Dissertations / Theses on the topic 'Vaccine engineering'
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Brune, Karl Dietrich. "Engineering modular platforms for rapid vaccine development." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:41d57165-6e7c-4ca7-8025-b5ec31794c8c.
Full textHanes, Justin Scott. "Polymer microspheres for vaccine delivery." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/10153.
Full textWebster, Gina. "Engineering immunoglobulin genes for novel Tuberculosis vaccine production in plants." Thesis, St George's, University of London, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.753991.
Full textKaczorowski, Kevin J. "Data-driven strategies for vaccine design." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/117327.
Full textCataloged from PDF version of thesis.
Includes bibliographical references.
Vaccination is one of the greatest achievements in immunology and in general medicine, and has virtually eradicated many infectious diseases that plagued humans in the past. Vaccination involves injecting an individual with some version of the pathogen in order to allow the individual to develop a memory immune response that will protect them from future challenge with the same pathogen. Until recently, vaccine development has largely followed empirical paradigms that have proven successful against many diseases. However, many pathogens have now evolved that defy success using the traditional approaches. Rational design of vaccines against such pathogens will likely require interdisciplinary approaches spanning engineering, immunology, and the physical sciences. In this thesis, we combine theoretical approaches with protein sequence and clinical data to address two contemporary problems in vaccinology: 1. Developing an antibody vaccine against HIV, an example of a highly mutable pathogen; and 2. Understanding how the many immune components work collectively to effect a systemic immune response, such as to vaccines. In HIV-infected individuals, antibodies produced by the immune system bind to specific parts of an HIV protein called Envelope (Env). However, the virus evades the immune response due to its high mutability, thus making effective vaccine design a huge challenge. To predict the mutational vulnerabilities of the virus, we developed a model (a fitness landscape) to translate sequence data into knowledge of viral fitness, a measure of the ability of the virus to replicate and thrive. The landscape accounts explicitly for coupling interactions between mutations at different positions within the protein, which often dictate how the virus evades the immune response. We developed new computational approaches that enabled us to tackle the large size and mutational variability of Env, since previous approaches have been unsuccessful in this case. A small fraction of HIV-infected individuals produce a class of antibodies called broadly neutralizing antibodies (bnAbs), which neutralize a diverse number of HIV strains and can thus tolerate many mutations in Env. To investigate the mechanisms underlying breadth of these bnAbs, we combined our landscape with 3D protein structures to gain insight into the spatial distribution of binding interactions between bnAbs and Env. Based on this, we designed an optimal set of immunogens (i.e. Env sequences), with mutations at key residues, that are potentially likely to lead to the elicitation of bnAbs via vaccination. We hope that these antigens will soon be tested in animal models. Even when the right immunogens are included in a vaccine, a potent immune response is not always induced. For example, some individuals do not respond to protective influenza vaccines as desired. The human immune system consists of many different immune cells that coordinate their actions to fight infections and respond to vaccines. The balance between these cell populations is determined by direct interactions and soluble factors such as cytokines, which serve as messengers between cells. A mechanistic understanding of how the various immune components cooperate to bring about the immune response can guide strategies to improve vaccine efficacy. To investigate whether differences in immune response could be explained by variation in immune cell compositions across individuals, we analyzed experimental measurements of various immune cell population frequencies in a cohort of healthy humans. We demonstrated that human immune variation in these parameters is continuous rather than discrete. Furthermore, we showed that key combinations of these immune parameters can be used to predict immune response to diverse stimulations, namely cytokine stimulation and vaccination. Thus, we defined the concept of an individual's "immunotype" as their location within the space of these key combinations of parameters. This result highlights a previously unappreciated connection between immune cell composition and systemic immune responses, and can guide future development of therapies that aim to collectively, rather than independently, manipulate immune cell frequencies.
by Kevin J. Kaczorowski.
Ph. D.
DeMuth, Peter C. (Peter Charles). "Engineered microneedles for transcutaneous vaccine delivery." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/81667.
Full textCataloged from PDF version of thesis.
Includes bibliographical references (p. 151-165).
Immunization is a powerful approach for the prevention and control of infectious disease, however despite the successes of modem vaccine development, there remain several notable obstacles for the advancement of vaccine-mediated improvements in global healthcare. Many of the current limitations in vaccine availability and administration are the result of obligate needle-based delivery, which in addition to contributing to reduced speed, ease, and compliance in administration, has been shown to contribute to reduced overall safety due to needle re-use and needle-based injuries. Needle-based vaccine delivery to immunologically passive tissues such as muscle may limit efficacy, thus motivating the targeting of more inherently potent immune-competent sites. These inherent limitations of needle-based vaccination on global health have led to a strong impetus to develop needle-free vaccination strategies which have the potential to improve vaccine efficacy and availability, enhance the ease, speed, and safety of vaccine administration, and reduce vaccination associated costs world-wide. Here we present the design and preclinical testing of several parallel materials strategies for the noninvasive delivery of subunit vaccines to the skin. We have utilized laser ablative micro-molding of poly(dimethylsiloxane) to generate bio resorbable poly(lactide-co-glycolide) micro-structured skin patches bearing -100 micron-scale needles arrayed across their surface. Upon topical application, these 'microneedle arrays' are able to safely, and painlessly insert into the immune-competent epidermal skin layers to generate microscopic conduits through which otherwise impermeant vaccines and therapeutics are able to passage into the body. We have leveraged this approach in combination with layer-by-layer (LbL) directed assembly to generate vaccine-loaded conformal coatings on the surface of these microneedle arrays, which are then delivered into the skin through topical patch application. The construction of coatings containing antigen-expressing plasmid DNA (pDNA), together with immune-stimulatory RNA, and degradable cationic polymers provided tunable control over vaccine dosage, rapid and effective vaccine delivery in murine and primate skin models, and potent immunogenicity against a model HIV antigen in mice. In this case, DNA vaccine delivery was able to elicit strong functional CD8' T cell and humoral responses matching or exceeding the potency of