Matching Items (334)
Description
Vaccinia virus (VACV) is the current vaccine for the highly infectious smallpox disease. Since the eradication of smallpox, VACV has been developed extensively as a heterologous vaccine vector for several pathogens. However, due to the complications associated with this replication competent virus, the safety and efficacy of VACV vaccine vector has been reevaluated. To evaluate the safety and efficacy of VACV, we study the interactions between VACV and the host innate immune system, especially the type I interferon (IFN) signaling pathways. In this work, we evaluated the role of protein kinase R (PKR) and Adenosine Deaminase Acting on RNA 1(ADAR1), which are induced by IFN, in VACV infection. We found that PKR is necessary but is not sufficient to activate interferon regulatory factor 3 (IRF3) in the induction of type I IFN; and the activation of the stress-activated protein kinase/ c-Jun NH2-terminal kinase is required for the PKR-dependent activation of IRF3 during VACV infection. Even though PKR was found to have an antiviral effect in VACV, ADAR1 was found to have a pro-viral effect by destabilizing double stranded RNA (dsRNA), rescuing VACVΔE3L, VACV deleted of the virulence factor E3L, when provided in trans. With the lessons we learned from VACV and host cells interaction, we have developed and evaluated a safe replication-competent VACV vaccine vector for HIV. Our preliminary results indicate that our VACV vaccine vector can still induce the IFN pathway while maintaining the ability to replicate and to express the HIV antigen efficiently. This suggests that this VACV vector can be used as a safe and efficient vaccine vector for HIV.
ContributorsHuynh, Trung Phuoc (Author) / Jacobs, Bertram L (Thesis advisor) / Hogue, Brenda (Committee member) / Chang, Yung (Committee member) / Ugarova, Tatiana (Committee member) / Arizona State University (Publisher)
Created2013
Description
ABSTRACT In terms of prevalence, human suffering and costs dengue infections are the most important arthropod-borne viral disease worldwide. Dengue virus (DENV) is a mosquito-borne flavivirus and the etiological agent of dengue fever and dengue hemorrhagic fever. Thus, development of a safe and efficient vaccine constitutes an urgent necessity. Besides the traditional strategies aim at generating immunization options, the usage of viral vectors to deliver antigenic stimulus in order to elicit protection are particularly attractive for the endeavor of a dengue vaccine. The viral vector (MVvac2) is genetically equivalent to the currently used measles vaccine strain Moraten, which adds practicality to my approach. The goal of the present study was to generate a recombinant measles virus expressing structural antigens from two strains of DENV (DENV2 and DENV4) The recombinant vectors replication profile was comparable to that of the parental strain and expresses either membrane bound or soluble forms of DENV2 and DENV4 E glycoproteins. I discuss future experiments in order to demonstrate its immunogenicity in our measles-susceptible mouse model.
