Phase II year
2020
(last award dollars: 2022)
Phase II Amount
$2,512,535
The illnesses caused by Streptococcus pneumoniaes transition from carriage to disease result in a mortality rate between approximately 3-10% in adults and 12-25% in elderly patients in the United States. Furthermore, pneumococcal disease devastates resource-poor countries, causing an estimated 476,000 people to succumb to pneumococcal infection annually (~32% of vaccine-preventable deaths in children below age five). The most effective vaccines, polysaccharide protein conjugates, require a complicated process of collecting polysaccharide antigens from pneumococci serotypes and conjugating them to a protein adjuvant. Abcombi Biosciences has developed a pneumococcal vaccine using liposomal encapsulation of polysaccharides (LEPS), which has demonstrated conjugate-like efficacy against 70+ serotypes of S. pneumoniae via animal challenge models and opsonophagocytosis activity (OPA). Since receiving our prior Phase I SBIR award, Abcombi Biosciences has completed all proposed milestones to address concerns regarding the risk for potential negative side effects associated with the LEPS vaccines formulation. Completion of this work has led to the development of a second generation LEPS vaccine. The enclosed Direct Phase II SBIR proposal outlines the remaining preclinical studies necessary to reach our next major milestone, a pre-IND meeting with the FDA. The completion of these studies will serve to address important considerations of the FDA regarding vaccine manufacturing and characterization (i.e., chemistry manufacturing and controls, CMC) and efficacy (i.e., the animal rule). Briefly, these studies will involve the completion the following key developmental steps: 1) optimization of our encapsulation process for all pneumococcal capsular polysaccharides (CPSs), 2) finalization of polysaccharide dosage, 3) evaluation of vaccine stability, and 4) a repeated-dose toxicology study in mice and rabbits. Optimization of our polysaccharide encapsulation process will be achieved by systematically varying our process conditions across all 24 polysaccharides to ensure efficient and consistent encapsulation for each antigen. Upon optimizing this process, we will then identify the optimal dosage of polysaccharide by measuring antibody titers and OPA assay performance to determine the dosage of each polysaccharide required for sufficient immunogenicity. We will then characterize the LEPS vaccine stability by evaluating protein pH and thermal stability as well as the integrity of the liposomes when stored over 12 months. Lastly, we will evaluate the vaccine for toxicity in a repeated dose study in mice and rabbits. Throughout the duration of this study, serum will be collected to evaluate organ toxicity and quantify antibody titers. In addition, post-mortem tissue samples will be extracted to visualize histopathology. Successful completion of this work will prepare our vaccine candidate for a pre-IND meeting with the FDA and ensure a smooth transition into clinical trials.
Public Health Relevance Statement: PROJECT NARRATIVE The proposed Direct Phase II SBIR project will finalize the formulation of Abcombi Biosciences liposome-based pneumococcal vaccine candidate to pre-IND meeting readiness. Success will achieve the next major milestone for Abcombi through performing the necessary characterization of vaccine stability, optimization of its manufacturing process, finalization of its composition, and demonstrating safety in a dosing regimen resembling anticipated clinical utilization.
Project Terms: Address; Adherence; Adjuvant; Adult; Age; animal rule; Animals; Antibodies; Antibody titer measurement; Antigens; Area; Automobile Driving; Autopsy; Award; Bacteremia; Bacterial Meningitis; base; Biological Assay; Biological Sciences; Blood; Chemistry; Child; Clinical; clinical application; clinical development; Clinical Trials; Communities; Country; Coupling; design; Development; Development Plans; Disease; dosage; Dose; Ensure; experience; experimental study; Formulation; Generations; Glycoconjugates; Goals; Histopathology; Human; human pathogen; immunogenicity; Immunoglobulin G; Immunoglobulin M; Immunologics; improved; Incidence; innovation; Liposomes; manufacturing process; Measures; meetings; Microbial Biofilms; Modeling; mortality; Mus; older patient; Organ; Oryctolagus cuniculus; Otitis Media; Outcome; Performance; Phase; Pneumococcal Colonization; Pneumococcal Infections; Pneumococcal vaccine; Pneumonia; Polysaccharides; pre-clinical; preclinical study; Preparation; preventable death; Process; process optimization; product development; programs; Property; Proteins; Readiness; Recommendation; Regimen; Research; research and development; Resources; Risk; Safety; Serotyping; side effect; Small Business Innovation Research Grant; Streptococcus pneumoniae; Study of serum; success; Tissue Sample; Toxic effect; Toxicology; United States; vaccine candidate; vaccine development; vaccine evaluation; Vaccines; Virulence; Work
