Madison, WI, United States

Pan Genome Systems, Inc

www.pangenosys.com
Madison, WI, United States

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Shippy D.C.,Pan Genome Systems, Inc | Lemke J.J.,Pan Genome Systems, Inc | Berry A.,University of Wisconsin - Madison | Nelson K.,University of Wisconsin - Madison | And 3 more authors.
Clinical and Vaccine Immunology | Year: 2017

Mycobacterium avium subsp. paratuberculosis (M. paratuberculosis) is the etiological agent of Johne's disease in ruminants. Johne's disease is an important enteric infection causing large economic losses associated with infected herds. In an attempt to fight this infection, we created two novel live-attenuated vaccine candidates with mutations in sigH and lipN (pgsH and pgsN, respectively). Earlier reports in mice suggested these vaccines are promising candidates to fight Johne's disease in ruminants. In this study, we tested the performances of the two constructs as vaccine candidates using the goat model of Johne's disease. Both vaccines appeared to provide significant immunity to goats against challenge from wild-type M. paratuberculosis. The pgsH and pgsN constructs showed a significant reduction in histopathological lesions and tissue colonization compared to nonvaccinated goats and those vaccinated with an inactivated vaccine. Unlike the inactivated vaccine, the pgsN construct was able to eliminate fecal shedding from challenged animals, a feature that is highly desirable to control Johne's disease in infected herds. Furthermore, strong initial cell-mediated immune responses were elicited in goats vaccinated with pgsN that were not demonstrated in other vaccine groups. Overall, the results indicate the potential use of live-attenuated vaccines to control intracellular pathogens, including M. paratuberculosis, and warrant further testing in cattle, the main target for Johne's disease control programs. © 2017 American Society for Microbiology. All Rights Reserved.


Settles E.W.,Pan Genome Systems, Inc | Settles E.W.,University of Wisconsin - Madison | Kink J.A.,Pan Genome Systems, Inc | Talaat A.,Pan Genome Systems, Inc | And 2 more authors.
Vaccine | Year: 2014

Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) is the causative agent of Johne's disease in ruminants. Johne's disease has a severe economic impact on the dairy industry in the USA and worldwide. In an effort to combat this disease, we screened several transposon mutants that were attenuated in the murine model of paratuberculosis for the potential use as live attenuated vaccines. Using the murine model, two vaccine candidates (pgs1360, pgs3965 with mutations of fabG2_2 and umaA1, respectively) were at or below the limit of detection for tissue colonization suggesting their low level persistence and hence safety. Prior to challenge, both candidates induced a M. paratuberculosis-specific IFN-γ, an indication of eliciting cell-mediated immunity. Following challenge with a virulent strain of M. paratuberculosis, the two vaccine candidates significantly reduced bacterial colonization in organs with reduced histological scores compared to control animals. In addition, one of the vaccine candidates (pgs3965) also induced IL-17a, a cytokine associated with protective immunity in mycobacterial infection. Our analysis suggested that the pgs3965 vaccine candidate is a potential live-attenuated vaccine that could be tested further in ruminant models of paratuberculosis. The analysis also validated our screening strategy to identify effective vaccine candidates against intracellular pathogens. © 2014 Elsevier Ltd.


PubMed | University of Wisconsin - Madison, Pan Genome Systems, Inc and University of Georgia
Type: Journal Article | Journal: Clinical and vaccine immunology : CVI | Year: 2016

Mycobacterium avium subsp. paratuberculosis (M. paratuberculosis) is the etiological agent of Johnes disease in ruminants. Johnes disease is an important enteric infection causing large economic losses associated with infected herds. In an attempt to fight this infection, we created two novel live-attenuated vaccine candidates with mutations in sigH and lipN (pgsH and pgsN, respectively). Earlier reports in mice suggested these vaccines are promising candidates to fight Johnes disease in ruminants. In this study, we tested the performances of the two constructs as vaccine candidates using the goat model of Johnes disease. Both vaccines appeared to provide significant immunity to goats against challenge from wild-type M. paratuberculosis The pgsH and pgsN constructs showed a significant reduction in histopathological lesions and tissue colonization compared to nonvaccinated goats and those vaccinated with an inactivated vaccine. Unlike the inactivated vaccine, the pgsN construct was able to eliminate fecal shedding from challenged animals, a feature that is highly desirable to control Johnes disease in infected herds. Furthermore, strong initial cell-mediated immune responses were elicited in goats vaccinated with pgsN that were not demonstrated in other vaccine groups. Overall, the results indicate the potential use of live-attenuated vaccines to control intracellular pathogens, including M. paratuberculosis, and warrant further testing in cattle, the main target for Johnes disease control programs.


