Chlamydia trachomatis Vaccine and Efficacy Evaluation in Nonhuman Primates

Dorothy L Patton, PhD, Principal Investigator

The objective of these studies is to further the development of topical microbicides aimed at the prevention and control of sexually transmitted infections (STIs) through preclinical testing in nonhuman primates (NHP), utilizing our established models for topical microbicide safety and efficacy evaluations. Macaque models of Chlamydia trachomatis and Trichomonas vaginalis are currently available for efficacy studies in this laboratory. All test products, provided by NIAID, will first complete safety evaluation with repeated intravaginal product application. If an acceptable safety profile results from these studies, a product will progress (upon NIAID recommendation) to efficacy studies involving one or more STIs. Safety measures include microbiologic and pH assessments and documentation of mucosal tissue responses as evidenced by colposcopic evaluation. Efficacy will be determined by a product's ability to prevent infection by the challenge pathogen.

Funding Source: National Institute of Allergy and Infectious Diseases (NIAID)
End Date: 6-30-16

Combination HIV Prevention in Drug-Eluting Fibers:  Designing for Efficacy and Use

Dorothy L Patton, PhD, Co-Investigator, with Kim Woodrow, PhD, Principal Investigator

We have developed an innovative dosage form for vaginal drug delivery using polymeric fibers fabricated by electrospinning. Drug-eluting fibers exhibit unique materials and processing features that distinguish them from existing microbicide products. Our work to date has shown the versatility of polymer fibers for rapid and sustained delivery of diverse ARV drugs alone and in combination, to fabricate composite materials of varying microstructure, and to be produced using a manufacturing scale electrospinning process. However, the further advancement and development of any single microbicide drug delivery system must prioritize that the product embody physical attributes that impact user perceptions without compromising the design for biological efficacy. While our previous results advance the concept of using drug-eluting fibers as a new dosage form for topical delivery of combination ARV drugs for HIV prevention, the feasibility of this new platform technology to be designed for chemoprophylactic protective efficacy against vaginal HIV challenge while exhibiting bulk material properties with adequate user perceptibility (geometry, texture, dissolution time and viscosity) has not been demonstrated. We propose here a project framework to inform the design of a first-generation, fiber-based, topical microbicide that is constrained for functions prioritized from user perception and NHP safety/PK studies. This proposal integrates three primary research areas:
1) fiber DDS prototype design and formulation
2) user-guided product design and evaluation, and
3) NHP safety/PK and efficacy testing
Our framework is an iterative process to design, test and select lead candidate fiber DDS prototypes that are optimized for user perceptions (Aim 1) and biological safety/PK (Aim 2), before advancing to a vaginal challenge efficacy study in NHPs (Aim 3). We selected a novel triple ARV drug combination to demonstrate the strength of the fiber DDS to deliver agents that are physico-chemicaly diverse, having differing mechanisms of action against HIV, and show instantaneous inhibitory potential in combination to halt virus replication. We also propose to design fiber fabrics that modulate drug release for both pericoital and sustained protection. Finally, we incorporate incisivie product acceptability studies early in the preclinical deelopment of a new microbicide product to help guide the design of the formulation's biophysical and other attributes to have the greatest impact on user adherence. These studies will be the first to confirm that fiber-based microbicides can be designed to prioritize physical properties that are critical to the user experience, while at the same time prioritizing functional properties that prevent vaginal HIV infection. The broader impact of these innovations will support the rapid advancement of a fiber microbicide to first-in-human clinical trials.

Funding Source: National Institutes of Health (NIH/NIAID)
End Date: 1-31-17

Project 2: Nonhuman Primate Studies of Tenofovir and Dapivirine

Dorothy L Patton, PhD, Principal Investigator

The revised aims are: 1) Determine optimal dosing level of TFV in film formulation in the nonhuman primate. Hypothesis: The drug release rate will be greater from the film formulation as compared to the gel formulation. 2) Perform product distribution and transport studies. Hypothesis: Vaginal film formulations will distribute throughout the lower genital tract as efficiently as vaginal gel formulation. 3) Describe the pharmacokinetics (PK) of film vs gel formulations of tenofovir and dapivirine. Hypothesis: TFV and dapivirine will be present in secretions, cells and tissues throughout the cervicovaginal site. Tenofovir will be detected in blood sera, dapivirine will not. 4) Employ the nonhuman primate safety model to help guide formulation optimization (Project 1, Core C) via vaginal safety measures. Hypothesis: Film formulations will be shown to have acceptable safety profiles. Intrinsic antibacterial activity will be minimally disrupted by film formulations.

