The recent successful trial of tenofovir vaginal gel provides important proof of concept indicating that a vaginal microbicide can prevent HIV. However, the limited protection observed (39% overall), argues for the development of additional microbicide agents and methods to deliver them. This IPCP application will develop a monoclonal antibody (Mab) based microbicide, distinct from the small molecule antiretrovirals that dominate the current microbicide pipeline. Mabs show promise in providing safe, potent, and specific, yet broad-spectrum microbicide action. Project 4 will attempt to enhance Mab effectiveness by its focus on the means of Mab delivery. Limitations on microbicide effectiveness can be divided into two categories: first, intrinsic failure of the method to provide protection when used (""""""""method failure"""""""");and second, failure to use the method consistently and correctly (""""""""user failure""""""""). We will attempt to reduce this second failure mode by developing three novel non-coital methods of microbicide delivery related by their emphasis on providing non-coital continuous dosing. Because these methods will not require action immediately in advance of coitus, we expect them to improve the proportion of coital acts wherein the microbicide is present. Moreover, we hypothesize an additional benefit: We believe inadequate distribution is responsible for many microbicide failures, and is responsible for the much higher concentrations of microbicide generally needed for in vivo protection compared to that required in vitro. We hypothesize that continuous or repeated dosing will improve microbicide distribution due to generous diffusion time for Mabs to cover the entire folded surface of the vagina. Our three Specific Aims will thus develop athe following three non-coital methods: SA1: Versaring, an intravaginal ring based on technology with proven clinical performance in sustained release of an antiviral, here to be adapted for sustained vaginal release of monoclonal antibodies;SA2: User-recharged Versaring, a modification of Versaring that will allow user replacement of Mab releasing units for production at lowest cost;SAS: Delivery of Mabs using the Duet? cervical barrier device.

Public Health Relevance

We propose to develop new ways to deliver microbicides to the vagina that will be more convenient, more long lasting, and more effective than previous methods. The microbicide we will deliver is composed of antibodies, which are substances naturally used by the human immune system to block infections. The antibodies will be delivered using a vaginal ring, or a vaginal diaphragm, which is a ring plus an attached cup-like dome that covers and protects the cervix.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096398-02
Application #
8377223
Study Section
Special Emphasis Panel (ZAI1-ESB-A)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$97,600
Indirect Cost
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Anderson, Deborah J; Politch, Joseph A; Zeitlin, Larry et al. (2017) Systemic and topical use of monoclonal antibodies to prevent the sexual transmission of HIV. AIDS 31:1505-1517
Daggett Jr, Gregory J; Zhao, Chunxia; Connor-Stroud, Fawn et al. (2017) Comparison of the vaginal environment in rhesus and cynomolgus macaques pre- and post-lactobacillus colonization. J Med Primatol 46:232-238
Zhao, Chunxia; Gunawardana, Manjula; Villinger, Francois et al. (2017) Pharmacokinetics and Preliminary Safety of Pod-Intravaginal Rings Delivering the Monoclonal Antibody VRC01-N for HIV Prophylaxis in a Macaque Model. Antimicrob Agents Chemother 61:
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Ayehunie, Seyoum; Islam, Ayesha; Cannon, Chris et al. (2015) Characterization of a Hormone-Responsive Organotypic Human Vaginal Tissue Model: Morphologic and Immunologic Effects. Reprod Sci 22:980-90
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Nunn, Kenetta L; Wang, Ying-Ying; Harit, Dimple et al. (2015) Enhanced Trapping of HIV-1 by Human Cervicovaginal Mucus Is Associated with Lactobacillus crispatus-Dominant Microbiota. MBio 6:e01084-15
Chen, Alex; McKinley, Scott A; Shi, Feng et al. (2015) Modeling of Virion Collisions in Cervicovaginal Mucus Reveals Limits on Agglutination as the Protective Mechanism of Secretory Immunoglobulin A. PLoS One 10:e0131351
Anderson, Deborah J; Politch, Joseph A (2015) Role of Seminal Plasma in Human Female Reproductive Failure: Immunomodulation, Inflammation, and Infections. Adv Exp Med Biol 868:159-69

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