in vivo electroporation, currently the most promising approach for clinical DNA delivery in humans. Further efforts have explored the use of LbL for encapsulation and delivery of soluble and particulate protein subunit vaccines, giving enhanced generation of diverse and potent humoral responses in mice. In other work, we have developed an approach enabling rapid delivery of micron-scale degradable polymer matrices or hydrogel depots using dissolvable composite microneedle structures for the delivery of vaccines with programmable kinetics. These efforts have demonstrated the potential of persistent vaccine release on tuning immune potency following non-invasive microneedle delivery, including induction of potent effector and memory CD8* T cell responses and more powerful and diverse antigen-specific humoral responses. Finally, we have developed an approach for simple loading and delivery of clinically advanced recombinant adenoviral vaccine vectors from sugar-glass coatings on bioresorbable microneedles. Formulation in microneedle coatings improved vaccine stability at room temperature and preclinical testing of these vaccine patches in mice and nonhuman primates demonstrated equivalent immunogenicity compared to parenteral injection, eliciting strong systemic and disseminated mucosal CD8' and CD4* T cell responses to a model HIV antigen. These cellular responses were correlated with a similarly potent systemic and mucosal humoral response, together suggesting the utility of this approach for non-invasive adenoviral immunization in a model close to humans. Together these results strongly demonstrate the potential of materials engineering strategies for the effective formulation, delivery, and release of recombinant vaccines by microneedle patches targeting the skin. In addition to the significant practical advantages enabled by microneedle delivery including improved safety, convenience, and storage, we have shown that advanced formulation strategies paired with controlled release are able to initiate humoral and cellular adaptive immunity more potently than possible through parenteral injection. Comprehensive tests in both mice and primates have suggested that these principles may be broadly applied to enhance various recombinant vaccination strategies potentially targeting numerous disease targets. Finally, initial tests performed in nonhuman primates have indicated the promise of engineered microneedle approaches for successful translation to humans. Overall, these findings provide a strong basis for the continued development of similar vaccination strategies for the comprehensive transformation of conventional vaccination enabling significant vaccine-mediated improvements in global health.
by Peter C. DeMuth.
Ph.D.
Wikman, Maria. "Rational and combinatorial protein engineering for vaccine delivery and drug targeting." Doctoral thesis, Stockholm : Department of Biotechnology, Royal Insitute of Technology, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-231.
Full textHowland, Shanshan W. "Yeast-based vaccine approaches to cancer immunotherapy." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/45949.
Full textIncludes bibliographical references.
Saccharomyces cerevisiae stimulates dendritic cells and represents a promising candidate for cancer immunotherapy development. Effective cross-presentation of antigen delivered to dendritic cells is necessary for successful induction of cellular immunity. Using a yeast vaccine model, we investigated the phagosome-to-cytosol pathway of cross-presentation. We demonstrate that the rate of antigen release from phagocytosed yeast directly affects cross-presentation efficiency, with an apparent time limit of about 25 min post-phagocytosis for antigen release to be productive. Antigen expressed on the yeast surface is cross-presented much more efficiently than antigen trapped in the yeast cytosol by the cell wall. The cross-presentation efficiency of yeast surface-displayed antigen can be increased by the insertion of linkers susceptible to cleavage in the early phagosome. Antigens indirectly attached to yeast through antibody fragments are less efficiently cross-presented when the antibody dissociation rate is extremely slow. Next, we present a yeast-based cancer vaccine approach that is independent of yeast's ability to express the chosen antigen, which is instead produced separately and conjugated to the yeast cell wall. The conjugation method is site-specific (based on the SNAP-tag) and designed to facilitate antigen release in the dendritic cell phagosome and subsequent translocation for cross-presentation.
(cont.) Phagosomal antigen release was further expedited through the insertion of the invariant chain ectodomain as a linker, which is rapidly cleaved by Cathepsin S. The dose of delivered antigen was increased in several ways: by using yeast strains with higher surface amine densities, by using yeast cell wall fragments instead of whole cells, and by conjugating multiple layers of antigen. The novel multi-layer conjugation scheme is site-specific and takes advantage of Sfp phosphopantetheinyl transferase, enabling the antigen dose to grow linearly. We show that whole yeast cells coated with one layer of the cancer-testis antigen NY-ESO-1 and yeast hulls bearing three layers were able to cross-prime naive CD8+ T cells in vitro, with the latter resulting in higher frequencies of antigen-specific cells after ten days. This cross-presentation-efficient antigen conjugation scheme is not limited to yeast and can readily be applied towards the development of other particulate vaccines.
by Shanshan W. Howland.
Ph.D.
Chen, Hongming. "Polymerized liposomes as potential oral vaccine delivery vehicles." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/10343.
Full textPanas, Cynthia Dawn Walker. "Design and manufacture of low cost vaccine cooler." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/40937.
Full textIncludes bibliographical references (p. 58).
Vaccines are very sensitive to temperature, needing to be held between 2 and 80°C to maintain potency. In developing countries where electricity and fuel supplies are unreliable, many vaccines are ruined due to thermal exposure. These are also the locations where vaccines are needed the most, yet often many of the vaccines given are ineffective. Long holdover vaccine coolers are designed to maintain a proper internal temperature during long periods of power loss. The most prevalent technology is the ice-lined cooler, but in the field these often have problem with freezing the vaccines. A vaccine cooler was designed that modifies the ice-jacket idea by separating the ice compartment and the vaccine chamber, connecting them through a heat transfer regulating device. The objective of this research is to design and prototype the heat transfer regulating device. After several design iterations a cooling loop filled with R-134a made of 1/8 piping, a 0.055 in ID capillary, and a Clippard normally-closed valve was combined with a modified car thermostat, using peanut oil as its working fluid, to create a thermosyphon type heat transfer device with a safety shutoff to prevent freezing. The prototype was manufactured and tested. It was found that with the proper amount of working fluid, it is possible to run the cooling loop at 4°C and pull heat from the vaccine chamber side to the ice. The peanut oil thermostat was tested and was found to open at a slightly lower temperature than expected, 2.5°C, but still within range. These results indicate that the concept is viable and should be tested in the vaccine cooler.
by Cynthia D. Walker.
S.B.
Kang, Myungsun(Myungsun Sunny). "Optimizing vaccine dosing kinetics for stronger antibody response." Thesis, Massachusetts Institute of Technology, 2018. https://hdl.handle.net/1721.1/124586.
