title: Long peptides induce polyfunctional T cells against conserved regions of HIV-1 with superior breadth to single-gene vaccines in macaques.
abstract: A novel T-cell vaccine strategy designed to deal with the enormity of HIV-1 variation is described and tested for the first time in macaques to inform and complement approaching clinical trials. T-cell immunogen HIVconsv, which directs vaccine-induced responses to the most conserved regions of the HIV-1, proteome and thus both targets diverse clades in the population and reduces the chance of escape in infected individuals, was delivered using six different vaccine modalities: plasmid DNA (D), attenuated human (A) and chimpanzee (C) adenoviruses, modified vaccinia virus Ankara (M), synthetic long peptides, and Semliki Forest virus replicons. We confirmed that the initial DDDAM regimen, which mimics one of the clinical schedules (DDDCM), is highly immunogenic in macaques. Furthermore, adjuvanted synthetic long peptides divided into sub-pools and delivered into anatomically separate sites induced T-cell responses that were markedly broader than those elicited by traditional single-open-reading-frame genetic vaccines and increased by 30% the overall response magnitude compared with DDDAM. Thus, by improving both the HIV-1-derived immunogen and vector regimen/delivery, this approach could induce stronger, broader, and theoretically more protective T-cell responses than vaccines previously used in humans.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, UK.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Rosario
authors.forename: Anne
authors.initials: A
authors.lastname: Bridgeman
authors.forename: Esther D
authors.initials: ED
authors.lastname: Quakkelaar
authors.forename: Maire F
authors.initials: MF
authors.lastname: Quigley
authors.forename: Brenna J
authors.initials: BJ
authors.lastname: Hill
authors.forename: Maria L
authors.initials: ML
authors.lastname: Knudsen
authors.forename: Virginia
authors.initials: V
authors.lastname: Ammendola
authors.forename: Karl
authors.initials: K
authors.lastname: Ljungberg
authors.forename: Nicola
authors.initials: N
authors.lastname: Borthwick
authors.forename: Eung-Jun
authors.initials: EJ
authors.lastname: Im
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Hui Yee
authors.initials: HY
authors.lastname: Greenaway
authors.forename: Vanessa
authors.initials: V
authors.lastname: Venturi
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Stefano
authors.initials: S
authors.lastname: Colloca
authors.forename: Peter
authors.initials: P
authors.lastname: Liljeström
authors.forename: Alfredo
authors.initials: A
authors.lastname: Nicosia
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Tomás
authors.initials: T
authors.lastname: Hanke
mesh_terms: D016915:AIDS Vaccines; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D017124:Conserved Sequence / Q000235:genetics; D016503:Drug Delivery Systems; D018604:Epitope Mapping / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D005822:Genetic Vectors; D015488:HIV Antigens / Q000008:administration & dosage* / Q000235:genetics; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007114:Immunization; D008213:Lymphocyte Activation / Q000187:drug effects; D008253:Macaca mulatta; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000235:genetics; D019151:Peptide Library; D037182:T-Cell Antigen Receptor Specificity / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D015488:HIV Antigens; D010446:Peptide Fragments; D019151:Peptide Library