title: A study of vaccine-induced immune pressure on breakthrough infections in the Phambili phase 2b HIV-1 vaccine efficacy trial.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: T
authors.initials: T
authors.lastname: Hertz
authors.affiliation: 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.
authors.forename: M G
authors.initials: MG
authors.lastname: Logan
authors.affiliation: Henry M. Jackson Foundation, U.S. Military HIV Research Program, Bethesda, MD 20817, United States.
authors.forename: M
authors.initials: M
authors.lastname: Rolland
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: C A
authors.initials: CA
authors.lastname: Magaret
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: Rademeyer
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: A
authors.initials: A
authors.lastname: Fiore-Gartland
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: P T
authors.initials: PT
authors.lastname: Edlefsen
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: A
authors.initials: A
authors.lastname: DeCamp
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: H
authors.initials: H
authors.lastname: Ahmed
authors.affiliation: 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.
authors.forename: N
authors.initials: N
authors.lastname: Ngandu
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, United States.
authors.forename: B B
authors.initials: BB
authors.lastname: Larsen
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: N
authors.initials: N
authors.lastname: Frahm
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Marais
authors.affiliation: 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.
authors.forename: R
authors.initials: R
authors.lastname: Thebus
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: D
authors.initials: D
authors.lastname: Geraghty
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: J
authors.initials: J
authors.lastname: Hural
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: L
authors.initials: L
authors.lastname: Corey
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: J
authors.initials: J
authors.lastname: Kublin
authors.affiliation: Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.|South African Medical Research Council, Cape Town, South Africa.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: G
authors.initials: G
authors.lastname: Gray
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: M J
authors.initials: MJ
authors.lastname: McElrath
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, United States.
authors.forename: J I
authors.initials: JI
authors.lastname: Mullins
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States.
authors.forename: P B
authors.initials: PB
authors.lastname: Gilbert
authors.affiliation: 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.|National Health Laboratory Services, Cape Town 7925, South Africa.
authors.forename: C
authors.initials: C
authors.lastname: Williamson
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000256:Adenoviridae; D015331:Cohort Studies; D004311:Double-Blind Method; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007110:Immunity, Active; D008297:Male; D018401:Sample Size; D000073887:Vaccination Coverage; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000939:Epitopes; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D014614:Vaccines, Synthetic; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; D054302:pol Gene Products, Human Immunodeficiency Virus
keywords: HIV-1 vaccine; HVTN-503; Phambili; Sieve analysis; Step