ContributorsAbdelgalel, Rowida (Author) / Reyes del Valle, Jorge (Thesis advisor) / Hogue, Brenda (Committee member) / Frasch, Wayne D (Committee member) / Arizona State University (Publisher)
Created2013
Description
Vaccination remains one of the most effective means for preventing infectious diseases. During viral infection, activated CD8 T cells differentiate into cytotoxic effector cells that directly kill infected cells and produce anti-viral cytokines. Further T cell differentiation results in a population of memory CD8 T cells that have the ability to self-renew and rapidly proliferate into effector cells during secondary infections. However during persistent viral infection, T cell differentiation is disrupted due to sustained antigen stimulation resulting in a loss of T cell effector function. Despite the development of vaccines for a wide range of viral diseases, efficacious vaccines for persistent viral infections have been challenging to design. Immunization against virus T cell epitopes has been proposed as an alternative vaccination strategy for persistent viral infections, such as HIV. However, vaccines that selectively engage T cell responses can result in inappropriate immune responses that increase, rather than prevent, disease. Quantitative models of virus infection and immune response were used to investigate how virus and immune system variables influence pathogenic versus protective T cell responses generated during persistent viral infection. It was determined that an intermediate precursor frequency of virus-specific memory CD8 T cells prior to LCMV infection resulted in maximum T cell mediated pathology. Increased pathology was independent of antigen sensitivity or the diversity of TCR in the CD8 T cell response, but was dependent on CD8 T cell production of TNF and the magnitude of initial virus exposure. The threshold for exhaustion of responding CD8 T cells ultimately influences the precursor frequency that causes enhanced disease.In addition, viral infection can occur in the context of co-infection by heterologous pathogens that modulate immune responses and/or disease. Co-infection of two unrelated viruses in their natural host, Ectromelia virus (ECTV) and Lymphocytic Choriomeningitis virus (LCMV) infection in mice, were studied. ECTV infection can be a lethal infection in mice due in part to the blockade of antiviral cytokines, including Type I Interferons (IFN-I). It was determined that ECTV/LCMV co-infection results in decreased ECTV viral load and amelioration of ECTV-induced disease, presumably due to IFN-I induction by LCMV. However, immune responses to LCMV in ECTV co-infected mice were also lower compared to mice infected with LCMV alone and biased toward effector-memory cell generation. Thus, providing evidence for bi-directional effects of viral co-infection that modulate disease and immunity. Together the results suggest heterogeneity in T cell responses during vaccination with viral vectors may be in part due to heterologous virus infection or vaccine usage and that TNF-blockade may be useful for minimizing pathology while maintaining protection during virus infection. Lastly, quantitative mathematical models of virus and T cell immunity can be useful to generate predictions regarding which molecular and cellular pathways mediate T cell protection versus pathology.
ContributorsMcAfee, Megan (Author) / Blattman, Joseph N (Thesis advisor) / Anderson, Karen (Committee member) / Jacobs, Bertram (Committee member) / Hogue, Brenda (Committee member) / Arizona State University (Publisher)
Created2015
Description
The concept of vaccination dates back further than Edward Jenner's first vaccine using cowpox pustules to confer immunity against smallpox in 1796. Nevertheless, it was Jenner's success that gave vaccines their name and made vaccinia virus (VACV) of particular interest. More than 200 years later there is still the need to understand vaccination from vaccine design to prediction of vaccine efficacy using mathematical models. Post-exposure vaccination with VACV has been suggested to be effective if administered within four days of smallpox exposure although this has not been definitively studied in humans. The first and second chapters analyze post-exposure prophylaxis of VACV in an animal model using v50ΔB13RMγ, a recombinant VACV expressing murine interferon gamma (IFN-γ) also known as type II IFN. While untreated animals infected with wild type VACV die by 10 days post-infection (dpi), animals treated with v50ΔB13RMγ 1 dpi had decreased morbidity and 100% survival. Despite these differences, the viral load was similar in both groups suggesting that v50ΔB13RMγ acts as an immunoregulator rather than as an antiviral. One of the main characteristics of VACV is its resistance to type I IFN, an effect primarily mediated by the E3L protein, which has a Z-DNA binding domain and a double-stranded RNA (dsRNA) binding domain. In the third chapter a VACV that independently expresses both domains of E3L was engineered and compared to wild type in cells in culture. The dual expression virus was unable to replicate in the JC murine cell line where both domains are needed together for replication. Moreover, phosphorylation of the dsRNA dependent protein kinase (PKR) was observed at late times post-infection which indicates that both domains need to be linked together in order to block the IFN response. Because smallpox has already been eradicated, the utility of mathematical modeling as a tool for predicting disease spread and vaccine efficacy was explored in the last chapter using dengue as a disease model. Current modeling approaches were reviewed and the 2000-2001 dengue outbreak in a Peruvian region was analyzed. This last section highlights the importance of interdisciplinary collaboration and how it benefits research on infectious diseases.