Full textCataloged from PDF version of thesis. "The pagination in this thesis reflects how it was delivered to the Institute Archives and Special Collections. The Table of Contents does not accurately represent the page numbering"--Disclaimer Notice page.
Includes bibliographical references (pages 95-102).
One of the barriers to rational vaccine design against evolving pathogens is our lack of mechanistic understanding of how innate and adaptive immune response systematically emerge and evolve. Immune response is comprised of dynamic events that require many components to cooperate collectively in a manner that spans a range of scales. These characteristics make it hard to predict mechanisms for immune response based solely on experimental observations. This thesis investigates various aspects of affinity maturation that are relevant to vaccination and therapeutic strategies but are not yet fully understood mechanistically, ranging from the evolution of the heterogeneity of the antibody population with respect to affinity to optimal design parameters for temporal dosing of vaccines. Our approach is to apply computational techniques to mathematically model the immune system, and being synergistic with complementary experiments. 1.
As affinity maturation ensues, average affinity of antibodies increase with time while resulting affinity distribution becomes increasingly heterogeneous. To shed light on how the extent of this heterogeneity evolves with time during affinity maturation, we have taken advantage of previously published data of antibodies isolated from individual serum samples. Using the ratio of the strongest to the weakest binding subsets as a metric of heterogeneity (or affinity inequality), we find that after a single injection of small antigen doses, the ratio decreases progressively over time. This is consistent with Darwinian evolution in the strong selection limit. By contrast, neither the average affinity nor the heterogeneity evolves much with time for high doses of antigen, as competition between clones of the same affinity is minimal. 2.
What are the aspects of affinity maturation being altered by various temporal patterns of antigen dosing? Certain extended-duration dosing profiles increase the strength of the humoral response, with exponentially-increasing(EI) dosage providing the greatest enhancement. While this is an exciting result, it is necessary to establish a mechanistic understanding of how immune response be enhanced to further engineer and optimize the temporal patterns. From our computational model, the effect is driven by enhanced capture of antigen in lymph nodes by evolving higher-affinity antibodies early in the GC response. We validate the prediction from independent experimental data, where EI dosage result in promoted capture and retention of the antigen in lymph nodes. To our knowledge, this work is the first to demonstrate a key mechanism for vaccine kinetics in the response of B cells to immunization, and may prove to be an effective method for increasing the efficacy of subunit vaccines. 3.
Are there optimal dosing profiles that maximize total protection? That is, lead to the evolution of the most antibodies of high affinity? In extension of mechanistic studies in 2, we propose a stochastic simulation method that can be used as a tool for optimizing dosage protocols for vaccine delivery. Using this tool, we analyze experimental conditions for EI dosage induce suboptimal immune response and investigate two approaches for the optimization. Specifically, reducing the total dosage optimizes affinity of resulting antibodies, while total protection is optimal neither at constant or EI dosage but that corresponding to a "linear-like" dosing profile. Our approach can be extended to broader applications in vaccine design.
by Myungsun (Sunny) Kang.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Chemical Engineering
Rao, Ankit Rohit. "Engineering an improved dendritic cell vaccine expressing whole antigen following non-viral transfection." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3622/.
Full textHanson, Melissa C. (Melissa Catherine). "Enhancement of HIV vaccine efficacy via lipid nanoparticle-based adjuvants." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/97975.
Full textCataloged from PDF version of thesis. "December 2014."
Includes bibliographical references (pages 93-108).
Adjuvants are immunomodulators and/or formulations/delivery vehicles which enhance immune responses to vaccines. The lack of progress in the development of an HIV humoral vaccine is due, in part, to the absence of available adjuvants which can be sufficiently potent with minimal adverse side effects. The main goal of this thesis was to develop nanoparticles as HIV vaccine adjuvants. Building upon previous work in the Irvine lab, we determined the potency of lipid-coated microparticles was due in part to the in situ generation of antigen-displaying liposomes. Synthetic liposomes were nearly as potent as lipid-coated microparticles, but with a 10-fold greater antigen conjugation efficiency. We subsequently optimized unilamellar liposomes as delivery vehicles for surface-displayed HIV antigens. For vaccines with a recombinant gpl20 monomer (part of the HIV envelope trimer), immunization at 0 and 6 weeks with 65 nm or 150 nm diameter liposomes with 7.5 pmol gpl20 was found to induce strong anti-gp120 titers which competed with the broadly-neutralizing antibody VRC01. The second HIV antigen used was a peptide derived from the membrane proximal external region (MPER) of the gp41 protein. High-titer IgG responses to MPER required the presentation of MPER on liposomes and the inclusion of molecular adjuvants such as monophosphoryl lipid A. Anti-MPER humoral responses were further enhanced optimizing the MPER density to a mean distance of -10-15 nm between peptides on the liposomes surfaces. Lastly, we explored the adjuvant potential of cyclic dinucleotides (CDNs) with MPER liposome vaccines. Encapsulation of CDN in PEGylated liposomes enhanced its accumulation in draining lymph nodes (dLNs) 15-fold compared to unformulated cyclic dinucleotide. Liposomal CDN robustly induced type I interferon in dLNs, and promoted durable antibody titers comparable to a 30-fold larger dose of unformulated CDN without the systemic toxicity of the latter. This work defines several key properties of liposome formulations that promote durable, high-titer antibody responses against HIV antigens and demonstrates the humoral immunity efficacy of nanoparticulate delivery of cyclic dinucleotides, which is an approach broadly applicable to small molecule immunomodulators of interest for vaccines and immunotherapy.
by Melissa C. Hanson.
Ph. D.
Werts, Kendall (Kendall Marie). "Synthesis of biodegradable hydrogel microparticles for vaccine protein delivery." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/44811.
Full textIncludes bibliographical references (p. 21).
