Memory-promoting Ad vaccine for long-lived protection against SARS-CoV-2

这笔赠款将为第二代SARS-CoV-2疫苗建立免疫学概念验证 提供非常持久的T细胞和抗体反应，共同保护呼吸道 并将抗体依赖增强(ADE)的风险降至最低。疫苗平台 将腺病毒载体疫苗的免疫刺激能力和已证实的安全性与新型疫苗相结合。 媒介佐剂和强大的体液成分。特别是，我们的初步数据显示，这种疫苗 候选刺激猕猴的T细胞反应，10个月后几乎不会减弱 接种疫苗。 我们假设，促进记忆的腺病毒(MPAD)驱动强大的CD4T细胞对SARS的反应- CoV-2，既提供呼吸道驻留保护，又具有卓越的B细胞辅助功能。 目标1：表现出对MPAD/N疫苗的强大、持久的CD4T细胞应答，定位于呼吸道 并且超过了传统广告载体的响应。在这里，我们测试关键的差异化功能 Tendel的促进记忆的Ad疫苗中，以前被证明用于免疫SIV Gag的是 在对SARS-CoV-2核衣壳免疫时也可见。我们的假设预测了平衡的CD4和 具有效应器记忆特性和对呼吸道的定位的CD8反应，维持在最低限度 在整个实验过程中都使用了双弹药。 里程碑1：证明MPAD疫苗在诱导呼吸道SARS-CoV-2特异性T细胞方面的优越性。 目的2：评价感染SARS-CoV-2的猕猴体内SARS-CoV-2中和抗体及其亚型 AD/RBD与MPAD/RBD。Tendel的目标是提供第二代SARS-CoV-2疫苗，以避免任何 通过结合适当的T细胞和B细胞反应来增强的趋势。此前的一些报道称 对IgG1类Th2相关抗体以及内源性抗体的外源性ADE增强 ADE与Th2相关的效应机制有关，尤其是IL-10。为了达到这个目的，我们测试了抗体 Ad/RBD与MPAD/RBD诱导的抗体亚类和增强能力 包括在第二代疫苗中的最佳成分。 里程碑2：选择最佳的B细胞靶向疫苗成分，该成分不会介导ADE，用于 与基于MPAD的T细胞组件相结合。 这些创新的第一阶段实验将足以建立技术优势和-鉴于 商业和政府对针对SARS-CoV-2的广告载体疫苗的兴趣-商业 坦德尔方法的潜力。

This grant will establish immunologic proof-of-concept for a second-generation SARS-CoV-2 vaccine providing extraordinarily durable T-cell and antibody responses, which together protect the respiratory mucosa and minimize the risk of antibody-dependent enhancement (ADE). The vaccine platform combines the immunostimulatory power and proven safety of adenovirus-vectored vaccines with novel in- vector adjuvants and a robust humoral component. In particular, our preliminary data show that this vaccine candidate stimulates T-cell responses in macaques that are virtually undiminished ten months after vaccination. We hypothesize that a memory-promoting adenovirus (MPAd) drives robust CD4+ T-cell responses to SARS- CoV-2 that provide both airway-resident protection and superior B-cell helper function. Aim 1: Demonstrate robust, durable CD4+ T-cell responses to MPAd/N vaccination, localized to airways and exceeding responses seen with conventional Ad vectors. Here we test if key differentiating features of Tendel’s memory-promoting Ad vaccine, previously demonstrated for immunization against SIV Gag, are also seen when immunizing against SARS-CoV-2 nucleocapsid. Our hypothesis predicts balanced CD4 and CD8 responses with effector-memory character and localization to airways, which are maintained with minimal dimunition throughout the experiment. Milestone 1: Demonstrate superiority of MPAd vaccine for eliciting SARS-CoV-2-specific T cells in airways. Aim 2: Evaluate SARS-CoV-2 neutralizing antibodies and subtypes in rhesus macaques receiving Ad/RBD vs. MPAd/RBD. Tendel aims to provide a second-generation SARS-CoV-2 vaccine that evades any tendency to enhancement by combining appropriate T-cell and B-cell responses. Some previous reports have demonstrated enhanced extrinsic ADE for Th2-associated antibodies of the IgG1 class, as well as intrinsic ADE that is linked to Th2-associated effector mechanisms, especially IL-10. In this aim we test the antibody subclasses and capacity for enhancement of antibodies elicited by Ad/RBD vs. MPAd/RBD, to determine the best component for inclusion in a second-generation vaccine. Milestone 2: Choose an optimal B cell-targeted vaccine component, which does not mediate ADE, for combination with an MPAd-based T-cell component. These innovative Phase I experiments will be sufficient to establish both the technical merit and—in light of the proven commercial and government interest in Ad-vectored vaccination against SARS-CoV-2—the commercial potential of Tendel’s approach.