ContributorsHolechek, Susan A (Author) / Jacobs, Bertram L (Thesis advisor) / Castillo-Chavez, Carlos (Committee member) / Frasch, Wayne (Committee member) / Hogue, Brenda (Committee member) / Stout, Valerie (Committee member) / Arizona State University (Publisher)
Created2011
Biological and immunological characterization of plant-produced HIV-1 Gag/dgp41 virus-like particles
Description
Anti-retroviral drugs and AIDS prevention programs have helped to decrease the rate of new HIV-1 infections in some communities, however, a prophylactic vaccine is still needed to control the epidemic world-wide. Despite over two decades of research, a vaccine against HIV-1 remains elusive, although recent clinical trials have shown promising results. Recent successes have focused on highly conserved, mucosally-targeted antigens within HIV-1 such as the membrane proximal external region (MPER) of the envelope protein, gp41. MPER has been shown to play critical roles in the viral mucosal transmission, though this peptide is not immunogenic on its own. Gag is a structural protein configuring the enveloped virus particles, and has been suggested to constitute a target of the cellular immunity potentially controlling the viral load. It was hypothesized that HIV-1 enveloped virus-like particles (VLPs) consisting of Gag and a deconstructed form of gp41 comprising the MPER, transmembrane, and cytoplasmic domains (dgp41) could be expressed in plants. Plant-optimized HIV-1 genes were constructed and expressed in Nicotiana benthamiana by stable transformation, or transiently using a tobacco mosaic virus-based expression system or a combination of both. Results of biophysical, biochemical and electron microscopy characterization demonstrated that plant cells could support not only the formation of HIV-1 Gag VLPs, but also the accumulation of VLPs that incorporated dgp41. These particles were purified and utilized in mice immunization experiments. Prime-boost strategies combining systemic and mucosal priming with systemic boosting using two different vaccine candidates (VLPs and CTB-MPR - a fusion of MPER and the B-subunit of cholera toxin) were administered to BALB/c mice. Serum antibody responses against both the Gag and gp41 antigens could be elicited in mice systemically primed with VLPs and these responses could be recalled following systemic boosting with VLPs. In addition, mucosal priming with VLPs allowed for a robust boosting response against Gag and gp41 when boosted with either candidate. Functional assays of these antibodies are in progress to test the antibodies' effectiveness in neutralizing and preventing mucosal transmission of HIV-1. This immunogenicity of plant-based Gag/dgp41 VLPs represents an important milestone on the road towards a broadly-efficacious and inexpensive subunit vaccine against HIV-1.
ContributorsKessans, Sarah (Author) / Mor, Tsafrir S (Thesis advisor) / Matoba, Nobuyuki (Committee member) / Mason, Hugh (Committee member) / Hogue, Brenda (Committee member) / Fromme, Petra (Committee member) / Arizona State University (Publisher)
Created2011
Description
Plants are a promising upcoming platform for production of vaccine components and other desirable pharmaceutical proteins that can only, at present, be made in living systems. The unique soil microbe Agrobacterium tumefaciens can transfer DNA to plants very efficiently, essentially turning plants into factories capable of producing virtually any gene. While genetically modified bacteria have historically been used for producing useful biopharmaceuticals like human insulin, plants can assemble much more complicated proteins, like human antibodies, that bacterial systems cannot. As plants do not harbor human pathogens, they are also safer alternatives than animal cell cultures. Additionally, plants can be grown very cheaply, in massive quantities.