Soluble protein antigens used in vaccines have shown lower immune responses when compared with certain particulate forms of these same antigens. For example, it has been shown that micro- and nano-particle mediated delivery of protein antigen can use up to 100 times less protein and still produce an effective immune response [1]. In order to use this phenomenon to make vaccines more efficient, we need a biodegradable delivery particle. This thesis modifies a particle created by Jain et al., which consists of a polymer network surrounding and trapping a protein, by removing the non-degradable crosslinker used in the original particle design and replacing it with a poly (ethylene glycol) acrylate molecule attached to ovalbumin protein. When a dendritic cell degrades the particle, the ovalbumin protein will be degraded, as will the connections between the polymer network that holds the particle together [2]. The particles degraded to 56% of their original size in 3 days, while the non-degradable particle degraded to only 80% of its original size.
by Kendall Werts.
S.B.
Lau, Ting Ting Alice. "Engineering a pro-apoptotic BCG strain to improve efficacy of the current tuberculosis vaccine." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/60692.
Full textMedicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
Graduate
Smith, Mark T. "Engineering Cell-Free Systems for Vaccine Development, Self-Assembling Nanoparticles and Codon Reassignment Applications." BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/4449.
Full textSandford, Erika J. (Erika Jaye). "Experimental technique for optimizing aerosolized vaccine efficacy by Erika J. Sandford." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/59930.
Full textCataloged from PDF version of thesis.
Includes bibliographical references (p. 26).
Vaccination via aerosol has been proven to be as safe, as effective, and more appropriate for transportation when compared with vaccination via injection. These advantages make aerosolized vaccinations a realistic alternative to traditional injection vaccines for the developing world, where cold chain systems are impractical and the use of hypodermic needles can be unsafe. However, more research is needed to determine optimal parameters for vaccine aerosolization. This thesis presents an experimental setup to test Aerovax, a device designed to deliver aerosolized vaccinations in developing regions of the world. The experimental technique is the first effort to optimize vaccine aerosols across multiple variables, including input pressure, nebulizer geometry, and vaccine reconstitution. The setup provides a pressure input, sensors for ambient properties, and a device to measure particle size distribution.
S.B.
Gallovic, Matthew D. "Acid-Sensitive Polymer Microparticles for Subunit Vaccine Delivery." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1468803443.
Full textBershteyn, Anna. "Lipid-coated micro- and nanoparticles as a biomimetic vaccine delivery platform." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/101866.
Full textVita. Cataloged from PDF version of thesis.
Includes bibliographical references (pages 128-146).
Biomaterials provide a unique opportunity to control the display, release, and in vivo trafficking of vaccine components. We have designed and characterized a system for vaccine delivery that uses a "lipid surfactants" approach to combine a degradable polymer core with a two-dimensionally fluid lipid bilayer shell. Using optical and electron microscopy, we characterized the distribution, lamellarity, nanostructure, and mobility of the lipid shell. Single, tightly apposed bilayers could be formed around either microparticles or nanoparticles, mimicking bacteria or viruses in size. Alternative nanostructures could be formed at different lipid concentrations and compositions, such as multilamellar lipid "onions" stacked against a polymer core, or lipid "flowers" with petal-like projections emanating from a polymer core. The lipid nanostructure was characterized during the process of emulsion and solvent evaporation, and during degradation by hydrolysis. Design of this carrier was guided foremost by the goal of properly displaying minimal peptide epitopes from the Membrane-Proximal External Region of HIV gp41 (MPER) and enhancing their immunogenicity. Display within a lipid context was needed to provide the chemical environment appropriate for neutralizing antibodies, such as 4E10, to bind efficiently. Multifunctional vaccines were created through a combination of multivalent display, delivery of helper stimuli, and insertion of lipophilic adjuvant molecules in the lipid shell. We further explored the ability of this system to potentiate humoral immune responses against recombinant protein vaccines, using ovalbumin as a model antigen. In studies of both cellular and humoral immune responses, we found that lipid-coated microparticles co-displaying protein and lipophilic adjuvant molecules could potentiate immune responses in vivo. Notably, we found that the dose-sparing capabilities of the particles reached a potency that is seldom reported: a single injection of 2 ng antigen co-displayed on particles with c-galactosylceramide elicited measurable titers, and a prime-boost regimen of 2.5 ng ovaparticles adjuvanted with monophosphoryl lipid A elicited high titers that were sustained for >150 days. No studies to our knowledge have reported dose sparing to this degree with titers sustained over time. The mechanism of this dose sparing effect is of great interest, and will be a subject of future work.
by Anna Bershteyn.
Ph. D.
Shi, Amy (Amy J. ). "Versatility of M13 bacteriophage in medicine : vaccine storage and cancer diagnostics." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/38583.
Full textIncludes bibliographical references (p. 88-94).
Two novel ways of engineering the filamentous bacteriophage, M13, for the prevention, diagnosis, and treatment of human disease are proposed. Both ways are founded on the unique structural properties of the M13 bacteriophage and the ability of its major and minor coat proteins, p3 and p8, to be manipulated to serve as virus-based multifunctional platforms. The first project addresses the problem of vaccine storage and the cold chain (requirement to store vaccines at 2-80C or lower). The need for refrigeration leads to high cost, difficult field delivery, and high potential for vaccine instability. By capitalizing on the liquid crystalline nature and unique diffraction patterns of phage films, we aim to encapsulate vaccines in a 3-D liquid crystalline matrix that would not only allow for stability at elevated temperatures but would also allow for easy detection of viability by using a laser light and noting the diffraction pattern. We chose luciferase as a model for a protein-based vaccine, and found several phage-borne peptide sequences with increased affinity to luciferase compared to controls. Two of these sequences, CKLHGTSRC and CTHKNQAC were chosen to form luciferase-encapsulated phage films. The second project addresses the need of more sensitive imaging techniques for early detection of cancer.
(cont.) M13 bacteriophage were used in combination with quantum dots and magnetic nanoparticles as bigger and brighter markers for cancer lesions. A 100% expressed p8 library was created for screening against potential cancer markers and work will soon proceed with screening against several cancer cell lines. In addition, a Type 83 phage was created that had a sequence directed against vascular cell adhesion molecule-1 (VCAM-1) expressed on the p3 and a tri-glutamate sequence (E3) on the p8 that could bind well to positively charge molecules like amines. Successful attachment of amine-terminated CdSe/ZnS quantum dots to p8E3 phage (E3 on p8 and wildtype on p3) was shown and III-V quantum dots (GaN and InN) were water solubilized for use in vivo. The goal is to combine all parts and start in vivo testing and screening, as well as to expand our cancer targeting repertoire.
by Amy Shi.
