Precision immunization vaccine for nicotine and other drugs of abuse

描述（由申请方提供）：针对尼古丁、可卡因、阿片类药物和PCP的疫苗已被提议作为药物滥用的治疗方法。通过在血浆中引发抗药抗体，这些疫苗将药物隔离在血液中，从而阻止它们进入大脑。如果没有中枢神经系统的影响作为药物滥用的正反馈，戒毒计划的有效性显着提高。然而，在尼古丁和可卡因疫苗的临床试验中，唯一得到帮助的受试者是那些抗体水平非常高的人。整整三分之二的受试者未能达到如此高的抗体水平，相应地未能保持药物戒断。这种僵局的原因是疫苗设计中的一个障碍：作为小分子，药物必须与载体结合才能引发抗体反应。因为载体也是免疫原性的，所以部分抗体反应转向载体，而不是直接针对药物。动物研究支持这样的概念，即阻断对载体的反应将导致更高的抗药物抗体水平（在本文中称为“半抗原”）。因此，该项目将探索一种新的疫苗接种方法，该方法分两个阶段进行：第一个“减免疫苗接种”用于消除脱靶的抗载体B细胞;随后的“选择疫苗接种”用于产生特异性针对药物半抗原靶标的抗体。这种方法，我们称之为“精确免疫”，预计将产生前所未有的抗药抗体水平，足以促进大多数接受者的戒毒。 公共卫生相关性：在美国，吸烟仍然是可预防的主要死因，每年约有五分之一的人（438，000人）死于吸烟。针对尼古丁的疫苗可以帮助个人实现戒烟，但目前的疫苗还不够强大，无法有效。通过开发一种新的疫苗接种方法，该项目将增强这些现有疫苗，使它们能够帮助患者。

DESCRIPTION (provided by applicant): Vaccines against nicotine, cocaine, opiates, and PCP have been proposed as treatments for drug abuse. By eliciting anti-drug antibodies in the plasma, these vaccines sequester drugs in the blood and thereby block their entry into the brain. Without the CNS effects as positive feedback for drug abuse, the effectiveness of drug abstinence programs is markedly improved. In clinical trials of nicotine and cocaine vaccines, however, the only subjects who were helped were those with very high antibody levels. Fully two-thirds of the subjects failed to reach this high level of antibodies and correspondingly failed to maintain drug abstinence. The reason for this impasse is a roadblock in vaccine design: as small molecules, drugs must be conjugated to a carrier in order to elicit an antibody response. Because the carrier is also immunogenic, part of the antibody response is diverted toward the carrier, rather than being directed against the drug. Studies in animals support the concept that blocking the response to the carrier will result in much higher antibody levels against the drug (called a "hapten" in this context). Consequently, this project will explore a novel approach to vaccination which works in two stages: a first "subtraction vaccination" is used to deplete off-target, anti-carrier B cells; a following "selection vaccination" is used to raise antibodies specifically directed against the drug hapten target. This approach, which we call "precision immunization," is anticipated to produce unprecedented levels of anti-drug antibodies that will be high enough to promote drug abstinence in the majority of recipients. PUBLIC HEALTH RELEVANCE: Cigarette smoking remains the leading preventable cause of death in the U.S. and accounts for about 1 of every 5 deaths (438,000 people) each year. Vaccines against nicotine could help individuals achieve abstinence, but the current vaccines are not yet strong enough to be effective. By developing a new approach to vaccination, this project will enhance these existing vaccines so that they are able to help patients.