In my research, I have studied the genetic mechanisms that underlie gene expression, in order to improve plant-based biopharmaceutical production. To do this, inspiration was drawn from naturally-occurring gene regulatory mechanisms, especially those from plant viruses, which have evolved mechanisms to co-opt the plant cellular machinery to produce high levels of viral proteins. By testing, modifying, and combining genetic elements from diverse sources, an optimized expression system has been developed that allows very rapid production of vaccine components, monoclonal antibodies, and other biopharmaceuticals. To improve target gene expression while maintaining the health and function of the plants, I identified, studied, and modified 5’ untranslated regions, combined gene terminators, and a nuclear matrix attachment region. The replication mechanisms of a plant geminivirus were also studied, which lead to additional strategies to produce more toxic biopharmaceutical proteins. Finally, the mechanisms employed by a geminivirus to spread between cells were investigated. It was demonstrated that these movement mechanisms can be functionally transplanted into a separate genus of geminivirus, allowing modified virus-based gene expression vectors to be spread between neighboring plant cells. Additionally, my work helps shed light on the basic genetic mechanisms employed by all living organisms to control gene expression.
In my research, I have studied the genetic mechanisms that underlie gene expression, in order to improve plant-based biopharmaceutical production. To do this, inspiration was drawn from naturally-occurring gene regulatory mechanisms, especially those from plant viruses, which have evolved mechanisms to co-opt the plant cellular machinery to produce high levels of viral proteins. By testing, modifying, and combining genetic elements from diverse sources, an optimized expression system has been developed that allows very rapid production of vaccine components, monoclonal antibodies, and other biopharmaceuticals. To improve target gene expression while maintaining the health and function of the plants, I identified, studied, and modified 5’ untranslated regions, combined gene terminators, and a nuclear matrix attachment region. The replication mechanisms of a plant geminivirus were also studied, which lead to additional strategies to produce more toxic biopharmaceutical proteins. Finally, the mechanisms employed by a geminivirus to spread between cells were investigated. It was demonstrated that these movement mechanisms can be functionally transplanted into a separate genus of geminivirus, allowing modified virus-based gene expression vectors to be spread between neighboring plant cells. Additionally, my work helps shed light on the basic genetic mechanisms employed by all living organisms to control gene expression.
ContributorsDiamos, Andy (Author) / Mason, Hugh S (Thesis advisor) / Mor, Tsafrir (Committee member) / Hogue, Brenda (Committee member) / Stout, Valerie (Committee member) / Arizona State University (Publisher)
Created2017
Description
The purpose of this paper is to understand how companies are finding high potential employees and if they are leaving top talent behind in their approach. Eugene Burke stated in 2014 that 55% of employees that are labeled as a High Potential Employee will turn over and move companies. Burke (2014) also states that the average high potential employee tenure is five years. The Corporate Leadership Council says that on average, 27% of a company's development budget is spent on its high potential program (CEB 2017). For a midsize company, the high potential development budget is almost a million dollars for only a handful of employees, only to see half of the investment walking out the door to another company . Furthermore, the Corporate Leadership Council said that a study done in 2005 revealed that 50% of high potential employees had significant problems within their job (Kotlyar and Karkowsky 2014). Are time and resources are being given to the wrong employees and the right employees are being overlooked? This paper exams how companies traditionally select high potential employees and where companies are potentially omitting employees who would be better suited for the program. This paper proposes that how a company discovers their top talent will correlate to the number of turnovers or struggles that a high potential employee has on their job. Future research direction and practical considerations are also presented in this paper.
