Safety, pharmacokinetics, and immunological activities of multiple intravenous or subcutaneous doses of an anti-HIV monoclonal antibody, VRC01, administered to HIV-uninfected adults: Results of a phase 1 randomized trial

Background VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed. Methods and findings HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens. Additionally, this study aimed to assess the effect that the human body has on the functional activities of VRC01 as measured by several in vitro assays. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range, 18–50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic), 11% were Hispanic, and 11% were non-Hispanic people of diverse origins. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 [T1], n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 [T3], n = 20); placebo (placebo group 3 [P3], n = 4) doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n = 20). Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities, nor evidence for anti-VRC01 antibodies observed. Serum VRC01 levels were detected through 12 weeks after final administration in all participants who received all scheduled doses. Mean peak serum VRC01 levels of 1,177 μg/ml (95% CI: 1,033, 1,340) and 420 μg/ml (95% CI: 356, 494) were achieved 1 hour after the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively. Mean trough levels at week 24 in the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively, were 16 μg/ml (95% CI: 10, 27) and 6 μg/ml (95% CI: 5, 9) levels, which neutralize a majority of circulating strains in vitro (50% inhibitory concentration [IC50] > 5 μg/ml). Post-infusion/injection serum VRC01 retained expected functional activity (virus neutralization, antibody-dependent cellular cytotoxicity, phagocytosis, and virion capture). The limitations of this study include the relatively small sample size of each VRC01 administration regimen and missing data from participants who were unable to complete all study visits. Conclusions VRC01 administered as either an IV infusion (10–40 mg/kg) given monthly or bimonthly, or as an SC injection (5 mg/kg) every 2 weeks, was found to be safe and well tolerated. In addition to maintaining drug concentrations consistent with neutralization of the majority of tested HIV strains, VRC01 concentrations from participants’ sera were found to avidly capture HIV virions and to mediate antibody-dependent cellular phagocytosis, suggesting a range of anti-HIV immunological activities, warranting further clinical trials. Trial registration Clinical Trials Registration: NCT02165267
In a phase 1 trial, Kenneth Mayer and colleagues investigate the safety and tolerability of VRC01, a broadly neutralizing anti-HIV antibody.
Author summary Why was this study done? Despite improvements in HIV treatment and prevention, there were close to 2 million new infections worldwide in 2016. There remains hope that the right preventive tool or combination of tools will eliminate new HIV infections. Immunotherapy and vaccines have been responsible for eliminating several major viral diseases, such as smallpox, and potentially very powerful HIV preventive tools are under development. Researchers have discovered that some antibodies can effectively neutralize many strains of HIV and protect nonhuman animals from getting infected; these are called broadly neutralizing antibodies (bnAbs). This study was designed to evaluate the safety, pharmacological profile, and immune functions of one such antibody administered either subcutaneously or intravenously as a foundation for future efficacy trials of this and other HIV-1 bnAbs. What did the research do and find? VRC01, an anti-HIV antibody, is safe and well tolerated when administered multiple times either subcutaneously or intravenously. The drug levels achieved with the different dosing regimens produced antibody levels that lasted many weeks at concentrations that could inhibit HIV when tested in vitro. The antibody in serum after administration showed evidence of a number of immune functions that are known to inhibit HIV transmission and replication. What do these findings mean? The safety and tolerability of VRC01, administered multiple times either subcutaneously or intravenously, support moving forward with larger trials. The concentrations achieved when dosed at 10 mg/kg or 30 mg/kg every 8 weeks produced drug levels that are predicted to protect against the acquisition of HIV infection. These data helped inform the development of 2 large efficacy trials of VRC01 in high-risk people in the US, South America, and southern Africa that will establish whether intravenous administration is protective against HIV transmission (www.ampstudy.org, ampstudy.org.za). Importantly, this work establishes the framework for subsequent analyses of effective levels of VRC01 or other bnAbs as well as the neutralization titers necessary to prevent HIV, which future HIV vaccines must aim to induce.