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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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Immunohistochemical detection of oriential antigen. (A) Analysis performed in the brain of a C3H/HeN mouse infected i.v., with 2 × 105 FFU of Orientia tsutsugamushi 11 days earlier (original magnification 400×). Alkaline phosphatase signal from the secondary antibody produces a red precipitate visible in endothelial cells of a microvessel (arrows) and in adjacent mononuclear leukocytes (asterisks). The section is counterstained with hematoxylin and eosin. (B) Analysis of the lungs of the same animals (original magnification 100×) with the same alkaline phosphatase technique shows multiple foci of oriential antigen in the alveolar walls. Courtesy of Thomas Shelite.
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Figure 2: Immunohistochemical detection of oriential antigen. (A) Analysis performed in the brain of a C3H/HeN mouse infected i.v., with 2 × 105 FFU of Orientia tsutsugamushi 11 days earlier (original magnification 400×). Alkaline phosphatase signal from the secondary antibody produces a red precipitate visible in endothelial cells of a microvessel (arrows) and in adjacent mononuclear leukocytes (asterisks). The section is counterstained with hematoxylin and eosin. (B) Analysis of the lungs of the same animals (original magnification 100×) with the same alkaline phosphatase technique shows multiple foci of oriential antigen in the alveolar walls. Courtesy of Thomas Shelite.

Mentions: After the identification of a combination of antigens that together can stimulate protective responses mediated by CD8+T cells, CD4+T, and B cells (antibodies), the next developmental step for a modern anti-Orientia vaccine will be the selection of the best strategy to optimally stimulate those immune system cells. The objective is to do better than nature by testing different adjuvants, immunization routes, and schedules. These concepts are evolving very rapidly; thus, the reader is referred to recent reviews (Coffman et al., 2010; Liu, 2010). This testing must be done in appropriate animal models, thus the generation of relevant animal models to identify correlates of protective immunity and to test vaccine candidates is essential in the vaccine development effort against scrub typhus. Non-human primates constitute excellent models because scrub typhus pathogenesis and immunity are very similar to that of humans; however, the high cost of these animals together with the necessity of performing experiments with O. tsutsugamushi in a biosafety-level-3 (BSL-3) environment preclude their general and consistent use. Although there are fundamental biological species differences between humans and mice that are likely to affect direct translation to humans (Marian, 2011), very valuable information can be obtained from mice as long as there is a serious attempt to mimic the pathophysiology of humans. The ideal model should include transmission by chiggers, and some progress has already been made in that direction (see earlier sections on this topic). Alternatively, intradermal injection of O. tsutsugamushi to mimic the natural path of infection may be more reproducible and easier to implement. Our group is currently developing this model in C3H/HeN mice infected with the Karp strain; results are very promising since the infection is systemic and predominantly endothelial (Figure 2). We have also developed an intravenous infection model with similar results; the reports of these models are forthcoming. Another model that may provide an improved bridge to direct translation for human studies is that provided by humanized mice. These are highly immunodeficient mice (Hiramatsu et al., 2003; Brehm et al., 2010; McDermott et al., 2010) transplanted with human hematopoietic stem cells to reconstitute the human hematolymphoid system. Since these humanized mice can mount adaptive human immune responses, they provide a relevant model for translational research (Shultz et al., 2007) and the study of infectious diseases (Rämer et al., 2011).


Approaches to vaccines against Orientia tsutsugamushi.

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

Immunohistochemical detection of oriential antigen. (A) Analysis performed in the brain of a C3H/HeN mouse infected i.v., with 2 × 105 FFU of Orientia tsutsugamushi 11 days earlier (original magnification 400×). Alkaline phosphatase signal from the secondary antibody produces a red precipitate visible in endothelial cells of a microvessel (arrows) and in adjacent mononuclear leukocytes (asterisks). The section is counterstained with hematoxylin and eosin. (B) Analysis of the lungs of the same animals (original magnification 100×) with the same alkaline phosphatase technique shows multiple foci of oriential antigen in the alveolar walls. Courtesy of Thomas Shelite.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Immunohistochemical detection of oriential antigen. (A) Analysis performed in the brain of a C3H/HeN mouse infected i.v., with 2 × 105 FFU of Orientia tsutsugamushi 11 days earlier (original magnification 400×). Alkaline phosphatase signal from the secondary antibody produces a red precipitate visible in endothelial cells of a microvessel (arrows) and in adjacent mononuclear leukocytes (asterisks). The section is counterstained with hematoxylin and eosin. (B) Analysis of the lungs of the same animals (original magnification 100×) with the same alkaline phosphatase technique shows multiple foci of oriential antigen in the alveolar walls. Courtesy of Thomas Shelite.
Mentions: After the identification of a combination of antigens that together can stimulate protective responses mediated by CD8+T cells, CD4+T, and B cells (antibodies), the next developmental step for a modern anti-Orientia vaccine will be the selection of the best strategy to optimally stimulate those immune system cells. The objective is to do better than nature by testing different adjuvants, immunization routes, and schedules. These concepts are evolving very rapidly; thus, the reader is referred to recent reviews (Coffman et al., 2010; Liu, 2010). This testing must be done in appropriate animal models, thus the generation of relevant animal models to identify correlates of protective immunity and to test vaccine candidates is essential in the vaccine development effort against scrub typhus. Non-human primates constitute excellent models because scrub typhus pathogenesis and immunity are very similar to that of humans; however, the high cost of these animals together with the necessity of performing experiments with O. tsutsugamushi in a biosafety-level-3 (BSL-3) environment preclude their general and consistent use. Although there are fundamental biological species differences between humans and mice that are likely to affect direct translation to humans (Marian, 2011), very valuable information can be obtained from mice as long as there is a serious attempt to mimic the pathophysiology of humans. The ideal model should include transmission by chiggers, and some progress has already been made in that direction (see earlier sections on this topic). Alternatively, intradermal injection of O. tsutsugamushi to mimic the natural path of infection may be more reproducible and easier to implement. Our group is currently developing this model in C3H/HeN mice infected with the Karp strain; results are very promising since the infection is systemic and predominantly endothelial (Figure 2). We have also developed an intravenous infection model with similar results; the reports of these models are forthcoming. Another model that may provide an improved bridge to direct translation for human studies is that provided by humanized mice. These are highly immunodeficient mice (Hiramatsu et al., 2003; Brehm et al., 2010; McDermott et al., 2010) transplanted with human hematopoietic stem cells to reconstitute the human hematolymphoid system. Since these humanized mice can mount adaptive human immune responses, they provide a relevant model for translational research (Shultz et al., 2007) and the study of infectious diseases (Rämer et al., 2011).

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