Preferential Targeting of Conserved Gag Regions after Vaccination with a Heterologous DNA Prime-Modified Vaccinia Virus Ankara Boost HIV-1 Vaccine Regimen

• Published in: Journal of virology 2017-09, Vol.91 (18), p.e00730
• Main Authors: Bauer, Asli, Podola, Lilli, Mann, Philipp, Missanga, Marco, Haule, Antelmo, Sudi, Lwitiho, Nilsson, Charlotta, Kaluwa, Bahati, Lueer, Cornelia, Mwakatima, Maria, Munseri, Patricia J, Maboko, Leonard, Robb, Merlin L, Tovanabutra, Sodsai, Kijak, Gustavo, Marovich, Mary, McCormack, Sheena, Joseph, Sarah, Lyamuya, Eligius, Wahren, Britta, Sandström, Eric, Biberfeld, Gunnel, Hoelscher, Michael, Bakari, Muhammad, Kroidl, Arne, Geldmacher, Christof
• Format: Article
• Language: English
• Subjects: AIDS Vaccines - administration & dosage; AIDS Vaccines - immunology; Drug Carriers; gag Gene Products, Human Immunodeficiency Virus - immunology; Healthy Volunteers; HIV-1 - immunology; Humans; Interferon-gamma - metabolism; Interleukin-2 - metabolism; Medicin och hälsovetenskap; T-Lymphocyte Subsets - immunology; T-Lymphocytes - immunology; Tanzania; Tumor Necrosis Factor-alpha - metabolism; Vaccination - methods; Vaccines and Antiviral Agents; Vaccines, DNA - administration & dosage; Vaccines, DNA - immunology; Vaccines, Subunit - administration & dosage; Vaccines, Subunit - immunology; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - immunology; Vaccinia virus - genetics
• ISSN: 0022-538X; 1098-5514; 1098-5514
• DOI: 10.1128/JVI.00730-17

Prime-boost vaccination strategies against HIV-1 often include multiple variants for a given immunogen for better coverage of the extensive viral diversity. To study the immunologic effects of this approach, we characterized breadth, phenotype, function, and specificity of Gag-specific T cells induced by a DNA-prime modified vaccinia virus Ankara (MVA)-boost vaccination strategy, which uses mismatched Gag immunogens in the TamoVac 01 phase IIa trial. Healthy Tanzanian volunteers received three injections of the DNA-SMI vaccine encoding a subtype B and AB-recombinant Gag and two vaccinations with MVA-CMDR encoding subtype A Gag Gag-specific T-cell responses were studied in 42 vaccinees using fresh peripheral blood mononuclear cells. After the first MVA-CMDR boost, vaccine-induced gamma interferon-positive (IFN-γ ) Gag-specific T-cell responses were dominated by CD4 T cells ( < 0.001 compared to CD8 T cells) that coexpressed interleukin-2 (IL-2) (66.4%) and/or tumor necrosis factor alpha (TNF-α) (63.7%). A median of 3 antigenic regions were targeted with a higher-magnitude median response to Gag regions, more conserved between prime and boost, compared to those of regions within Gag (not primed) and Gag (less conserved; < 0.0001 for both). Four regions within Gag each were targeted by 45% to 74% of vaccinees upon restimulation with DNA-SMI-Gag matched peptides. The response rate to individual antigenic regions correlated with the sequence homology between the MVA- and DNA Gag-encoded immunogens ( = 0.04, = 0.47). In summary, after the first MVA-CMDR boost, the sequence-mismatched DNA-prime MVA-boost vaccine strategy induced a Gag-specific T-cell response that was dominated by polyfunctional CD4 T cells and that targeted multiple antigenic regions within the conserved Gag protein. Genetic diversity is a major challenge for the design of vaccines against variable viruses. While including multiple variants for a given immunogen in prime-boost vaccination strategies is one approach that aims to improve coverage for global virus variants, the immunologic consequences of this strategy have been poorly defined so far. It is unclear whether inclusion of multiple variants in prime-boost vaccination strategies improves recognition of variant viruses by T cells and by which mechanisms this would be achieved, either by improved cross-recognition of multiple variants for a given antigenic region or through preferential targeting of antigenic regions more conserved betwee