VaxCelerate 3.0: A Scalable and Efficient Self-Assembling Vaccine Platform to Enable Rapid Development of US Military Vaccines

Background: The long and expensive development process for military vaccines is rooted in part in the bespoke nature of vaccine development for each pathogen. An alternative is the use of a common vaccine platform that can be deployed across a breadth of pathogen types. The Vaccine and Immunotherapy Center (VIC) at the Massachusetts General Hospital (MGH) has developed a self-assembling vaccine (SAV) platform that could also form the basis of a common template for vaccine development for the U.S. military. It is composed of two components: a broadly immune activating adjuvant and carrier protein (Mycobacterium tuberculosis Heat Shock Protein 70) fused to chicken avidin (MAV) that is the same for all vaccines, as well as a set of biotinylated peptides that contain the unique antigenic pathogen targeting components for the vaccine. VIC has focused past work on using concatemers of selected, immunogenic epitopes capable of inducing both Th1 and Th2 protective responses, resulting in combined antibody and cytotoxic T cell responses. Our vaccine platform was first tested for Lassa fever virus. More recently, this platform was licensed to Voltron Therapeutics and is being deployed for treatment of Human papillomavirus (HPV)-induced cancer. SAV-HPV has demonstrated highly significant immunogenicity and efficacy in an extensively used mouse model of HPV induced cancer. Objective/Hypothesis: The central hypothesis of this proposal is that our SAV platform can be optimized to permit rapid, cost-efficient synthesis of new safe, effective vaccines against a wide range of viral pathogens. Dependent Hypothesis 1: SAV can provide protective immunity against significantly different types of viral pathogens using the same vaccine approach, engaging both Th1- and Th2-type immune responses. Dependent Hypothesis 2: The generation of long, multiepitope peptides used in SAV can be rapidly produced using a scalable, GMP-translatable manufacturing process. Dependent Hypothesis 3: The MAV portion of SAV can be optimized for efficient, scalable, and well-characterized production in a GMP-ready CHO cell expression system. Specific Aims: Aim 1. Demonstrate SAV provides protective immunity against different types of viral pathogens (influenza A and vaccinia). Aim 2. Improve critical portions of SAV component production. The key questions to be answered are: 1. Is there a more rapid and efficient mean of producing long epitope peptides than standard solid-state synthesis? 2. Can the CHO cell-based expression system for the MAV protein moiety be scaled to support high-volume production for clinical use? Aim 3. Perform a "live fire" test of optimized SAV with hantavirus, a viral pathogen of military interest, to demonstrate whether the optimized SAV can be used for efficient and rapid development of a new vaccine against a priority viral pathogen. Study Design: Aim 1. In year 1, VIC at MGH will produce immunogenic peptide sets for influenza A and vaccinia, which will be synthesized by the MGH Protein and Peptide Core. VIC will conduct studies to evaluate dose responses and then conduct challenge studies to show the efficacy of the vaccine platform against these viruses in established murine models of the diseases. Aim 2. In year 1, Texas A&M University will work on a click chemistry method of making peptides more rapidly using model peptides. Dyadic International will use the same model peptides to establish a fungal expression method of peptide production. In year 2, VIC will test the peptides made using these two methods against peptides made the standard way and select the approach that shows the best results with rapid, efficient production. In parallel, during years 1-2, KBI Pharma (KBI) will optimize MAV protein production to prepare for advanced preclinical development. In year 3, KBI will conduct a demonstration of scaled production using a 200 L production system. Aim 3. In year 3, VIC will perform a live fire exercise by rapidly producing a new vaccine for hantavirus using the optimized protein and the best-performing peptide method. VIC will conduct dose studies and then do a challenge study to show vaccine efficacy in an established murine model. Relevance: The evolved vaccine platform will have demonstrated a facility to efficiently and rapidly produce multiple safe and effective vaccines against diverse pathogens, addressing key contributors to the cost and time required to create new vaccines. If results of the live-fire demonstration are positive, the hantavirus vaccine could be advanced further toward clinical testing. Less