Abstract
Vaginal mucosal surfaces naturally offer some protection against sexually transmitted infections (STIs) including Human Immunodeficiency Virus-1, however topical preventative medications or vaccine designed to boost local immune responses can further enhance this protection. We previously developed a novel mucosal vaccine strategy using viral vectors integrated into mouse dermal epithelium to induce virus-specific humoral and cellular immune responses at the site of exposure. Since vaccine integration occurs at the site of cell replication (basal layer 100-400 micrometers below the surface), temporal epithelial thinning during vaccine application, confirmed with high resolution imaging, is desirable. In this study, strategies for vaginal mucosal thinning were evaluated noninvasively using optical coherence tomography (OCT) to map reproductive tract epithelial thickness (ET) in macaques to optimize basal layer access in preparation for future effective intravaginal mucosal vaccination studies. Twelve adolescent female rhesus macaques (5-7kg) were randomly assigned to interventions to induce vaginal mucosal thinning, including cytobrush mechanical abrasion, the chemical surfactant spermicide nonoxynol-9 (N9), the hormonal contraceptive depomedroxyprogesterone acetate (DMPA), or no intervention. Macaques were evaluated at baseline and after interventions using colposcopy, vaginal biopsies, and OCT imaging, which allowed for real-time in vivo visualization and measurement of ET of the mid-vagina, fornices, and cervix. P value ≤0.05 was considered significant. Colposcopy findings included pink, rugated tissue with variable degrees of white-tipped, thickened epithelium. Baseline ET of the fornices was thinner than the cervix and vagina (p<0.05), and mensing macaques had thinner ET at all sites (p<0.001). ET was decreased 1 month after DMPA (p<0.05) in all sites, immediately after mechanical abrasion (p<0.05) in the fornix and cervix, and after two doses of 4% N9 (1.25ml) applied over 14 hrs in the fornix only (p<0.001). Histological assessment of biopsied samples confirmed OCT findings. In summary, OCT imaging allowed for real time assessment of macaque vaginal ET. While varying degrees of thinning were observed after the interventions, limitations with each were noted. ET decreased naturally during menses, which may provide an ideal opportunity for accessing the targeted vaginal mucosal basal layers to achieve the optimum epithelial thickness for intravaginal mucosal vaccination.
Highlights
The vaginal surface epithelium is a primary portal of entry for all sexually transmissible diseases including the Human Immunodeficiency Virus -1 (HIV-1)
We evaluated mechanical, chemical (N9), and hormonal (DMPA) methods to modify the thickness of the cervicovaginal epithelium as a means to access the basal layers
Creating a consistent protocol for accessing the epithelial basal cell layers for use in either virus challenge or vaccine administration via epithelial thinning can be achieved by various means and quantitated noninvasively by optical coherence tomography (OCT)
Summary
The vaginal surface epithelium is a primary portal of entry for all sexually transmissible diseases including the Human Immunodeficiency Virus -1 (HIV-1). Intravaginal PrEP treatments are designed to address this limitation by the administration of medication at the site of infection to prevent the transmission of sexually transmitted infections (STI) and HIV. Well-established barriers associated with the use of oral or vaginal PrEP by women include stigma, cost, and adherence to the requirements of frequent use. These are some of the factors driving the interest for alternative strategies to prevent sexual infection transmission at the vagina, the primary site of viral entry in women, especially long acting prevention strategies that include medications or vaccines
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