Safety, Acceptability, And Pharmacokinetics Of A Monoclonal Antibody-Based Vaginal Multipurpose Prevention Film (Mb66): A Phase I Randomized Trial

BackgroundMB66 film is a multipurpose prevention technology (MPT) product with monoclonal antibodies (mAbs) against HIV-1 (VRC01-N) and HSV-1 and 2 (HSV8-N). The mAbs were produced by transient expression in Nicotiana benthamiana (N). We conducted a Phase I clinical trial to assess the safety, pharmacokinetics (PK), and ex vivo efficacy of single and repeated doses of MB66 when used intravaginally.Methods and findingsThe clinical trial enrolled healthy reproductive-aged, sexually abstinent women. In Segment A, 9 women received a single MB66 film which was inserted into the vaginal posterior fornix by a clinician. In Segment B, 29 women were randomly assigned to MB66 (Active) or Placebo film groups and were instructed to insert 1 film vaginally for 7 consecutive days. Visits and clinical sampling occurred predose and at various time points after single and repeated film doses. The primary endpoint was number of adverse events (AEs) Grade 2 or higher related to product use. Secondary endpoints included film dissolution rate, Nugent score (a Gram stain scoring system to diagnose bacterial vaginosis), vaginal pH, post-use survey results, cytokine concentrations in cervicovaginal lavage (CVL) specimens (assessed by Luminex assay), mAb concentrations in vaginal fluid collected from 4 sites (assessed by ELISA), and HIV and HSV neutralization activity of CVL samples ex vivo (assessed by TZM-bl and plaque reduction assay, respectively).The product was generally safe and well tolerated, with no serious AEs recorded in either segment. The AEs in this study were primarily genitourinary in nature with the most commonly reported AE being asymptomatic microscopic hematuria. There were no differences in vaginal pH or Nugent scores or significant increases in levels of proinflammatory cytokines for up to 7 days after film insertion in either segment or between Active and Placebo groups. Acceptability and willingness to use the product were judged to be high by post-use surveys.Concentrations of VRC01-N and HSV8-N in vaginal secretions were assessed over time to generate pharmacokinetic curves. Antibody levels peaked 1 hour postdosing with Active film (median: 35 mu g/mL) and remained significantly elevated at 24 hours post first and seventh film (median: 1.8 mu g/mL). Correcting for sample dilution (1:20), VRC01-N concentrations ranged from 36 to 700 mu g/mL at the 24-hour time point, greater than 100-fold the IC50 for VRC01 (0.32 mu g/mL); HSV8-N concentrations ranged from 80 to 601 mu g/mL, well above the IC50 of 0.1 mu g/m. CVL samples collected 24 hours after MB66 insertion significantly neutralized both HIV-1 and HSV-2 ex vivo. Study limitations include the small size of the study cohort, and the fact that no samples were collected between 24 hours and 7 days for pharmacokinetic evaluation.ConclusionsSingle and repeated intravaginal applications of MB66 film were safe, well tolerated, and acceptable. Concentrations and ex vivo bioactivity of both mAbs in vaginal secretions were significantly elevated and thus could provide protection for at least 24 hours postdose. However, further research is needed to evaluate the efficacy of MB66 film in women at risk for HIV and HSV infection. Additional antibodies could be added to this platform to provide protection against other sexually transmitted infections (STIs) and contraception.Author summaryWhy was this study done?Human immunodeficiency virus-type 1 (HIV-1) and herpes simplex virus-type 2 (HSV-2) are 2 relatively common sexually transmitted pathogens associated with significant morbidity and mortality.Antiviral drugs have been introduced to suppress viral concentrations and ameliorate some of the worst effects of these viruses, but the infections are incurable. Therefore, considerable effort is being directed toward prevention strategies.Many women have a preference for multipurpose prevention technology (MPT) products, effective short-term pericoital methods and natural products (i.e., antibodies).What did the researchers do and find?We conducted a Phase I clinical trial to assess the safety, acceptability, pharmacokinetics (PK), and ex vivo efficacy of single and repeated doses of MB66, a vaginal film product containing monoclonal antibodies (mAbs) against HIV-1 (VRC01-N) and HSV-1 and 2 (HSV8-N).No serious adverse events (AEs) associated with product use were observed.Antibody levels peaked in vaginal secretions 1 hour postdosing with Active film and remained significantly elevated through 24 hours.Vaginal samples collected 24 hours after MB66 insertion significantly neutralized both HIV-1 and HSV-2 ex vivo.What do these findings mean?Single and repeated intravaginal applications of MB66 film were safe, well tolerated, and acceptable.Concentrations and ex vivo bioactivity of both mAbs in vaginal secretions were consistent with protection for at least 24 hours after film use.Phase II/III clinical trials are needed to further evaluate safety and efficacy of MB66 film in women at risk for HIV and HSV infection.