Passive immunization using highly potent broadly neutralizing antibodies (bNAbs) against HIV is a promising strategy for pre-exposure prophylaxis. In preclinical models, bNAbs 3BNC117 and 10-1074, which target the CD4 binding site and V3 glycan supersite on HIV Env, respectively, have been shown to protect macaques against rectal SHIV challenge. Here we compared the protective efficacy of a single subcutaneous injection of these antibodies against repeated vaginal SHIV challenges in macaques.
Groups of six female rhesus macaques were injected subcutaneously once with either a single bNAb (3BNC117, 10mg/kg) or two bNAbs (3BNC117 and 10-1074, 10mg each/kg) and repeatedly challenged (once weekly) intravaginally with 300 TCID[sub]50[/sub] SHIV[sub]AD8-EO[/sub], until systemic SHIV infection was confirmed via a plasma viral load assay. Three control macaques were challenged similarly. All study macaques received DMPA (30mg) intramuscularly at 2 weeks before the first SHIV challenge (corresponding to 1 week before bNAb injection in treatment groups), and every 4 weeks thereafter to normalize SHIV susceptibility. Longitudinal plasma samples were assayed to determine bNAb concentrations.
Maximum bNAb concentrations were observed in plasma at 1 week post-administration. Mean Cmax for 10-1074 (38.8ug/ml) was ~6 times as high as 3BNC117 (6.5ug/ml; P=0.001, t-test). Estimated plasma half-life of 3BNC117 (t1/2 = 10.7+/-2.9 days) was similar to 10-1074 (t1/2 = 8.4+/-1.9 days). Macaques administered 3BNC117 alone exhibited significantly delayed SHIV acquisition (median of 5 challenges to infection vs 2 in untreated controls, P=0.002, Log-rank test). Initial detection of SHIV viremia correlated with plasma 3BNC117 levels ≤0.8ug/ml (mean = 0.5+/-0.2 ug/ml). Animals that received 10-1074 in combination with 3BNC117 exhibited significantly greater protection against SHIV acquisition (median 11.5 challenges) compared to 3BNC117-alone (P=0.0005) or to untreated controls (P=0.002, Log-rank test). In this group, first SHIV acquisition corresponded to a plasma 10-1074 level <0.4ug/ml, at which time 3BNC117 was undetectable in all animals.
One subcutaneous administration of 3BNC117 singly, or in combination with 10-1074, conferred significant protection in macaques against repeated vaginal challenges with SHIV. The greater protection observed in the 2-bNAb group appears due to the longer persistence of 10-1074.