UMD Theses and Dissertations
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Item Psychological inoculation against vaccine misinformation: why and how it works(2023) Wang, Yuan; Nan, Xiaoli; Communication; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Vaccine misinformation has posed a significant threat to public health. Drawing upon inoculation theory, this dissertation investigates whether exposure to an inoculation message – a message that forewarns and refutes potential persuasive attacks – can confer resistance to misinformation about COVID-19 vaccines. Based on two online experiments, this research seeks to answer four overarching questions: Can exposure to an inoculation message reduce susceptibility to misinformation? Through which mechanisms does inoculation message confer resistance to misinformation? Does the effect of inoculation messages vary among initially informed, uninformed, and misinformed individuals? How do partisan source cues (in-group vs. out-group) impact the effectiveness of inoculation messages among politically affiliated individuals? Study 1 investigated the effectiveness, mechanisms, and recipient factors related to inoculation messages. A two-condition (inoculation vs. control) between-subject experiment was conducted (N = 659). Results indicated that exposure to an inoculation message effectively reduced individuals' susceptibility to misinformation. Inoculation message not only counteracted beliefs in misinformation but also protected positive attitudes and intentions toward COVID-19 vaccination. Moreover, perceived ease of counterarguing and anger were identified as significant mediators underlying the persuasive effects of the inoculation message, while counterarguing was not a significant mediator. Furthermore, the effectiveness of inoculation message remained consistent among initially informed, uninformed, or misinformed groups, suggesting that inoculation message offers both prophylactic and therapeutic effects. Study 2 examined how partisan source cues impacted inoculation message effectiveness. A 2 (in-group vs. out-group inoculation) X 2 (in-group vs. out-group misinformation) between-subject online experiment was conducted among politically affiliated individuals (N = 448). Results showed no main or interaction effects of in-group (vs. out-group) inoculation and in-group (vs. out-group) misinformation on persuasive outcomes, suggesting that the efficacy of inoculation messages in conferring resistance to misinformation did not differ based on whether the inoculation or misinformation messages came from an in-group or out-group source. Additionally, party identification strength moderated the impact of in-group (vs. out-group) inoculation on beliefs in COVID-19 vaccine misinformation and COVID-19 vaccination attitudes. Surprisingly, the advantage of in-group inoculation over out-group inoculation was stronger among individuals with lower levels of party identification. Moreover, out-group inoculation appeared to be more persuasive than in-group inoculation among individuals with extremely strong political identification. This dissertation offers several theoretical and practical implications for health communication research and practice. First, this research contributes to inoculation theory by examining two alternative mechanisms – perceived ease of counterarguing and anger – underlying inoculation message effects. The findings underscore the importance of considering cognitive, meta-cognitive, and affective routes that underlie resistance to persuasion. Additionally, this research expands the scope of inoculation theory by demonstrating its effectiveness among initially informed, uninformed, and misinformed individuals. These results suggest that inoculation messages can be useful beyond the traditional scope of cultural truisms, offering both prophylactic and therapeutic effects. Furthermore, the study challenges the conventional assumption that messages from in-group sources are more persuasive than those from out-group sources, indicating that political groups should work together to address vaccine hesitancy. Overall, this dissertation supports the use of inoculation messages as an effective tool in counteracting misinformation and promoting vaccination acceptance.Item LEVERAGING SELF-ASSEMBLY AND BIOPHYSICAL DESIGN TO BUILD NEXT-GENERATION IMMUNOTHERAPIES(2022) Froimchuk, Yevgeniy; Jewell, Christopher M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The immune system has evolved mechanisms to respond not only to specific molecular signals, but also to biophysical cues. Interestingly, research at the interface of