Engineering a physiologically-tuned reservoir intravaginal ring releasing lactic acid for the treatment and prevention of bacterial vaginosis

Project Summary Millions of women in the U.S. suffer from bacterial vaginosis (BV), a vaginal condition initiated by marked overgrowth of polymicrobial bacterial populations that not only leads to foul-smelling discharge but also greatly increases the risks to diverse sexually transmitted infections and pre-term birth. Antibiotics can provide transient relief from initial BV infection, but they do not prevent BV from recurring, with BV recurring as frequently as twice a month). Nearly half of women treated with antibiotics will experience at least one episode of BV recurrence within a year. There is no product on the market that can provide sustained protection against BV. Interestingly, some women are incredibly resistant to BV; they typically have a Lactobacilli crispatus- dominant vaginal microbiome that results in high levels of both D- and L- lactic acid (LA), which serves as a potent and broad-spectrum microbicide against numerous sexually transmitted pathogens and BV-associated polymicrobials. Motivated by this clinical observation, we have been developing an intravaginal ring (IVR) that can sustain high vaginal levels of LA. However, we face an important question: how much LA release is needed to do so in humans? Unfortunately, virtually nothing is known about the rate of loss of LA in the vagina. This lack of knowledge in turn increases the product development risks of advancing an intervention that is ineffective due to insufficient LA release. Here, we seek to directly address this question by directly measuring the rate of LA loss from the vagina of both women with healthy, L.crispatus-dominant microbiota and women with BV-infection, including determining both transepithelial loss and loss via introital discharge (Aim 1). Based on the findings, we would then engineer LA-IVR with LA release rates that match the human physiology, enabling us to sustain high levels of LA for over 30 days (Aim 2). Towards this goal, we have now developed a proprietary reservoir-IVR system that allows us to precisely tune LA release rates with near zero-order release kinetics, achieving LA release at rates orders of magnitude greater than what had been previously reported. Successful measurements of the steady-state rates of loss of LA in the human vagina not only will enhance our understanding of human vaginal physiology, but also ensures we are advancing a LA-IVR that can dose sufficient amounts of LA to likely make a clinical impact (thus minimizing the risks of advancing an inadequate product). The simplicity of our LA-IVR design ensures both ease of production and low manufacturing costs of the eventual product, which in turn should maximize potential public health impact and commercial viability of the product, both in the U.S. and in other low- and middle-income countries suffering the greatest societal and economic burden from BV infections.