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Approaches to vaccines against Orientia tsutsugamushi.

Valbuena G, Walker DH - Front Cell Infect Microbiol (2013)

Bottom Line: Delayed antibiotic treatment is common due to the lack of effective commercially available diagnostic tests and the lack of specificity of the early clinical presentation.In survivors, immunity does not last long, and is poorly cross-reactive among numerous strains.We finish with a proposal for development of an effective and safe vaccine for scrub typhus through a new approach with a strong focus on T cell-mediated immunity, empirical testing of the immunogenicity of proteins encoded by conserved genes, and assessment of protection in relevant animal models that truly mimic human scrub typhus.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Texas Medical Branch Galveston, TX, USA. gvalbuen@utmb.edu

ABSTRACT
Scrub typhus is a severe mite-borne infection caused by Orientia tsutsugamushi, an obligately intracellular bacterium closely related to Rickettsia. The disease explains a substantial proportion of acute undifferentiated febrile cases that require hospitalization in rural areas of Asia, the North of Australia, and many islands of the Pacific Ocean. Delayed antibiotic treatment is common due to the lack of effective commercially available diagnostic tests and the lack of specificity of the early clinical presentation. The systemic infection of endothelial cells that line the vasculature with Orientia can lead to many complications and fatalities. In survivors, immunity does not last long, and is poorly cross-reactive among numerous strains. In addition, chronic infections are established in an unknown number of patients. All those characteristics justify the pursuit of a prophylactic vaccine against O. tsutsugamushi; however, despite continuous efforts to develop such a vaccine since World War II, the objective has not been attained. In this review, we discuss the history of vaccine development against Orientia to provide a clear picture of the challenges that we continue to face from the perspective of animal models and the immunological challenges posed by an intracellular bacterium that normally triggers a short-lived immune response. We finish with a proposal for development of an effective and safe vaccine for scrub typhus through a new approach with a strong focus on T cell-mediated immunity, empirical testing of the immunogenicity of proteins encoded by conserved genes, and assessment of protection in relevant animal models that truly mimic human scrub typhus.

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Diagram of a strategy to discover subdominant antigens recognized by T cells.
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Figure 1: Diagram of a strategy to discover subdominant antigens recognized by T cells.

Mentions: A comprehensive discovery program for cross-reacting antigens of O. tsutsugamushi guided by genomic information, which has not been attempted to date, is likely to yield the most relevant vaccine candidates. This approach is now possible because genomic information, although limited to two strains, is now available (Cho et al., 2007; Nakayama et al., 2008, 2010) and is expected to keep growing. The construction of libraries with all conserved open-reading-frames (ORFs) of Orientia (the ORFeome) is possible through PCR-mediated amplification of those ORFs or through gene synthesis; those genes can then be expressed in histocompatible antigen presenting cells (APCs). Such a project is feasible because the number of conserved genes is not excessive; if one includes the genomes of several species of Rickettsia to determine the most conserved genes, the number is about 500 genes (Nakayama et al., 2010). Although anti-Orientia immune T cells could be used for screening and antigen detection, those T cells would necessarily be memory cells that can only recognize immunodominant epitopes; that is, of course, the nature of a physiological immune response. Thus, the resultant candidates may not be protective because, as explained previously, O. tsutsugamushi can establish chronic infections in the face of an immune response against immunodominant antigens. Consequently, we propose that a better antigen identification method would consist of in vivo screening in immunologically naive animals (Figure 1); such animals would be vaccinated with APCs expressing conserved ORFs from O. tsutsugamushi or, alternatively, with appropriate vaccine DNA vectors expressing those ORFs. This second option is similar to expression library immunization (ELI) (Sykes, 2008). This method, like the one we propose, allows the priming of naïve T cells by the expressed cloned microbial genes regardless of whether they are subdominant or dominant during a natural infection as long as the appropriate T cell receptors are present; however, it relies on a DNA immunization strategy so antigen expression is not guaranteed in all cases. In either method, protection from challenge with O. tsutsugamushi would identify subdominant or cryptic antigens among those proteins of O. tsutsugamushi encoded by conserved genes. This approach is likely to identify immunogenic and protective proteins from the normally subdominant pool of proteins. This outcome will likely be the case given the evidence from other models of intracellular infection that vaccination against subdominant epitopes can produce effective cellular immune responses (Riedl et al., 2009; Ruckwardt et al., 2010; Im et al., 2011). An additional consideration that would support our approach is that, from the perspective of the T cell response, cross-reactivity is also favored by the T cells themselves since the T cell receptor is multispecific due to structural flexibility and interactions with only a few residues within the presented peptides. Thus, the T cell repertoire has a tremendous capacity for cross-reactivity (Mason, 1998; Sewell, 2012). If resources are not available for testing all conserved ORFs, the testing could be prioritized using other criteria including antigenicity predictions (with the caveats already mentioned) and levels of expression of bacterial proteins in vivo (Rollenhagen et al., 2004; Mahdi et al., 2012).