biomaterials and immunology has also revealed that the biophysical properties and form of vaccines and immunotherapies impact immunological outcomes. For example, the intermolecular distance between antigen molecules on the surface of nanoparticles can impact formation of T cell receptor clusters that are critical during T cell activation. Despite the importance of biophysical cues in tuning the immune response, the connections between these parameters and immunological outcomes are poorly understood in the context of immunotherapy. Immunotherapies harness an individual’s immune system to battle diseases such as autoimmunity. During autoimmune disease, the immune system malfunctions and mistakenly attacks self-tissue. Immunotherapies can help tailor and guide more effective responses in these settings, as evidenced by recent advances with monoclonal antibodies and adoptive cell therapies. However, despite the transformative gains of immunotherapies for patients, many therapies are not curative, work only for a small subset of patients, and lack specificity in distinguishing between healthy and diseased cells, which can cause severe side effects. To overcome these challenges, experimental strategies are attempting to co-deliver self-antigens and modulatory cues to reprogram dysfunctional responses against self-antigens without hindering normal immune function. These strategies have shown exciting potential in pre-clinical models of autoimmune disease but are unproven in clinical research. Understanding how biophysical features are linked to immunological mechanisms in these settings would add a critical dimension to designing translatable, antigen-specific immunotherapies. Self-assembling materials are a class of biomaterials that spontaneously assemble in aqueous solution. Self-assembling modalities are useful technologies to study the links between biophysical parameters and immune outcomes because they offer precise control and uniformity of the biophysical properties of assembled moieties. Our lab leveraged the benefits of self-assembly to pioneer development of “carrier-free” immunotherapies composed entirely of immune signals. The therapies are composed of self-antigens modified with cationic amino acid residues and anionic, nucleic acid based modulatory cues. These signals are self-assembled into nanostructured complexes via electrostatic interactions. The research in this dissertation utilizes this platform as a tool to understand how tuning the biophysical properties of self-antigens impacts molecular interactions during self-assembly and in turn, how changes in biophysical features are linked to immunological outcomes. Surface plasmon resonance studies revealed that the binding affinity between signals can be tuned by altering overall cationic charge and charge density of self-antigen, and by anchoring the self-antigen with arginine or lysine residues. For example, the binding affinity between signals can be increased by increasing the total cationic charge on the self-antigen, and by anchoring the self-antigen with arginine residues rather than lysine residues. Computational modeling approaches generated insights into how molecular interactions between signals, such as hydrogen bonding, salt-bridges, and hydrophobic interactions, change with different design parameters. In vitro assays revealed that a lower binding affinity between self-assembled signals was associated with greater reduction of inflammatory gene expression in dendritic cells and more differentiation of self-reactive T cells towards regulatory phenotypes that are protective during autoimmunity. Taken all together, these insights help intuit how to use biophysical design to improve modularity of the self-assembly platform to incorporate a range of antigens for distinct disease targets. This granular understanding of nanomaterial-immune interactions contributes to more rational immunotherapy design.Item CHEMOENZYMATIC MODULATION OF GLYCOPEPTIDE ANTIGENS AS TARGETS FOR HIV VACCINE DISCOVERY AND LIVER CANCER DIAGNOSIS(2020) Zhang, Roushu; Wang, Lai-Xi; Biochemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Glycosylation is a critical post-translational modification of proteins. Viral pathogens use the host glycosylation machinery to facilitate their entry and hide them from the host immune recognition. Moreover, changing the glycosylation pattern is often related to the development of diseases, such as the emergence of carcinomas. Therefore, carbohydrates are attractive targets for various infectious diseases and pathogenic disorders. Nonetheless, as the synthesis of glycans is not template-driven, glycoforms