Ghosh P.,University of Wisconsin - Madison | Ghosh P.,Harvard University | Shippy D.C.,University of Wisconsin - Madison | Shippy D.C.,Pan Genome Systems, Inc | And 2 more authors.
Vaccine | Year: 2015

Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) causes Johne's disease, a chronic enteric infection in ruminants with severe economic impact on the dairy industry in the USA and worldwide. Currently, available vaccines have limited protective efficacy against disease progression and does not prevent spread of the infection among animals. Because of their ability to elicit wide-spectrum immune responses, we adopted a live-attenuated vaccine approach based on a sigH knock-out strain of M. paratuberculosis (δ. sigH). Earlier analysis of the δ. sigH mutant in mice indicated their inadequate ability to colonize host tissues, unlike the isogenic wild-type strain, validating the role of this sigma factor in M. paratuberculosis virulence. In the present study, we evaluated the performance of the δ. sigH mutant compared to inactivated vaccine constructs in a vaccine/challenge model of murine paratuberculosis. The presented analysis indicated that δ. sigH mutant with or without QuilA adjuvant is capable of eliciting strong immune responses (such as interferon gamma-γ, IFN-γ) suggesting their immunogenicity and ability to potentially initiate effective vaccine-induced immunity. Following a challenge with virulent strains of M. paratuberculosis, δ. sigH conferred protective immunity as indicated by the reduced bacterial burden accompanied with reduced lesions in main body organs (liver, spleen and intestine) usually infected with M. paratuberculosis. More importantly, our data indicated better ability of the δ. sigH vaccine to confer protection compared to the inactivated vaccine constructs even with the presence of oil-adjuvant. Overall, our approach provides a rational basis for using live-attenuated mutant strains to develop improved vaccines that elicit robust immunity against this chronic infection. © 2015 Elsevier Ltd.


Grant
Agency: Department of Agriculture | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 99.85K | Year: 2016

Johne's disease (JD) is a contagious, chronic, and potentially fatal infection caused by Mycobacterium avium subsp. paratuberculosis (M. ap) affecting the small intestine of all ruminants, including dairy cattle. Infected cattle can suffer from chronic diarrhea, weight loss, reduced milk yield, and low, but persistent mortality, causing significant economic losses to the dairy industry, with estimated annual losses of $200 to $500 million in the USA alone. The licensed killed vaccine (Mycopar®) does not prevent infection and infected animals will continue to shed M. ap in their feces and milk. In this Phase I application, we will optimize the vaccine delivery route of a vaccine candidate in goats, as a first stage for further testing in a more expensive calf challenge model by 1) Optimize delivery route of Johne's Disease LAV candidate. We will optimize pgsN vaccine by testing its safety and immunogenicity in goats following oral delivery (vs. S/C injection) to develop a safe and more effective vaccine against JD. In addition, we will 2) Develop simple assays to differentiate between infected and vaccinated animals (DIVA) by taking advantage of the defined genetic mutation introduced in pgsN. Overall, the development of an efficient, safe and commercially viable vaccine against JD is an arduous and prolonged process. Our novel application of an oral vaccine and the development of sensitive DIVA assays will further improve our chances to commercialize PGS vaccines to the dairy operations in the USA and worldwide, a goal that is supported by USDA-SBIR program.


Grant
Agency: Department of Agriculture | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 449.72K | Year: 2013

Johne & #39;s disease (JD) or paratuberculosis in animals (infection with M. avium ss. paratuberculosis, M. ap) is a contagious, chronic, and potentially fatal disease affecting the small intestine of ruminants. All ruminants are susceptible, but the largest economic impact is felt in dairy farming, where infected cattle suffer from chronic diarrhea, weight loss, low milk yield and low (but persistent) mortality. Estimated annual losses to U.S. dairy farms range up to $500M. Evidence indicates a link between JD in dairy herds and Crohn & #39;s disease in humans. Currently, no feasible antibiotic regimen or efficient control strategy exists to combat JD. It spreads through fecal shedding of M. ap by infected cattle. The current (killed) vaccine does not prevent shedding from vaccinated and infected animals;failing to control JD transmission within a herd. Because of these deficiencies, some farmers no longer use the vaccines, instead using a reactive test and cull strategy: diagnose JD infection and isolate affected cattle. However, the lack of reliable diagnostic tools to detect early stage JD means that farmers rely M. ap antibody development and shedding, which can occur two to four years after initial infection. In addition, whole organism vaccines can cause false positive antibody diagnostic tests. Thus, a diagnostic that can differentiate vaccinated from infected animals is important for any vaccine/monitoring strategy. An efficient vaccine and a reliable diagnostic assay together represent cornerstones of an effective control strategy for JD. These are the ultimate aims of this Phase II project. During the Phase I project (USDA-SBIR), we tested the performance of 2 live attenuated vaccine (LAV) candidates using a mouse paratuberculosis model. We deactivated key genes involved in M. ap & #39;s virulence and persistence in our candidates. Our analysis showed initial replication and host colonization, followed by a significant decline to levels undetectable by culturing. However, the candidates generated robust cellular, humoral, and protective immune responses in a challenge. Compared to controls, vaccinated animals showed significantly lower M. ap tissue levels after challenge. Additionally, during Phase I, we also developed a proprietary LAMP-based assay that can differentiate infected and vaccinated animals. In Phase II of this project, we will evaluate the performance and safety of our candidates in ruminant (goat and calf) paratuberculosis models. Our specific goals for this project are to optimize the vaccine candidates for use in farm animals, evaluate their protective efficacy in ruminants (goats and young calves), and then characterize the candidates immune responses and environmental impact. LAV candidates will be compared to na & iuml;ve controls and commercially-vaccinated animals. We will also evaluate our diagnostic assay to differentiate infected and vaccinated/infected animals. If this project is successful, we will have identified a very promising LAV vaccine candidate that will elicit a strong and consistent immune response while allowing for little tissue colonization and shedding. We will also have an efficient assay that can differentiate vaccinated animals from infected animals. This research will provide a basis for licensing, and commercialization of these necessary products. Once commercialized, these products will provide two vital components for the world-wide goal of controlling JD and limiting its economic impact. With more than 100 million head of cattle worldwide, the commercialization potential for these two products is enormous. In addition, this research lays a foundation for vaccination of other ruminants (sheep, goats, and camels) that are harmed by M. paratuberculosis.


