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LABORATORY OF RETROVIRUS RESEARCH: LAB STRUCTURE. SECTION OF RETROVIRAL PATHOGENESIS Hana Golding, Ph.D. (PI, Lab Chief) Keith Peden, Ph.D. (PI) Marina Zaitseva, Ph.D. (Senior Staff Fellow) SECTION OF RETROVIRAL IMMUNOLOGY Dennis Klinman, MD, Ph.D. (PI) SECTION OF MOLECULAR RETROVIROLOGY
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LABORATORY OF RETROVIRUS RESEARCH:LAB STRUCTURE • SECTION OF RETROVIRAL PATHOGENESIS • Hana Golding, Ph.D. (PI, Lab Chief) • Keith Peden, Ph.D. (PI) • Marina Zaitseva, Ph.D. (Senior Staff Fellow) SECTION OF RETROVIRAL IMMUNOLOGY Dennis Klinman, MD, Ph.D. (PI) SECTION OF MOLECULAR RETROVIROLOGY Arifa Khan, Ph.D. (PI)
LABORATORY OF RETROVIRUS RESEARCH:REGULATORY MISSION (I) • Review of HIV vaccines (pre-IND, original IND submissions, IND amendments, pre-BLA, BLA) • Provide expert opinions to other CBER Laboratories and Divisions on: • Novel Cell Substrates • Adventitious agents detection • Retrovirus contamination • Lentivirus vectors • Plasmid DNA vaccines • CpG oligonucleotides and other adjuvants
LABORATORY OF RETROVIRUS RESEARCH:REGULATORY MISSION (II) • Presentations to CBER Advisory Committees • Presentations to the World Health Organization and to other international regulatory authorities • Participation in Interagency Working Groups • Organization and/or participation in special workshops on HIV vaccines, plasmid DNA vaccines, and novel cell substrates
LABORATORY OF RETROVIRUS RESEARCH:REGULATORY MISSION (III) Preparation of Guidance Documents for sponsors of new vaccines: • Considerations for plasmid DNA vaccines for infectious disease indications (Klinman) • Characterization and qualification of cell substrates and other biological starting materials for the production of viral vaccines (Peden, Khan) • Preclinical toxicity assessments of preventive vaccines to support phase 1 clinical trials (Golding)
SECTION OF RETROVIRAL IMMUNOLOGY Dennis Klinman (PI) Monitor the Safety and Immunomodulatory Activity of DNA-based Products DNA-based products regulated by the FDA: • DNA vaccines • Synthetic oligodeoxynucleotides (ODN) for therapy, immune modulation, adjuvants • Regulated products in which DNA exists as a “contaminant”: • Proteins produced in bacteria containing bacterial DNA. • Vaccines produced in mammalian cell lines containing mammalian DNA.
Dennis Klinman : Accomplishments • Discovered and patented a new class of stimulatory CpG ODN. • vaccine adjuvants • immunoprotective agents • anti-allergens. • Discovered and patented a new class of suppressive ODN. • for prevention or treatment of autoimmune and inflammatory diseases. • mechanism of action of these ODN.
SECTION OF RETROVIRAL PATHOGENESIS Hana Golding (PI) • STUDIES ON HIV CELL ENTRY • HIV coreceptor expression and function in primary human cells • new entry inhibitors targeting the HIV coreceptor CCR5 • HIV VACCINE TRIALS • new HIV EIA for differential diagnosis of HIV infections in the presence of vaccine-generated antibodies • COUNTER TERRORISM PREPAREDNESS • new in vitro assays and animal models for evaluation of smallpox vaccines potency and safety.
Hana Golding: Accomplishments • HIV-SELECTEST • Uninfected vaccine trial participants score negative, while all HIV infections are diagnosed early • Simple and economical test. Can be implemented in sites of future HIV vaccine trials and in blood collection centers around the globe. • SMALLPOX VACCINE EVALUATION • Reporter-gene based vaccinia neutralization assay (high throughput) • Collaborative work on monkeypox primate challenge for “2-animal rule” • Mouse models for tracking vaccinia dissemination: vaccine safety and post-exposure prophylaxis
SECTION OF RETROVIRAL PATHOGENESISMarina Zaitseva (Senior Staff Fellow): Accomplishments CELLULAR GENES INVOLVED IN THYMIC RECONSTITUTION AND IMMUNE MODULATION • Murine models of transient thymic atrophy: low-dose irradiation; dexamethasone; estrogen. • Use models to identify salvage mechanisms important for thymic regeneration.
Marina Zaitseva (Senior Satff Fellow) CELLULAR GENES INVOLVED IN IMMUNE RECONSTITUTION • ongoing experiments in irradiated mice: reconstitution of T cells in the Gut-associated lymphoid tissues
SECTION OF RETROVIRAL PATHOGENESIS Keith Peden (PI) • Safety of tumorigenic cell substrates for vaccine manufacture • SV40 contamination in human vaccines • HIV coreceptor evolution and pathogenesis
Keith Peden: Accomplishments Animal models to assess the oncogenic activity of cellular DNA - combination of oncogene-expressing plasmids induced tumors in newborn mice. • ready to test DNA from new cell-substrate Quantitative assays to measure infectivity of integrated retroviral DNA - estimates for safe levels of residual cell-substrate DNA in viral vaccines - tools to evaluate removal of cellular DNA
Keith Peden: Accomplishments (2) •quantitative assays to detect the presence of primate polyomavirus DNA in biological specimens • single-cycle, reporter-gene based neutralization assays for BKV, JCV, and SV40
MOLECULAR RETROVIROLOGY SECTION Arifa Khan (PI): Accomplishments Simian Foamy Virus Transmission Studies - assess risk of human infection by SFV-infected blood donors. Studies of Simian Foamy Virus Replication - potential risk of SFV propagation in simian and human cells used for vaccine manufacturing.
Arifa Khan: Accomplishments Strategies for Detection of Infectious Agents in Vaccine Cell Substrates • quantitative assays for detection of retroviruses • induction of endogenous retroviruses in cells from different animal species • induction of HHV-8 as a model of latent DNA virus