Funding Source: National Institutes of Health (NIH/NIAID)
End Date: 5-31-16

Systems and Carcinogenic Impact Assessment of Topical Microbicides on the Human Mucosa

Florian Hladik, MD, PhD, Principal Investigator

Several drugs, including NRTIs like tenofovir, and non-NRTIs like dapivirine, are being tested for vaginal or rectal application to prevent sexual HIV transmission. However, NRTI drugs have side effects that could undermine their effectiveness and cause serious safety concerns with long-term, topical use. In this proposal, we study these side effects with a particular focus on tenofovir's possibly carcinogenic effects at the currently-tested concentrations, and determine whether non-NRTIs could be a safer alternative.

Funding Source: National Institutes of Health (NIH/NIAID)
End Date: 4-30-20

Nanoparticle Microbicides for Delivery of Combination Antiretroviral Drugs (R21/R33)

Florian Hladik, MD, PhD, Co-Principal Investigator

Sexual transmission through the genital tract or rectal mucosa is the most common route for acquiring new HIV infections and accounted for ~70% of the 2.7 million people worldwide who became newly infected in 2007. A cure or effective vaccine that would contain the global spread of this epidemic is not expected in the near term, and new HIV infections continue to outpace advances made in treatment with antiretroviral drugs. There is consequently an urgent need to develop agents that can be applied topically to mucosal surfaces to prevent the sexual transmission of HIV. However, several large-scale clinical trials testing the efficacy of agents that disrupt the integrity of the viral envelope (detergents) or prevent adsorption or fusion of the virus with its target cells (polyanions) have failed to protect against HIV infection. The success of highly active antiretroviral therapy (HAART) provides a paradigm for developing the next generation of microbicides, raising the possibility that a combination of potent and broadly active inhibitors that exhibit multiple and complementary mechanisms of action may be vastly superior to the delivery of single compounds. To fully realize the potential of these potent antiretroviral (ARV) drugs, the challenges of formulating and delivering compounds with markedly different chemical stability and aqueous solubility in a topical combination product must be overcome. This research plan is designed to evaluate nanoparticle-based vaginal drug delivery systems for HIV prevention. The experimental focus is to achieve protection against vaginal transmission of HIV-1 by topical delivery of a combination of antiretroviral drugs using mucus- and tissue-diffusing nanoparticle microbicides. This research would be the first to control the temporal and spatial co-delivery of a combination of antiretroviral agents that have different mechanisms of action against HIV-1 (Aim 1). If successful, our studies would be the first to determine the size range and penetration depth accessible for nanoparticulate drug delivery systems in the vaginal mucosa (Aim 2). Our proposed research will also provide valuable data on the transport, biodistribution, and pharmacokinetics of encapsulated and released antiretroviral agents that are administered topically to the vaginal mucosa using nanoparticle microbicides (Aim 3). Finally, we will conduct preclinical safety and anti-HIV efficacy studies to rapidly advance our nanoparticle-based microbicides to human safety and efficacy trials (Aim 4). The outcomes from our proposed research may highly impact the field of microbicide research for HIV and other sexually-transmitted infections.

Funding Source: NIH/NIAID
End Date: 5-31-16

Film Antiretroviral Microbicide Evaluation

Dorothy L Patton, PhD, Principal Investigator

The broad objective of the Nonhuman Primate Core is to support the development of optimized formulations(s) for microbicide/biomedical prevention (MBP) delivery that result in reliable administration and sustained drug presence at specified target sites. Macaque models will be utilized to determine the pharmacokinetics of MK-2048 when delivered in an extended release vaginal film, to establish the safety profile for film use in the presence and absence of coitus, and to assess the developed product’s efficacy in preventing HIV infection.

Funding Source: Magee-Womens Hospital
End Date: 5-31-16