Early antigen-specific B cell responses as markers of oxycodone vaccine efficacy

早期抗原特异性 B 细胞反应作为羟考酮疫苗功效的标志

• 批准号: 8402476
• 负责人: Marco Pravetoni
• 金额: $ 15.43万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8402476
• 关键词: Antibodies; Antibody Formation; Antigen Targeting; Antigens; B cell repertoire; B-Cell Activation; B-Lymphocytes; Behavioral; Biological Assay; Biopsy; Brain; Carrier Proteins; Clinic; Clinical; Conjugate Vaccines; Dependence; Detection; Drug Addiction; Drug Formulations; Drug Kinetics; Flow Cytometry; Haptens; Health; Immune response; Immunization; Immunotherapy; Individual; Keyhole Limpet Hemocyanin; Marker Vaccines; Measures; Memory B-Lymphocyte; Methods; Mus; Oxycodone; Oxymorphone; Patients; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Production; Proteins; Rattus; Reporting; Research; Rodent; Screening procedure; Serum; Spleen; Structure of germinal center of lymph node; Testing; Time; Translations; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; addiction; base; clinically significant; drug of abuse; immunogenicity; improved; novel vaccines; pre-clinical; preclinical study; prescription drug abuse; prescription opioid; prescription opioid abuse; response; vaccine development; vaccine efficacy; vaccine evaluation

DESCRIPTION (provided by applicant): Drug addiction vaccines show encouraging efficacy in pre-clinical studies, yet translation to the clinic has been slowed by the variability of serum antibody concentrations reported in immunized subjects. Establishing early markers of vaccine immunogenicity would help predict efficacy, accelerate screening of vaccine designs, and individualize vaccine design selection in clinical settings. The overall hypothesis of this study i that clinically significant responses to drug addiction vaccines (drug hapten-protein conjugate) can be predicted from the number of hapten-specific B cells in naive (unimmunized) and immunized subjects. Specifically oxycodone (OXY)-specific B cells will be compared between different OXY vaccines and will correlate with OXY-specific serum antibodies and OXY distribution before and after immunization with OXY vaccines in rodents. A recently developed strategy detects rare antigen-specific B cells in naive and immunized subjects. Antigen-specific B cells are selected from the total B cell repertoire present in an unimmunized or immunized host by a fluorescent antigen-based enrichment method and then characterized by flow cytometry. This method can be adapted to drug conjugate vaccines by conjugating drug haptens to a fluorescent carrier protein used to detect hapten-specific B cells. Our lab has developed two OXY vaccines showing a range of effects in reducing brain distribution and behavioral effects of OXY, one of the most commonly abused prescription opioids. These vaccines will be used to test if OXY-specific B cells can be used to explain variability between structurally different vaccines and individual variability between subjects after immunization. We will test the hypotheses that: 1) the numbers of pre- and post-immunization OXY-specific B cells will be higher for the more efficient OXY vaccine in both mice and rats 2) the numbers of pre- and post- immunization OXY-specific B cells will correlate with OXY-specific serum antibody titers and with the effect of immunization on OXY distribution to the brain in rats. This will be tested by: aim 1A) characterizing the time course of OXY-specific B cell and OXY-specific antibody responses to two OXY vaccines in mice to determine B cell responses; aim 1B) assessing the same method in a second species (rats); aim 2A) correlating pre- immunization na¿ve OXY-specific B cells to OXY-specific antibody titers and their effects on OXY distribution to the brain in rats, and aim 2B) correlating early post- immunization activated OXY-specific B cells to OXY- specific serum antibody titers and their effects on OXY distribution to brain in rats PUBLIC HEALTH SIGNIFICANCE. Prescription drug abuse is the fastest-growing drug problem in the US, with oxycodone and oxymorphone among the most abused. Drug addiction vaccines offer a promising advantage to current pharmacotherapies to treat dependence. Early screening of immunogenicity will enable individualized treatment by matching the vaccine to patient and rapid treatment adjustment. This approach could be expanded to other drug-conjugate vaccines. PUBLIC HEALTH RELEVANCE: Prescription drug abuse is the fastest-growing drug problem in the US, with oxycodone and oxymorphone among the most abused. Drug addiction vaccines offer a promising advantage to current pharmacotherapies to treat dependence. Early screening of immunogenicity will enable individualized treatment by matching the vaccine to patient and rapid treatment adjustment. This approach could be expanded to other drug-conjugate vaccines.

描述（由应用提供）：药物成瘾疫苗在临床前研究中表现出令人鼓舞的效率，但是被免疫抑制受试者报道的血清抗体浓度的变化减慢了诊所。建立疫苗免疫原性的早期标志物将有助于预测效率，加速疫苗设计的筛查以及在临床环境中个性化疫苗设计选择。这项研究的总体假设I可以预测临床上对药物成瘾疫苗（药物蛋白蛋白结合物）的临床意义反应，可以从天真（未免疫）和免疫受试者中的Hapten特异性B细胞数量中预测。特异性的氧氧化物（Oxy） - 特异性B细胞将在不同的氧气疫苗之间进行比较，并将与啮齿动物中的氧疫苗进行免疫抑制之前和之后与氧特异性血清抗体和氧气分布相关。最近开发的策略检测到幼稚和免疫抑制受试者中罕见的抗原特异性B细胞。抗原特异性B细胞是从基于荧光抗原的富集方法中存在于未经抑制或免疫抑制宿主中的总B细胞库中选择的，然后以流式细胞仪为特征。该方法可以通过将药物触发结合到用于检测触觉特异性B细胞的荧光载体蛋白上，以适应药物共轭疫苗。我们的实验室已经开发了两种氧疫苗，显示了减少脑分布的一系列影响以及氧气的行为影响，这是最常见的处方阿片类药物之一。这些疫苗将用于测试是否可以使用氧气特异性B细胞来解释在结构上不同的疫苗和免疫抑制后受试者之间的个体变异性之间的变异性。我们将测试以下假设：1）对于小鼠和大鼠的效率更有效的氧疫苗2）氧气疫苗的数量将更高。这将通过以下方式测试：AIM 1A）表征对小鼠中两种氧疫苗的氧特异性B细胞和氧特异性抗体反应的时间过程，以确定B细胞反应；目标1b）在第二种（大鼠）中评估相同的方法； AIM 2A）将免疫前的NA已与氧特异性抗体滴度与大鼠的氧分布对大脑的影响相关联，而AIM 2B）将免疫后的早期激活后的氧气特异性B细胞与氧气特异性血清抗体及其对氧及其对大脑的影响的影响。处方药滥用是美国增长最快的药物问题，其中羟考酮和矛盾的是最受虐待的药物。药物成瘾疫苗为当前的药物治疗提供了有望的优势来治疗依赖性。免疫原性的早期筛查将通过将疫苗与患者和快速治疗调整相匹配来实现个性化治疗。这种方法可以扩展到其他偶联的疫苗。 公共卫生相关性：处方药滥用是美国增长最快的药物问题，氧气和氧合最受虐待。药物成瘾疫苗为当前的药物治疗提供了有望的优势来治疗依赖性。免疫原性的早期筛查将通过将疫苗与患者和快速治疗调整相匹配来实现个性化治疗。这种方法可以扩展到其他偶联的疫苗。