S.M.
O'Keeffe, Roderic S. "The production, harvest and adsorptive recovery of an infectious herpes simplex virus vaccine." Thesis, Aston University, 1999. http://publications.aston.ac.uk/9630/.
Full textJain, Siddhartha Ph D. Massachusetts Institute of Technology. "Synthesis of a hydrogel-based vaccine to mimic dendritic cell responses to pathogens." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/37957.
Full textIncludes bibliographical references (p. 143-160).
Live or attenuated pathogens are the basis of many successful vaccines due in part to the orchestrated response of dendritic cells (DCs) triggered by these immunizations, which includes (1) DC and DC precursor attraction to the immunization site, (2) efficient antigen delivery to class I and class II MHC loading pathways coincident with maturation of DCs, and (3) emigration to draining lymph nodes for T cell activation. We have developed a model immunization system designed to allow these steps in the DC life cycle to be controlled in the context of a subunit vaccine. The system is comprised of microspheres encapsulating chemokines and hydrogel nanoparticles; each nanoparticle contains antigen and DC maturation signals (e.g., TLR ligands). The nanoparticles remain sequestered within the carrier microspheres but the chemokine is released at a controllable rate, creating a local chemoattractant gradient centered on each microsphere. DCs are attracted to individual microspheres where nanoparticles are concentrated; attracted DCs extract nanoparticles from the carrier microspheres, and receive maturation signals coincident with the delivery of antigen into both class I and class II MHC processing pathways.
(cont.) In addition, the nanoparticles may be labeled to allow subsequent tracking of particle-carrying DCs in vivo. These components allow the attraction (or if desired, emigration) of dendritic cells and their precursors to be selectively modulated at an immunization site, and the activation signals received by these cells when they encounter antigen to be tailored. In vitro experiments indicate that chemokine-releasing microspheres effectively attract DCs and monocytes over significant distances, and that the gel nanoparticles efficiently trigger DC maturation and lead to both CD4+ and CD8+ T cell activation in vitro and in vivo. This system provides both a platform for rational immunotherapy as well as a powerful set of tools by which the function of dendritic cells can be manipulated and dissected to improve our understanding of how DC trafficking and functional state impacts immune responses.
by Siddhartha Jain.
Ph.D.
Nicholson, Laura A. (Laura Ann). "Design of experimental setup for identification of parameters for optimal aerosolization of measles vaccine." Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/54520.
Full textCataloged from PDF version of thesis.
Includes bibliographical references (p. 29).
Given the pressing worldwide need for measles vaccination coverage, measles vaccine administration via inhalation is a viable option which overcomes many obstacles currently facing vaccine distribution. Although aerosolization is well understood, studies have focused on pharmaceuticals and very little data is available regarding vaccines. The proposed study analyzes the relationships between various pre- and post-aerosolization parameters in order to calculate the "aerosol fingerprint," or combination of pre-aerosolization parameters optimized to produce the most effective aerosol particle size distribution for measles vaccination. Relevant pre-aerosolization parameters are identified as relative humidity, nebulizer temperature, vaccine reconstitution, solution pH, surface tension, viscosity, air pressure, and nebulizer geometry. Relevant post-aerosolization parameters are identified particle size distribution, aerosolization endurance and bioavailability, and drug delivery rate. Sensing, actuation, automation and special concerns for each variable are considered.
by Laura A. Nicholson.
S.B.
Little, Steven (Steven Ronald). "Poly ([beta]-amino ester)s as pH sensitive biomaterials for microparticulate genetic vaccine delivery." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/34159.
Full textIn title on t.p., "beta" appears as lower-case Greek letter.
Includes bibliographical references.
Genetic vaccination is the administration of nucleic acids to induce cellular expression of antigens, leading to an immune response. Unlike traditional vaccines, this technology has tremendous potential for treating or preventing diseases such as HIV, malaria, and cancer. However, this potential is currently unrealized because of the safety concerns which plague viral vaccine carriers and the inefficiency of nonviral delivery systems when compared to their viral counterparts. A promising and versatile nonviral delivery method for genetic vaccines involves microencapsulation of antigen-encoding DNA, because such particles protect their payload and target it to phagocytic, antigen-presenting immune cells. However, the biomaterial conventionally used in these microparticle formulations, an FDA-approved polyester called poly lactic-co-glycolic acid (PLGA), was not designed specifically to deliver DNA, takes too long to release encapsulated payload, and therefore fails to induce high levels of target gene expression. A new class of novel biomaterials have been synthesized called poly([beta]-amino ester)s which are biodegradable and can have similar physical properties to PLGA, but are pH-sensitive and have gene delivery functionalities.
(cont.) Using these materials we can fabricate microparticle-based delivery systems which have relatively high DNA loadings and can significantly buffer the destructive acidic pH microenvironment created by ester bond degradation. These formulations generate an increase of up to 5 orders of magnitude in DNA delivery efficiency when compared to PLGA alone and can be potent stimulators of antigen presenting cells in vitro. We have also demonstrated that incorporating these new biomaterials into microparticulate genetic vaccines can lead to antigen-specific, immune-mediated rejection of a lethal tumor dosage in vivo, a significant advance over conventional formulations. Finally, with the synthesis of libraries containing thousands of structurally diverse PBAEs, it is warranted to develop new methods of fabrication which enable the high-throughput screening of such libraries. Herein, we describe, for the first time, such a rapid fabrication technique and demonstrate that plasmid encapsulated in these formulations is transcriptionally active.
by Steven Little.
Ph.D.
El, Meleigy May Ahmed Nagib. "Schistosoma mansoni heat shock protein 60 : cloning, expression and preliminary vaccine testing." Thesis, University of London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272135.
Full textFung, Peter W. (Peter Waitak). "Evaluation of polyelectrolyte multilayer thin-film coated microneedle arrays for transcutaneous vaccine delivery." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/69787.
Full textCataloged from PDF version of thesis.
