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LABORATORY OF RETROVIRUS RESEARCH DIVISION OF VIRAL PRODUCTS Site Visit 11 th June, 2009 OVERVIEW LRR PRINCIPAL INVESTIGATORS Hana Golding, Ph.D. (PI and Lab Chief) Unit of Viral Immunology and Pathogenesis Keith Peden, Ph.D. (PI) Unit of Cell Biology and Molecular Genetics

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lrr principal investigators
LRR PRINCIPAL INVESTIGATORS
  • Hana Golding, Ph.D. (PI and Lab Chief)

Unit of Viral Immunology and Pathogenesis

  • Keith Peden, Ph.D. (PI)

Unit of Cell Biology and Molecular Genetics

  • Arifa Khan, Ph.D. (PI)

Unit of Molecular Retrovirology

lab of retrovirus research regulatory responsibilities
LAB OF RETROVIRUS RESEARCHRegulatory Responsibilities
  • Vaccines against Viral Diseases:
    • HIV
    • Influenza
    • Adenovirus
  • Non replicating and replicating viral vectors for delivery of selected genes from targeted pathogens:
    • Poxviruses, Adenoviruses, Alpha viruses, Adeno-associated viruses, VSV, Lentiviruses
  • DNA Vaccines
  • Novel Adjuvants and vaccine delivery systems
  • Novel cell substrates for vaccine production:
    • Continuous cell lines: non-tumorigenic and tumorigenic cells
lab of retrovirus research other regulatory activities
LAB OF RETROVIRUS RESEARCHOther Regulatory Activities

GUIDANCE DOCUMENTS

  • Considerations for plasmid DNA vaccines for infectious disease indications
  • Characterizations and qualifications of cell substrates for production of viral vaccines
  • Nonclinical safety evaluation of vaccine adjuvants and adjuvanted preventative vaccines for infectious diseases indications

WHO CONSULTATIONS AND VRBPAC PRESENTATIONS

lab of retrovirus research other regulatory activities6
LAB OF RETROVIRUS RESEARCHOther Regulatory Activities

WORKSHOPS (Co-organized & Presenters):

  • Potency Assays for Novel Vaccines(NIAID/CBER)
  • Immune Correlates of Protection Against Influenza A Virus in Support of pandemic Vaccine Development (CBER/NIAID/WHO)
  • Workshop on Adjuvants and Adjuvanted Preventative and Therapeutic Vaccines for Infectious Disease Indications (CBER/NIAID)
  • New Cells for New Vaccines III: From Lab Bench to Clinical Trials (IABS)
  • Workshop on Microbial Agents in Animal Cell Substrates (NIAID/IABS)
lab of retrovirus research research programs
LAB OF RETROVIRUS RESEARCHRESEARCH PROGRAMS
  • HANA GOLDING

HIV-1, Influenza, and Smallpox vaccines; Development of new assays and animal models for evaluation of vaccine safety and efficacy

  • KEITH PEDEN

Development of quantitative in vitro and in vivo assays to evaluate the safety of novel cell substrates for vaccine production

  • ARIFA KHAN

Development of sensitive assays for detection of latent viruses in vaccine cell substrates and risk-assessment of human infections with agents of potential concern

hana golding research projects update of publications since the june 2009 sv
HANA GOLDING Research Projects: Update of publications since the June 2009 SV
  • HIV-SELECTEST: a new HIV-1 EIA and Rapid test for differential diagnosis of HIV infections in the face of vaccine-induced antibodies

S. Khurana et al. 2006. A novel assay for diagnosis of HIV infections in the presence of

antibodies induced by candidate HIV preventive vaccine J. Virol 80:2092

S. Khurana et al. 2006. Novel approach for differential diagnosis of HIV infections in the face of

vaccine generated antibodies: Utility for detection of diverse HIV-1 subtypes. J. Acquired

Immunodefficiency 43:304

S. Khurana et al. 2009. HIV-SELECTEST EIA and Rapid Test: Utility for detection of seroconversion

following acute HIV-1 infections J. Clin. Microb. (in press)

The HIV SELECTEST (EIA and Rapid test) is currently being developed for

licensure by two companies under a three year contract from the NHBLI

hana golding research projects update of publications since june 2009 sv
HANA GOLDING Research Projects: Update of publications since June 2009 SV

II. Pandemic influenza preparedness: Development of new molecular

tools for the evaluation of antibody repertoires in vaccine recipients

and H5N1 recovered individuals

S. Khurana, A.L. Suguitan Jr, Y. Rivera, C. P. Simmons, A. Lanzavecchia, F. Sallusto, J. Manischewitz, L.R. King, K. Subbarao and H. Golding. 2009. Antigenic fingerprinting of an H5N1 avian influenza virus using convalescent sera and human monoclonal antibodies reveals potential vaccine and serodiagnostic targets. PLoS Med 6(4): e1000049

S. Khurana, W. Chearwae, F. Castellino, J. Manischewitz, L. R. King, A. Honorkiewicz, M. T. Rock, K. M. Edwards, G. Del Giudice, R. Rappouli, and H. Golding 2009. MF59 adjuvanted vaccines expand antibody repertoires targeting protective sites of pandemic influenza virus Science Translational Medicine (in press)

hana golding research projects update of publications since june 2009 sv10
HANA GOLDING: Research Projects: Update of publications since June 2009 SV

