Immunogenicity and efficacy analyses of EPC002, ECA006, and EPCP009 protein subunit combinations as tuberculosis vaccine candidates |
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| Institution: | 1. State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China;2. Community Health Management Service Center, Longgang District People’s Hospital of Shenzhen, Shenzhen, China;3. Department of Infection Control, Longgang District People’s Hospital of Shenzhen, Shenzhen, China;1. Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Québec-Université Laval, Québec, Canada;2. Département d’anthropologie, Université Laval, Québec, Canada;3. Axe Santé des populations et pratiques optimales en santé, Centre de recherche du CHU de Québec-Université Laval, Québec, Canada;4. School of Public Health Sciences, University of Waterloo, Waterloo, Canada;5. Department of Pediatrics, Dalhousie University, Halifax, Canada;6. Vaccine Evaluation Center, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, Canada;7. Faculty of Nursing, University of Alberta, Edmonton, Canada;8. Department of Community Health Sciences, University of Manitoba, Winnipeg, Canada;9. Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada;10. Direction des risques biologiques et de la santé au travail, Institut national de santé publique du Québec, Québec, Canada;1. Laboratório de Bacteriologia, Instituto Butantan, São Paulo, Brazil;2. Institut Pasteur, Université de Paris Cité, CNRS UMR 3528, Unité de Biochimie des Interactions Macromoléculaires, Paris, France;1. Fondazione IRCCS Ca'' Granda Ospedale Maggiore Policlinico, Cystic Fibrosis Center, Milan, Italy;2. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy;3. Fondazione IRCCS Ca'' Granda Ospedale Maggiore Policlinico, Microbiology Unit, Milan, Italy;4. Department of Pediatrics, ASST Spedali Civili, Brescia, Italy;5. Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili, Brescia, Italy;6. Fondazione IRCCS Ca'' Granda Ospedale Maggiore Policlinico, Respiratory Unit and Cystic Fibrosis Adult Center, Milan, Italy |
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| Abstract: | Tuberculosis (TB) is the leading cause of death from infectious diseases worldwide, and developing a new TB vaccine is a priority for TB control. Combining multiple immunodominant antigens to form a novel multicomponent vaccine with broad-spectrum antigens to induce protective immune responses is a trend in TB vaccine development. In this study, we used T-cell epitope-rich protein subunits to construct three antigenic combinations: EPC002, ECA006, and EPCP009. Fusion expression of purified protein EPC002f (CFP-10-linker-ESAT-6-linker-nPPE18), ECA006f (CFP-10-linker-ESAT-6-linker-Ag85B), and EPCP009f (CFP-10-linker-ESAT-6-linker-nPPE18-linker-nPstS1) and recombinant purified protein mixtures EPC002m (mix of CFP-10, ESAT-6, and nPPE18), ECA006m (mix of CFP-10, ESAT-6, and Ag85B), and EPCP009m (mix of CFP-10, ESAT-6, nPPE18, and nPstS1) were used as antigens, formulated with alum adjuvant, and the immunogenicity and efficacy were analyzed using immunity experiments with BALB/c mice. All protein-immunized groups elicited higher levels of humoral immunity, including IgG and IgG1. The IgG2a/IgG1 ratio of the EPCP009m-immunized group was the highest, followed by that of the EPCP009f-immunized group, which was significantly higher than the ratios of the other four groups. The multiplex microsphere-based cytokine immunoassay revealed that EPCP009f and EPCP009m induced the production of a wider range of cytokines than EPC002f, EPC002m, ECA006f, and ECA006m, which included Th1-type (IL-2, IFN-γ, TNF-α), Th2-type (IL-4, IL-6, IL-10), Th17-type (IL-17), and other proinflammatory cytokines (GM-CSF, IL-12). The enzyme-linked immunospot assays demonstrated that the EPCP009f- and EPCP009m-immunized groups had significantly higher amounts of IFN-γ than the other four groups. The in vitro mycobacterial growth inhibition assay demonstrated that EPCP009m inhibited Mycobacterium tuberculosis (Mtb) growth most strongly, followed by EPCP009f, which was significantly better than that of the other four vaccine candidates. These results indicated that EPCP009m containing four immunodominant antigens exhibited better immunogenicity and Mtb growth inhibition in vitro and may be a promising candidate vaccine for the control of TB. |
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| Keywords: | Multicomponent protein Vaccines T-cell epitope-rich protein TB vaccine |
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