Accessible Requires Authentication Published by De Gruyter June 6, 2017

Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials

Peter B Gilbert, Michal Juraska, Allan C. deCamp, Shelly Karuna, Srilatha Edupuganti, Nyaradzo Mgodi, Deborah J Donnell, Carter Bentley, Nirupama Sista, Philip Andrew, Abby Isaacs, Yunda Huang, Lily Zhang, Edmund Capparelli, Nidhi Kochar, Jing Wang, Susan H Eshleman, Kenneth H Mayer, Craig A Magaret, John Hural, James G Kublin, Glenda Gray, David C Montefiori, Margarita M Gomez, David N Burns, Julie McElrath, Julie Ledgerwood, Barney S Graham, John R Mascola, Myron Cohen and Lawrence Corey

Abstract

Background

Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans.

Methods

The AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants are randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial is designed (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection.

Results

Each AMP trial is designed to have 90 % power to detect PE > 0 % if PE is ≥ 60 %. The AMP trials are also designed to identify VRC01 properties (i. e., concentration and effector functions) that correlate with protection and to provide insight into mechanistic CoPs. CoPs are assessed using data from breakthrough HIV-1 infections, including genetic sequences and sensitivities to VRC01-mediated neutralization and Fc effector functions.

Conclusions

The AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark for future vaccine evaluation and constituting a bridge to other bnAb approaches for HIV-1 prevention.

Funding statement: Funding sources: This work was supported by the National Institute of Allergy and Infectious Disease at the National Institutes of Health [2 R37 AI054165-11 to P.B.G., UM1 AI068635 to P.B.G., UM1 AI068617 to D.J.D., UM1 AI068619 to M.C., UM1 AI068618 to J.M., UM1 AI068614 to L.C.]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Acknowledgments

The authors would like to thank the protocol team of the AMP trials and the many groups and individuals dedicated to planning and conducting these trials, as well as the AMP trial participants. The authors also thank Lindsay Carpp for technical writing.

  1. Conflict of interest statement: All authors have no potential conflicts of interest to declare.

  2. Meetings where this research was presented: P.B.G. presented an early version of this research at the Passive Immunization Trials to Inform Vaccine Design Workshop at the Global HIV Vaccine Enterprise in August of 2014 in New York City, with talk title “Statistical issues in assessing treatment efficacy and correlates of protection in monoclonal antibody efficacy trials.”

Abbreviations

ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; ADCVI, antibody-dependent cell-mediated viral inhibition; AMP, Antibody Mediated Prevention; ARVs, antiretroviral drugs; bnAb, broadly neutralizing antibody; CoP, correlate of protection; DSMB, Data Safety and Monitoring Board; IC50, 50 % inhibitory concentration; ITT, intention-to-treat; IV, intravenous; mAb, monoclonal antibody; MITT, modified intention-to-treat; MSM, men who have sex with men; NHP, non-human primate; PE, prevention efficacy; PEP, post-exposure prophylaxis; PK, pharmacokinetic; PrEP, pre-exposure prophylaxis; RSV, respiratory syncytial virus; TG, transgender persons; tMLE, targeted minimum loss based estimation; VRC, Vaccine Research Center.

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Supplementary Material

The online version of this article offers supplementary material (DOI: https://doi.org/10.1515/scid-2016-0001).

Received: 2016-4-28
Revised: 2017-3-29
Accepted: 2017-4-27
Published Online: 2017-6-6

© 2017 Walter de Gruyter GmbH, Berlin/Boston