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.
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.
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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|
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