III.BioDefense project: In vivo reporter gene-based assay for comparative evaluation of novel prophylactic smallpox vaccines and therapies in small animal models

M. Zaitseva, S.M. Kapnick, J. Scott, L. R. King, J. Manischewitz, L. Sirota, and H. Golding 2009.Application of bioluminescence imaging to the prediction of lethality in vaccinia virus infectedmice J. Virol. 83:10437–10447.

hana golding research projects update since june 2009 sv
HANA GOLDING Research Projects: Update Since June 2009 SV

Novel Vaccine Adjuvants( manuscripts in preparation):

Development of in vitro Human Cell Line-based assays predictive of in vivo toxicities of adjuvants

Validation of new biomarkers for preclinical evaluation of novel adjuvants in rabbits

slide12

ARIFA KHAN Research Projects: progress since Last SV

CELL SUBSTRATE AND VACCINE SAFETY

  • An algorithm for chemical virus induction of endogenous retroviruses and latent DNA viruses was developed. Activation of retroviral particles from Vero cells supports the use of the algorithm for evaluation of known and unknown viruses in novel vaccine cell substrates
  • Investigation of histone deacetylase (HDAC) activity as a potential biological marker for chemical induction of endogenous and latent viruses indicated a correlation of drug treatment with virus induction

STUDIES OF SIMIAN FOAMY VIRUS (SFV) TO EVALUATE IMPACT ON PRECLINICAL

VACCINE STUDIES IN NHPs AND RISK OF HUMAN INFECTIONS

  • Evaluation of SFV natural infection in the SIV monkey model indicated that SFV infection had an impact on the SIV-rhesus macaque highlighting the need to determine SFV status in monkeys used in preclinical testing of HIV-1 vaccines. Further analysis is ongoing to investigate consequences of dual-infection.

IV. Investigation of SFV latency and replication by in vitro functional analysis of regulatory elements using different SFV isolates identified role of internal promoter and transactivator protein (Tas) in cell-specific replication and efficiency of virus replication, respectively.

slide13

ARIFA KHAN: Status of Research Papers

• Ma, Y.K. and Khan, A.S. Evaluation of different RT enzyme standards for quantitation of

retroviruses using the single-tube fluorescent product-enhanced reverse transcriptase assay.

J. Virol. Methods 157:133-140, 2009

• Khan, A.S. Proposed algorithm to investigate latent and occult viruses in vaccine cell substrates

by chemical induction. Biologicals 37: 196-201, 2009

• Khan, A.S. Simian foamy virus infection in humans. Prevalence and management. Expert Rev.

Anti Infect. Ther. 7: 569-580, 2009

• Khan, A.S. Characterization and qualification of cell substrates for manufacture of viral vaccines

in the United States. BioProcessing Journal. 8- 12, 2009

• Williams, D.K. and Khan A.S. 2009 Role of neutralizing antibodies in controlling simian foamy

virus transmission and infection. Transfusion Aug. 28, 2009 (Epub ahead of print)

• Galvin, T.A. Shahabuddin, M., Bryan, T., Sears, J.F., Viswanathan, K., Kaushal, M., and Khan,

A.S. Evaluation of transcriptional regulatory elements in two simian foamy virus serotypes

reveals difference in Tas activity. Re-submitted addressing reviewer’s comments

• Ma, H., Ma, Y, Ma, W, Williams, D.k., Galvin, T.A, Baptista, C.S., Sotelo-Silveira, J., Munroe,

D.J, and Khan, A.S. Endogenous retrovirus particles induced from the VERO cell line of African

green monkeys. Re-submitted addressing reviewer’s comments

slide14

KEITH PEDEN Research Projects: progress since last SV

  • Development of in vivo assay to assess the potential oncogenic risk associated with residual cell-substrate DNA
  • The most sensitive mouse model to assess oncogenicity is the CD3 epsilon mouse
  • Cellular DNA up to 100 µg does not interfere with induction of tumors by the positive control ras/myc plasmid
  • Cellular DNA from several tumorigenic cell substrates were evaluated and failed to induce tumors
  • Preliminary studies with the p53-defective mouse indicate that this mouse may also be sensitive to oncogenic activity of DNA
  • Current work is directed at determining whether the p53-defective mouse detects a different spectrum of oncogenic activity than the CD3 epsilon mouse
slide15

KEITH PEDEN Research Projects: progress Since Last SV

  • Studies on primate polyomaviruses: Development of neutralization assays for human polyomaviruses
  • A qPCR-based neutralization assay for SV40 has been developed; such assays can be adapted to high throughput
  • Current work is directed to developing similar assays for RNA viruses, including respiratory viruses
slide16

KEITH PEDEN Research Projects: progress since last SV

  • Investigation of whether the tumorigenic potential of a cell substrate affects vaccine safety:VERO cells
  • MicroRNA expression patterns in primary African green monkey kidney cells, non-tumorigenic VERO cells, and tumorigenic VERO cells were compared
  • Several miRNAs were identified that correlated with progression from a non-tumorigenic to a tumorigenic phenotype
  • Preliminary data indicate that ectopic expression of some of these miRNAs can alter the phenotype of the cell
  • The potential for miRNAs to be biomarkers for the acquisition of a tumorigenic phenotype is being investigated, with the possible replacement of a tumorigenicity assay for VERO cells