Abstract for the RCE

Bacillus anthracis Host Interactions

Discovery of Subunit Vaccine Candidates                             against Glanders

Alphavirus Vaccines for Biodefense

Novel Genetic Tools for Viral Biodefense

Development and Evaluation of Human
                     Brucellosis Vaccines

Rapid Diagnostic Tools for Q Fever

New Diagnostic Methods for Accute Rickettsial
                      Infections

Risks and Interventions for Pandemic Influenza

Development of Novel Pseudoinfectious Flavivirus                             Vaccines

Development of Diagnostic Reagents for the detection
                            of Francisella and
                             Francisella Infection

Toward Control of Rift Valley Fever Virus
                             Replication

Novel Vaccine Technology for Biodefense

Nucleocapsid-specific Small Molecule Inhibitors
                             of the Bunyaviridae

New Technologies for Creating Affinity Reagents

New Opportunities Projects

Identification and Characterization of Novel
                             Flavivirus Antivirals

Biosafety Containment Training Program

Passive Immunotherapeutics for
                             Select Agents

Preclinical Testing of YF17D/LAS, a Bivalent
                              Vaccine for Lassa and
                             Yellow Fever

Passive Immunotherapeutics for Select Agents

Collaborating Institutions:

University of Texas Medical Branch (UTMB), Galveston, TX (WRCE)
Columbia University, New York, NY (NBC)
Vanderbilt University, Nashville, TN (SERCEB)

Principal Investigator: CJ Peters, MD

Co-Investigators:
Thomas Briese, PhD – Columbia University, New York, NY (NBC)
Ilya Trakht, PhD – Columbia University, New York, NY (NBC)
James Crowe Jr., MD – Vanderbilt University, Nashville, TN (SERCEB)

Expected Product: Immunotherapeutics for Junin and Rift Valley fever viruses, and possibly for Nipah virus.

Description: Post-exposure prophylaxis and treatment are critical challenges in the management of emerging viral diseases. Vaccines may be helpful in post-exposure prophylaxis where agents replicate slowly or are initially sequestered in the periphery. However, in most instances, active immunity does not occur in a time frame wherein disease can be prevented or ameliorated. Passive immunotherapy has an established track record in management of infections with rabies, respiratory syncytial, and variola viruses. Except in rare instances where antibodies cross react with host tissues to cause disease or enhance virus uptake to accelerate progression of infection, the effects of passive immunotherapy are specific. Antivirals have been used with success in many infections, and the repertoire of effective compounds will undoubtedly improve. Nonetheless, passive immunotherapy will continue to be a significant primary or complementary line of defense. Reagents for passive immunotherapy include both convalescent serum and monoclonal antibodies (MAbs). MAbs have the advantages of defined reactivity and specificity, and enhanced safety profiles.

Through previous work in pathogen detection in context of the WHO laboratory network we enjoy access to peripheral blood lymphocytes (PBL) from victims recovered from infection with high-risk pathogens. We have established that PBL can be stored frozen and used for fusion several months after collection with only insignificant loss of Ig production. This Trans-RCE project will exploit these materials and an efficient human hybridoma fusion partner cell line (MFP-2) to produce fully human MAbs (fhMAB) specific for two select agents: Junin virusand Rift Valley fever virus. The choice of targets is based on data indicating a potential therapeutic role for passive immunotherapy and the availability of well-characterized clinical materials. A limited evaluation of MFP-2 has been conducted in the context of filing an IND with the FDA. Furthermore, a commercial relationship has been established with the goal of producing GMP-grade fhMAbs for treatment of non-Hodgkin lymphomas. These factors will enable transition of fhMAbs with antiviral activity from animal models to clinical use. Specific aims include: (1) establishing serologic assays for screening of convalescent donor sera and human hybridoma supernatants, (2) characterizing donor sera and PBLs, and generating human hybridoma lines, and (3) testing neutralizing fhMAbs for protective activity in animal models.