Date Published: November 14, 2017
Publisher: Public Library of Science
Author(s): Kenneth H. Mayer, Kelly E. Seaton, Yunda Huang, Nicole Grunenberg, Abby Isaacs, Mary Allen, Julie E. Ledgerwood, Ian Frank, Magdalena E. Sobieszczyk, Lindsey R. Baden, Benigno Rodriguez, Hong Van Tieu, Georgia D. Tomaras, Aaron Deal, Derrick Goodman, Robert T. Bailer, Guido Ferrari, Ryan Jensen, John Hural, Barney S. Graham, John R. Mascola, Lawrence Corey, David C. Montefiori, Linda-Gail Bekker
Abstract: BackgroundVRC01 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 findingsHIV 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.ConclusionsVRC01 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 registrationClinical Trials Registration: NCT02165267
Partial Text: Antiretroviral (ARV) therapy for HIV-1 treatment and prevention is increasingly available globally; nonetheless, about 2 million new HIV-1 infections occurred in 2016 . Although ARV treatment can decrease HIV transmission  and the use of pre-exposure prophylaxis can decrease acquisition , the logistics and costs of scaling up these approaches remain daunting and expensive. Given the magnitude of ongoing HIV spread, the continued development of other novel, safe, and effective preventive strategies is urgently needed [1,4].
The current study (HVTN 104) has expanded the safety, pharmacokinetic, and functional understanding of the bnAb VRC01 by evaluating multiple doses administered either intravenously or subcutaneously over a 16–22-week period of time in a total of 88 HIV-uninfected participants (including 4 who were randomized to placebo injections), 57 of whom completed all scheduled doses. Participants were followed for 32 weeks after their first VRC01 administration. No SAEs, dose-limiting toxicities, nor evidence for anti-VRC01 antibodies were observed. Serum VRC01 levels were detected through 12 weeks after final administration in all participants who received all scheduled doses. Mean trough concentrations after 3 IV infusions of 30 mg/kg and 10 mg/kg doses administered every 8 weeks were above levels known to neutralize a majority of circulating strains in vitro (IC50 > 5 μg/ml). Post-infusion/injection serum VRC01 retained expected functional activity including virus neutralization, ADCC, phagocytosis, and virion capture.
VRC01 administered intravenously or subcutaneously was safe and well tolerated. Product-related AEs were uncommon and generally transient and mild. After a 40 mg/kg IV loading dose, VRC01 levels were maintained at >30 μg/ml for several weeks through either IV or SC administration every 2 weeks. Trough levels of 4, 16, or 27 μg/ml were maintained with IV infusions of 10, 30, and 40 mg/kg every 8 weeks, respectively. The trough data support the rationale that VRC01 administered every 8 weeks intravenously should be evaluated in studies of HIV-1 immunoprophylaxis. The first efficacy trials of VRC01 are underway in the AMP studies (Clinicaltrials.gov NCT02716675 and NCT02568215, and http://www.ampstudy.org, ampstudy.org.za), evaluating anti-HIV-1 activity among 4,200 at-risk men and transgender people who have sex with men in North and South America and at-risk young women in sub-Saharan Africa. The findings should help inform the development of both passive and active immunization strategies to prevent HIV-1 infection. The trough levels seen after SC administered VRC01 every 2 weeks suggest that this approach may be particularly appropriate for immunoprophylaxis for infants born to HIV-infected mothers. Studies are being developed to test this hypothesis. In summary, HVTN 104 found that VRC01 delivered via IV or SC routes was safe and well tolerated, and results from in vitro assays suggest that the levels achieved in clinical specimens displayed a wide range of functional anti-HIV activities.