Grant
Agency: Department of Agriculture | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 99.68K | Year: 2012

Our company has several vaccine candidates that could help in protecting animals from Johne's disease. In this phase of the project, we will test the performance of these vaccines in mice. Once proven protective, we will be able to run more tests on a ruminant model of infection that pave the way for field testing of these vaccine in dairy farms.


PubMed | Pan Genome Systems, Inc
Type: Journal Article | Journal: Vaccine | Year: 2014

Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) is the causative agent of Johnes disease in ruminants. Johnes disease has a severe economic impact on the dairy industry in the USA and worldwide. In an effort to combat this disease, we screened several transposon mutants that were attenuated in the murine model of paratuberculosis for the potential use as live attenuated vaccines. Using the murine model, two vaccine candidates (pgs1360, pgs3965 with mutations of fabG2_2 and umaA1, respectively) were at or below the limit of detection for tissue colonization suggesting their low level persistence and hence safety. Prior to challenge, both candidates induced a M. paratuberculosis-specific IFN-, an indication of eliciting cell-mediated immunity. Following challenge with a virulent strain of M. paratuberculosis, the two vaccine candidates significantly reduced bacterial colonization in organs with reduced histological scores compared to control animals. In addition, one of the vaccine candidates (pgs3965) also induced IL-17a, a cytokine associated with protective immunity in mycobacterial infection. Our analysis suggested that the pgs3965 vaccine candidate is a potential live-attenuated vaccine that could be tested further in ruminant models of paratuberculosis. The analysis also validated our screening strategy to identify effective vaccine candidates against intracellular pathogens.


PubMed | University of Wisconsin - Madison and Pan Genome Systems, Inc
Type: Journal Article | Journal: Vaccine | Year: 2015

Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) causes Johnes disease, a chronic enteric infection in ruminants with severe economic impact on the dairy industry in the USA and worldwide. Currently, available vaccines have limited protective efficacy against disease progression and does not prevent spread of the infection among animals. Because of their ability to elicit wide-spectrum immune responses, we adopted a live-attenuated vaccine approach based on a sigH knock-out strain of M. paratuberculosis (sigH). Earlier analysis of the sigH mutant in mice indicated their inadequate ability to colonize host tissues, unlike the isogenic wild-type strain, validating the role of this sigma factor in M. paratuberculosis virulence. In the present study, we evaluated the performance of the sigH mutant compared to inactivated vaccine constructs in a vaccine/challenge model of murine paratuberculosis. The presented analysis indicated that sigH mutant with or without QuilA adjuvant is capable of eliciting strong immune responses (such as interferon gamma-, IFN-) suggesting their immunogenicity and ability to potentially initiate effective vaccine-induced immunity. Following a challenge with virulent strains of M. paratuberculosis, sigH conferred protective immunity as indicated by the reduced bacterial burden accompanied with reduced lesions in main body organs (liver, spleen and intestine) usually infected with M. paratuberculosis. More importantly, our data indicated better ability of the sigH vaccine to confer protection compared to the inactivated vaccine constructs even with the presence of oil-adjuvant. Overall, our approach provides a rational basis for using live-attenuated mutant strains to develop improved vaccines that elicit robust immunity against this chronic infection.


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PGS L ThePGS Lvaccine is a single dose live-attenuated vaccine. This vaccine uses a live bacterial strain that has been attenuated (altered) ...

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