Subcutaneous administration of broadly neutralizing antibodies (bnAb) VRC07-523LS and PGT121 for protection against HIV infection were found to be safe and well tolerated among young women in South Africa, according to results of a study published in the Journal of Infectious Diseases.
Investigators conducted a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 trial to assess the safety and pharmacokinetics (PK) of bnAbs VRC07-532LS and PGT121 for protection against HIV infection among young women in South Africa. They enrolled a total of 45 patients who were negative for HIV infection. Eligible patients included those who were aged 18 to 40 years, at decreased risk for HIV infection, and receiving effective contraceptive medication. Patients were allocated to 9 groups with 5 patients in each group. Among the 5 patients in each group, 4 were randomly assigned to receive VRC07-523LS and/or PGT121 and 1 received placebo. Repeat doses in groups 3, 4 and 6 were given at 12 or 24 weeks. The primary endpoint was safety, defined as reactogenicity and adverse events up to 24 weeks after subcutaneous administration of bnAbs VRCO7-523LS and PGT121; secondary endpoints included PK, evidence of antidrug antibodies, and the acceptability of subcutaneous injections.
Investigators collected plasma, serum, and peripheral blood mononuclear cell samples at predetermined timepoints for endpoint analysis. They also performed PK modeling to predict steady-state concentrations for 12- and 24-week dosing intervals. Reactogenicity was assessed in person immediately following treatment initiation and subsequently on days 1 and 3, and via telephone on day 2. In addition, patients self-reported symptoms that occurred within 3 days of treatment initiation using a daily symptom diary. At the conclusion of the study, patients received questionnaires to assess the acceptability of subcutaneous injections.
Among 45 patients included, 44 completed the study and 1 was lost to follow-up after 58 weeks. The median patient age was 24 years. The most common reactogenicity events were injection site tenderness and headache, both of which resolved within 3 days. A total of 161 adverse events were reported, of which 9 were related to the study treatment and occurred within 7 days of initial treatment administration. The 9 adverse events comprised proteinuria and increased alanine aminotransferase and aspartate aminotransferase in 7 and 2 patients, respectively; all adverse events resolved after a median of 7 days and were of mild or moderate severity.
The median concentrations of detectable VRC07-523LS antibodies after administration of 20 mg/kg doses were 9.65 µg/mL at 16 weeks and 3.86 µg/mL at 24 weeks, showing concentration increases in proportion to dose. The median PGT121 concentration following administration at a dose of 10 mg/kg was 8.27 µg/mL at week 8, after which it was below the limit of quantitation for the 3 mg/kg dose but still detectable through week 24 in patients who received the 10 mg/kg dose.
PK modeling of VRC07-523LS administered at a dose of 20 mg/kg showed median concentrations of 8.1 µg/mL at 16 weeks and 3.2 µg/mL at 24 weeks. PK modeling of PGT121 at a dose of 20 mg/kg showed median concentrations of 1.1 µg/mL at 16 weeks and 0.13 µg/mL at 24 weeks. Concentrations of detectable VRC07-523LS antibodies were found to be similar among patients who received bnAbs VRC07-523LS and PGT121 in combination. The VRC07-523LS half-life was 29 days and the PGT121 half-life was 20 days.
Both antibody treatments showed potent neutralizing activity (50% minimum inhibitory concentration [ID50] >1000 µg/mL) after administration, with peak neutralization occurring between days 3 and 7 among all patients. No anti-drug antibodies were detected.
Most patients (86.7%) found the injection schedule of 2 to 3 injections yearly acceptable. In addition, 96% of patients stated they would likely recommend the injection to others if it were found to be safe and effective, and 91% stated they would willing to disclose their treatment to their partners.
Study limitations included the small sample size of each group and relatively decreased confidence in regard to PGT121 modeling results due to missing data.
“Overall, VRC07-523LS was found to be a suitable bnAb to take forward in developing combination bnAbs as a long-acting prevention technology to [decrease] HIV incidence among young women in Southern Africa,” the investigators concluded.
Mahomed S, Garrett N, Capparelli EV, et al. Safety and pharmacokinetics of monoclonal antibodies VRC07-523LS and PGT121 administered subcutaneously for HIV prevention. J Infect Dis. Published online February 4, 2022. doi:10.1093/infdis/jiac041