Assessment of BAFF as a mucosal HIV DNA vaccine adjuvant

BAFF 作为粘膜 HIV DNA 疫苗佐剂的评估

• 批准号: 6872949
• 负责人: DAVID NEMAZEE
• 金额: $ 28.16万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6872949
• 关键词: AIDS vaccines; B lymphocyte; CD40 molecule; HIV envelope protein; HIV envelope protein gp120; Salmonella; antigen antibody reaction; attenuated microorganism; bioengineering /biomedical engineering; biotechnology; gene expression; immune response; immunoglobulin A; immunomodulators; laboratory mouse; mucosal immunity; neutralizing antibody; oral administration; tumor necrosis factor alpha; vaccine development; vector vaccine; virus antigen

DESCRIPTION (provided by applicant): DNA vaccines have shown promise as a means to develop meaningful CTL responses in HIV and in other settings, but antibody responses are often poor. The goal of this proposal is to employ a series of improvements that are designed to overcome the poor neutralizing antibody responses to HIV envelope (Env) DNA vaccine. The key hypotheses to be explored are as follows: i) Coexpression of the extremely potent B cell stimulatory molecules BAFF or CD40L will promote enhanced antibody responses, and physical linkage between Env and these TNF family ligands will provide an even more potent stimulus, ii) HIV gp120 or gp140 variants that mask irrelevant portions of the surface with N-linked glycans will focus the antibody response to relevant epitopes, iii) Expressing HIV gp120/gp140 genes as fusion proteins with molecules that have a strong propensity to trimerize can facilitate the expression of the most relevant form of HIV Env. iv) Oral delivery of the DNA vaccine using an attenuated Salmonella typhimurium vector will promote a strong immune response in mucosal immune tissue, v) A combination of these features will yield a more effective vaccine candidate. These goals will be approached through the following Specific Aims: 1) To determine if selected HIV gp120 variants stimulate a better antibody response to DNA vaccination when introduced along with BAFF expressed either as a fusion gene or in the unlinked form. 2) To test the ability of linked or unlinked expression of BAFF or CD40L to improve the antibody responses to DNA vaccine delivered orally by attenuated Salmonella typhimurium. While the long-term goal is to generate an effective HIV vaccine, important achievable intermediate goals will be i) to assess the adjuvanticity of BAFF and other TNF family members, ii) to determine if gp120/BAFF or gp140/BAFF fusion molecules enforce envelope protein trimerization, and iii) to determine if these bioengineering steps facilitate the production of a broadly neutralizing antibody.

描述（由申请人提供）：DNA疫苗已显示出有望作为在HIV和其他环境中发展有意义的CTL反应的一种手段，但是抗体反应通常很差。该提案的目的是采用一系列改进，这些改进旨在克服对HIV INVELOPE（ENK）DNA疫苗的中和抗体反应不佳。要探索的关键假设如下：i）极有效的B细胞刺激分子BAFF或CD40L的共表达将促进增强的抗体响应，ENV与这些TNF家族配体之间的身体连接将提供更有效的刺激，II）与HIV GP120或GP140变体的效果相比，将提供更有效的刺激。对相关表位的抗体反应，iii）表达HIV GP120/gp140基因作为融合蛋白，其具有强大的修剪倾向的分子可以促进最相关的HIV Env形式的表达。 iv）使用衰减的伤寒沙门氏菌载体的口服DNA疫苗将促进粘膜免疫组织中强烈的免疫反应，v）这些特征的组合将产生更有效的疫苗候选者。这些目标将通过以下特定目的实现：1）确定选定的HIV GP120变体是否与BAFF一起以融合基因或未连接形式表达的BAFF一起刺激对DNA疫苗接种的更好抗体反应。 2）测试BAFF或CD40L连接或未连接表达的能力，以改善通过鼠伤寒沙门氏菌口服的对DNA疫苗的抗体反应。 While the long-term goal is to generate an effective HIV vaccine, important achievable intermediate goals will be i) to assess the adjuvanticity of BAFF and other TNF family members, ii) to determine if gp120/BAFF or gp140/BAFF fusion molecules enforce envelope protein trimerization, and iii) to determine if these bioengineering steps facilitate the production of a broadly neutralizing antibody.