Intranasal Vaccination with Outer-Membrane Protein of<i>Orientia tsutsugamushi</i>induces Protective Immunity Against Scrub Typhus

Park, Sung-Moo; Gu, Min; Ju, Young-Jun; Cheon, In Su; Hwang, Kyu-Jam; Gill, Byoungchul; Shim, Byoung-Shik; Jeong, Hang-Jin; Son, Young Min; Choi, Sang‐Ho; Jeung, Woonhee; Han, Seung Hyun; Chu, Hyuk

doi:10.4110/in.2021.21.e14

Cited by 8 publications

(3 citation statements)

References 56 publications

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“…The 47 kDa (p47) antigen has been described as partially protective on the basis of reduction in eschars, delayed onset, and shortened course of illness in vaccinated nonhuman primates and absence of fever and bacteria in sampled blood in 25% of animals, but the great majority of the animals developed fever and bacteremia 48 . In a study of mice immunized intranasally three times with recombinant p47 and cholera toxin adjuvant, all animals became ill with disseminated infection with O. tsutsugamushi present in the heart, lung, liver, and spleen 49 . Other investigations at the Naval Medical Research Center that were reported as unpublished data stated that immunization with a 110 kDa DNA vaccine stimulated partial protection against homologous challenge without information on illness and death of the challenged animals or statistical analysis of protection and that a 22 kDa DNA vaccine was not protective 50 .…”

Section: Scabmentioning

confidence: 99%

A scrub typhus vaccine presents a challenging unmet need

Walker

Mendell

2023

npj Vaccines

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Scrub typhus caused by the obligately intracellular bacterium, Orientia tsutsugamushi, is a major cause of life-threatening acute undifferentiated febrile illness in eastern Asia and the islands of the Western Pacific and Indian oceans. Since the estimation of an incidence of 1 million cases annually two decades ago, the number of cases has increased substantially in endemic regions, reappeared where the disease was forgotten, and spread northward. Trombiculid mites are both reservoir and vector. Despite 80 years of efforts to develop a vaccine, there is none. Protective immunity is mediated by antibodies and CD8 and CD4 T cells. Previous efforts have failed because of gaps in understanding immunity to O. tsutsugamushi, particularly the requirements for vaccine-induced immunity, lack of knowledge regarding immune memory in scrub typhus, and lack of attention to addressing the issue of cross-protection between strains. There are numerous strains of O. tsutsugamushi, and modestly durable immunity is strain-specific. Antibodies to the strain that caused infection are protective against challenges with the homologous strain but, despite reactivity with other immunodominant antigens, the immune serum does not protect against heterologous strains. Among the antigens detected by western immunoblot in immune sera (22-, 47-, 56-, 58-, and 110 kDa proteins), only the 56 kDa protein stimulates strong protection. This protein contains four hypervariable regions which are likely, on the basis of limited data, to be the targets of neutralizing antibodies. However, a method that definitively detects neutralizing antibody has yet to be developed. Only one study has used genomic data to pursue the discovery of protective antigens. Three conserved autotransporters were identified, and only immunization with ScaA provided protection against the homologous strain, but only 40% of animals were protected against challenge with a heterologous strain. A multiplex vaccine containing conformational antigens of the hypervariable regions of the 56 kDa protein of the strains of the greatest clinical and epidemiological importance, as well as conserved regions of the 56 kDa protein, ScaA, and other protective antigens identified by future genomic and bioinformatics methods should be developed and tested.

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Section: Scabmentioning

confidence: 99%

A scrub typhus vaccine presents a challenging unmet need

Walker

Mendell

2023

npj Vaccines

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“…Upon immunizing mice with a DNA construct containing TSA47, outbred CD-1 mice were found to produce polyfunctional splenocytes secreting IFNγ, IL-4, and IL-13 in addition to a strong antibody response ( Chattopadhyay and Richards, 2007 ). In challenge studies using TSA47 as the immunizing antigen delivered intranasally, mice developed high antibody titers, including IgG and IgA in bronchoalveolar lavage (BAL) fluid, as well as cellular immunity correlative with a Th1 response ( Choi et al., 2017 ; Park et al., 2021 ). In both studies, mice were significantly protected against a lethal challenge with O. tsutsugamushi Boryong.…”

Section: Orientia Spp Vaccinesmentioning

confidence: 99%

Vaccine development: obligate intracellular bacteria new tools, old pathogens: the current state of vaccines against obligate intracellular bacteria

van Schaik,

Fratzke,

Gregory

et al. 2024

Front. Cell. Infect. Microbiol.

