High Mannose Type Carbohydrate-based HIV/AIDS Vaccine

高甘露糖型碳水化合物艾滋病疫苗

• 批准号: 7495757
• 负责人: Yu Geng
• 金额: $ 30万
• 依托单位: PROSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495757
• 关键词: Adjuvant; Animals; Antibodies; Antibody Formation; Antigens; Binding; Blocking Antibodies; CD209 gene; Carbohydrates; Cell Surface Receptors; Cells; Clinical Trials; Cross Reactions; Cyanovirin-N; Daily; Dendritic Cells; Dose; Drug Formulations; Enzyme-Linked Immunosorbent Assay; Epitopes; Gene Deletion; Gene Family; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Humoral Immunities; Immune; Immune Sera; Immunization; Immunization Schedule; Immunofluorescence Immunologic; Infection; Link; Mammalian Cell; Mannose; Measures; Membrane; Monoclonal Antibodies; Mucous Membrane; Numbers; Oryctolagus cuniculus; Pathway interactions; Peptides; Play; Polysaccharides; Principal Investigator; Procedures; Proteins; Public Health; Range; Role; Route; SIV; Saccharomyces cerevisiae; Serum; Site; Specificity; Structure; T-Lymphocyte; Testing; Upper arm; Vaccines; Virus; Western Blotting; Yeasts; base; cross reactivity; density; design; env Gene Products; env Glycoproteins; glycosylation; immunogenicity; improved; inhibitor/antagonist; mutant; neutralizing antibody; novel; novel vaccines; pandemic disease; pre-clinical; success; transmission process; yeast protein; Adjuvant; Animals; Antibodies; Antibody Formation; Antigens; Binding; Blocking Antibodies; CD209 gene; Carbohydrates; Cell Surface Receptors; Cells; Clinical Trials; Cross Reactions; Cyanovirin-N; Daily; Dendritic Cells; Dose; Drug Formulations; Enzyme-Linked Immunosorbent Assay; Epitopes; Gene Deletion; Gene Family; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Humoral Immunities; Immune; Immune Sera; Immunization; Immunization Schedule; Immunofluorescence Immunologic; Infection; Link; Mammalian Cell; Mannose; Measures; Membrane; Monoclonal Antibodies; Mucous Membrane; Numbers; Oryctolagus cuniculus; Pathway interactions; Peptides; Play; Polysaccharides; Principal Investigator; Procedures; Proteins; Public Health; Range; Role; Route; SIV; Saccharomyces cerevisiae; Serum; Site; Specificity; Structure; T-Lymphocyte; Testing; Upper arm; Vaccines; Virus; Western Blotting; Yeasts; base; cross reactivity; density; design; env Gene Products; env Glycoproteins; glycosylation; immunogenicity; improved; inhibitor/antagonist; mutant; neutralizing antibody; novel; novel vaccines; pandemic disease; pre-clinical; success; transmission process; yeast protein

DESCRIPTION (provided by applicant): Although humoral immunity is a critical component in an effective HIV/AIDS vaccine to control the rampant spread of HIV-1, few of the vaccine candidates currently in preclinical and clinical trials appear to elicit broadly neutralizing antibodies. Several lines of evidences show that high mannose type carbohydrates on the HIV-1 glycoprotein gp120 are a novel and promising target to develop broadly neutralizing antibodies. First, high mannose glycans on gp120 play a critical role in HIV transmission and infection through interaction with immune cells, including dendritic cells. Second, one of the few broadly neutralizing HIV monoclonal antibodies, 2G12, recognizes a conformational epitope of high mannose type glycans on gp120. Third, a potent inhibitor of HIV, Cyanovirin-N, binds to terminal a1,2-linked mannose residues on high mannose glycans. Last, the carbohydrates on gp120 are well exposed and conserved among different HIV-1 subtypes and strains. To target the high mannose glycans on gp120, we have created N-glycosylation mutants of S. cerevisiae, identified several yeast glycoproteins that cross-react with 2G12, elicited immune sera that cross-react with Env glycoproteins of HIV-1 and SIV, and neutralized HIV-1 pseudoviruses. The gp120 binding and pseudovirus neutralization activities of these sera are broad, but the antibody titer and neutralization potency of the immune sera need to be improved. We hypothesize that higher levels of Mana1,2Man-specific antibodies with stronger gp120 binding and neutralizing activities can be induced in some of the proposed multiple groups of animals immunized with this new vaccine formulation. The Specific Aims are, (1) optimization of immunization procedures with the whole cells from triple mutant yeast of S. cerevisiae to elicit stronger gp120 cross-reactive and neutralizing antibodies; and (2) analyses of antigenicity and immunogenicity of 2G12 cross-reactive yeast glycoproteins, and elicitation of potent and broadly neutralizing antibodies using a prime-boost strategy. If success, this novel formulation of immunogen from yeast mutant strain will be a safe, cheap, and effective HIV/AIDS vaccine against a broad range of HIV-1 primary isolates. PUBLIC HEALTH RELEVANCE: Although humoral immunity is a critical component in an effective HIV/AIDS vaccine to control the rampant spread of HIV-1, few of the vaccine candidates currently in preclinical and clinical trials appear to elicit broadly neutralizing antibodies. Several lines of evidences show that high mannose type carbohydrates on the HIV-1 glycoprotein gp120 are a novel and promising target to develop broadly neutralizing antibodies. First, high mannose glycans on gp120 play a critical role in HIV transmission and infection through interaction with immune cells, including dendritic cells. Second, one of the few broadly neutralizing HIV monoclonal antibodies, 2G12, recognizes a conformational epitope of high mannose type glycans on gp120. Third, a potent inhibitor of HIV, Cyanovirin-N, binds to terminal a1,2-linked mannose residues on high mannose glycans. Last, the carbohydrates on gp120 are well exposed and conserved among different HIV-1 subtypes and strains. To target the high mannose glycans on gp120, we have created N-glycosylation mutants of S. cerevisiae, identified several yeast glycoproteins that cross-react with 2G12, elicited immune sera that cross-react with Env glycoproteins of HIV-1 and SIV, and neutralized HIV-1 pseudoviruses. The gp120 binding and pseudovirus neutralization activities of these sera are broad, but the antibody titer and neutralization potency of the immune sera need to be improved. We hypothesize that higher levels of Mana 1,2Man-specific antibodies with stronger gp120 binding and neutralizing activities can be induced in some of the proposed multiple groups of animals immunized with this new vaccine formulation. The Specific Aims are, (1) optimization of immunization procedures with the whole cells from triple mutant yeast of S. cerevisiae to elicit stronger gp120 cross-reactive and neutralizing antibodies; and (2) analyses of antigenicity and immunogenicity of 2G12 cross-reactive yeast glycoproteins, and elicitation of potent and broadly neutralizing antibodies using a prime-boost strategy. If success, this novel formulation of immunogen from yeast mutant strain will be a safe, cheap, and effective HIV/AIDS vaccine against a broad range of HIV-1 primary isolates.

