heme: Immunoprophylactic Strategies to Control Emerging Enteric Infections
Overall Broad Specific Aims
Broad objective 1: To perform research exploring the hypothesis that active (vaccines) or passive (administration of antibodies) immunoprophylactic strategies can be formulated to prevent enteric disease caused by several of the most important bacterial and protozoal Category B enteric pathogens.
Broad objective 2: To address the hypothesis that by identifying candidate vaccine antigens for pathogens for which there do not currently exist leading vaccine candidates (e.g., Cryptosporidium hominis) and by utilizing innovative animal models, we can convincingly prove that antibodies directed against these antigens can prevent clinical disease.
Broad objective 3: To address the hypothesis that for important enteric pathogens for which the ultimate human targets will be elderly subjects (e.g., Clostridium difficile, non-typhoidal Salmonella), we can translate promising basic research and test candidate immunoprophylactic products (e.g., candidate vaccines or passively delivered antibodies [monoclonal or immunoglobulin concentrates]) in relevant immunosenescent animal models.
Broad objective 4: To explore the hypothesis that by adapting innovative as well as established classical animal models we can prove the concept that broad spectrum protection can be achieved against a panoply of major bacterial and protozoal enteropathogens.
Project 1. Immunologic Basis for Broad Protection against Enteric Fever Salmonella (Project Leader: Marcelo Sztein)
Overall goal: Advance the development of cross-protective vaccines against enteric fevers by identifying vaccine-derived humoral and T effector and regulatory immune responses which might be involved in protection. A secondary overall aim is to provide data to validate the S.Typhi /S. Paratyphi A bivalent vaccine approach to vaccination against enteric fevers.
Project 2. Novel Immunoprophylaxes against Clostridium difficile infection (Project Leader: Hanping Feng)
Overall goal: Develop novel immunoprophylactics against both primary and recurrent CDI in a defined, high-risk population. We have generated a tetra-specific antibody consisting of four distinct neutralizing VHH monomers (two against TcdA and two against TcdB), designated as ABBA. ABBA is a rationally designed single binding compound with substantially enhanced affinity (Kd = ~2 pM) and neutralizing activity (~2 logs more potent than Merck monoclonal antibodies that are undergoing phase III clinical trials) over the individual VHHs. In addition, we have developed a novel chimeric toxin vaccine cTxAB that is currently under pre-clinical evaluation. In this project, we aim to optimize and finalize several delivery strategies for ABBA in preclinical animal models. Moreover, we will optimize cTxAB immunizations for protection against recurrent CDI in aged mice after their initial episode of CDI.
Project 3. Shigella Live vector-Based Multivalent Vaccine (Project Leader: Eileen Barry)
Overall goal: Construct a multivalent vaccine that is protective against the enteropathogens Shigella, enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC) and Shiga toxin producing E. coli (STEC). All are category B risk agents of biodefense concern and are of significant public health importance in the US. We will use our live attenuated strains of Shigella as the platform for expression of critical antigens from the other pathogens. The multivalent vaccines will be tested in relevant novel animal models tp assess safety, immunogenicity and protective capacity of each component.
Project 4. Salmonella Group C as part of a Multivalent Salmonella Vaccine (Project Leader: Sharon Tennant; Co-Project Leader: Raphael Simon)
Overall goal: Develop Salmonella Group C live attenuated and conjugate vaccines. Our central hypothesis is that appropriately engineered attenuated strains of Salmonella enterica Group C1 (S. Choleraesuis) and C2 (S. Newport) serovars can: 1) allow safe, high yield preparation of core-O polysaccharide (COPS) and flagella protein for making conjugate vaccines, and 2) serve as protective live attenuated vaccines.
Project 5. Development of Strategies to Achieve Immunoprotection against C. hominis and C.parvum (Project Leader: Saul Tzipori; Co-Project Leader: Abhineet Sheoran)
Overall goal: Undertake studies in the piglet model to address the fundamental hypothesis that specific antibodies can protect againstCryptosporidium. This critical translational research will pave the way to develop a Cryptosporidium vaccine for humans.