Background/Objectives: The prevention of sexual HIV-1 acquisition in women and girls in sub-Saharan Africa remains an important public health priority. Expanding the existing biomedical product portfolio to include long-acting vaginal products, such as intravaginal rings (IVRs), is expected to appeal to end users and drive adoption. Methods: We formulated two different triple-combination antiretroviral IVRs, both delivering the acid salt tenofovir (TFV), disoproxil fumarate (TDF), and the free base emtricitabine (FTC), with one delivering elvitegravir (EVG) as the free acid and the other as the sodium salt. The devices were evaluated for pharmacokinetics and local safety in two established preclinical models, sheep and pig-tailed macaques. Results: The IVRs were safe and maintained cervicovaginal fluid (CVF) drug concentrations that were above our efficacy targets derived from prior humanized mouse studies. All three agents were uniformly distributed vaginally, as evidenced by CVF and vaginal tissue measurements. Elevated drug concentrations were observed in macaque vaginal tissue samples collected three days after IVR removal, suggesting a possible forgiveness window. TFV and FTC concentrations in rectal tissue and fluid suggested potential for dual-compartment HIV-1 protection, although the vaginal-to-rectal drug transport mechanism appeared to differ across both species. The humanized mouse vaginal HIV-1 efficacy model was used to empirically compare combination effects when TDF, FTC, and EVG were co-administered, and TDF-EVG was identified as a promising combination to be developed further for IVR delivery in parallel with the triple combination.

Background: The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease 2019 (COVID-19) have precipitated a global pandemic heavily challenging our social behavior, economy, and healthcare infrastructure. Public health practices currently represent the primary interventions for managing the spread of the pandemic. We hypothesized that frequent, longitudinal workplace disease surveillance would represent an effective approach to controlling SARS-CoV-2 transmission among employees and their household members, reducing potential economic consequences and loss of productivity of standard isolation methods, while providing new insights into viral-host dynamics. Methodology and Findings: On March 23, 2020 a clinical study (OCIS-05) was initiated at a small Southern California organization. Results from the first 3 months of the ongoing study are presented here. Study participants (27 employees and 27 household members) consented to provide frequent nasal or oral swab samples that were analyzed by RT-qPCR for SARS-CoV-2 RNA using CDC protocols. Only participants testing negative were allowed to enter the “safe zone” workplace facility. Optional blood samples were collected at baseline and throughout the 3-month study. Serum virus-specific antibody concentrations (IgG, IgM, and IgA) were measured using a selective, sensitive, and quantitative ELISA assay developed in house. A COVID-19 infection model, based on traditional SEIR compartmental models combined with Bayesian non-linear mixed models and modern machine learning, was used to predict the number of employees and household members who would have become infected in the absence of workplace surveillance. Two study participants were found to be infected by SARS-CoV-2 during the study. One subject, a household member, tested positive clinically by RT-qPCR prior to enrollment and experienced typical COVID-19 symptoms that did not require hospitalization. While on study, the participant was SARS-CoV-2 RNA positive for at least 71 days and had elevated virus-specific antibody concentrations (medians: IgM, 9.83 µg mL ^-1 ; IgG, 11.5 µg mL ^-1 ; IgA, 1.29 µg mL ^-1 ) in serum samples collected at three timepoints. A single, unrelated employee became positive for SARS-CoV-2 RNA over the course of the study, but remained asymptomatic with low associated viral RNA copy numbers. The participant did not have detectable serum IgM and IgG concentrations, and IgA concentrations decayed rapidly (half-life: 1.3 d). The employee was not allowed entry to the safe zone workplace until testing negative three consecutive times over 7 d. No other employees or household members contracted COVID-19 over the course of the study. Our model predicted that under the current prevalence in Los Angeles County without surveillance intervention, up to 7 employees (95% CI = 3-10) would have become infected with at most 1 of them requiring hospitalizations and 0 deaths. Conclusions: Our clinical study met its primary objectives by using intense longitudinal testing to provide a safe work environment during the COVID-19 pandemic, and elucidating SARS-CoV-2 dynamics in recovering and asymptomatic participants. The surveillance plan outlined here is scalable and transferrable. The study represents a powerful example on how an innovative public health initiative can be dovetailed with scientific discovery.