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 粘膜和抗体依赖性增强（ADE）的风险最小化。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免疫抑制剂结合起来， 载体佐剂和强大的体液成分。特别是，我们的初步数据显示， 候选人刺激猕猴的T细胞反应，在10个月后几乎没有减弱 预防针 我们假设，一种记忆促进腺病毒（MPAd）驱动了对SARS的强烈的CD 4 + T细胞应答。 提供气道驻留保护和上级B细胞辅助功能的CoV-2。 目的1：证明对MPAd/N疫苗接种的稳健、持久的CD 4 + T细胞应答，定位于气道 并且超过了用传统广告载体看到的响应。在这里，我们测试关键的差异化特征 Tendel的促进记忆的Ad疫苗，以前被证明用于免疫SIV Gag， 在对SARS-CoV-2核衣壳免疫时也观察到。我们的假设预测平衡的CD 4和 具有效应记忆特征和定位于气道的CD 8应答，其维持在最低限度 在整个实验过程中。 里程碑1：证明MPAd疫苗在诱导气道中SARS-CoV-2特异性T细胞方面的优越性。 目的2：评估接受SARS-CoV-2中和抗体和亚型的恒河猴 Ad/RBD与MPAd/RBD。Tendel旨在提供第二代SARS-CoV-2疫苗， 通过结合适当的T细胞和B细胞应答而增强的趋势。以前的一些报告 证明了IgG 1类Th 2相关抗体的外源性ADE增强，以及内源性ADE增强。 ADE与Th 2相关效应器机制有关，尤其是IL-10。为此，我们测试抗体 通过比较Ad/RBD与MPAd/RBD引起的抗体的亚类和增强能力，以确定Ad/RBD引起的抗体的亚类和增强能力。 是第二代疫苗的最佳组成部分。 里程碑2：选择不介导ADE的最佳B细胞靶向疫苗组分， 在一个实施方案中，本发明提供了与基于MPAD的T细胞组分组合的组合。 这些创新的第一阶段实验将足以建立技术优点， 已证实商业和政府对SARS-CoV-2的广告载体疫苗接种感兴趣-商业 Tendel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.