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Vaccines are modern medicine’s best way of combating the majority of viral and bacterial illnesses and contagions to date. Thanks to the introduction of vaccines since the first uses of them in 1796 (Jenner’s smallpox vaccine), they have drastically reduced figures of disease worldwide, turning once lethal and life changing

Vaccines are modern medicine’s best way of combating the majority of viral and bacterial illnesses and contagions to date. Thanks to the introduction of vaccines since the first uses of them in 1796 (Jenner’s smallpox vaccine), they have drastically reduced figures of disease worldwide, turning once lethal and life changing conditions into minor annoyances; Some of these afflictions have even become nonexistent or even extinct in certain parts of the world outside of a controlled laboratory setting. With many advancements and overwhelming evidence proving their efficiency, it is clear that vaccines have become nothing less than a necessity for everyday healthcare in today’s world. <br/>The greatest contributor to the creation and evolution of vaccines throughout the years is by far the progress and work done in the field of molecular and cellular biology. These advancements have become the bedrock of modern vaccination, as shown by the differing types of vaccines and their methodology. The most common varieties of vaccines are include ‘dead’ or inactivated vaccines, one such example being the pertussis strain of vaccines, which have either dead or torn apart cells for the body to easily fight off, allowing the immune system to easily and quickly counter the illness; Additionally, there are also live attenuated vaccines (LAVs) in which a weaker version of the pathogen is introduced to the body to stimulate an immune response, or a recombinant mRNA vaccine where mRNA containing the coding for an antigen is presented for immunological response, the latter being what the current COVID-19 vaccines are based on. This is in part aided by the presence of immunological adjuvants, antigens and substances that the immune system can recognize, target, and remember for future infections. However, for more serious illnesses the body needs a bigger threat to analyze, which leads to live vaccines- instead of dead or individual components of a potential pathogen, a weakened version is created in the lab to allow the body to combat it. The idea behind this is the same, but to a larger degree so a more serious illness such as measles, mumps, and rubella (MMR) do not infect us.<br/>However, for the past couple of decades the public’s views on vaccination has greatly varied, with the rise of fear and disinformation leading those to believe that modern medicine is a threat in disguise. The largest of these arguments began in the late 90’s, when Dr. Andrew Wakefield published an article under the Lancet with false information connecting vaccinations to the occurrence of autism in younger children- a theory which has since then been proven incorrect numerous times over. Unfortunately, the rise of hysteria and paranoia in people, along with more misinformation from misleading sources, have strengthened the anti-vaccination cause and has made it into a serious threat to the health of those world-wide.<br/>The aim of this thesis is to provide an accurate and thorough analysis on these three themes- the history of vaccines, their inner workings and machinations in providing immune defenses for the body, and the current controversy of the anti-vaccination movement. Additionally, there will be two other sections going in-depth on two specific areas where vaccination is highly important; The spread and fear of the Human Immunodeficiency Virus (HIV) has been around for nearly four decades, so it begs the question: what makes this such a difficult virus, and how can a vaccine be created to combat it? Additionally, in the last year the world has encountered a new virus that has evolved into a global pandemic, SARS-COV 2. This new strain of coronavirus has shown itself to be highly contagious and rapidly mutating, and the race to quickly develop a vaccine to counteract it has been on-going since its first major infections in Wuhan, China. Overall, this thesis will go in-depth in providing the most accurate, up-to-date, and critical information regarding vaccinations today.

ContributorsKolb Celaya, Connor Emilio (Author) / Topal, Emel (Thesis director) / Huffman, Holly (Committee member) / College of Integrative Sciences and Arts (Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
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White-nose syndrome (WNS) is a fungal infection devastating bat populations throughout eastern North America. WNS is caused by a fungus, Pseudogymnoascus destructans (Pd), that invades the skin of hibernating bats. While there are a number of treatments being researched, there is currently no effective treatment for WNS that is deployed

