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The exploration and identification of safe and effective vaccines for the SARS-CoV-2 pandemic have captured the world's attention and remains an ongoing issue due to concerns of balancing protection against emerging variants of concern while also generating long-lasting immunity. Here, we report the synthesis of a novel messenger ribonucleic acid encoding the spike protein in a lipid nanoparticle formulation (STI-7264) that generates robust humoral and cellular immunity following immunization of C57Bl6 mice. In an effort to improve immunity, a clinically focused lymphatic drug delivery device (MuVaxx) was engineered to modulate immune cells at the injection site (epidermis and dermis) and draining lymph node (LN) and tested to measure adaptive immunity. Using MuVaxx, immune responses were elicited and maintained at a 10-fold dose reduction compared to traditional intramuscular (IM) administration as measured by anti-spike antibodies, cytokine-producing CD8 T cells, neutralizing antibodies against the Washington (wild type) strain and South African (Beta) variants, and LN-resident spike-specific memory B cells. Remarkably, a 4-fold-elevated T cell response was observed in MuVaxx-administered vaccination compared to that of IM-administered vaccination. Thus, these data support further investigation into STI-7264 and lymphatic-mediated delivery using MuVaxx for SARS-CoV-2 and VoC vaccines.

新型信使核糖核酸疫苗的研发与鉴定

针对 SARS-CoV-2 大流行的安全有效疫苗的研发一直是全球关注的焦点，因为人们担心在平衡针对新出现的关注变异株的保护作用的同时，还需要产生持久的免疫力。在这里，我们报告了一种新型信使核糖核酸的合成，该信使核糖核酸在脂质纳米颗粒制剂中编码刺突蛋白（STI-7264），在 C57Bl6 小鼠免疫接种后可产生强大的体液和细胞免疫。为了提高免疫力，设计了一种临床重点的淋巴药物递送装置（MuVaxx），以调节注射部位（表皮和真皮）和引流淋巴结（LN）中的免疫细胞，并进行了适应性免疫测试。使用 MuVaxx，与传统的肌肉内（IM）给药相比，免疫反应被激发并维持在 10 倍的剂量减少，如抗刺突抗体、产生细胞因子的 CD8 T 细胞、针对华盛顿（野生型）株和南非（Beta）变异株的中和抗体以及 LN 驻留的刺突特异性记忆 B 细胞。值得注意的是，与肌肉内给药相比，MuVaxx 给药的疫苗接种引起的 T 细胞反应提高了 4 倍。因此，这些数据支持进一步研究 STI-7264 和使用 MuVaxx 进行 SARS-CoV-2 和 VoC 疫苗的淋巴介导递送。