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（由申请人提供）：药物成瘾疫苗在临床前研究中显示出令人鼓舞的功效，但由于免疫受试者中报告的血清抗体浓度的变异性，其向临床的转化已经放缓。建立疫苗免疫原性的早期标记将有助于预测功效、加速疫苗设计的筛选以及临床环境中个体化疫苗设计的选择。本研究的总体假设是，可以根据初次（未免疫）和免疫受试者中半抗原特异性 B 细胞的数量来预测对药物成瘾疫苗（药物半抗原-蛋白缀合物）的临床显着反应。具体来说，将比较不同 OXY 疫苗之间的羟考酮 (OXY) 特异性 B 细胞，并将与啮齿类动物中使用 OXY 疫苗免疫前后的 OXY 特异性血清抗体和 OXY 分布相关联。最近开发的策略可检测初始和免疫受试者中罕见的抗原特异性 B 细胞。通过基于荧光抗原的富集方法从未免疫或免疫宿主中存在的总 B 细胞库中选择抗原特异性 B 细胞，然后通过流式细胞术进行表征。通过将药物半抗原与用于检测半抗原特异性 B 细胞的荧光载体蛋白缀合，该方法可以适用于药物缀合物疫苗。我们的实验室开发了两种 OXY 疫苗，显示出在减少 OXY（最常滥用的处方阿片类药物之一）的大脑分布和行为影响方面的一系列作用。这些疫苗将用于测试 OXY 特异性 B 细胞是否可用于解释结构不同疫苗之间的变异性以及免疫后受试者之间的个体变异性。我们将测试以下假设：1）对于小鼠和大鼠中更有效的 OXY 疫苗，免疫前和免疫后 OXY 特异性 B 细胞的数量将更高 2）免疫前和免疫后 OXY 特异性 B 细胞的数量将与 OXY 特异性血清抗体滴度以及免疫对大鼠大脑中 OXY 分布的影响相关。这将通过以下方式进行测试：目标 1A) 表征小鼠体内两种 OXY 疫苗的 OXY 特异性 B 细胞和 OXY 特异性抗体反应的时间过程，以确定 B 细胞反应；目标 1B) 在第二个物种（大鼠）中评估相同的方法；目标 2A) 将免疫前初始 OXY 特异性 B 细胞与 OXY 特异性抗体滴度及其对大鼠大脑 OXY 分布的影响相关联，目标 2B) 将免疫后早期激活的 OXY 特异性 B 细胞与 OXY 特异性血清抗体滴度相关及其对大鼠大脑 OXY 分布的影响 公共卫生意义。处方药滥用是美国增长最快的药物问题，其中羟考酮和羟吗啡酮是滥用最严重的药物。毒瘾疫苗为目前治疗毒瘾的药物疗法提供了一个有前途的优势。早期筛查免疫原性将通过将疫苗与患者相匹配并快速调整治疗来实现个体化治疗。这种方法可以扩展到其他药物结合疫苗。 公共卫生相关性：处方药滥用是美国增长最快的药物问题，其中羟考酮和羟吗啡酮是滥用最严重的药物。毒瘾疫苗为目前治疗毒瘾的药物疗法提供了一个有前途的优势。早期筛查免疫原性将通过将疫苗与患者相匹配并快速调整治疗来实现个体化治疗。这种方法可以扩展到其他药物结合疫苗。