is dedicated to thedevelopment of vaccines for infectious diseases. In particular, Crucell has pioneered the development of rAdvector-based vaccines and has developed vectors from Ad serotypes that have low seroprevalence inhuman populations. Crucell has also been a leader in the preclinical-to-clinical translational development ofrAd vector-based vaccines for a variety of pathogens. In particular, Crucell has developed robust productionand purification methods to manufacture clinical-grade rAd vaccines. Crucell has also standardized andvalidated release assays and has developed several packaging cell lines that support pharmaceutical-scalemanufacturing in full compliance with Good Manufacturing Practice (GMP) guidelines. Vaccine candidatesbased on several different Ad serotypes have been manufactured and released by Crucell and have recentlyentered clinical trials for Ebola, malaria, and tuberculosis in both the United States and South Africa.Crucell will guarantee uniform, high quality manufacturing of the rAd vaccines as well as strictadherence to Standard Operating Procedures (SOPs) and rigorous quality control / quality assurance(QC/QA) standards in full compliance with all pertinent regulatory authorities. Research-grade vaccines willbe provided for the GLP preclinical toxicology studies in rabbits, and clinical-grade vaccines will bemanufactured for the phase 1 and phase 2a clinical trials described in Project 2.In our current IPCAVD AI066305 program, we have developed rAd26 and rAd5HVR48 GMPmanufacturing processes and release assays that have already been approved by the FDA. In Project 3,we propose to utilize and to improve these existing production processes and analytical assays tomanufacture and release the multivalent rAd26 and rAd5HVR48 clinical vaccine products. Toaccomplish these goals, we propose the following three Specific Aims:1. To manufacture and release clinical-grade master virus seed stocks for rAd26 and rAd5HVR48vectors expressing the optimal HIV-1 Gag-Nef, Pol, and Env antigens under GMP conditions;2. To improve our current manufacturing processes for rAd26 and rAd5HVR48 vectors by optimizingvector yields at harvest and downstream purification steps; and3. To manufacture, purify, release, and monitor the stability of trivalent, clinical-grade rAd26 andrAd5HVR48 vaccines expressing the optimal HIV Gag-Nef, Pol, and Env antigens under GMP conditions.
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