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

描述(由申请人提供)：减毒活疫苗在控制天花、黄热病、麻疹、腮腺炎、风疹和水痘等人类感染方面非常有效。这些活疫苗刺激强大的体液和细胞介导的免疫，在接种疫苗后可以持续数十年。尽管有效，但使用减毒活疫苗也有缺点，包括恢复毒力、严重的不良反应以及对怀孕和免疫受损个体的禁忌症。鉴于这些风险，疫苗配方越来越多地以高度纯化的亚单位抗原和/或重组DNA技术产生的抗原为基础。然而，亚单位抗原本质上是免疫原性差的，因此与称为佐剂的物质混合以增强免疫原性。目前只有几种佐剂被批准用于人类使用，目前使用的佐剂灭活疫苗/亚单位疫苗在很大程度上可以诱导体液免疫，通常需要重复免疫以维持保护性免疫水平，并且通常刺激较差的CD8 T细胞反应。一个新的共识是，针对艾滋病毒、结核分枝杆菌和疟疾等复杂病原体的疫苗将同时需要抗体和CD8T细胞。对于免疫学家来说，开发结合了活疫苗的免疫原性(引发强大的抗体和CD8 T细胞免疫)和亚单位疫苗安全性的疫苗配方仍然是一个令人生畏的挑战。卡波姆(丙烯酸聚合物)已被用于制药工业，以实现药物在片剂中的控制释放，并在粘膜应用中用作生物粘合剂。我们已经确定了一种基于卡波姆的佐剂，在单次免疫后，它能刺激对可溶性抗原的惊人强大的CD8T细胞反应。值得注意的是，这种佐剂诱导的CD8T细胞反应与重组李斯特菌和痘苗病毒感染的CD8 T细胞反应一样强，这两种病毒被认为能刺激强大的细胞免疫。中心假说是，“就像活疫苗一样，卡波姆佐剂亚单位疫苗规划了持久和保护性的CD8 T细胞记忆的发展，从而赋予对全身和呼吸道病毒感染的长期免疫力”。该建议的具体目的是：(1)研究活体复制和卡波姆佐剂亚单位非复制型抗原诱导的效应性和记忆性CD8 T细胞分化是否不同；(2)确定活疫苗和非复制型卡波姆佐剂疫苗诱导的记忆性CD8 T细胞对全身和呼吸道病毒感染的保护能力是否不同。这项研究将为通过复制和非复制可溶性抗原来编程效应器和记忆性CD8T细胞提供基础的见解，并有望在CD8T细胞记忆领域产生重大影响。这一提议的高度创新方面是开发安全的亚单位疫苗的潜力，这种亚单位疫苗在刺激针对人类细胞内病原体的细胞介导免疫方面与活疫苗一样具有免疫原性。

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.