Preferential Targeting of Conserved Gag Regions after Vaccination with a Heterologous DNA Prime-Modified Vaccinia Virus Ankara Boost HIV-1 Vaccine Regimen
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 
Published: July 2017

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
p37
and two vaccinations with MVA-CMDR encoding subtype A Gag
p55
. 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 (
P
< 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
p24
regions, more conserved between prime and boost, compared to those of regions within Gag
p15
(not primed) and Gag
p17
(less conserved;
P
< 0.0001 for both). Four regions within Gag
p24
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 (
P
= 0.04,
r
2
= 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
p24
protein.

IMPORTANCE
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 between prime and boost. Engineering vaccines to induce adaptive immune responses that preferentially target conserved antigenic regions of viral vulnerability might facilitate better immune control after preventive and therapeutic vaccination for HIV and for other variable viruses.