描述（由申请人提供）：尽管体液免疫是有效的HIV/AIDS疫苗中的关键组成部分，以控制HIV-1的猖sprive，但目前在临床前和临床试验中目前几乎没有候选疫苗似乎会引起广泛中和的抗体。几条证据表明，HIV-1糖蛋白GP120上的高甘露糖型碳水化合物是一种新颖而有希望的靶标，可以开发出广泛中和抗体。首先，GP120上的高甘露糖聚糖通过与免疫细胞（包括树突状细胞）相互作用在HIV传播和感染中起关键作用。其次，是少数几个广泛中和的HIV单克隆抗体2G12之一，它识别出GP120上高甘露糖型聚糖的构象表位。第三，一种有效的HIV的抑制剂Cyanovirin-N与高甘露糖的高甘露糖的末端A1,2连接的甘露糖残基结合。最后，在不同的HIV-1亚型和菌株中，GP120上的碳水化合物暴露且保守。为了瞄准GP120上的高甘露糖糖，我们创建了酿酒酵母的N-糖基化突变体，确定了几种与2G12交叉反应的酵母糖蛋白，引起了免疫血清，它们与HIV-1和SIV的Env Glycopotins进行了交叉反应，并具有HIV-1和SIV的ENV糖蛋白，并中性地中性HIV-1 Pseudosed。这些血清的GP120结合和假病毒中和活​​性很广，但是需要改善免疫血清的抗体滴度和中和效力。 我们假设在某些新的疫苗配方免疫的拟议多组动物中，可以诱导较高水平的mana1,2Man特异性抗体具有更强的GP120结合和中和活性的抗体。具体目的是：（1）用酿酒酵母三重突变酵母的整个细胞优化免疫程序，以引起更强的gp120交叉反应和中和抗体； （2）2G12交叉反应性酵母糖蛋白的抗原性和免疫原性的分析，以及使用Prime-Bood-Bood策略对有效和广泛中和抗体的诱导。如果成功，则这种新型的来自酵母突变菌株免疫原的配方将是一种安全，便宜且有效的HIV/AIDS疫苗，以针对广泛的HIV-1主要分离株。公共卫生相关性：尽管体液免疫是有效的艾滋病毒/艾滋病疫苗的关键组成部分，以控制HIV-1的猖sprive，但目前在临床前和临床试验中目前几乎没有候选疫苗的候选者似乎会引起广泛中和的抗体。几条证据表明，HIV-1糖蛋白GP120上的高甘露糖型碳水化合物是一种新颖而有希望的靶标，可以开发出广泛中和抗体。首先，GP120上的高甘露糖聚糖通过与免疫细胞（包括树突状细胞）相互作用在HIV传播和感染中起关键作用。其次，是少数几个广泛中和的HIV单克隆抗体2G12之一，它识别出GP120上高甘露糖型聚糖的构象表位。第三，一种有效的HIV的抑制剂Cyanovirin-N与高甘露糖的高甘露糖的末端A1,2连接的甘露糖残基结合。最后，在不同的HIV-1亚型和菌株中，GP120上的碳水化合物暴露且保守。为了瞄准GP120上的高甘露糖糖，我们创建了酿酒酵母的N-糖基化突变体，确定了几种与2G12交叉反应的酵母糖蛋白，引起了免疫血清，它们与HIV-1和SIV的Env Glycopotins进行了交叉反应，并具有HIV-1和SIV的ENV糖蛋白，并中性地中性HIV-1 Pseudosed。这些血清的GP120结合和假病毒中和活​​性很广，但是需要改善免疫血清的抗体滴度和中和效力。我们假设在一些新的疫苗配方免疫的拟议多组动物中，可以诱导较高水平的法力1,2人具有更强GP120结合和中和活性的抗体。具体目的是：（1）用酿酒酵母三重突变酵母的整个细胞优化免疫程序，以引起更强的gp120交叉反应和中和抗体； （2）2G12交叉反应性酵母糖蛋白的抗原性和免疫原性的分析，以及使用Prime-Bood-Bood策略对有效和广泛中和抗体的诱导。如果成功，则这种新型的来自酵母突变菌株免疫原的配方将是一种安全，便宜且有效的HIV/AIDS疫苗，以针对广泛的HIV-1主要分离株。