obtained from natural resources are heterogeneous. We address this issue by employing glycosidase inhibitors to modulate protein glycosylation during expression, and also by chemoenzymatic glycan remodeling of glycopeptide antigens. Three projects related to this topic are described herein.In the first project, a series of glycan-defined HIV-gp120-derived glycoprotein immunogens were expressed and engineered. We successfully demonstrated the glycan-dependency of a variety of HIV-targeting broadly neutralizing antibodies (bnAbs). Our immunogens bearing the high-mannose glycosylation have adequate antigenicity towards the bnAbs evaluated, rendering these immunogens promising vaccine candidates for HIV/AIDS. The second project focused on designing novel glycopeptide immunogens for raising glycan-specific antibodies to detect the early stage of liver cancer. Here we chose the fucosylated alpha-fetoprotein as our target since it is related to the development of liver cancer. There is no available antibody specifically recognizing this glycoform and therefore it is still challenging to utilize this parameter to evaluate the condition of patients. We chemoenzymatically synthesized alpha-fetoprotein-derived glycopeptides with core-fucosylation and subjected these immunogens to animal studies. The antisera displayed glycan-dependent IgG responses, laying a foundation to develop monoclonal antibodies that target the fucosylated alpha-fetoprotein. The discovery of such antibodies will be valuable to sensitively diagnose liver cancer in clinics. Lastly, developing enzyme tools is equally important to harness the field. In the final project of my dissertation, we revisited the substrate preference of the human α(1-6) fucosyltransferase. The enzyme exhibited a relaxed substrate preference when a proper glycoprotein, glycopeptide, or an Fmoc modification is attached to the acceptor substrates. This discovery provides new insights into studying glycosyltransferases and offers new approaches to chemoenzymatically synthesizing core-fucosylated glycoproteins and glycopeptides. Together, the studies present new avenues for studying glycan-related biological processes and diseases.Item Deconstructing The Polyclonal Antibody Response To Dengue Virus(2015) VanBlargan, Laura Anne; Pierson, Theodore C; Simon, Anne E; Molecular and Cell Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Dengue viruses are mosquito-borne flaviviruses that circulate in nature as four related serotypes (DENV1-4). These emerging pathogens are responsible for an estimated 390 million human infections each year. The outcome of human DENV infection ranges from clinically inapparent disease (~75% of infections), to a self-limiting febrile illness, to severe disease characterized by hemorrhage and shock. Severe clinical manifestations of disease are predominantly associated with secondary infections by a heterotypic DENV serotype. The increased risk of severe disease in DENV-sensitized populations significantly complicates vaccine development, as a vaccine should confer protection against all four DENV serotypes. As the development of a neutralizing antibody response is a correlate of protection for successful vaccines for several other flaviviruses, eliciting a protective tetravalent neutralizing antibody response is a major goal of ongoing DENV vaccine development efforts. Understanding the neutralizing antibody response to infection and vaccination is an important step toward the development and evaluation of safe DENV vaccines. While considerable insights have been gained from studies of monoclonal antibodies, the individual contributions and dynamics of the repertoire of circulating antibody specificities elicited by infection and vaccination are poorly understood on a functional and molecular level. We studied polyclonal antibody responses elicited by monovalent DENV1 vaccination and sought to identify epitopes recognized by serotype-specific neutralizing antibodies. DENV1 structural gene variants were produced and screened for reduced sensitivity to neutralization by DENV1 sera but unaltered sensitivity to control antibodies. We identified amino acid residues that contribute significantly to type-specific recognition by polyclonal DENV1 immune sera. These findings provide an important step towards deconvoluting the functional complexity of DENV serology following vaccination.Item THE CONCORDANCE OF INFLUENZA VACCINATION BEHAVIORS AMONG ADULTS AND CHILDREN RESIDING WITHIN THE SAME HOUSEHOLD IN THE DISTRICT OF COLUMBIA, MARYLAND, AND VIRGINIA(2014) Motley, Danielle Olon; Butler, III, James; Public and Community