Evaluation of Francisella tularensis ΔpdpC as a candidate live attenuated vaccine against respiratory challenge by a virulent SCHU P9 strain of Francisella tularensis in a C57BL/6J mouse model

Tian, Debin; Uda, Akihiko; Park, Eun-Sil; Hotta, Akitoyo; Fujita, Osamu; Yamada, Akio; Hirayama, Kazuhiro; Hotta, Kozue; Koyama, Yuuki; Azaki, Mika; Morikawa, Shigeru

doi:10.1111/1348-0421.12555

Cited by 7 publications

(9 citation statements)

References 55 publications

(65 reference statements)

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“…The high levels of specific Ab responses were often observed at 3 weeks post-vaccination in a tularemia mouse model, as previously reported 11,34 . Similarly, because high levels of MA test titers in two animals in Group 1 (animal #4550 and #4552) were confirmed at 3 weeks post vaccination in this study, the two animals were intratracheally challenged with virulent strain SCHU P9 at 3 weeks post-vaccination.…”

Section: Discussionsupporting

confidence: 82%

“…The pdpC gene of the virulent strain SCHU P9 was disrupted by group II intron insertion using the TargeTron gene knockout system 37,38 to generate the Δ pdpC mutant strain 39 . Thus, the genetic stability of strain ∆ pdpC was confirmed by in vivo passages in mice for 10 generations 34 . These data suggest that the mutant strain Δ pdpC is a promising vaccine candidate for tularemia.…”

Section: Discussionmentioning

confidence: 89%

“…Among the many methods applied to this disease, attenuated live vaccines are often applied 18,36 . A previous study reported that the ∆ pdpC mutant strain had the potential to protect mice from lethal intranasal challenge with a virulent strain via subcutaneous immunization 34 . The pdpC gene of the virulent strain SCHU P9 was disrupted by group II intron insertion using the TargeTron gene knockout system 37,38 to generate the Δ pdpC mutant strain 39 .…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study, we established a novel knockout mutant strain with an attenuated phenotype by intron insertion into the pathogenicity determinant protein C gene ( ΔpdpC ) of F. tularensis strain SCHU P9, which showed good protection against 100 LD 50 virulent strain challenge in a mouse model 34 . In the present study, the Δ pdpC mutant was further evaluated as a candidate live attenuated vaccine against tularemia in cynomolgus macaques challenged with a massive lethal dose (10 6 CFU) of virulent strain SCHU P9 because the respiratory infection is thought to cause the most serious consequences of F. tularensis if used as a biological weapon.…”

Section: Introductionmentioning

confidence: 99%

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Protective effects of the Francisella tularensis ΔpdpC mutant against its virulent parental strain SCHU P9 in Cynomolgus macaques

Tian

Uda

Ami

et al. 2019

Sci Rep

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Tularemia is a severe infectious zoonotic disease caused by Francisella tularensis . Although F. tularensis is considered to be a potential biological weapon due to its high infectivity and mortality rate, no vaccine has been currently licensed. Recently, we reported that F. tularensis SCHU P9 derived Δ pdpC strain lacking the pathogenicity determinant protein C gene conferred stable and good protection in a mouse lethal model. In this study, the protective effect of Δ pdpC was evaluated using a monkey lethal model. Two cynomolgus macaques ( Macaca fascicularis ) intratracheally challenged with the virulent strain SCHU P9 were euthanized on 7 and 11 days post-challenge after the development of severe clinical signs. The bacterial replication in alveolar macrophages and type II epithelial cells in the lungs would cause severe pneumonia accompanied by necrosis. Conversely, two animals subcutaneously immunized with Δ pdpC survived 3 weeks after SCHU P9 challenge. Though one of the two animals developed mild symptoms of tularemia, bacterial replication was limited in the respiratory organs, which may be due to a high level of humoral and cellular immune responses against F. tularensis . These results suggest that the Δ pdpC mutant would be a safe and promising candidate as a live attenuated tularemia vaccine.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protective effects of the Francisella tularensis ΔpdpC mutant against its virulent parental strain SCHU P9 in Cynomolgus macaques

