Recently methicillin resistant Staphylococcus aureus (MRSA) has surpased HIV as the most deadly pathogen in the United States, accounting for over 100,000 deaths per year. In Orthopaedics, MRSA osteomyelitis (OM) has become the greatest concern in patient care, desite the fact that improvements in surgical technique and aggressive antibiotic prophylaxis have decreased the infection rate for most procedures to less than 1-5%. In order to better understand pathogen-host interactions during the establishment of OM, develop new interventions and an effective diagnostic, we have developed a novel murine model of implant- associated OM in which a stainless steel pin is coated with S. aureus and implanted transcortically through the tibial metaphysis. This leads to a highly reproducible infection with osteolysis by day 9, fractures within three weeks, and closely resembles clinical OM around an external fixation pin. Furthermore, we have developed real time quantitative-PCR (RTQ-PCR) to determine nuc gene copy number in infected bone tissue, which is accurate to ~100 copies;and in vivo bioluminescence imaging to quantify the bacterial load longitudinally. We used this model to clone the glucosaminidase subunit of autolysin as an immuno-dominant antigen and demonstrated its potential as an active vaccine. However, as the target populations for this vaccine are immuno-compromised or elderly patients, Codevax LLC has initiated development of a passive immunization that can be given to high-risk patients prior to surgery. Currently, the company has 13 monoclonal antibodies against glucosaminidase that it needs to screen to derive a primary, secondary and tertiary candidate for clinical trials based on their ability to: 1) bind an epitope within a highly concerned domain (100%amino acid identity of all know S. aureus strains) with high affinity (<10-9M;2);2) mediate enzyme inhibition, cytostasis or cytolysis of the bacteria in vitro;and 3) significantly protect mice from implant associated OM. Here we propose the pivotal experiments to test these mAbs accordingly, and derive the candidates to be developed as the first passive immunization for MRSA.
Anti-Autolysin Passive Immunity for MRSA Osteomyelitis Methicillin resistant Staphylococcus aureus (MRSA) has surpased HIV as the most deadly pathogen in the United States, accounting for over 100,000 deaths per year. In Orthopaedics, MRSA osteomyelitis (OM) has become the greatest concern in patient care. To address this need, Codevax, Inc.
aims to develop the first passive immunization to prevent MRSA infections in patients undergoing total joint replacement surgery.
| Nishitani, Kohei; Sutipornpalangkul, Werasak; de Mesy Bentley, Karen L et al. (2015) Quantifying the natural history of biofilm formation in vivo during the establishment of chronic implant-associated Staphylococcus aureus osteomyelitis in mice to identify critical pathogen and host factors. J Orthop Res 33:1311-9 |
| Varrone, John J; de Mesy Bentley, Karen L; Bello-Irizarry, Sheila N et al. (2014) Passive immunization with anti-glucosaminidase monoclonal antibodies protects mice from implant-associated osteomyelitis by mediating opsonophagocytosis of Staphylococcus aureus megaclusters. J Orthop Res 32:1389-96 |
| Varrone, John J; Li, Dan; Daiss, John L et al. (2011) Anti-Glucosaminidase Monoclonal Antibodies as a Passive Immunization for Methicillin-Resistant Staphylococcus aureus (MRSA) Orthopaedic Infections. Bonekey Osteovision 8:187-194 |