ContributorsHarrison, Carrie (Author) / Mizzi, Philip (Thesis director) / Ruediger, Stefan (Committee member) / Department of Management and Entrepreneurship (Contributor) / School of Sustainability (Contributor) / Department of Supply Chain Management (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The goal of our project was to determine how to create the most marketable hockey team. To do this, consumer needs, team psychology, and financing were all researched and evaluated. With this information, a business plan was designed around the next NHL expansion team. Two surveys, one for marketing distributed to the general public, and one for team psychology distributed to current and former hockey players were created and sent out, while data for the financing aspect was collected by comparing data from other NHL teams and franchises from different sports. In terms of financials, this comes in lower than average ticket prices, a nice and expensive stadium, the ideal city to generate capital, and sufficient money spent on advertising. Our ticket prices of $140 is based on having a low enough price to generate lots of demand while high enough to make a profit. The $600 million stadium (which will be fully funded) will surely draw a significant crowd. Choosing Seattle as a city is the most ideal to meet these goals and lastly, in meeting with an NHL GM, we determined $4 million in yearly advertising costs as sufficient in creating the most marketable team. Throughout this whole process, we remained data focus. We focused on data from a customized marketing survey, organizational structures, salary cap, and attendance. What our marketing survey results showed us is that our potential fans wanted three characteristics in a hockey team: speed, intensity, and scoring. In looking at organizational structures teams that exemplified these characteristics had a heavy emphasis on development and scouting. So we built our organizational tree around those two ideals. We hired GM Mike Futa, a current director of player personnel for the L.A. Kings, and Head Coach Adam Oates, a current skills development coach for top players to bring those ideals to fruition. In constructing our team we replicated the rules set forth for the Vegas Knights' expansion draft and hypothesized a likely protected list based off of last years lists. As a result we were able to construct a team that statistically out performed the Vegas Knights draft numbers by double, in goals, assists, and points, while also beating them in PIM. Based off of these numbers and an analysis of how goals translate into game attendance we are confident that we have constructed a team that has the highest potential for marketability. For the team psychology area, when creating a roster and scouting players, some of our main findings were that it is important to pursue players who get along well with their teammates and coaching staff, are aggressive, are leaders on the team, and are vocal players who communicate effectively. We also recommended avoiding players who significantly portrayed any "pet-peeve" traits, with the most emphasis placed on "disrespectful toward teammates," and the least emphasis placed on "over-aggression." By following all of these recommendations, we believe the most marketable hockey team possible can be created.
ContributorsQuinn, Colin Christopher (Co-author) / Spigel, Carlos (Co-author) / Meyer, Matt (Co-author) / Eaton, John (Thesis director) / McIntosh, Daniel (Committee member) / Department of Marketing (Contributor) / Sandra Day O'Connor College of Law (Contributor) / Department of Management and Entrepreneurship (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Innovation Space is a program within Arizona State University in which two different sponsors fund three teams up to two thousand dollars so they may attempt to solve a prompt given by the sponsor. The teams consist of one student from each of the different schools Arizona State University contains. This includes one student from the W.P.Carey School of Business, Fulton School of Engineering, the School of Design, and School of Sustainability. This year, we had the opportunity to work with Johnson & Johnson and Adidas. Over the course of the year, we worked with Johnson & Johnson to deliver a more organic solution to typical mosquito repellent. The entire year consisted of seven phases. The first four phases dealt with customer research; much of this work involved secondary research online, surveys, interviews, and observations to discover our customer and validate that they would buy our product. Once we discovered who our customer was, then we had to brainstorm a solution to their customer pains. At the end of phase four, we had narrowed our brainstorming down to the top three ideas. Phases five through seven consisted of picking our top idea based off of our presentation to the stakeholders at Johnson & Johnson. Phases five through seven focused on how we would launch our product. At the end of the year, we had multiple business reports that continued to build on each other over the course of the year, as well as many other reports such as SWOT analysis, external forces conditions, and market fit plan.
ContributorsHammes, Christopher James (Author) / Trujillo, Rhett (Thesis director) / Montoya, Tara (Committee member) / Department of Management and Entrepreneurship (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The City of Phoenix has historically been developed in an unsustainable way based on the way that autocentric cities have come to mature. By learning from a few European cities, Phoenix can focus on improving in a few key areas that will make the valley more walkable, enjoyable, and beautiful. This process of learning from other European cities can help developers, designers, and others in the development community to improve all of the valley’s different communities with a consistent plan of increasing urban density and ending outward sprawl while redefining the connective tissue that makes up Phoenix. This paper is meant to provide a set of example cities in order to pull specific recommendations and create a system of guidelines for all autocentric cities.
ContributorsCava, Daniel (Author) / Coseo, Paul (Thesis director) / Azevedo, Justin (Committee member) / The Design School (Contributor) / Department of Management and Entrepreneurship (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05