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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) respectively1,2,3,4,5,6,7,8, 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, 10, 11, 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.

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Figure 1: HIV MAbs delay virus acquisition after repeated low-dose intrarectal SHIVAD8-EO challenges.
Figure 2: Kaplan–Meier analysis and magnitude of protection by HIV MAbs in repeated low-dose challenge.
Figure 3: Plasma concentrations of the infused MAbs in macaques correlate with long-term protection from SHIV infection.
Figure 4: The decline of neutralizing antibody titres in plasma over time in macaques corresponds to the time of virus acquisition.

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Acknowledgements

We thank R. Plishka, A. Peach, and T. Lewis for determining plasma viral RNA loads, and K. Rice, R. Engel, R. Petros, and S. Fong for assisting in the maintenance of animals and assisting with procedures. We also thank R. Schwartz for clinical-grade VRC01 and VRC01-LS, and X. Chen for protein reagents for ELISA. We thank the National Institutes of Health (NIH) AIDS Research and Reference Reagent Program for TZM-bl cells. We thank R. Fast for ultrasensitive plasma SIV RNA assays and W. Bosche and M Hull for ultrasensitive peripheral blood mononuclear cell SIV RNA/DNA assays. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH and, in part, with federal funds from the National Cancer Institute, NIH, under contract number HHSN261200800001E (to J.D.L.). The research was also funded in part by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery Grants OPP1033115 and OPP1092074 (to M.C.Nu.), by the NIH under award numbers AI-100148, UM1 AI100663-01. M.C.Nu. is supported by the Robertson Foundation and the The Howard Hughes Medical Institute.

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Authors and Affiliations

Authors

Contributions

R.G., Y.N., M.A.M., M.C.Nu., and J.R.M. designed experiments; R.G., Y.N., A.P., F.K., A.G., J.G., A.B.W., R.S., K.W., Z.M., and S.D.S. performed experiments; R.G., Y.N., M.C.Na., M.A.M., M.C.Nu., J.R.M., and J.D.L. analysed data; R.G., Y.N., M.A.M., M.C.Nu., J.R.M., and J.D.L. wrote the manuscript.

Corresponding author

Correspondence to Malcolm A. Martin.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Neutralization sensitivity of SHIVAD8-EO to four broadly acting neutralizing anti-HIV-1 MAbs.

a, Neutralizing activity of the indicated bNAbs was determined against SHIVAD8-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 SHIVAD8-EO in a single round TZM-bl infectivity assay. The calculated IC50 and IC80 values are shown at the bottom. The assay was performed 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.

ad, Longitudinal analysis of anti-VRC01, anti-3BNC117, anti-10-1074, and anti-VRC01-LS antibody responses, respectively, after 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 modelled 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.

Extended Data Table 1 Plasma viral RNA and cell-associated viral RNA/DNA in rhesus macaques before breakthrough of infection
Extended Data Table 2 VRC01 and 3BNC117 antibody concentrations in the plasma of macaques after a single administration of the indicated MAbs
Extended Data Table 3 10-1074 and VRC01-LS antibody concentrations in the plasma of macaques after a single administration of the indicated MAbs

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Gautam, R., Nishimura, Y., Pegu, A. et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533, 105–109 (2016). https://doi.org/10.1038/nature17677

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