Includes bibliographical references (p. 43-46).
The skin is an ideal organ for the safe and convenient delivery of vaccines, small molecules, and other biologics. Members of the Irvine and Hammond groups have developed a polyelectrolyte multilayer thin film-coated microneedle platform that can achieve simultaneous DNA and nanoparticle delivery. This delivery platform has the advantage of direct delivery of DNA or polymer nanoparticles to immune-active cells at the interface between the dermis and epidermis, enhancing uptake of the delivered cargo by resident immune cells. Ideal for the delivery of DNA vaccines, this platform aims to bridge the gap in the lack of efficient delivery platforms hampering the effectiveness of DNA vaccines. The ability to co-deliver polymer nanoparticles can serve as a conduit for delivering immune stimulating adjuvants or other drugs for therapeutic applications. An overview of current vaccine and delivery system research is presented. Market factors for the commercialization of the polyelectrolyte multilayer thin film-coated microneedle delivery platform are considered along with the risk factors in bringing this invention to market. An assessment of the intellectual property surrounding the platform is performed and a preliminary market entry strategy is developed for minimizing the risks commercialization.
by Peter W. Fung.
M.Eng.
Atukorale, Prabhani U. (Prabhani Upeka). "Amphiphilic gold nanoparticles: mechanisms for interaction with membranes and applications in drug and vaccine delivery." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/90145.
Full textCataloged from PDF version of thesis.
Includes bibliographical references (pages 70-82).
Materials that can interact with and transit membranes without toxic bilayer disruption or poration are of great interest in the drug delivery field. These materials can presumably bypass endocytosis to directly enter the cell cytosol through the plasma membrane, which is often the desired site of action for therapeutics, thereby avoiding potential and likely cargo degradation if trapped in endosomes. Alternatively, if these materials are endocytosed, they are often able to escape the endosome by interacting with and transiting the endosomal membrane, and moving into the cytosol. Here, we present a unique membrane-interacting, amphiphilic gold nanoparticle (amph-AuNP) system, which we show can interact with, embed within, and even penetrate through multiple adjacent lipid bilayers without evidence of membrane disruption or poration. By virtue of these key properties, we also present these amph-AuNPs as effective carriers for therapeutic molecules. Using a one-step reaction, we synthesized small -2-4 nm core size amph- AuNPs with an amphiphilic ligand shell comprised of one or two alkanethiols. Each amph-AuNP is coated by a mixture of long-chain mercaptoundecanesulfonate (MUS) terminated by a water-soluble sulfonate group, and in some cases, short-chain hydrophobic octanethiol (OT). First, we describe our efforts to adapt and develop a method to synthesize giant multilamellar model membranes to study amph-NP-membrane interaction in a well-defined setting. We show that giant membranes can be synthesized and fine-tuned by varying lipid composition and buffer salt concentration, can be fluorescently labeled with lipid tracers, and can be analyzed robustly with confocal microscopy and flow cytometry. Second, we describe our systematic analysis of amph- AuNP and membrane characteristics that influence mechanisms of NP association with bilayers. We study effects of general membrane properties such as electrostatics and phase that govern NP-membrane interactions, and found that NP penetration of bilayers was blocked under conditions where strong electrostatic repulsion or gel-phase lipids were employed. We further studied effects of AuNP core diameter, surface charge, and surface hydrophobicity on NP-membrane interactions at the nanoscale. We found that MUS particles with an optimal gold core size -2- 3nm in diameter and MUS:OT particles of a broader size range were capable of inducing hemifusion between liposomal membranes, while MUS:OT 2:1 particles of intermediate hydrophobicity were capable of spontaneously aggregating within the bilayer of vesicles to form Janus egg-like morphologies. Third, we built on these NP membrane-embedding properties to explore and characterize NP-embedding in erythrocyte membranes, with particular attention to the glycocalyx and membrane fluidity, for the future application of constructing therapeutic erythrocyte 'pharmacytes' in situ. Finally, we describe work in engineering amph-AuNPs to carry short antigenic peptide cargoes for in vivo vaccine applications, where immunization experiments have shown much promise for antigen-ferrying amph-AuNPs in eliciting robust and long-lasting CD8+ T cell responses.
by Prabhani U. Atukorale.
Ph. D.
Deitche, Alexandra. "Refrigerated Vaccine Transport: A Heat Transfer Analysis of Periodic Heating Through a Multi-Layer Cylinder." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17417573.
Full textMechanical Engineering
Rynda, Agnieszka. "Low dose tolerance vaccine platform, reovirus protein sigma 1 and treatment of autoimmunity." Thesis, Montana State University, 2008. http://etd.lib.montana.edu/etd/2008/rynda/RyndaA0808.pdf.
Full textJames, Emmanuel Robin. "Optimisation of a recombinant Hepatitis B vaccine through the cultivation and fermentation of Aspergillus Niger." Thesis, Link to the online version, 2005. http://hdl.handle.net/10019/1058.
Full textLeong, Tein Foong. "Engineering novel antibody-based molecules to probe the role of the immunoglobulin hinge and generate a potential cancer vaccine." Thesis, University of Dundee, 2017. https://discovery.dundee.ac.uk/en/studentTheses/5fe856e6-ce7a-4ff8-92c3-40c555aafd14.
Full textPatel, Bindi Patel. "Plant Viral Nanoparticle-based Vaccine Targeting NY-ESO-1+ Triple Negative Breast Cancer." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1523873757595623.
Full textKotze, Lara. "Development of Pichia pastoris as a production system for HPV16 L1 virus-like particles as component to a subunit vaccine." Thesis, Stellenbosch : University of Stellenbosch, 2007. http://hdl.handle.net/10019.1/1946.
Full textBhattacharjee, Partha Sarathi S. M. Massachusetts Institute of Technology. "VacSeen : semantically enriched automatic identification and data capture for improved vaccine logistics." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/107582.
Full textThesis: S.M. in Engineering and Management, Massachusetts Institute of Technology, School of Engineering, Institute for Data, Systems, and Society, System Design and Management Program, 2016.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 79-82).
