HIVIS-DNA or HIVISopt-DNA priming followed by CMDR vaccinia-based boosts induce both humoral and cellular murine immune responses to HIV
J Hinkula,
S Petkov,
K Ljungberg,
D Hallengärd,
A Bråve,
M Isaguliants,
T Falkeborn,
S Sharma,
V Liakina,
M Robb,
M Eller,
B Moss,
G Biberfeld,
E Sandström,
C Nilsson,
K Markland,
P Blomberg,
B Wahren
Affiliations
J Hinkula
Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden; Corresponding author.
S Petkov
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
K Ljungberg
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
D Hallengärd
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
A Bråve
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
M Isaguliants
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
T Falkeborn
Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden
S Sharma
Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden
V Liakina
Faculty of Medicine, Vilnius University 2, 08661 Vilnius, Lithuania
M Robb
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, 20892 MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, 20892 MD, USA
M Eller
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, 20892 MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, 20892 MD, USA
B Moss
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892 MD, USA
G Biberfeld
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
E Sandström
Department of South Hospital, Karolinska Institutet, 11883 Stockholm, Sweden
C Nilsson
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
K Markland
Clinical Research Center and Vecura, Karolinska University Hospital, 17176 Stockholm, Sweden
P Blomberg
Clinical Research Center and Vecura, Karolinska University Hospital, 17176 Stockholm, Sweden
B Wahren
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
Background: In order to develop a more effective prophylactic HIV-1 vaccine it is important optimize the components, improve Envelope glycoprotein immunogenicity as well as to explore prime-boost immunization schedules. It is also valuable to include several HIV-1 subtype antigens representing the world-wide epidemic. Methods: HIVIS-DNA plasmids which include Env genes of subtypes A, B and C together with Gag subtypes A and B and RTmut/Rev of subtype B were modified as follows: the Envelope sequences were shortened, codon optimized, provided with an FT4 sequence and an immunodominant region mutated. The reverse transcriptase (RT) gene was shortened to contain the most immunogenic N-terminal fragment and fused with an inactivated viral protease vPR gene. HIVISopt-DNA thus contains fewer plasmids but additional PR epitopes compared to the native HIVIS-DNA. DNA components were delivered intradermally to young Balb/c mice once, using a needle-free Biojector® immediately followed by dermal electroporation. Vaccinia-based MVA-CMDR boosts including Env gene E and Gag-RT genes A were delivered intramuscularly by needle, once or twice. Results: Both HIVIS-DNA and HIVISopt-DNA primed humoral and cell mediated responses well. When boosted with heterologous MVA-CMDR (subtypes A and E) virus inhibitory neutralizing antibodies were obtained to HIV-1 subtypes A, B, C and AE. Both plasmid compositions boosted with MVA-CMDR generated HIV-1 specific cellular responses directed against HIV-1 Env, Gag and Pol, as measured by IFNγ ELISpot. It was shown that DNA priming augmented the vector MVA immunological boosting effects, the HIVISopt-DNA with a trend to improved (Env) neutralization, the HIVIS-DNA with a trend to better (Gag) cell mediated immune reponses. Conclusions: HIVIS-DNA was modified to obtain HIVISopt-DNA that had fewer plasmids, and additional epitopes. Even with one DNA prime followed by two MVA-CMDR boosts, humoral and cell-mediated immune responses were readily induced by priming with either DNA construct composition. Priming by HIV-DNA augmented neutralizing antibody responses revealed by boosting with the vaccinia-based heterologous sequences. Cellular and antibody responses covered selected strains representing HIV-1 subtypes A, B, C and CRF01_AE. We assume this is related to the inclusion of heterologous full genes in the vaccine schedule.
