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Production and Evaluation of Ag85B:HspX:hFcγ1 Immunogenicity as an Fc Fusion Recombinant Multi-Stage Vaccine Candidate Against Mycobacterium tuberculosis

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Abstract

An urgent need is to introduce an effective vaccine against Mycobacterium tuberculosis (M.tb) infection. In the present study, a multi-stage M.tb immunodominant Fcγ1 fusion protein (Ag85B:HspX:hFcγ1) was designed and produced, and the immunogenicity of purified protein was evaluated. This recombinant fusion protein was produced in the Pichia pastoris expression system. The HiTrap-rPA column affinity chromatography purified and confirmed the fusion protein using ELISA and Western blotting methods. The co-localisation assay was used to confirm its proper folding and function. IFN-γ, IL-12, IL-4, and TGF-β expression in C57BL/6 mice then evaluated the immunogenicity of the construct in the presence and absence of BCG. After expression optimisation, medium-scale production and the Western blotting test confirmed suitable production of Ag85B:HspX:hFcγ1. The co-localisation results on antigen-presenting cells (APCs) showed that Ag85B:HspX:hFcγ1 properly folded and bound to hFcγRI. This strong co-localisation with its receptor can confirm inducing proper Th1 responses. The in vivo immunisation assay showed no difference in the expression of IL-4 but a substantial increase in the expression of IFN-γ and IL-12 (P ≤ 0.02) and a moderate increase in TGF-β (P = 0.05). In vivo immunisation assay revealed that Th1-inducing pathways have been stimulated, as IFN-γ and IL-12 strongly, and TGF-β expression moderately increased in Ag85B:HspX:hFcγ1 group and Ag85B:HspX:hFcγ1+BCG. Furthermore, the production of IFN-γ from splenocytes in the Ag85B:HspX:hFcγ1 group was enormously higher than in other treatments. Therefore, this Fc fusion protein can make a selective multi-stage delivery system for inducing appropriate Th1 responses and is used as a subunit vaccine alone or in combination with others.

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Data Availability

All data supporting this study's findings are included in the manuscript and available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank the National Institute for Medical Research Development (NIMAD), Tehran, Iran, for granting this study [NIMAD 958012, recipient: SAR. Rezaee]. The authors especially thank the Vice-Chancellor for Research and Technology, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran.

The results described in this paper were part of the student thesis. This study was subjected to a Ph.D. thesis in Medical Bacteriology by Mohsen Karbalaei at MUMS, under Grant [MUMS 951414, recipient: SAR. Rezaee]. The experiments were conducted in Immunology Research Lab, Inflammation and Inflammatory Diseases Division, Immunology Research Center, and Antimicrobial Resistance Research Center, the Mashhad University of Medical Sciences, Mashhad, Iran.

Funding

This study was financially supported by the National Institute for Medical Research Development, Tehran, Iran, under Grant [NIMAD 958012, recipient: SAR. Rezaee] and the Vice-Chancellor for Research and Technology, Mashhad University of Medical Sciences, Mashhad, Iran, under Grant [MUMS 951414, recipient: SAR. Rezaee].

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Author notes

  1. Arman Mosavat is the co-first author of this paper and has equal credit.

Authors and Affiliations

  1. Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran

    Mohsen Karbalaei

  2. Blood Borne Infections Research Center, Academic Center for Education, Culture, and Research (ACECR), Razavi Khorasan, Mashhad, Iran

    Arman Mosavat

  3. Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Saman Soleimanpour, Hadi Farsiani & Kiarash Ghazvini

  4. Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Saman Soleimanpour, Hadi Farsiani & Kiarash Ghazvini

  5. Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran

    Abbas Ali Amini

  6. Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Mojtaba Sankian

  7. Inflammation and Inflammatory Diseases Division, Faculty of Medicine, Immunology Research Center, Mashhad University of Medical Sciences, Azadi-Square, Medical Campus, Mashhad, 9177948564, Iran

    Seyed Abdolrahim Rezaee

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Contributions

Doing experiments and manuscript drafting: MK, AM, SS, and HF; In Silico protein modelling: AA; Research advisors: SS, HF, MS, and AM; Research director, Conception and design of the study, and Data analysis: SAR and KG. All authors have read and approved the final manuscript.

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Correspondence to Seyed Abdolrahim Rezaee.

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Conflict of interest

This study was the subject of a Patent for the National Institute for Medical Research Development in the territory of Iran (NIMAD). The authors declare no conflict of interest regarding this manuscript in other regions.

Ethical Approval

The animal experiments were reviewed and approved by the Biomedical Research Ethics Committee of NIMAD [IR.NIMAD.REC.958012] that was performed according to National Institutes of Health guidelines (NIH publication No. 85-23, revised 1985). All methods were performed following relevant guidelines and regulations. All surgery was performed under sodium pentobarbital anaesthesia, and all efforts were made to minimise suffering. During the experiments, the vaccinated mice were monitored every day.

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Karbalaei, M., Mosavat, A., Soleimanpour, S. et al. Production and Evaluation of Ag85B:HspX:hFcγ1 Immunogenicity as an Fc Fusion Recombinant Multi-Stage Vaccine Candidate Against Mycobacterium tuberculosis. Curr Microbiol 81, 127 (2024). https://doi.org/10.1007/s00284-024-03655-3

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