Health; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Background: The distinctive barking sound of whooping cough and rubella's birth defects highlight vaccinations' importance as a public health initiative and medical advancement of the twentieth century. However, little research examines concordance of influenza vaccination uptake between same-household adults and children. Methods: A secondary data analysis of CDC's 2009 National H1N1 Flu Survey (NHFS) examined concordance between adults' influenza vaccination behaviors and responses to NHFS questions representing HBM constructs with the influenza vaccination of same-household children from the District of Columbia, Maryland, and Virginia (DMV). Results: Concordance existed between influenza vaccination statuses of adults and same-household children. HBM constructs of perceived susceptibility, severity, and the cue to action of physician vaccine recommendation were associated with more vaccinated children. Conclusions: This research highlights adults' influenza vaccination status impact on same-household DMV children. Future research is needed to examine parental influenza vaccination effects on influenza vaccination status of their biological children.Item Reverse Genetics of Influenza B and the Development of a Novel LAIV Vaccine(2014) Finch, Courtney LaPaglia; Perez, Daniel R; Molecular and Cell Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Due to the disease burden of influenza virus types A and B, vaccines, which are manufactured as formalin-inactivated killed virus (KV) and live-attenuated virus (LAIV), are produced to provide coverage against currently circulating influenza A (IAV) and B (IBV) viruses. Although the licensed LAIV vaccine provides enhanced coverage over the KV vaccine, it is only licensed for immunocompetent individuals ages 2-49 years without pre-existing conditions, so individuals who are most at risk cannot receive it. Previously, our lab showed that incorporation of an 8 amino acid HA tag in frame at the C-terminus of the PB1 open-reading frame (ORF) in addition to the mutations found in the PB2 and PB1 segments of the licensed LAIV vaccine yielded a stable, efficacious alternative LAIV vaccine for IAV; however, to develop a complete vaccine, a corresponding IBV candidate is required. Towards this goal, a contemporary IBV strain, B/Brisbane/60/2008, was cloned and recovered by reverse genetics (RG-B/Bris). Subsequently, it was demonstrated that the parental and RG-B/Bris show similar growth kinetics in vitro. An initial vaccine attempt, which combined PB2 cap-binding mutants with the HA tag in PB1, was made but led to the realization of the PB2 cap-binding mutations, PB2 W359F and F406Y, as virulence factors. In a subsequent vaccine attempt, mutations analogous to those found only in segment 2 of the A/Ann Arbor/6/60 cold-adapted LAIV backbone were introduced into the homologous segment of RG-B/Bris. The following mutations were introduced into the PB1 gene segment of RG-B/Bris, either in the presence or absence of a C-terminal HA tag: K391E, E580G, and S660A. Two viruses were rescued, referred to as RG-B/Bris ts and RG-B/Bris att, both containing the set of three amino acid mutations but differing in the absence or presence of the HA tag, respectively. Both viruses showed ideal attenuation, safety, and immunogenicity in DBA/2 mice and conferred protection against lethal IBV challenge. More importantly, RG-B/Bris att, but not RG-B/Bris ts, showed ideal stability with no reverting mutations over 8 passages in eggs. Taken together, a stable, immunogenic, and live attenuated virus alternative to the current live influenza B virus vaccine was produced.Item MOLECULAR PATHOGENESIS OF INFLUENZA IN SWINE AND ENGINEERING OF NOVEL RECOMBINANT INFLUENZA VIRUSES(2011) Pena, Lindomar Jose; Perez, Daniel R; Veterinary Medical Science; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Influenza A viruses (IAVs) belong to the family Orthomyxoviridae and represent major pathogens of both humans and animals. Swine influenza virus is an important pathogen that affects not only the swine industry, but also represents a constant threat to the turkey industry and is of particular concern to public health. In North America, H3N2 triple reassortant (TR) IAVs first emerged in 1998 and have since become endemic in swine populations. In the first part of this dissertation, we focused on the role of surface glycoproteins and PB1-F2 to unravel their roles in the virulence of TR IAVs in this important natural host. We found that surface glycoproteins are necessary and sufficient for the lung pathology, whereas the internal genes play