Long peptides induce polyfunctional T cells against conserved regions of HIV-1 with superior breadth to single-gene vaccines in macaques.
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.
Rosario
Maximillian
M
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, UK.
Bridgeman
Anne
A
Quakkelaar
Esther D
ED
Quigley
Maire F
MF
Hill
Brenna J
BJ
Knudsen
Maria L
ML
Ammendola
Virginia
V
Ljungberg
Karl
K
Borthwick
Nicola
N
Im
Eung-Jun
EJ
McMichael
Andrew J
AJ
Drijfhout
Jan W
JW
Greenaway
Hui Yee
HY
Venturi
Vanessa
V
Douek
Daniel C
DC
Colloca
Stefano
S
Liljeström
Peter
P
Nicosia
Alfredo
A
Price
David A
DA
Melief
Cornelis J M
CJ
Hanke
Tomás
T
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
D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D015488:HIV Antigens; D010446:Peptide Fragments; D019151:Peptide Library