Virologic effects of broadly neutralizing antibodies VRC01LS and VRC07-523LS on chronic HIV-1 infection

Abstract

BACKGROUNDHIV-1-specific broadly neutralizing monoclonal antibodies (bNAbs) have emerged as promising interventions with the potential to effectively treat and prevent HIV-1 infections. We conducted a phase I clinical trial evaluating the potent CD4-binding site-specific (CD4bs-specific) bNAbs VRC01LS and VRC07-523LS in people with HIV-1 (PWH) not receiving antiretroviral therapy (ART).METHODSParticipants received a single intravenous 40 mg/kg dose of either VRC01LS (n = 7) or VRC07-523LS (n = 9) and did not initiate ART for a minimum of 14 days. The primary study objective was to evaluate safety and tolerability; the secondary study objectives were to evaluate pharmacokinetics (PK) and the impact of administered bNAbs on viral loads (VL) and CD4+ T cell counts in the absence of ART.RESULTSThis trial enrolled 16 PWH aged 20 to 57 years. Both bNAbs were safe and well tolerated. Mild local reactogenicity was only reported in participants who received VRC07-523LS, while both bNAbs were associated with mild systemic symptoms. Maximum serum concentrations (Cmax) following VRC01LS or VRC07-523LS were 1,566 ± 316 and 1,295 ± 376 μg/mL, respectively. VRC07-523LS administration significantly decreased VL in 8 out of 9 participants, with an average decline of 1.7 ± 0.8 log10 copies/mL within 14 days after administration. In contrast, VRC01LS administration resulted in a smaller average decline (0.8 ± 0.8 log10 copies/mL), and 3 out of 7 participants showedno change in VL. Postinfusion maximum decline in VL correlated with post hoc baseline in vitro viral susceptibility results for both bNAbs.CONCLUSIONThe results of this trial support inclusion of potent CD4bs-specific bNAbs, such as VRC07-523LS, into next-generation treatment regimens for HIV-1.TRIAL REGISTRATIONClinicalTrials.gov NCT02840474.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID)/NIH (grants UM1 AI068634, UM1 AI068636, UM1 AI106701, UM1AI069424, UM1AI069501, UM1AI69415, UM1AI069534, UM1AI69494); the Intramural Research Program of the NIAID/NIH; National Center for Advancing Translational Sciences/NIH (grants UM1TR004548, UL1TR001881, and UL1TR001878); and the National Cancer Institute/NIH (contract 75N91019D00024).

Keywords: AIDS/HIV; Clinical trials; Drug therapy.

Figure 1. Study CONSORT diagram.

Seven people with HIV-1 (PWH) were enrolled into Part A of the trial between April 2017 and October 2017 to receive VRC01LS, and 9 PWH were enrolled into Part B of the trial between November 2018 and January 2019 to receive VRC07-523LS. Study participants were not screened for susceptibility to VRC01LS or VRC07-523LS. Both study products were administered i.v. at a single dose of 40 mg/kg.

Figure 2. Reactogenicity followed VRC01LS and VRC07-523LS infusions.

Number of participants (x axes) reporting solicited local or systemic symptoms (y axes) in the 3 days after infusion.

Figure 3. PK of VRC01LS and VRC07-523LS.

Serum concentrations by individual study participants after a single 40 mg/kg i.v. infusion of VRC01LS (A) or VRC07-523LS (B). Geometric mean serum concentrations with error bars indicating SD of VRC01LS (C) and VRC07-523LS (D) administered at a single dose of 40 mg/kg i.v. to people with HIV-1 (PWH) as compared with previously published data in people without HIV-1 (PWOH) (7, 8). (E and F) Comparisons between C_max and CL in PWH vs. PWOH were performed using t test with unequal variance. C_max, maximum serum concentration; CL, clearance.

Figure 4. The effect of VRC01LS and VRC07-523LS on HIV-1 viral load and CD4⁺ T cell counts after infusion.

Plasma viral load (VL) after a single 40 mg/kg i.v. infusion of VRC01LS (A) and VRC07-523LS (B) for the first 28 days prior to initiation of antiretroviral therapy (ART). (C) Maximum VL decline in participants infused with VRC01LS or VRC07-523LS prior to ART initiation (by day 14); P = 0.055 based on Wilcoxon’s rank-sum test. Solid horizontal lines indicate group median. (D) Changes in CD4⁺ T cell counts after a single 40 mg/kg i.v. infusion of VRC01LS and VRC07-523LS from baseline to peak CD4⁺ T cell counts by day 14 prior to ART. Wilcoxon’s rank-sum test was used for comparisons; lines indicate group means with SD; P value was calculated based on Wilcoxon’s signed-rank test.

Figure 5. Baseline sensitivity of participants’ viruses to VRC01LS and VRC07-523LS.

Preinfusion baseline virus from all participants in the trial were tested for sensitivity to VRC01LS (A) and VRC07-523LS (B) using the Monogram PhenoSense assay. Individual inhibitory concentrations for 50%, 80%, 90%, and 95% neutralization were inferred and indicated with different colors and graphed from most sensitive participant virus to least sensitive for each antibody. The results are graphed by which part of the trial the participants were enrolled (Part A participants went on to be infused with VRC01LS and Part B participants went on to be infused with VRC07-523LS). (C) Maximum viral load (VL) decline by day 14 in participants is associated with baseline sensitivity of the virus to the infused antibody. Each dot represents a single participant and is filled with color to indicate which antibody was infused. MPI, maximum percentage inhibition. Spearman’s rank correlation test was used to derive r and P values.

Figure 6. Baseline sensitivity of participants’ viruses to VRC01LS and VRC07-523LS.

ENVs cloned from baseline and 1 month after infusion for each participant were tested for neutralization sensitivity to the infused antibody VRC01LS (A) or VRC07-523LS (B). IC₈₀ values of each ENV clone are plotted for 2 time points (before infusion is open symbol and after infusion is filled symbol). ENVs could not be amplified from postinfusion participant 3. Black line indicates geometric mean IC₈₀. Pre- and postsensitivity was compared by Mann-Whitney U test. *P < 0.05, **P < 0.01. Black-filled symbols indicate the IC₈₀ calculated by the Monogram PhenoSense assay, which could not be calculated for participants 2 and 3. The post time point was only measured at the matched time point for participants 1, 4, 5, and 6.