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Stat Commun Infect Dis. 2017 Jan;9(1). pii: 20160001. doi: 10.1515/scid-2016-0001. Epub 2017 Jun 6.

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

Author information

1
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
2
Department of Biostatistics, University of Washington, Seattle, Washington, USA.
3
Department of Medicine, Emory University, Atlanta, Georgia, USA.
4
University of Zimbabwe - University of California San Francisco Research Program, Harare, Zimbabwe.
5
FHI 360 Durham, North Carolina, USA.
6
Department of Pediatrics, University of California, San Diego, California, USA.
7
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
8
The Fenway Institute, Boston, Massachusetts, USA.
9
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
10
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
11
South African Medical Research Council, Cape Town, South Africa; Perinatal HIV Research Unit, University of the Witwatersrand, Braamfontein, Johannesburg, South Africa.
12
Duke University Medical Center, Durham, North Carolina, USA.
13
Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
14
Prevention Sciences Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
15
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
16
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.

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.

KEYWORDS:

Clinical trial; Correlates of protection; HIV prevention; Monoclonal antibody; Sieve analysis; Surrogate endpoint; VRC01

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