Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global threat. The only approved vaccine against TB, Mycobacterium bovis bacillus Calmette–Guérin (BCG), provides insufficient protection and, being a live vaccine, can cause disseminated disease in immunocompromised individuals. Previously, we found that intradermal cDNA tattoo immunization with cDNA of tetanus toxoid fragment C domain 1 fused to cDNA of the fusion protein H56, comprising the Mtb antigens Ag85B, ESAT-6, and Rv2660c, induced antigen-specific CD8+ T cell responses in vivo. As cDNA tattoo immunization would be safer than a live vaccine in immunocompromised patients, we tested the protective efficacy of intradermal tattoo immunization against TB with H56 cDNA, as well as with H56_E, a construct optimized for epitope processing in a mouse model. As Mtb antigens can be used in combination with BCG to boost immune responses, we also tested the protective efficacy of heterologous prime-boost, using dermal tattoo immunization with H56_E cDNA to boost BCG immunization in mice. Dermal H56 and H56_E cDNA immunization induced H56-specific CD4+ and CD8+ T cell responses and Ag85B-specific IgG antibodies, but did not reduce bacterial loads, although immunization with H56_E ameliorated lung pathology. Both subcutaneous and intradermal immunization with BCG resulted in broad cellular immune responses, with increased frequencies of CD4+ T effector memory cells, T follicular helper cells, and germinal center B cells, and resulted in reduced bacterial loads and lung pathology. Heterologous vaccination with BCG/H56_E cDNA induced increased H56-specific CD4+ and CD8+ T cell cytokine responses compared to vaccination with BCG alone, and lung pathology was significantly decreased in BCG/H56_E cDNA immunized mice compared to unvaccinated controls. However, bacterial loads were not decreased after heterologous vaccination compared to BCG alone. CD4+ T cells responding to Ag85B- and ESAT-6-derived epitopes were predominantly IFN-γ+TNF-α+ and TNF-α+IL-2+, respectively. In conclusion, despite inducing appreciable immune responses to Ag85B and ESAT-6, intradermal H56 cDNA tattoo immunization did not substantially enhance the protective effect of BCG under the conditions tested.
Highlights
Tuberculosis (TB) remains a global health threat, with 10.4 million cases and 1.7 million deaths reported for 2016 [1, 2]
Mice were immunized with bacillus Calmette–Guérin (BCG) (s.c. or i.d.), with H56, a DNA vector containing the full-length codon-optimized H56 gene fused to tetanus toxin fragment C domain 1 (TTFC) cDNA, or with H56_E, in which six CD8+ T cell epitope flanking residues in the H56 sequence were optimized to enhance proteasome-mediated processing [43] (Figure 1A)
The results demonstrate that i.d. tattoo vaccination with an optimized H56_E cDNA sequence fused to TTFC cDNA, either as a standalone vaccine or as a booster to BCG, did not reduce Mycobacterium tuberculosis (Mtb) burdens in the lung compared to BCG alone, it showed a tendency to improve lung pathology
Summary
Tuberculosis (TB) remains a global health threat, with 10.4 million cases and 1.7 million deaths reported for 2016 [1, 2]. It is estimated that approximately a quarter of the world’s population has latent TB infection (LTBI) [3] Socioeconomic factors such as poor living conditions, stress and malnutrition, play a major role in susceptibility to developing TB disease, with the HIV pandemic a major driver [4]. HIV contributes to the increased risk of TB by depleting CD4+ T cells, affecting macrophage effector functions, tipping the Th1/Th1 balance and influencing granuloma formation [5]. The risk of those with LTBI developing active disease is approximately 10% over a lifetime, but rises to 5–10% per year in those with HIV infection [6]. HIV-exposed uninfected infants are another group at high risk of TB infection, as they have poorer T cell generation and IFN-γ production compared to HIV-unexposed infants [7]
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