Vaccines are globally recognized as a critical public health intervention. Routine immunization coverage in large parts of the developing world is around 80%. Technology and policy initiatives are presently underway to improve vaccine access in such countries. Efforts to deploy AIDC technologies, such as barcodes, on vaccine packaging in developing countries are currently ongoing under the aegis of the 'Decade of Vaccines' initiative by key stakeholders. Such a scenario presents an opportunity to evaluate novel approaches for enhancing vaccine access. In this thesis I report the development of VacSeen, a Semantic Web technology-enabled platform for improving vaccine access in developing countries. Furthermore, I report results of evaluation of a suite of constituent software and hardware tools pertaining to facilitating equitable vaccine access in resource-constrained settings through data linkage and temperature sensing. I subsequently discuss the value of such linkage and approaches to implementation using concepts from technology, policy, and systems analysis.
by Partha Sarathi Bhattacharjee.
S.M. in Technology and Policy
S.M. in Engineering and Management
Reid, Sandy M. "Nano-sized Polymeric Particles for Safe Delivery of Vaccine Adjuvants to Combat Fungal Pathogens." Ohio University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1543927420834628.
Full textYang, Fan [Verfasser], and Frank [Akademischer Betreuer] Rösl. "Re-engineering a Nanoparticle Human Papillomavirus Prophylactic Vaccine Antigen Based on the Minor Capsid Protein L2 / Fan Yang ; Betreuer: Frank Rösl." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/121816798X/34.
Full textAhmed, Kawther Khalid. "Assembly and characterization of a cell-particle hybrid system as a potential cancer vaccine." Thesis, University of Iowa, 2013. https://ir.uiowa.edu/etd/3034.
Full textChebolu, Seethamahalakshmi. "EXPRESSION OF GAL/GALNAC LECTIN OF ENTAMOEBA HISTOLYTICA IN TRANSGENIC CHLOROPLASTS TO DEVELOP A VACCINE FOR AMEBIASIS." Master's thesis, University of Central Florida, 2005. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/3081.
Full textM.S.
Department of Biology
Arts and Sciences
Biology
Regele, Oliver Brian. "Applied discrete event simulation for root cause analysis and evaluation of corrective process change Efficacy within vaccine manufacturing." Thesis, Massachusetts Institute of Technology, 2020. https://hdl.handle.net/1721.1/126896.
Full textThesis: S.M., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, May, 2020
Cataloged from the official PDF of thesis.
Includes bibliographical references (pages 137-141).
Digital Transformation of the Biopharmaceutical industry is enabling improved operations through smart manufacturing. One area of interest is the application of advanced data analytics techniques to supplement traditional workflows. The focus of this research was developing a process simulation model to address a defect observed at a manufacturing line at the Sanofi Pasteur Lyon site. This defect entailed a series of Out-of-Trend batches with abnormally low content of a certain attribute, at the end of a two-year process with complex product batch genealogy, which complicated the use of a traditional approaches to Root Cause Analysis. This study performed a statistical analysis of the defect batch attribute content through production stages to determine which contained a Root Cause. Once this analysis identified the Valence Assembly process as a stage of origin, a Discrete Event Simulator for this process was developed based on historical process data and specifications. This simulator was able to model the current process and replicate the defect in-silico. The simulator identified a specific Root Cause in the batch testing protocol as well as the expected incidence rate of the defect over future campaigns. Finally, the simulator evaluated the efficacy of two potential Corrective Process Changes. This work functions as a practical exploration of integrating novel data analysis and simulation techniques into traditional vaccine manufacturing activities.
by Oliver Brian Regele.
M.B.A.
S.M.
M.B.A. Massachusetts Institute of Technology, Sloan School of Management
S.M. Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science
Khodami, Pantea. "An evaluation of novel lipid-enveloped nanoparticles for adjuvant and antigen delivery for an HIV vaccine : stepping from laboratory into potential markets." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/62742.
Full text"February 2011." Cataloged from PDF version of thesis.
Includes bibliographical references (p. 69-80).
Enormous effort has been devoted to the development of a vaccine against human immunodeficiency virus (HIV). The purpose of this paper is to evaluate the technological and economical aspects of a potential vaccine designed by Professor Irvine's group. Lipid-enveloped virion-sized nano-particles with a biodegradable polymer core are used as synthetic pathogens to deliver HIV specific antigens and adjuvants. The nano-particles are designed to display multiple copies of the antigen on their surfaces and to elicit humoral immunity response. Topics such as patent ability, obtaining an FDA licensure, storage, cost of manufacturing, and supply of the vaccine are explored. A business model for commercialization of the vaccine is outlined, and some possible future business opportunities for the nano-particles are discussed.
by Pantea Khodami.
M.Eng.
Zuma, Medeiros Mauricio. "Industrial development in a high tech sector of a developing country : the unfinished technological transition in the Brazilian vaccine industry." Thesis, University of Sussex, 2011. http://sro.sussex.ac.uk/id/eprint/6322/.
Full textRichard, Emeline. "Synthèse par ingénierie métabolique d'oligosaccharides sialylés pour l'élaboration de glycoconjugués d'intérêt médical." Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV007/document.
Full textSialylation is an important feature of glycolipids and glycoproteins of animal cell surfaces. Sialylatedmotifs are involved in many biological processes through lectin interactions or because of theirphysico-chemical properties. There is a great variety of sialylated structural motifs, and in manycases, there is a structure-relationship between the sialylated profile of and some pathologicprocesses. In cancer, there is an increase of sialylation including the apparition of newly andspecifically related sialylated structures belonging to the so-called tumor-associated carbohydrateantigens (TACA). Those structures present a particular interest, but their chemical or chemoenzymaticsynthesis is costly and quite unappropriated for preparative scale.This work addresses to the bacterial synthesis of sialylated motifs through the metabolic engineeringof Escherichia coli. The first part of the thesis deals with the biosynthesis of polysialylatedconjugatable motifs. Those motifs present various biological properties, such as an increase of thelife-time of therapeutic proteins; they also belong to the TACA family since over-expressed incancers. In addition, some of them are bacterial-specific motifs such as in pathogenic Neisseriameningitidis. Altogether, polysialylated conjugates can be useful for the synthesis of therapeuticdrugs and vaccines. The second part of the thesis describes a new way of producing sialylated Tn andTF carbohydrate antigens by metabolic engineering. The sialylTN motif was coupled to a peptidic andimmunogenic scaffold being a potential vaccine candidate, and its ability of raising specific antibodieswas assayed in mouse
Kou, Peng Meng. "Elucidation of dendritic cell response-material property relationships using high-throughput methodologies." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/44911.
