BpOmpW Antigen Stimulates the Necessary Protective T-Cell Responses Against Melioidosis

Abstract

Melioidosis is a potentially fatal bacterial disease caused by Burkholderia pseudomallei and is estimated to cause 89,000 deaths per year in endemic areas of Southeast Asia and Northern Australia. People with diabetes mellitus are most at risk of melioidosis, with a 12-fold increased susceptibility for severe disease. Interferon gamma (IFN-γ) responses from CD4 and CD8 T cells, but also from natural killer (NK) and natural killer T (NKT) cells, are necessary to eliminate the pathogen. We previously reported that immunization with B. pseudomallei OmpW (BpOmpW antigen) protected mice from lethal B. pseudomallei challenge for up to 81 days. Elucidating the immune correlates of protection of the protective BpOmpW vaccine is an essential step prior to clinical trials. Thus, we immunized either non-insulin-resistant C57BL/6J mice or an insulin-resistant C57BL/6J mouse model of type 2 diabetes (T2D) with a single dose of BpOmpW. BpOmpW induced strong antibody responses, stimulated effector CD4+ and CD8+ T cells and CD4+ CD25+ Foxp3+ regulatory T cells, and produced higher IFN-γ responses in CD4+, CD8+, NK, and NKT cells in non-insulin-resistant mice. The T-cell responses of insulin-resistant mice to BpOmpW were comparable to those of non-insulin-resistant mice. In addition, as a precursor to its evaluation in human studies, humanized HLA-DR and HLA-DQ (human leukocyte antigen DR and DQ isotypes, respectively) transgenic mice elicited IFN-γ recall responses in an enzyme-linked immune absorbent spot (ELISpot)-based study. Moreover, human donor peripheral blood mononuclear cells (PBMCs) exposed to BpOmpW for 7 days showed T-cell proliferation. Finally, plasma from melioidosis survivors with diabetes recognized our BpOmpW vaccine antigen. Overall, the range of approaches used strongly indicated that BpOmpW elicits the necessary immune responses to combat melioidosis and bring this vaccine closer to clinical trials.

Evaluation of two different vaccine platforms for immunization against melioidosis and glanders

“…A variety of defined proteins and polysaccharides, alone or as conjugates, that elicit varying degrees of protection have been previously assessed as potential vaccine components. These are exemplified by T3SS proteins (such as Bip), T6SS proteins (such as Hcp1), proteases, outer membrane proteins (OMPs, LolC), CPS, and LPS or purified OPS (Harland et al, 2007 ; Chin et al, 2012 ; Scott et al, 2014a , b , 2016 ; Gregory et al, 2015 ; Casey et al, 2016 ; Burtnick et al, 2018 ; Tomas-Cortazar et al, 2021 ). Hcp1 is required for assembly of the secretion apparatus and for the export of the T6SS virulence proteins (Mougous et al, 2006 ; Pukatzki et al, 2007 ; Brunet et al, 2014 ; Lim et al, 2015 ).…”

GlnH, a Novel Antigen That Offers Partial Protection against Verocytotoxigenic Escherichia coli Infection

“…We have previously developed a proteomic cell blot approach to identify bacterial proteins involved in epithelial cell attachment with a high potential to be effective vaccine antigens [ 34 ]. Using this approach, we have already identified an effective melioidosis vaccine candidate that protected mice for up to 81 days against Burkholderia pseudomallei, and that will be progressing to human studies in the near future [ 35 , 36 ]. Our aim was to extend this platform to identify novel protein adhesins specific to VTEC strains that may be effective vaccine antigens, either on their own or in combination with other antigens, to prevent human colonisation.…”

Burkholderia pseudomallei Complex Subunit and Glycoconjugate Vaccines and Their Potential to Elicit Cross-Protection to Burkholderia cepacia Complex

“…model in C57BL/6 mice demonstrated more promising results, with OmpW1 + SAS affording 75% protection on day 80 compared to 12.5% in the adjuvant alone group [ 174 ]. Splenocytes from vaccinated animals secreted significant levels of IFN-γ upon ex vivo stimulation with OmpW1, suggesting a strong Th1 response was mounted [ 175 ]. A notable downside of these experiments is that the study reported significant issues with protein solubility that could only be overcome by solubilizing the protein in urea.…”