Project 2 - GMP Manufacturing of mRNA Immunogens

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HIV vaccine candidates entering into clinical testing generally fall into three categories: 1) recombinant envelope (Env) protein immunogens, 2) viral vectors, and 3) plasmid DNA. Numerous vaccine Env designs are being tested in clinical trials. Likewise, numerous HIV vaccine inserts, such as mosaic sequences, have been designed to induce broad, protective T-cell responses. However, to date, no specific vaccine regimen has been able to initiate and expand broadly neutralizing antibody (bnAb) lineages in non-human primates or humans, nor have induced durable antibody responses. Furthermore, the current platforms have multiple challenges; the manufacturing processing for sequential protein vaccines may be complex and time- consuming, viral vectors may have potential pitfalls of anti-vector immunity, and plasmid DNA may have the need for complex delivery systems to enhance immunogenicity. These potential hurdles highlight the need for a next generation vaccine platform that possesses favorable production, safety, and immunogenicity characteristics such as nucleoside-modified messenger (m) RNAs in lipid nanoparticles (LNPs). To execute this project, we will select CDMO partners to manufacture two non-neutralizing antibody(NNAb)-inducing gp120 mRNA immunogens (ADCC Mosaic or WT Env) chosen in overall Aim 1 for use in a Phase I clinical trial that will start at the mid- to end of year 5 of this grant. By leveraging the existing expertise for this novel platform, we will accelerate the timeline for evaluating a vaccine in the clinic. The scope of this work will span knowledge transfer to the selected CDMO through successful IND filing for the final vaccine candidate. A technical CDMO management team, including CDMO project leaders and Haynes, Weissman, Maughan and Denny will be assembled to oversee the process and ensure successful delivery of the program. The following specific aims are proposed for the project. • Aim 1. Transfer pre-production knowledge and processes for mRNA immunogens to contract development and manufacturing organizations (CDMOs). • Aim 2. Deliver final drug substances and drug products for toxicology studies and clinical testing. • Aim 3. Develop and deliver regulatory strategies to enable Phase I proof of concept clinical studies.