Graduate Thesis Or Dissertation

 

Rational vaccine development 1) Design of a Triantigen Nasal Anthrax Vaccine Candidate 2) A Novel Lecithin Based Nanoparticle as a Vaccine Delivery System Public Deposited

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  • Currently, the only anthrax vaccine licensed for human use in the United States is the Anthrax-vaccine-absorbed (AVA or Biothrax®). AVA suffers from several drawbacks, including a complicated and lengthy dosing schedule that requires six initial injections administered over eighteen months, followed by annual boosters. Therefore, a new generation anthrax vaccine that can be easily administered for rapid mass immunization and induce strong immune responses not only against the anthrax protective antigen protein, but also against the other virulent factors of Bacillus anthracis. To address these needs, a prototypic triantigen nasal anthrax vaccine candidate that contains a truncated PA (rPA63), the anthrax lethal factor (LF), and the capsular poly-γ-D-glutamic acid (γDPGA) as the antigens and a synthetic double-stranded RNA, polyriboinosinic-polyribocytidylic (pI:C) acid as the adjuvant. This study identified the optimal dose of nasal pI:C in mice, as well as showed that pI:C enhanced the proportion of dendritic cells (DCs) in local draining lymph nodes (LNs) and stimulated DC maturation. The γDPGA was shown to be immunogenic when conjugated to a carrier protein and dosed intranasally to mice. Further, the anti-PGA antibodies (Abs) were shown to be functional because they were able to activate complement and kill PGA-producing bacteria. Nasal immunization with LF alone and PA alone induced strong, functional anti-LF and anti-PA Abs. Nasal immunization of mice with the prototypic tri-antigen vaccine candidate induced strong immune responses against all three antigens. The immune responses protected macrophages against an anthrax lethal toxin challenge in vitro and enabled the immunized mice to survive a lethal dose of anthrax lethal toxin challenge in vivo. When used as a nasal vaccine adjuvant, pI:C is generally considered to be safe. However, repeated high doses of pI:C tended to induce some side effects, including fever and abnormal liver functions. Therefore, new adjuvants are constantly being sought. Over the past several decades, an accumulation of research has demonstrated the usefulness of nanoparticles as antigen carriers with adjuvant activity. A novel lecithin-based nanoparticle was engineered from emulsions. Bovine serum albumin (BSA) and PA proteins were covalently conjugated onto the nanoparticles. Mice immunized with BSA conjugated nanoparticles developed strong anti-BSA Ab responses comparable to that induced by BSA adjuvanted with incomplete Freund’s adjuvant and 6.5-fold stronger than that induced by BSA adsorbed onto aluminum hydroxide. Immunization of mice with the PA-conjugated nanoparticles elicited a quick, strong, and durable anti-PA Ab response that afforded protection of the mice against a lethal dose of anthrax lethal toxin challenge. The adjuvanticity of the nanoparticles was likely due to their ability to move antigens into local draining LNs, to enhance the uptake of the antigens by antigen-presenting cells (APCs), and to activate APCs. Most vaccines require cold-chain refrigeration for storage and distribution. A major challenge in the vaccine development field is to develop formulations that do not require refrigeration. The most commonly used process in the pharmaceutical field to convert vaccine suspensions into solids of sufficient stability for distribution and storage is lyophilization. Using 5% of mannitol plus 1% of polyvinylpyrrolidone, the immunogenicity of the lyophilized protein conjugated nanoparticles (BSA-NPs or PA-NPS) was found to be undamaged after a relatively extended period of storage at room temperature or under accelerated conditions (37oC).
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