Approaches to vaccines against Orientia tsutsugamushi.

Valbuena G, Walker DH - Front Cell Infect Microbiol (2013)

Diagram of a strategy to discover subdominant antigens recognized by T cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539663&req=5

Figure 1: Diagram of a strategy to discover subdominant antigens recognized by T cells.
Mentions: A comprehensive discovery program for cross-reacting antigens of O. tsutsugamushi guided by genomic information, which has not been attempted to date, is likely to yield the most relevant vaccine candidates. This approach is now possible because genomic information, although limited to two strains, is now available (Cho et al., 2007; Nakayama et al., 2008, 2010) and is expected to keep growing. The construction of libraries with all conserved open-reading-frames (ORFs) of Orientia (the ORFeome) is possible through PCR-mediated amplification of those ORFs or through gene synthesis; those genes can then be expressed in histocompatible antigen presenting cells (APCs). Such a project is feasible because the number of conserved genes is not excessive; if one includes the genomes of several species of Rickettsia to determine the most conserved genes, the number is about 500 genes (Nakayama et al., 2010). Although anti-Orientia immune T cells could be used for screening and antigen detection, those T cells would necessarily be memory cells that can only recognize immunodominant epitopes; that is, of course, the nature of a physiological immune response. Thus, the resultant candidates may not be protective because, as explained previously, O. tsutsugamushi can establish chronic infections in the face of an immune response against immunodominant antigens. Consequently, we propose that a better antigen identification method would consist of in vivo screening in immunologically naive animals (Figure 1); such animals would be vaccinated with APCs expressing conserved ORFs from O. tsutsugamushi or, alternatively, with appropriate vaccine DNA vectors expressing those ORFs. This second option is similar to expression library immunization (ELI) (Sykes, 2008). This method, like the one we propose, allows the priming of naïve T cells by the expressed cloned microbial genes regardless of whether they are subdominant or dominant during a natural infection as long as the appropriate T cell receptors are present; however, it relies on a DNA immunization strategy so antigen expression is not guaranteed in all cases. In either method, protection from challenge with O. tsutsugamushi would identify subdominant or cryptic antigens among those proteins of O. tsutsugamushi encoded by conserved genes. This approach is likely to identify immunogenic and protective proteins from the normally subdominant pool of proteins. This outcome will likely be the case given the evidence from other models of intracellular infection that vaccination against subdominant epitopes can produce effective cellular immune responses (Riedl et al., 2009; Ruckwardt et al., 2010; Im et al., 2011). An additional consideration that would support our approach is that, from the perspective of the T cell response, cross-reactivity is also favored by the T cells themselves since the T cell receptor is multispecific due to structural flexibility and interactions with only a few residues within the presented peptides. Thus, the T cell repertoire has a tremendous capacity for cross-reactivity (Mason, 1998; Sewell, 2012). If resources are not available for testing all conserved ORFs, the testing could be prioritized using other criteria including antigenicity predictions (with the caveats already mentioned) and levels of expression of bacterial proteins in vivo (Rollenhagen et al., 2004; Mahdi et al., 2012).

Bottom Line: Delayed antibiotic treatment is common due to the lack of effective commercially available diagnostic tests and the lack of specificity of the early clinical presentation.In survivors, immunity does not last long, and is poorly cross-reactive among numerous strains.We finish with a proposal for development of an effective and safe vaccine for scrub typhus through a new approach with a strong focus on T cell-mediated immunity, empirical testing of the immunogenicity of proteins encoded by conserved genes, and assessment of protection in relevant animal models that truly mimic human scrub typhus.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Texas Medical Branch Galveston, TX, USA. gvalbuen@utmb.edu

ABSTRACT
Scrub typhus is a severe mite-borne infection caused by Orientia tsutsugamushi, an obligately intracellular bacterium closely related to Rickettsia. The disease explains a substantial proportion of acute undifferentiated febrile cases that require hospitalization in rural areas of Asia, the North of Australia, and many islands of the Pacific Ocean. Delayed antibiotic treatment is common due to the lack of effective commercially available diagnostic tests and the lack of specificity of the early clinical presentation. The systemic infection of endothelial cells that line the vasculature with Orientia can lead to many complications and fatalities. In survivors, immunity does not last long, and is poorly cross-reactive among numerous strains. In addition, chronic infections are established in an unknown number of patients. All those characteristics justify the pursuit of a prophylactic vaccine against O. tsutsugamushi; however, despite continuous efforts to develop such a vaccine since World War II, the objective has not been attained. In this review, we discuss the history of vaccine development against Orientia to provide a clear picture of the challenges that we continue to face from the perspective of animal models and the immunological challenges posed by an intracellular bacterium that normally triggers a short-lived immune response. We finish with a proposal for development of an effective and safe vaccine for scrub typhus through a new approach with a strong focus on T cell-mediated immunity, empirical testing of the immunogenicity of proteins encoded by conserved genes, and assessment of protection in relevant animal models that truly mimic human scrub typhus.

Show MeSH
Related in: MedlinePlus