White-nose syndrome (WNS) is a fungal infection devastating bat populations throughout eastern North America. WNS is caused by a fungus, Pseudogymnoascus destructans (Pd), that invades the skin of hibernating bats. While there are a number of treatments being researched, there is currently no effective treatment for WNS that is deployed in the field, except a few being tested on a limited scale. Bats have lowered immune function and response during hibernation, which may increase susceptibility to infection during the winter months. Antimicrobial peptides (AMPs) are a crucial component of the innate immune system and serve as barriers against infection. AMPs are constitutively expressed on skin and facilitate wound healing, stimulate other immune responses, and may also stay active on bat skin during hibernation. AMPs are expressed by all tissues, have direct killing abilities against microbes, and are a potential treatment for bats infected with Pd. In this investigation, the fungicidal activity of several readily available commercial AMPs were compared, and killing assay protocols previously investigated by Frasier and Lake were replicated to establish a control trial for use in future killing assays. Another aim of this investigation was to synthesize a bat-derived AMP for use in the killing assay. Sequences of bat-derived AMPs have been identified in bat skin samples obtained from a large geographic sampling of susceptible and resistant species. Contact was made with GenScript Inc., the company from which commercially available AMPs were purchased, to determine the characteristics of peptide sequences needed to synthesize an AMP for lab use. Based on recommendations from GenScript Inc., peptide sequences need to have a hydrophobicity of less than 50% and a sequence length of less than 50 amino acids. These criteria serve as a potential barrier because none of the known bat-derived sequences analyzed satisfy both of these requirements. The final aim of this study was to generate a conceptual model of the immune response molecules activated when bats are exposed to a fungal pathogen such as Pd. Overall, this work investigated sources of variability between trials of the killing assay, analyzed known bat-derived peptide sequences, and generated a conceptual model that will serve as a guideline for identification of immune response molecules on the skin of bats in future proteomics work.
ContributorsBarton, Madisen L (Author) / Moore, Marianne (Thesis director) / Penton, Christopher (Committee member) / College of Integrative Sciences and Arts (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
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Phytohemagglutinin (PHA) is a plant lectin commonly used to stimulate and test responses of the immune system and is known to induce T cell proliferation, agglutinate human leukocytes, and yield adjustments in lymphocyte populations. What is not well know is how responses to PHA correlate with a host's ability to

Phytohemagglutinin (PHA) is a plant lectin commonly used to stimulate and test responses of the immune system and is known to induce T cell proliferation, agglutinate human leukocytes, and yield adjustments in lymphocyte populations. What is not well know is how responses to PHA correlate with a host's ability to resist or recover from pathogen invasion. This study uses information from previously published studies to determine whether or not PHA can be a good indicator of disease severity or disease resistance in a host. With PHA having the abilities that it does, immune responses to PHA may correlate with responses important for pathogen resistance and clearance. Such a relationship could only be uncovered if in vivo or in vitro responses to PHA are measured and, independent from the PHA challenge, symptoms and/or mortality rates of hosts are documented after pathogen exposure. An in vitro response can be detected by measuring cellular proliferation in response to PHA followed by separate cell cultures exposed to a pathogen. While an in vivo response can be detected by measuring variation in swelling in response to an injection of PHA. In reviewing a broad range of articles that meet my criteria, the majority of articles failed to show a strong relationship between PHA and disease severity or disease resistance. Therefore, immunologists must consider the usefulness of the PHA tests as a measure of immunocompetence, which is a host's ability to predict response to a pathogen. According to the literature, using PHA does not predict responses to pathogen invasion. However, it is possible that with carefully designed experiments, it could be determined that PHA does provide an indication of pathogen resistance in certain host species exposed to specific pathogen.
ContributorsMackey, Tracy Michelle (Author) / Moore, Marianne (Thesis director) / Penton, Ryan (Committee member) / College of Integrative Sciences and Arts (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
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Computational models have long been used to describe and predict the outcome of complex immunological processes. The dissertation work described here centers on the construction of multiscale computational immunology models that derives biological insights at the population, systems, and atomistic levels. First, SARS-CoV-2 mortality is investigated through the lens of

