Vaccines Against Botulism

肉毒杆菌疫苗

• 批准号: 10434672
• 负责人: Joseph T Barbieri
• 金额: $ 67.07万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434672
• 关键词: Address; Animal Model; Animals; Antibodies; Antibody Response; Bacterial Toxins; Biological; Biological Assay; Bontoxilysin; Botulinum Toxins; Botulism; Catalysis; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Clostridium botulinum; Collection; Developed Countries; Developing Countries; Development; Disease; Disease Outbreaks; Dose; Engineering; Enzyme-Linked Immunosorbent Assay; Family; Funding; Future; GTP-Binding Protein alpha Subunits, Gs; Genetic; Genetic Engineering; Human; Immune response; Immunize; Immunodominant Epitopes; Immunoglobulin G; Immunoglobulin M; Immunologics; Inactivated Vaccines; Incidence; Informatics; Intoxication; JTB gene; Laboratories; Length; Mediating; Memory; Military Personnel; Modeling; Modification; Mus; Mutate; Mutation; Oryctolagus cuniculus; Pentas; Population; Populations at Risk; Production; Property; Proteins; Recombinants; Research Personnel; Residual state; Risk; Serotyping; Structure; Structure-Activity Relationship; Terrorism; Testing; Toxic effect; Toxin; Toxoids; Translating; Vaccinated; Vaccination; Vaccines; Variant; Zinc; antitoxin; base; botulinum; botulinum toxin type B; botulinum toxin type C; cross immunity; exposed human population; first responder; genetic manipulation; improved; neurotoxin 5; neutralizing antibody; next generation; novel vaccines; potency testing; prevent; prophylactic; receptor binding; response; vaccine strategy; vaccinology

The botulinum neurotoxins (BoNT) are a large protein toxin family grouped into seven BoNT serotypes (A-G) based upon limited cross protection of -sera against each BoNT serotype. BoNT are the most toxic proteins known for humans and the causative agent of botulism. Currently, there is no licensed vaccine against botulism and the experimental penta-serotype toxoid vaccine previously available from the CDC for at-risk populations was discontinued in 2011. Thus, there is a need to develop a potent and effective BoNT vaccine against all BoNT serotypes to protect at-risk humans from exposure, including civilians in harm’s way, first responders, the military, and researchers. BoNT are organized into three domains involved in catalysis (LC), LC translocation (HCN), and receptor binding (HCC). Earlier efforts have focused on developing recombinant HCC-based vaccines to overcome the shortcomings of chemically inactivated toxoids, but recent studies have shown that recombinant full-length BoNT vaccines are more potent than vaccines comprising the receptor binding domain. In addition, ELISA studies implicated the HCN translocation domain as the immunodominant domain, not the HCC receptor binding domain, in recombinant full-length BoNT vaccinated mice surviving native botulinum toxin challenge. This supports the hypothesis that a recombinant full-length non-toxic BoNT mutated to inactivate the three independent functions of toxin action (catalysis, LC translocation, and receptor binding) will improve vaccine potency for outbred populations. The current study will utilize informatics and assessment of structure-function alignments of the seven serotypes of botulinum toxin, along with cell biological analysis and immunological assessment of the antibody (IgM and IgG) response of animals immunized with recombinant, full-length BoNT vaccine versus chemically inactivated botulinum toxoid. Two models for botulinum toxin vaccines will be tested: a single high dose BoNT vaccine for rapid response to threats of BoNT exposure and a low dose BoNT vaccine for long term protection against BoNT exposure. The low dose protective vaccine will be tested versus chemically inactivated botulinum toxoid in mice and rabbits. Understanding of the structure-function properties of bacterial toxins allows production of Next Generation vaccines that are safer, less expensive, easier to produce, and genetically malleable for rapid modification than chemically inactivated toxoids. The studies proposed in this application provide future directions for these advances in toxin vaccinology.

肉毒杆菌神经毒素(BoNT)是一个大的蛋白质毒素家族，分为7个BoNT血清型(A-G)。 基于-血清对每种BONT血清型的有限交叉保护。BONT是毒性最强的蛋白质 为人类所知，也是肉毒杆菌中毒的病原体。目前，还没有获得许可的疫苗。 肉毒杆菌中毒和先前从疾控中心获得的高危五血清型实验性类毒素疫苗 人口在2011年停产。因此，有必要开发一种有效的BONT疫苗。 针对所有BONT血清型，以保护处于危险中的人，包括处于危险中的平民，首先 应急者、军方和研究人员。BONT被组织成三个涉及催化的域(LC)， LC易位(HCN)和受体结合(HCC)。早期的努力集中在开发重组 以肝癌为基础的疫苗克服了化学灭活类毒素的缺点，但最近的研究已经 显示重组全长BONT疫苗比含有受体的疫苗更有效。 结合结构域。此外，酶联免疫吸附试验表明，hcn易位结构域是免疫显性的。 重组全长BONT免疫存活小鼠的肝癌受体结合域，而不是肝癌受体结合域 本土肉毒杆菌毒素挑战赛。这支持了一种假设，即一种重组的全长无毒BONT 突变使毒素作用的三个独立功能(催化、LC转位和受体)失活 (有约束力)将提高异种繁殖群体的疫苗效力。 目前的研究将利用信息学和评估结构-功能比对的七个 肉毒杆菌毒素的血清型及其抗体的细胞生物学分析和免疫学评价 重组全长BoT疫苗免疫动物的免疫应答(IgM和Ig G)与化学免疫的比较 灭活肉毒杆菌类毒素。将测试两种型号的肉毒毒素疫苗：单一大剂量BONT 对BONT暴露威胁快速反应的疫苗和长期保护的低剂量BONT疫苗 防止暴露在邦特身上。低剂量保护性疫苗将进行测试，而不是化学灭活 小白鼠和兔子体内的肉毒杆菌类毒素。对细菌毒素结构与功能特性的认识 允许生产更安全、更便宜、更容易生产的下一代疫苗，以及 与化学灭活的类毒素相比，在基因上可延展性更强，可快速修饰。在这篇文章中提出的研究 应用为毒素疫苗学的这些进展提供了未来的方向。