Full textMahajan, Rutuja. "Analyzing Public View towards Vaccination using Twitter." Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright1578379698895464.
Full textPelin, Adrian. "Bio-Engineering Vaccinia Viruses for Increased Oncolytic Potential." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39909.
Full textMurphy, Jane Clare. "The engineering of viral fusion proteins in the baculovirus expression system." Thesis, University of Southampton, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240912.
Full textChewachong, Godwill Mih. "Engineering Plant Virus " Vaccines" Using Pepino mosaic virus as a Model." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1384203201.
Full textMehta, Naveen K. Ph D. Massachusetts Institute of Technology. "Engineering more potent vaccines for the treatment of cancer and autoimmunity." Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/123065.
Full textCataloged from PDF version of thesis.
Includes bibliographical references (pages 171-181).
Vaccination against infectious diseases has long been heralded as one of the greatest advancements in public health, yet its application to other clinical indications has fallen short of expectations. In this thesis, we apply engineering principles to develop more potent vaccines in the treatment of cancer and autoimmunity. Both major components of molecular vaccines, antigen and adjuvant, are independently explored as a part of this work. Our antigen studies sought to improve the delivery of peptide epitopes to lymphoid organs by fusing epitopes to inert protein carriers with defined pharmacokinetic properties. To promote anti-tumor immunity, we found that antigen carriers should 1) protect peptide cargo from proteolytic degradation, 2) be appropriately bulky to drain into the lymphatics, and 3) be rapidly cleared once in the blood to prevent tolerization at distal poorly inflamed organs.
Applying these principles, we identified transthyretin as an optimal delivery protein, and demonstrated efficacy against a number of clinically relevant antigens. Because our protein-epitope fusion approach is fully recombinant in nature, we were able to convert our protein vaccines into nucleic acid modalities, including plasmid DNA and self-replicating RNA, which are significantly easier and cheaper to manufacture at scale. Finally, we applied our learnings to purposefully induce tolerization in the treatment of autoimmunity, and found that albumin is a particularly efficacious antigen carrier protein for this application due to its extended half-life. On the adjuvant front, we attempted to engineer novel Toll-like receptor 3 (TLR3) agonists via yeast surface display. Although we successfully developed high affinity TLR3 binders, all tested clones failed to agonize TLR3 despite the utilization of several multimerization strategies.
Separately, in an effort to better understand adjuvant biology, we conducted a detailed mechanistic study of lipo-CpG, a particularly potent amphiphilic CpG variant previously developed by the Irvine lab. We uncovered a cascade of inflammatory signals originating from monocytes that facilitates the induction of high magnitude T cell responses, largely by acting in trans rather than directly on the antigen-presenting cell. Overall, these studies have elucidated a number of design principles that should aid in the engineering of next generation vaccines to better treat cancer and autoimmunity.
by Naveen K. Mehta.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biological Engineering
Wang, Nick X. "Controlled Delivery of Protein Therapeutics for HIV Prevention." Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1327614039.
Full textVan, der Westhuizen Maria Jacoba. "The engineering and optimization of expression of rotavirus-like particles in insect cells using a South African G9P[6] rotavirus strain / by Maria J. van der Westhuizen." Thesis, North-West University, 2012. http://hdl.handle.net/10394/9852.
Full textThesis (MSc (Biochemistry))--North-West University, Potchefstroom Campus, 2013.
Moynihan, Kelly D. (Kelly Dare). "Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/113960.
Full textCataloged from PDF version of thesis.
Includes bibliographical references (pages 127-140).
Checkpoint blockade with antibodies against CTLA-4 or PD-1 has demonstrated that an endogenous adaptive immune response can be stimulated to elicit durable tumor regressions in metastatic cancer, but these dramatic responses are confined to a minority of patients¹-³. This outcome is likely due in part to the complex network of immunosuppressive pathways present in advanced tumors, which necessitates the development of novel therapeutics and combination immunotherapies to generate a counter-directed network of pro-immunity signals⁴-⁸. In Chapters 2 and 3 of this thesis, we describe methods for enhancing T cell priming against tumor antigens via covalent modification of molecular vaccines to enhance lymphatic drainage, serum stability, or cytosolic access to improve presentation on MHC class I. In Chapter 4, we demonstrate a combination immunotherapy that recruits a diverse set of innate and adaptive effector cells, enabling robust elimination of large tumor burdens that to my knowledge have not previously been curable by treatments relying on endogenous immunity. Maximal anti-tumor efficacy required four components: a tumor antigen targeting antibody, an extended half-life IL-2⁹, anti-ƯPD-1, and a powerful T-cell vaccine¹⁰. This combination elicited durable cures in a majority of animals, formed immunological memory in multiple transplanted tumor models, and induced sustained tumor regression in an autochthonous BRraf[superscript V600E]/Pten[superscript -/-] melanoma model. Finally, in Chapter 5, we show preliminary data on combination immunotherapies used to treat antigenically heterogeneous tumors. Taken together, these data define design criteria for enhancing the immunogenicity of molecular vaccines and elucidate essential characteristics of combination immunotherapies capable of curing a majority of tumors in experimental settings typically viewed as intractable.
"During my doctorate by the John and Fanny Hertz Foundation Fellowship (specifically the Wilson Talley Hertz Fellowship), the NSF Graduate Research Fellowship Program, and the Siebel Scholarship"--Page 141. "This thesis work was supported in part by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, the US National Institutes of Health (NIH) grant CA174795, the Bridge Project partnership between the Koch Institute for Integrative Cancer Research and the Dana Farber-Harvard Cancer Center (DF-HCC), the V Foundation, the Ragon Institute, and the Howard Hughes Medical Institute"--Page 141.
by Kelly D. Moynihan.
Ph. D.