Computational models have long been used to describe and predict the outcome of complex immunological processes. The dissertation work described here centers on the construction of multiscale computational immunology models that derives biological insights at the population, systems, and atomistic levels. First, SARS-CoV-2 mortality is investigated through the lens of the predicted robustness of CD8+ T cell responses in 23 different populations. The robustness of CD8+ T cell responses in a given population was modeled by predicting the efficiency of endemic MHC-I protein variants to present peptides derived from SARS-CoV-2 proteins to circulating T cells. To accomplish this task, an algorithm, called EnsembleMHC, was developed to predict viral peptides with a high probability of being recognized by CD T cells. It was discovered that there was significant variation in the efficiency of different MHC-I protein variants to present SARS-CoV-2 derived peptides, and countries enriched with variants with high presentation efficiency had significantly lower mortality rates. Second, a biophysics-based MHC-I peptide prediction algorithm was developed. The MHC-I protein is the most polymorphic protein in the human genome with polymorphisms in the peptide binding causing striking changes in the amino acid compositions, or binding motifs, of peptide species capable of stable binding. A deep learning model, coined HLA-Inception, was trained to predict peptide binding using only biophysical properties, namely electrostatic potential. HLA-Inception was shown to be extremely accurate and efficient at predicting peptide binding motifs and was used to determine the peptide binding motifs of 5,821 MHC-I protein variants. Finally, the impact of stalk glycosylations on NL63 protein dynamics was investigated. Previous data has shown that coronavirus crown glycans play an important role in immune evasion and receptor binding, however, little is known about the role of the stalk glycans. Through the integration of computational biology, experimental data, and physics-based simulations, the stalk glycans were shown to heavily influence the bending angle of spike protein, with a particular emphasis on the glycan at position 1242. Further investigation revealed that removal of the N1242 glycan significantly reduced infectivity, highlighting a new potential therapeutic target. Overall, these investigations and associated innovations in integrative modeling.
ContributorsWilson, Eric Andrew (Author) / Anderson, Karen (Thesis advisor) / Singharoy, Abhishek (Thesis advisor) / Woodbury, Neal (Committee member) / Sulc, Petr (Committee member) / Arizona State University (Publisher)
Created2022
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Elucidation of Antigen-Antibody (Ag-Ab) interactions is critical to the understanding of humoral immune responses to pathogenic infection. B cells are crucial components of the immune system that generate highly specific antibodies, such as IgG, towards epitopes on antigens. Serum IgG molecules carry specific molecular recognition information concerning the antigens that

Elucidation of Antigen-Antibody (Ag-Ab) interactions is critical to the understanding of humoral immune responses to pathogenic infection. B cells are crucial components of the immune system that generate highly specific antibodies, such as IgG, towards epitopes on antigens. Serum IgG molecules carry specific molecular recognition information concerning the antigens that initiated their production. If one could read it, this information can be used to predict B cell epitopes on target antigens in order to design effective epitope driven vaccines, therapies and serological assays. Immunosignature technology captures the specific information content of serum IgG from infected and uninfected individuals on high density microarrays containing ~105 nearly random peptide sequences. Although the sequences of the peptides are chosen to evenly cover amino acid sequence space, the pattern of serum IgG binding to the array contains a consistent signature associated with each specific disease (e.g., Valley fever, influenza) among many individuals. Here, the disease specific but agnostic behavior of the technology has been explored by profiling molecular recognition information for five pathogens causing life threatening infectious diseases (e.g. DENV, WNV, HCV, HBV, and T.cruzi). This was done by models developed using a machine learning algorithm to model the sequence dependence of the humoral immune responses as measured by the peptide arrays. It was shown that the disease specific binding information could be accurately related to the peptide sequences used on the array by the machine learning (ML) models. Importantly, it was demonstrated that the ML models could identify or predict known linear epitopes on antigens of the four viruses. Moreover, the models identified potential novel linear epitopes on antigens of the four viruses (each has 4-10 proteins in the proteome) and of T.cruzi (a eukaryotic parasite which has over 12,000 proteins in its proteome). Finally, the predicted epitopes were tested in serum IgG binding assays such as ELISAs. Unfortunately, the assay results were inconsistent due to problems with peptide/surface interactions. In a separate study for the development of antibody recruiting molecules (ARMs) to combat microbial infections, 10 peptides from the high density peptide arrays were tested in IgG binding assays using sera of healthy individuals to find a set of antibody binding termini (ABT, a ligand that binds to a variable region of the IgG). It was concluded that one peptide (peptide 7) may be used as a potential ABT. Overall, these findings demonstrate the applications of the immunosignature technology ranging from developing tools to predict linear epitopes on pathogens of small to large proteomes to the identification of an ABT for ARMs.
ContributorsCHOWDHURY, ROBAYET (Author) / Woodbury, Neal (Thesis advisor) / LaBaer, Joshua (Committee member) / Sulc, Petr (Committee member) / Arizona State University (Publisher)
Created2020