The first two mRNA vaccines against infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that were approved by regulators require a cold chain and were designed to elicit systemic immunity via intramuscular injection. Here we report the design and preclinical testing of an inhalable virus-like-particle as a COVID-19 vaccine that, after lyophilisation, is stable at room temperature for over three months. The vaccine consists of a recombinant SARS-CoV-2 receptor-binding domain (RBD) conjugated to lung-derived exosomes which, with respect to liposomes, enhance the retention of the RBD in both the mucus-lined respiratory airway and in lung parenchyma. In mice, the vaccine elicited RBD-specific IgG antibodies, mucosal IgA responses and CD4⁺ and CD8⁺ T cells with a Th1-like cytokine expression profile in the animals’ lungs, and cleared them of SARS-CoV-2 pseudovirus after a challenge. In hamsters, two doses of the vaccine attenuated severe pneumonia and reduced inflammatory infiltrates after a challenge with live SARS-CoV-2. Inhalable and room-temperature-stable virus-like particles may become promising vaccine candidates.

监管机构批准的前两种针对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染的 mRNA 疫苗需要冷链，旨在通过肌肉注射激发全身免疫。在此，我们报告了一种可吸入病毒样颗粒作为 COVID-19 疫苗的设计和临床前测试，该疫苗冻干后可在室温下稳定三个月以上。该疫苗由与肺源性外泌体缀合的重组 SARS-CoV-2 受体结合域 (RBD) 组成，相对于脂质体，可增强 RBD 在粘液衬里的呼吸道和肺实质中的保留。在小鼠中，该疫苗在动物肺部引发了 RBD 特异性 IgG 抗体、粘膜 IgA 反应以及具有 Th1 样细胞因子表达谱的 CD4 ⁺和 CD8 ⁺ T 细胞，并在攻击后清除了它们的 SARS-CoV-2 假病毒。在仓鼠中，在受到活 SARS-CoV-2 攻击后，注射两剂疫苗可减轻严重肺炎并减少炎症浸润。可吸入且室温稳定的病毒样颗粒可能成为有希望的候选疫苗。