a major role in the febrile response induced by TR H3N2 IAVs in swine. With respect to PB1-F2, we found that PB1-F2 exerts pleiotropic effects in the swine host, which are expressed in a strain-dependent manner. Pathogenicity studies in swine revealed that the presence of PB1-F2 leads the following effects in context of three TR strains tested: no effect in the context of sw/99 strain; increases the virulence of pH1N1; and decreases the virulence of ty/04. Next, we developed temperature-sensitive live attenuated influenza vaccines for use in swine and shown that these vaccines are safe and efficacious against aggressive intratracheal challenge with pH1N1. Lastly, we rearranged the genome of an avian H9N2 influenza virus to generate replication competent influenza virus vectors that provide a robust system for expression and delivery of foreign genes. As a proof-of-principle, we expressed the hemagglutinin from a prototypical highly pathogenic avian influenza virus (HPAIV) H5N1 and shown that this vectored H5 vaccine retained its safety properties in avian and mammalian species, and induced excellent protection against aggressive HPAIV H5N1 challenges in both mice and ferrets. Taken together, these studies have advanced our understanding of molecular basis of pathogenesis of influenza in the swine host and have contributed to the development of improved vaccines and influenza-based vectors with potential applications in both human and veterinary medicine.Item FACTORS ASSOCIATED WITH COMPLETION OF THE HUMAN PAPILLOMAVIRUS VACCINE SERIES AMONG HISPANIC AND NON-HISPANIC WHITE ADOLESCENT GIRLS IN THE UNITED STATES(2011) Demarco, Maria Teresa; Carter-Pokras, Olivia; Epidemiology and Biostatistics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Despite recommendations of three Human Papillomavirus (HPV) vaccine shots for all adolescent girls, only 29.1% of non-Hispanic Whites and 23.4% of Hispanics achieve completion. This study describes factors associated with completion of the HPV vaccine series among Hispanic and non-Hispanic White 13-17 year old girls who initiated the series. A secondary data analysis was performed of the cross-sectional 2009 National Immunization Survey-Teen survey. Despite similar initiation rates (one in five), Hispanic girls who had initiated the series (59.9%) were less likely to complete the series than non-Hispanic Whites (76.4%). After accounting for poverty status and home ownership, Hispanics were less likely to complete the HPV vaccine series. Factors associated with HPV vaccine series initiation were age at interview and age at HPV vaccine series initiation for Hispanics; and continuous health insurance since age of 11, mother's marital status, and number of children in the household for non-Hispanic Whites.Item The development and characterization of transgenic Leishmania major expressing murine CD40L(2007-05-18) Field, Ann Elizabeth; Mosser, David M; Cell Biology & Molecular Genetics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Leishmanization is the inoculation of live Leishmania into the host to vaccinate against subsequent infections. This approach has been largely discontinued due to safety concerns. We have previously shown that combining CD40L with Leishmania antigen preferentially induces a type 1 immune response and provides some protection to vaccinated mice. In the present study, we developed transgenic L. major which express and secrete the extracellular portion of CD40L (L. major CD40LE). We hypothesized that these organisms would be less virulent but more immunogenic than wild-type organisms, and therefore be more effective at leishmanization. Transgenic parasites expressing CD40L mRNA and protein were developed. These parasites had similar growth characteristics to wild-type organisms. Susceptible BALB/c mice infected with these parasites developed significantly smaller lesions containing fewer parasites than animals infected with wild-type organisms. Infection of C57BL/6 CD40L-/- mice with transgenic L. major resulted in significantly smaller lesions than infection with wild-type L. major, indicating in vivo biological activity of the transgenic protein. Infection of resistant C57BL/6 mice with low doses of transgenic parasites induced a significant amount of protection against subsequent high dose infection with wild-type organisms. These results demonstrate that transgenic organisms expressing CD40L are less virulent than wild-type organisms while retaining full immunogenicity. The implications of this study are that parasites expressing immune-modulatory molecules may be improved alternatives to traditional leishmanization.