Abstract
Despite the availability of anti-retroviral therapy, HIV-1 infection remains a massive burden on healthcare systems. Bacillus Calmette-Guérin (BCG), the only licensed vaccine against tuberculosis, confers protection against meningitis and miliary tuberculosis in infants. Recombinant BCG has been used as a vaccine vehicle to express both HIV-1 and Simian Immunodeficiemcy Virus (SIV) immunogens. In this study, we constructed an integrative E. coli-mycobacterial shuttle plasmid, p2auxo.HTI.int, expressing the HIVACAT T-cell immunogen (HTI). The plasmid was transformed into a lysine auxotrophic Mycobacterium bovis BCG strain (BCGΔLys) to generate the vaccine BCG.HTI2auxo.int. The DNA sequence coding for the HTI immunogen and HTI protein expression were confirmed, and working vaccine stocks were genetically and phenotypically characterized. We demonstrated that the vaccine was stable in vitro for 35 bacterial generations, and that when delivered in combination with chimpanzee adenovirus (ChAd)Ox1.HTI in adult BALB/c mice, it was well tolerated and induced HIV-1-specific T-cell responses. Specifically, priming with BCG.HTI2auxo.int doubled the magnitude of the T-cell response in comparison with ChAdOx1.HTI alone while maintaining its breadth. The use of integrative expression vectors and novel HIV-1 immunogens can aid in improving mycobacterial vaccine stability as well as specific immunogenicity. This vaccine candidate may be a useful tool in the development of an effective vaccine platform for priming protective responses against HIV-1/TB and other prevalent pediatric pathogens.
Highlights
According to the latest reports, there are currently 37 million people infected with HIV, the majority of whom live in sub-Saharan Africa [1]
We demonstrate that priming with Recombinant BCG (rBCG), in some mice, can alter the immunodominance profile of the vaccine-induced T-cell response
In the p2auxo.HTIint E. coli-mycobacterial shuttle vector, the heterologous open reading protein expression cassette is under the control of the Mtb α-antigen promoter, which is a weak promoter that has been shown to enhance protein stability [37]
Summary
According to the latest reports, there are currently 37 million people infected with HIV, the majority of whom live in sub-Saharan Africa [1]. Despite the existence of anti-retroviral therapy, 1.8 million people were newly infected in 2017, and almost one million people died due to HIV-related disease [1]. Developing a safe, efficacious, and accessible HIV vaccine would be the optimal solution for the prevention of HIV-1 infection as well as reduction of HIV-related diseases. Vaccines 2019, 7, 78 the role of T-cell responses directed against HIV-1 in the control of viral replication is growing [2,3]. HIV-1-specific CD8+ T-cells have been detected in exposed seronegative individuals, and CD8+. Cytotoxic T-lymphocytes (CTL) responses targeting HIV-1 Gag have been associated with reduced viral loads in infected individuals [4,5,6].
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