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SAFETY & PHARMACOKINETICS OF THE MONOCLONAL ANTIBODY, VRC01, IN HIV-EXPOSED NEWBORNS
Coleen K. Cunningham1, Elizabeth J. McFarland2, Edmund V. Capparelli3, Petronella Muresan4, Charlotte Perlowski5, Megan Valentine5, Elizabeth Smith6, John R. Mascola7, Barney S. Graham7
1Duke Univ Med Cntr, Durham, NC,2Univ of Colorado Sch of Med, Aurora, CO,3Univ of California San Diego, La Jolla, CA,4Harvard T.H. Chan SPH, Boston, MA,5FHI360, Durham, NC,6DAIDS, Rockville, MD,7Vaccine Rsr Cntr, Bethesda, MD
Despite advances in the use of antiretroviral therapy (ART) to prevent mother to child HIV transmission (MCTC), children still become infected for a variety of reasons. A long acting monoclonal antibody might provide a strategy to further prevent transmission.
This is an ongoing, prospective, open label, dose escalating study of a HIV neutralizing, monoclonal antibody, VRC01, administered as a single 20 or 40 mg/kg subcutaneous (SC) dose within 72 hours of birth to infants at increased risk of HIV transmission. Healthy infants and their mothers receive ART as indicated to prevent MTCT. Infants complete safety assessments over 4 hours immediately after dosing and then have safety and pharmacokinetic (PK) measures at 24 hours, days 3, 7, 14, 28, weeks 8, 16 and 24. A non-compartmental PK analysis is used except for CL./F and Vss/F which are estimated using a 2-compartment model. Target VRC01 level is 50 mcg/mL on day 28.
Both dose groups are fully accrued (13 each) from 10 sites in the continental US, Puerto Rico, and South Africa. Approximately half enrollees are male (56%) and black (52%). VRC01 was administered soon after birth, at a mean age of 1.8 (SD 1.0) days. Most infants (12/13) in the lower dose group received a single injection (average volume 0.6 mL) while 12/13 infants in the higher dose group received two injections (average volume 0.7 mL). Safety data are available for 25/26 subjects and PK data through day 28 for the lower dose are available for 12/13 (one child was under-dosed and excluded from PK analysis). Overall, VRC01 was well tolerated with no attributable serious systemic reactions. Local reactions were common, occurring in six (46%) and nine (75%) infants in the low and high dose groups, respectively. None of the local reactions were serious and 100% and 90% in the 20 and 40 mg dose groups, respectively, resolved within four hours of injection. Pain at the injection site was reported in only two infants, both grade 1. The PK measures for 12 infants in the 20 mg/kg group are shown in the table.
These preliminary results indicate that VRC01 administered to neonates via the SC route is safe and well tolerated. The PK for the lower dose demonstrate circulating antibody through day 28 of life close to but below the target in 9/12 (75%). The half-life of VRC01 would support monthly injections for infants at ongoing risk of HIV infection through breastfeeding.