Tian

Uda

Ami

et al. 2019

Sci Rep

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“…Vaccination with Schu S4ΔaroD conferred protection against high dose WT Schu S4 challenge of 1,000 CFU. This level of protection has not been achieved previously for any tularemia vaccine candidate in the mouse model [35][36][37][38][39][40][41][42]. In fact, it is even possible that the protective capacity of this strain is higher, as we have not yet tested higher challenge doses.…”

Section: Discussionmentioning

confidence: 77%

Characterization of Schu S4 aro mutants as live attenuated tularemia vaccine candidates

et al. 2020

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There is a need for development of an effective vaccine against Francisella tularensis, as this potential bioweapon has a high mortality rate and low infectious dose when delivered via the aerosol route. Moreover, this Tier 1 agent has a history of weaponization. We engineered targeted mutations in the Type A strain F. tularensis subspecies tularensis Schu S4 in aro genes encoding critical enzymes in aromatic amino acid biosynthesis. F. tularensis Schu S4ΔaroC, Schu S4ΔaroD, and Schu S4ΔaroCΔaroD mutant strains were attenuated for intracellular growth in vitro and for virulence in vivo and, conferred protection against pulmonary wild-type (WT) F. tularensis Schu S4 challenge in the C57BL/6 mouse model. F. tularensis Schu S4ΔaroD was identified as the most promising vaccine candidate, demonstrating protection against high-dose intranasal challenge; it protected against 1,000 CFU Schu S4, the highest level of protection tested to date. It also provided complete protection against challenge with 92 CFU of a F. tularensis subspecies holarctica strain (Type B). Mice responded to vaccination with Schu S4ΔaroD with systemic IgM and IgG2c, as well as the production of a functional T cell response as measured in the splenocytemacrophage co-culture assay. This vaccine was further characterized for dissemination, histopathology, and cytokine/chemokine gene induction at defined time points following intranasal vaccination which confirmed its attenuation compared to WT Schu S4. Cytokine, chemokine, and antibody induction patterns compared to wild-type Schu S4 distinguish protective vs. pathogenic responses to F. tularensis and elucidate correlates of protection associated with vaccination against this agent.

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Interpretative immune targets and contemporary position for vaccine development against SARS‐CoV‐2: A systematic review

Chauhan

Soni

Gupta

et al. 2020

Journal of Medical Virology

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The year 2020 started with the emergence of novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), which causes COVID‐19 infection. Soon after the first evidence was reported in Wuhan, China, the World Health Organization declared global public health emergency and imminent need to understand the pathogenicity of the virus was required in limited time. Once the genome sequence of the virus was delineated, scientists across the world started working on the development of vaccines. Although, some laboratories have been using previously developed vaccine platforms from severe acute respiratory syndrome coronavirus (SARS) and middle east respiratory syndrome‐related coronavirus and apply them in COVID‐19 vaccines due to genetic similarities between coronaviruses. We have conducted a literature review to assess the background and current status of COVID‐19 vaccines. The worldwide implementation and strategies for COVID‐19 vaccine development are summarized from studies reported in years 2015–2020. While discussing the vaccine candidates, we have also explained interpretative immune responses of SARS‐CoV‐2 infection. There are several vaccine candidates at preclinical and clinical stages; however, only 42 vaccines are under clinical trials. Therefore, more industry collaborations and financial supports to COVID‐19 studies are needed for mass‐scale vaccine development. To develop effective vaccine platforms against SARS‐CoV‐2, the genetic resemblance with other coronaviruses are being evaluated which may further promote fast‐track trials on previously developed SARS‐CoV vaccines.

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Evaluation of Francisella tularensis ΔpdpC as a candidate live attenuated vaccine against respiratory challenge by a virulent SCHU P9 strain of Francisella tularensis in a C57BL/6J mouse model

Cited by 7 publications

References 55 publications

Protective effects of the Francisella tularensis ΔpdpC mutant against its virulent parental strain SCHU P9 in Cynomolgus macaques

Protective effects of the Francisella tularensis ΔpdpC mutant against its virulent parental strain SCHU P9 in Cynomolgus macaques

Characterization of Schu S4 aro mutants as live attenuated tularemia vaccine candidates

Interpretative immune targets and contemporary position for vaccine development against SARS‐CoV‐2: A systematic review

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