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Thesis MABGEL 1: C2F5, C4E10 & C2G12 as a vaginal microbicide Topical microbicides are being developed as a female-controlled method for preventing HIV-1 infection. Non-antiretroviral (ARV)-based candidates may be advantageous given increasing levels of ARV resistance in low and middle- income countries.MABGEL 1 was a phase 1 trial designed to evaluate the pharmacokinetics and safety of a vaginal microbicide containing the broadly HIV-1 neutralizing monoclonal antibodies (mAbs) C2F5, C4E10 and C2G12 in a hydroxyethylcellulose-based gel vehicle. It was the first study of topical mAb application to the human female genital tract.Twenty-eight healthy women were randomised to apply either high dose Mabgel (containing 20mg/g of each mAb) (n= 10), low dose Mabgel (containing 10mg/g of each mAb) (n=9) or placebo gel (n=9). Doses (2.5ml) were applied over 12 consecutive days. Genital tract sampling was performed at baseline, 1 hour, 8 hours and 24 hours post 1st dose and 12 and 36 hours post 12th dose with serum samples collected at baseline, 8 hours post 1st dose and 12 hours post 12th dose. Safety was assessed through participant report and clinical examination, including colposcopy.Residence half-lives (t ½) in vaginal secretions (Weck-Cel samples) were estimated to be between 4 and 5.5 hours for C4E10 and C2F5. In contrast, vaginal levels of C2G12 did not conform to a single overall exponential decay, displaying a more rapid initial rate of decline, which then slowed at lower concentrations. The estimated early t ½ of C2G12 was 1.4 hours (95% CI 1.2 to 1.8). There was no evidence of systemic absorption.Daily vaginal application of up to 50g of each mAb over 12 days was safe. Although adverse events (AEs) were reported by all but 1 participant, 95 % were mild, none were serious and only 4 were moderate. There was no statistically significant difference in the number of AEs reported per participant between the 3 study arms.Although there are a number of caveats, results demonstrate ‘proof of principle’ of the potential for combinations of HIV-1 neutralizing mAbs to be used as a coitally-dependent microbicide. Morris, Georgina Claire MD Doctoral 2012-12-01 Hull York Medical School, the University of Hull and the University of York oai:hull-repository.worktribe.com:4214589 https://hull-repository.worktribe.com/4214589/1/Thesis Medicine https://hull-repository.worktribe.com/output/4214589 2012 en openAccess Public