A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges

Abstract

Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long-term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg(-1)) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9 - 12)) in blocking repeated weekly low-dose virus challenges of the clade B SHIVAD8. Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half-life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half-life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission.

Extended Data Figure 1. Neutralization sensitivity of SHIV_AD8-EO to four broadly acting neutralizing anti-HIV-1 MAbs

a, Neutralizing activity of the indicated bNAbs was determined against SHIV_AD8-EO pseudovirions using TZM-bl target cells. The calculated IC₅₀ and IC₈₀ values are shown at the bottom. b, Neutralizing activity of the indicated bNAbs was determined against replication competent SHIV_AD8-EO in a single round TZM-bl infectivity assay. The calculated IC₅₀ and IC₈₀ values are shown at the bottom. The assay was carried out in the presence of indinavir. Both experiments were performed twice.

Extended Data Figure 2. Development of anti-MAb immune responses in recipients of anti-HIV-1 bNAbs

a, b, c, d, Longitudinal analysis of anti-VRC01, anti-3BNC117, anti-10-1074 and anti-VRC01-LS antibody responses respectively, following a single intravenous infusion of indicated MAbs. This assay was performed twice.

Extended Data Figure 3. Predicted probability of infection as a function of antibody levels

The per-challenge probability of infection was modeled as a function of antibody concentration at the time of each challenge using a probit regression model. The fitted probabilities from the models are plotted separately for each MAb group, with the estimated probability of infection for the control animals (0.27) indicated by the open circle adjacent to each ordinate. The VRC01 and VRC01-LS curves are superimposed. The points on each curve represent the median concentration at the time of breakthrough infection for each group of monkeys.

Figure 1. HIV MAbs delay virus acquisition following repeated low-dose intrarectal SHIV_AD8-EO challenges

a, Plasma viral loads in macaques receiving no MAb (controls). b, Diagrammatic representation of the regimen used to assess the protective efficacy of MAbs. Macaques were administered the indicated MAbs at a dose of 20 mg kg⁻¹ and challenged one week later and subsequently, every week thereafter. c, d, e, f, Plasma viral loads in macaques administered VRC01, 3BNC117, 10-1074 and VRC01-LS bNAbs, respectively.

Figure 2. Kaplan-Meier analysis and magnitude of protection by HIV MAbs in repeated low-dose challenge

a, The Kaplan-Meier survival curves for recipients of the four bNAbs and the cohort of control animals. The percentage of macaques remaining uninfected is plotted against the number of 10 TCID₅₀ SHIV_AD8-EO intrarectal challenges required to establish infections. b, Statistical differences are represented as P-values (Wilcoxon Rank sum test) by comparing the number of challenges resulting in infection between control animals and an individual MAb recipient group or between different MAb treated groups.

Figure 3. Plasma concentrations of the infused MAbs in macaques correlate with long-term protection from SHIV infection

a, b, c, d, Plasma antibody concentrations in macaques administered VRC01, 3BNC117, 10-1074, and VRC01-LS decay over time. e, The median plasma concentrations at the times of virus breakthrough in bNAb recipients were 0.169 (10-1074), 0.330 (3BNC117), 1.825 (VRC01), and 6.446 (VRC01-LS), respectively.

Figure 4. The decline of neutralizing antibody titers in plasma over time in macaques corresponds to the time of virus acquisition

a, Plasma IC₅₀ titers of the indicated MAbs were determined longitudinally using the TZM-bl cell assay. b, Plasma neutralizing titers at the time of virus acquisition for the four groups of MAb recipients. Boxes represent the 25^th and 75^th percentiles and the heavier line represents the median value for each group.