Preliminary results suggest that VRC01 -- an investigational HIV neutralising monoclonal antibody -- administered subcutaneously to neonates is safe and well tolerated. Its half-life would support monthly injections for those at risk of HIV through breastfeeding. These data from IMPAACT P1112 were presented at CROI 2017.
IMPAACT P1112 is an ongoing, prospective, open label, dose escalating study of VRC01, given to infants at increased risk of HIV transmission as a single 20 or 40 mg/kg subcutaneous dose within 72 hours of birth. Study sites are in US, Puerto Rico, and South Africa.
Increased risk of infant HIV infection is defined as one or more of the following maternal risk factors: no antiretrovirals (ARV) in pregnancy; began or restarted ARV in third trimester; detectable viral load; prolonged ruptured membranes; two class ARV resistance.
Eligible infants were 36 weeks of gestation or more weighing at least 2 kg at birth. All infants received ARV prophylaxis according to local standard of care. After VRC01 immunisation they received safety assessments for 4 hours followed by safety and pharmacokinetic (PK) measurements at 24 hours, days 3, 7, 14, 28, weeks 8, 16 and 24. Target VRC01 level is 50 mcg/mL on day 28.
The study enrolled 27 infants: 52% male, 61% black, median age 2 days and birth weight 3105 grams. One infant in the 20 mg/kg group was incorrectly enrolled and one in the 40 mg/kg group was under dosed and excluded from the PK analysis.
VCR01 was well tolerated with no grade 3 and above systemic adverse events. Local injection site reactions were common, occurring in 6 and 11 infants in the 20 mg/kg and 40 mg/kg groups respectively. These resolved in four hours for 100% and 55% of infants in the respective dosing groups. The PK results are shown in Table 1.
|Table 1: Infant PK of VRC01 After Single 20 or 40 mg/kg Subcutaneous Dose|
|Cday28 (mcg/mL)||20 mg/kg||39.33||14.94||39.19||16.71 to 76.56|
|40 mg/kg||75.22||21.38||74.79||47.61 to 122.59|
|Cmax (mcg/mL)||20 mg/kg||226.64||30.78||233.32||153.63 to 260.64|
|40 mg/kg||378.37||79.20||390.27||247.44 to 536.60|
|Tmax (d)||20 mg/kg||2.7||2.2||2||1 to 7|
|40 mg/kg||1.4||0.8||1||1 to 3|
|Half-life (d)||20 mg/kg||19.73||4.99||20.17||13.11 to 28.60|
These preliminary results showed persistent levels of VRC01 through day 28 of life. The 40 mg/kg dose achieved the target level at day 28 compared with adults receiving 20 mg/kg intravenously.
The investigators suggest that the half-life of VRC01 supports monthly injections for infants at ongoing risk of vertical transmission of HIV through breastfeeding.
Despite the massive success in preventing vertical transmission of HIV with ARVs, children still become infected for a number of reasons. A long acting monoclonal antibody might further prevent transmission during breastfeeding.
Cunningham CK et al. Safety & pharmacokinetics of the monoclonal antibody, VRC01, in HIV-exposed newborns. CROI 2017. 13-17 February 2017. Seattle. Poster abstract 760.
www.croiconference.org/sessions/safety-pharmacokinetics-monoclonal-antibody-vrc01-hiv-exposed-newborns (Abstract and poster)