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 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 Extended half-life bNAb, VRC01LS, was administered subcutaneously (SC) at 80 mg/dose after birth to HIV-1-exposed, non-breastfed (Cohort 1, n=10) and breastfed (Cohort 2, n=11) infants. Cohort 2 received a second dose (100mg) 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 administrated SC achieved a mean +SD plasma level of 222.3 + 71.6 mcg/mL by 24 hours and 44.0 + 11.6 mcg/mL at week 12, prior to Dose 2. The pre-established target of > 50 mcg/mL was attained in 95% and 32% at week 8 and 12, respectively. The terminal half-life was 37-41 days. VRC01LS level after one dose was significantly greater (p=<0.002) than after a VRC01 dose (20mg/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 ARVs to prevent infant HIV-1 transmission.

Contribution to HIV Prevention and Treatment by Antibody-Mediated Effector Function and Advances in Broadly Neutralizing Antibody Delivery by Vectored Immunoprophylaxis

“…AAVs are non-enveloped viruses that belong to the Parvoviridae family (85,86). AAVs are unable to replicate on their own, and as such require a helper virus, such as an adenovirus or herpesvirus to productively replicate within cells (87)(88)(89)(90). They are composed of an icosahedral protein capsid surrounding a single stranded DNA genome of approximately 4700 base pairs.…”

“…The rep gene encodes proteins necessary for virion assembly, including Rep78, Rep68, Rep52 and Rep40. The cap gene encodes for three capsid proteins, VP1, VP2 and VP3 and the assembly activating protein (AAP) and membrane-associated accessory protein (MAAP) in alternative reading frames (87,(92)(93)(94)(95)(96)(97). AAV virions are comprised of 60 VP subunits, and each subunit has nine variable regions that dictate tropism and intracellular trafficking (91).…”

Immunotherapy with Cell-Based Biological Drugs to Cure HIV-1 Infection

“…Together with studies in adult subjects, VRC01 (along with VRC01LS and VRC07-523LS neutralizing mAbs) entered ongoing clinical studies involving the study of mother-to-child transmission of HIV-1 (NCT02256631). Preliminary data revealed that subcutaneous VRC01 as single or multiple doses is safe and well-tolerated in very young infants [ 64 ] as well as VRC01LS [ 65 ]. VRC01 efficacy was also tested in HIV-1-infected adults under antiretroviral therapy who experienced a brief analytical treatment interruption (ATI) (NCT02463227).…”

Vaccine-Induced, High-Magnitude HIV Env-Specific Antibodies with Fc-Mediated Effector Functions Are Insufficient to Protect Infant Rhesus Macaques against Oral SHIV Infection

“…In nonhuman primate (NHP) models of HIV, infection of neonatal and infant rhesus macaques (RM) with simian-human immunodeficiency virus (SHIV) can be prevented by passive administration of broadly neutralizing HIV envelope (Env)-specific antibodies (bNAbs) ( 19 – 21 ). The use of bNAbs as potential prevention strategy in HIV-exposed infants is supported by results from ongoing clinical trials that indicate that bNAbs (e.g., VRC01) are safe and well tolerated in human neonates ( 22 ). Clinical studies in human adults, however, demonstrated only a minimal risk reduction of HIV infection by preventative treatment with bNAbs ( 23 , 24 ).…”