A study of vaccine-induced immune pressure on breakthrough infections in the Phambili phase 2b HIV-1 vaccine efficacy trial.

N Frahm, C Williamson, P B Gilbert, J I Mullins, M J McElrath, G Gray, J Kublin, L Corey, J Hural, D Geraghty, R Thebus, J Marais, T Hertz, B B Larsen, N Ngandu, H Ahmed, A DeCamp, P T Edlefsen, A Fiore-Gartland, C Rademeyer, C A Magaret, M Rolland, M G Logan

Journal: Vaccine 2018;34(47):5792-5801

PMID: 27756485

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Abstract

INTRODUCTION

The Merck Adenovirus-5 Gag/Pol/Nef HIV-1 subtype-B vaccine evaluated in predominately subtype B epidemic regions (Step Study), while not preventing infection, exerted vaccine-induced immune pressure on HIV-1 breakthrough infections. Here we investigated if the same vaccine exerted immune pressure when tested in the Phambili Phase 2b study in a subtype C epidemic.

MATERIALS AND METHODS

A sieve analysis, which compares breakthrough viruses from placebo and vaccine arms, was performed on 277 near full-length genomes generated from 23 vaccine and 20 placebo recipients. Vaccine coverage was estimated by computing the percentage of 9-mers that were exact matches to the vaccine insert.

RESULTS

There was significantly greater protein distances from the vaccine immunogen sequence in Gag (p=0.045) and Nef (p=0.021) in viruses infecting vaccine recipients compared to placebo recipients. Twenty-seven putative sites of vaccine-induced pressure were identified (p<0.05) in Gag (n=10), Pol (n=7) and Nef (n=10), although they did not remain significant after adjustment for multiple comparisons. We found the epitope sieve effect in Step was driven by HLA A∗02:01; an allele which was found in low frequency in Phambili participants compared to Step participants. Furthermore, the coverage of the vaccine against subtype C Phambili viruses was 31%, 46% and 14% for Gag, Pol and Nef, respectively, compared to subtype B Step virus coverage of 56%, 61% and 26%, respectively.

DISCUSSION

This study presents evidence of sieve effects in Gag and Nef; however could not confirm effects on specific amino acid sites. We propose that this weaker signal of vaccine immune pressure detected in the Phambili study compared to the Step study may have been influenced by differences in host genetics (HLA allele frequency) and reduced impact of vaccine-induced immune responses due to mismatch between the viral subtype in the vaccine and infecting subtypes.

Address: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.; Division of Medical Virology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town 7925, South Africa.; Henry M. Jackson Foundation, U.S. Military HIV Research Program, Bethesda, MD 20817, United States.; Department of Microbiology, University of Washington, Seattle, WA, United States.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.; Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; South African Medical Research Council, Cape Town, South Africa.; National Health Laboratory Services, Cape Town 7925, South Africa.

DOI: 10.1016/j.vaccine.2016.09.054