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Obligate intracellular bacteria have remained those for which effective vaccines are unavailable, mostly because protection does not solely rely on an antibody response. Effective antibody-based vaccines, however, have been developed against extracellular bacteria pathogens or toxins. Additionally, obligate intracellular bacteria have evolved many mechanisms to subvert the immune response, making vaccine development complex. Much of what we know about protective immunity for these pathogens has been determined using infection-resolved cases and animal models that mimic disease. These studies have laid the groundwork for antigen discovery, which, combined with recent advances in vaccinology, should allow for the development of safe and efficacious vaccines. Successful vaccines against obligate intracellular bacteria should elicit potent T cell memory responses, in addition to humoral responses. Furthermore, they ought to be designed to specifically induce strong cytotoxic CD8+ T cell responses for protective immunity. This review will describe what we know about the potentially protective immune responses to this group of bacteria. Additionally, we will argue that the novel delivery platforms used during the Sars-CoV-2 pandemic should be excellent candidates to produce protective immunity once antigens are discovered. We will then look more specifically into the vaccine development for Rickettsiaceae, Coxiella burnetti, and Anaplasmataceae from infancy until today. We have not included Chlamydia trachomatis in this review because of the many vaccine related reviews that have been written in recent years.

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“…As reported by many studies, serological antibodies from immunized or infected animals may lack cross-reactivity, but T cells from these animals are highly cross-protective against different Orientia strains [5]. Despite the significance of cellular immune responses, effective elicitation of T cell responses has yet to be achieved to date using various vaccine platforms, including formalin inactivated O. tsutsugamushi [6][7][8], DNA vectors [9,10], and soluble recombinant antigens [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Dual-Antigen Subunit Vaccine Nanoparticles for Scrub Typhus

Park,

Zhang,

Belinskaya

et al. 2023

Pathogens

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Orientia tsutsugamushi is the causative pathogen of scrub typhus, an acute febrile disease prevalent in the Asia–Pacific region that is spread to people through chigger bites. Despite the emerging threat, there is no currently available vaccine against O. tsutsugamushi. Here, we developed dual-antigen subunit vaccine nanoparticles using recombinant 47 kD and 56 kD proteins, which are immunogenic outer membrane antigens of O. tsutsugamushi. The biocompatible protein vaccine nanoparticles were formed via desolvation of r56 or r47E antigens with acetone, coating with an additional layer of the 56 kD protein, and stabilization with reducible homobifunctional DTSSP and heterobifunctional SDAD crosslinkers. The dual-antigen subunit vaccine nanoparticles significantly improved antigen-specific antibody responses in vaccinated mice. Most importantly, the dual-antigen nanoparticles coated with an additional layer of the 56 kD protein were markedly more immunogenic than soluble antigens or single-antigen nanoparticles in the context of cellular immune responses. Given the significance of cellular immune responses for protection against O. tsutsugamushi, these results demonstrate the potent immunogenicity of dual-layered antigen nanoparticles and their potential as a promising strategy for developing vaccines against scrub typhus.

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Intranasal Vaccination with Outer-Membrane Protein ofOrientia tsutsugamushiinduces Protective Immunity Against Scrub Typhus

Cited by 8 publications

References 56 publications

A scrub typhus vaccine presents a challenging unmet need

A scrub typhus vaccine presents a challenging unmet need

Vaccine development: obligate intracellular bacteria new tools, old pathogens: the current state of vaccines against obligate intracellular bacteria

Dual-Antigen Subunit Vaccine Nanoparticles for Scrub Typhus

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