Programming of Protective CD8 T-Cell Memory by Live and Adjuvanted Subunit Vaccin

描述（由申请方提供）：减毒活疫苗在控制人类感染（如天花、黄热病、麻疹、腮腺炎、风疹和水痘）方面非常有效。这些活疫苗刺激强大的体液和细胞介导的免疫力，可在接种疫苗后持续数十年。尽管它们有效，但使用减毒活疫苗也存在缺点，包括毒力返强、严重的不良反应以及孕妇和免疫功能低下个体的禁忌症。鉴于这些风险，疫苗制剂越来越多地基于高度纯化的亚单位抗原和/或通过重组DNA技术产生的抗原。然而，亚单位抗原本质上是弱免疫原，因此与称为佐剂的物质混合以增强免疫原性。只有少数佐剂被批准用于人类使用，并且目前使用的佐剂灭活/亚单位疫苗主要引起体液免疫，通常需要重复免疫以维持免疫的保护水平，并且通常刺激差的CD 8 T细胞应答。人们逐渐达成共识，针对复杂病原体的疫苗，如艾滋病毒，M。结核病和疟原虫将需要抗体和CD 8 T细胞。结合活疫苗的免疫原性（引发强抗体和CD 8 T细胞免疫）和亚单位疫苗的安全性的联合收割机的疫苗制剂的开发仍然是免疫学家的艰巨挑战。 卡波姆（丙烯酸的聚合物）已在制药工业中用于实现片剂中药物的受控释放，并在粘膜应用中用作生物粘合剂。我们已经鉴定了一种基于卡波姆的佐剂，其在单次免疫后刺激了对可溶性抗原的令人惊讶的强效CD 8 T细胞应答。值得注意的是，由这种佐剂引起的CD 8 T细胞应答与用重组牛痘病毒和牛痘病毒感染诱导的那些一样强，已知重组牛痘病毒和牛痘病毒刺激稳健的细胞介导的免疫。中心假设是，“像活疫苗一样，卡波姆佐剂亚单位疫苗编程持久和保护性CD 8 T细胞记忆的发展，赋予针对全身和呼吸道病毒感染的长期免疫力”。本提案的具体目的是：（1）研究效应和记忆CD 8 T细胞的分化是否因活复制型和卡波姆佐剂亚基非复制型抗原而不同;（2）确定由活疫苗和非复制型卡波姆佐剂疫苗诱导的记忆CD 8 T细胞是否在其针对全身性和呼吸道病毒感染的保护能力方面不同。所提出的研究将通过复制和非复制可溶性抗原提供对效应和记忆CD 8 T细胞的编程的基本见解，并且预计将在CD 8 T细胞记忆领域产生重大影响。该提议的高度创新方面是开发安全的亚单位疫苗的潜力，所述亚单位疫苗在刺激针对人类细胞内病原体的细胞介导的免疫中与活疫苗一样具有免疫原性。 公共卫生相关性：开发有效的疫苗是控制人类传染病的经过时间考验的方法。目前使用的灭活或亚单位疫苗是安全的，但主要诱导抗体，不能刺激足够的CD 8 T细胞免疫。关键是要开发亚单位疫苗，刺激有效的抗体和CD 8 T细胞反应，以防止艾滋病，结核病和疟疾。这项建议的研究可能会导致鉴定一种佐剂，可以刺激有效的体液和细胞介导的免疫力，对细胞内的病原体的人。

DESCRIPTION (provided by applicant): Live attenuated vaccines have been highly effective in controlling human infections such as smallpox, yellow fever, measles, mumps, rubella, and chicken pox. These live vaccines stimulate robust humoral and cell-mediated immunity that can persist for decades after vaccination. Despite their effectiveness, there are disadvantages of using live attenuated vaccines, which include reversion to virulence, severe adverse effects, and contraindication in pregnant and immunocompromised individuals. In light of these risks, vaccine formulations are increasingly based on highly purified subunit antigens and/or antigens produced by recombinant DNA technology. However, subunit antigens are intrinsically poor immunogens and therefore mixed with substances called adjuvants to enhance immunogenicity. There are only a few adjuvants approved for human use and currently used adjuvanted inactivated/subunit vaccines largely elicit humoral immunity, often require repeated immunization to maintain protective levels of immunity, and typically stimulate poor CD8 T cell responses. There is emerging consensus that vaccines against complex pathogens like HIV, M. tuberculosis, and Plasmodium will require both antibodies and CD8 T cells. Development of vaccine formulations that combine the immunogenicity of live vaccines (elicit strong antibody and CD8 T cell immunity) and the safety of subunit vaccines remains a daunting challenge for immunologists. Carbomers (polymers of acrylic acid) have been used in the pharmaceutical industry to achieve controlled release of medications in tablets and as a bioadhesive in mucosal applications. We have identified a carbomer-based adjuvant that stimulated a surprisingly potent CD8 T cell response to a soluble antigen, following a single immunization. Remarkably, the CD8 T cell response elicited by this adjuvant was as strong as those induced by infection with recombinant listeria and vaccinia virus, which are known to stimulate robust cell-mediated immunity. The central hypothesis is that, "Like live vaccines, carbomer-adjuvanted subunit vaccine programs the development of durable and protective CD8 T cell memory that confers long-term immunity against systemic and respiratory viral infections". The specific aims of this proposal are to: (1) investigate whether differentiation of effector and memory CD8 T cells differs for live replicating and carbomer- adjuvanted subunit non-replicating antigens; (2) determine whether memory CD8 T cells induced by live vaccines and non-replicating carbomer-adjuvanted vaccine differ in their protective abilities against systemic and respiratory viral infections. The proposed studies will provide fundamental insights into the programming of effector and memory CD8 T cells by replicating and non-replicating soluble antigens, and are expected to have high impact in the field of CD8 T cell memory. The highly innovative aspect of this proposal is the potential for developing safe subunit vaccines that are as immunogenic as live vaccines in stimulating cell-mediated immunity against intracellular pathogens of humans. PUBLIC HEALTH RELEVANCE: Development of effective vaccines is the time-tested approach for controlling infectious diseases of humans. Currently used inactivated or subunit vaccines are safe but primarily induce antibodies and fail to stimulate adequate CD8 T cell immunity. It is crucial to develop subunit vaccines that stimulate potent antibodies and CD8 T cell responses to protect against AIDS, tuberculosis, and malaria. Studies in this proposal might lead to the identification of an adjuvant that can stimulate potent humoral and cell-mediated immunity against intracellular pathogens of humans.