Safety, Tolerability, and Pharmacokinetics of a Long-Acting Broadly Neutralizing Human Immunodeficiency Virus Type 1 (HIV-1) Monoclonal Antibody VRC01LS in HIV-1-Exposed Newborn Infants

Abstract

Background: Perinatal human immunodeficiency virus type 1 (HIV-1) continues to occur due to barriers to effective antiretroviral prevention that might be mitigated by long-acting broadly neutralizing monoclonal antibodies (bNAbs).

Methods: An extended half-life bNAb, VRC01LS, was administered subcutaneously at 80 mg/dose after birth to HIV-1-exposed, nonbreastfed (cohort 1, n = 10) and breastfed (cohort 2, n = 11) infants. Cohort 2 received a second dose (100 mg) at 12 weeks. All received antiretroviral prophylaxis. VRC01LS levels were compared to VRC01 levels determined in a prior cohort.

Results: Local reactions (all grade ≤2) occurred in 67% and 20% after dose 1 and dose 2, respectively. The weight-banded dose (mean 28.8 mg/kg) of VRC01LS administered subcutaneously achieved a mean (standard deviation) plasma level of 222.3 (71.6) µg/mL by 24 hours and 44.0 (11.6) µg/mL at week 12, prior to dose 2. The preestablished target of ≥50 µg/mL was attained in 95% and 32% at weeks 8 and 12, respectively. The terminal half-life was 37-41 days. VRC01LS level after 1 dose was significantly greater (P <.002) than after a VRC01 dose (20 mg/kg). No infants acquired HIV-1.

Conclusions: VRC01LS was well tolerated with pharmacokinetics that support further studies of more potent long-acting bNAbs as adjunct treatment with antiretrovirals to prevent infant HIV-1 transmission.

Keywords: HIV-1; HIV-1 prevention; VRC01; VRC01LS; bNAb; broadly neutralizing antibodies; monoclonal antibodies; neonates; passive immunization; perinatal HIV-1 transmission; pharmacokinetics.

Figure 1.

Pharmacokinetics of VRC01LS after 1 subcutaneous (SC) dose of 80 mg (solid black line) or 2 SC doses (80 mg followed by 100 mg at 12 weeks) (dashed gray line). The plasma pharmacokinetic sampling for VRC01LS (µg/mL) is described in the Methods. Error bars indicate the standard deviation (SD).

Figure 2.

VRC01LS concentrations at 4-week intervals after the first dose. Box plot describes median, interquartile range (25th–75th percentiles; box), and 5th–95th percentiles in additional to the individual concentrations.

Figure 3.

First-dose VRC01LS (fixed at 80 mg) mean concentration–time profile (solid black line) compared to single-dose VRC01 (20 mg/kg) profile (dashed gray line) determined in the prior stage for this study and previously reported [12]. Error bars indicate the standard deviation. Abbreviations: SC, subcutaneous; SD, standard deviation.