Vertical HIV-transmission continues to occur due to barriers to antiretroviral therapy (ART). Prevention of infection might be improved with a potent, broadly neutralizing, monoclonal antibody (bNAb) administered to exposed infants. VRC07-523LS is 5-fold more potent and has a prolonged T1/2 compared to VRC01 and may provide protective levels over the duration of breastfeeding.
This is an open label study of VRC07-523LS administered to HIV-exposed infants at increased risk of HIV infection. Formula-fed infants receive 80 mg subcutaneous (SC) within 72 hrs of birth (Cohort 1) and breast-fed infants receive 80mg SC within 5d of birth and 100 mg SC at week 12 (Cohort 2) if still breastfeeding. Infants and their mothers also receive ART to prevent HIV transmission. Infant safety assessments and VRC07-523LS levels are collected out to 24 weeks. The target week 12 (C12wk) level is 10 mcg/mL: the level needed to neutralize >90% of tier II viruses in a multiclade panel.
Infants in Cohorts 1 (N=11; 4 US sites) and 2 (N=11; 2 African sites) received 80mg VRC07-523LS as a single SC injection at a median of 1 and 4d after birth, respectively, resulting in an average dose of 26 mg/kg (range 18-35 mg/kg). Enrollees were 59% male, 86% Black, and 9% Hispanic. Three in Cohort 2 did not receive week 12 dose, 2/3 due to cessation of breastfeeding. VRC07-523LS was well tolerated. In Cohort 1, 1 infant had injection site erythema of 0.5cm and 1 had tenderness (Grade 1). In Cohort 2, every infant had a local reaction after each injection. Most local reactions were Grade 1; but 3/11 and 2/8 infants had Grade 2 induration after dose 1 and 2, respectively. Most (76%) local reactions resolved within 24 hrs. All ?Grade 3 events within 30 days of VRC07-523LS occurred after dose 1: 4 infants in Cohort 1 (vomiting [N=2], neutropenia, parainfluenza sepsis); and 1 infant in Cohort 2 (sepsis), none related to study treatment. Cmax, Tmax, and C12wk were 203±48 mcg/mL, 1.8±1.6 d, and 16.7+6.8 mcg/mL. T1/2 was approximately 34d, similar to adults, but C12WK levels were lower than adults, suggesting infant SC bioavailability <1. Growth contributed to the fall in VRC07-523LS concentration, but levels remained over the target of 10 mcg/mL at week 12 (figure).
SC VRC07-523LS is safe and well-tolerated when administered to neonates. VRC07-523LS, with its enhanced potency, rapid absorption, and slow elimination, can quickly achieve and maintain target levels with dosing every 3 months.