Many vaginal microbicides being evaluated for the prevention of sexually transmitted diseases (STDs) have broad-spectrum actions that are not limited to pathogens, e.g. detergents may disrupt epithelial integrity: In contrast, antibodies are microbicides that are highly specific, yet, by working in combination can achieve broad spectrum protection without injuring healthy tissues or commensals. The specificity of antibodies together with their versatility and diversity make them leading candidates (as well as tools) for developing specific microbicides that can block pathogen entry across the vaginal mucosa. Biotechnology products are now being produced in plants both to achieve low cost and high capacity production, and the first specific aim is to determine the pharmacokinetics in the mouse and rabbit vagina of a human antibody to HSV2 produced transgentically in corn as a """"""""plantibody"""""""". After determining the most efficacious targets using existing mouse antibodies in mouse models, the next aims are to generate protective human monoclonal antibodies in mouse models, the next two aims are to generate protective human monoclonal antibodies to HPV 16 by phage display and to cell-associated HIV, chlamydia and gonorrhea in transgenic mice. These human monoclonal antibodies will be evaluated in vitro and in STD/mouse models for protective efficacy. Since antibodies may help create a vaginal environment in which protective commensals can flourish, the final aim is to test the concept that typically applied antibodies can specifically reduce a potentially harmful vaginal commensal in mice. A combination of these human monoclonal antibodies will form the basis for the development of a broad-spectrum yet specific microbicide to prevent sexually transmitted diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI045967-01
Application #
6226580
Study Section
Special Emphasis Panel (ZAI1-ALR-M (M4))
Project Start
1999-09-30
Project End
2003-08-31
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
O'Hanlon, Deirdre E; Moench, Thomas R; Cone, Richard A (2013) Vaginal pH and microbicidal lactic acid when lactobacilli dominate the microbiota. PLoS One 8:e80074
O'Hanlon, Deirdre E; Moench, Thomas R; Cone, Richard A (2011) In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide. BMC Infect Dis 11:200
O'Hanlon, Deirdre E; Lanier, Blair R; Moench, Thomas R et al. (2010) Cervicovaginal fluid and semen block the microbicidal activity of hydrogen peroxide produced by vaginal lactobacilli. BMC Infect Dis 10:120
Chancey, Caren J; Khanna, Kristen V; Seegers, Jos F M L et al. (2006) Lactobacilli-expressed single-chain variable fragment (scFv) specific for intercellular adhesion molecule 1 (ICAM-1) blocks cell-associated HIV-1 transmission across a cervical epithelial monolayer. J Immunol 176:5627-36
Cone, Richard A; Hoen, Timothy; Wong, Xixi et al. (2006) Vaginal microbicides: detecting toxicities in vivo that paradoxically increase pathogen transmission. BMC Infect Dis 6:90
Tien, Deborah; Schnaare, Roger L; Kang, Feirong et al. (2005) In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials. AIDS Res Hum Retroviruses 21:845-53
Olmsted, Stuart S; Khanna, Kristen V; Ng, Erina M et al. (2005) Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model. BMC Infect Dis 5:79
Spencer, Steven E; Valentin-Bon, Iris E; Whaley, Kevin et al. (2004) Inhibition of Neisseria gonorrhoeae genital tract infection by leading-candidate topical microbicides in a mouse model. J Infect Dis 189:410-9
Moench, Thomas; Mehrazar, Karim; Cone, Richard et al. (2004) Sensitive methods to detect epithelial disruption: tests for microhemorrhage in cervicovaginal lavages. J Acquir Immune Defic Syndr 37 Suppl 3:S194-200
Boskey, Elizabeth R; Moench, Thomas R; Hees, Paul S et al. (2003) A self-sampling method to obtain large volumes of undiluted cervicovaginal secretions. Sex Transm Dis 30:107-9

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