HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells.
To be effective against HIV type 1 (HIV-1), vaccine-induced T cells must selectively target epitopes, which are functionally conserved (present in the majority of currently circulating and reactivated HIV-1 strains) and, at the same time, beneficial (responses to which are associated with better clinical status and control of HIV-1 replication), and rapidly reach protective frequencies upon exposure to the virus. Heterologous prime-boost regimens using virally vectored vaccines are currently the most promising vaccine strategies; nevertheless, induction of robust long-term memory remains challenging. To this end, lentiviral vectors induce high frequencies of memory cells due to their low-inflammatory nature, while typically inducing only low anti-vector immune responses. Here, we describe construction of novel candidate vaccines ZVex.tHIVconsv1 and ZVex.tHIVconsv2, which are based on an integration-deficient lentiviral vector platform with preferential transduction of human dendritic cells and express a bivalent mosaic of conserved-region T cell immunogens with a high global HIV-1 match. Each of the two mosaic vaccines was individually immunogenic. When administered together in heterologous prime-boost regimens with chimpanzee adenovirus and/or poxvirus modified vaccinia virus Ankara (MVA) vaccines to BALB/c and outbred CD1-Swiss mice, they induced a median frequency of over 6,000 T cells/106splenocytes, which were plurifunctional, broadly specific, and cross-reactive. These results support further development of this vaccine concept.
The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
Edmund G
EG
Wee
The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
Beatrice
B
Ondondo
Immune Design Corp., Seattle, WA 98102, USA.
Peter
P
Berglund
Immune Design Corp., Seattle, WA 98102, USA.
Jacob
J
Archer
Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, UK.
Andrew J
AJ
McMichael
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
David
D
Baltimore
Immune Design Corp., Seattle, WA 98102, USA.
Jan H
JH
Ter Meulen
The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK; International Research Center for Medical Sciences, Kumamoto University, Kumamoto 860-8555, Japan. Electronic address: tomas.hanke@ndm.ox.ac.uk.
Tomáš
T
Hanke
D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology; D000818:Animals; D017124:Conserved Sequence; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D010455:Peptides / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D016915:AIDS Vaccines; D000939:Epitopes; D010455:Peptides
HIV vaccines; conserved regions; lentivirus vectors; mosaic proteins