Current vaccines have greatly diminished the severity of the COVID-19 pandemic, even though they do not entirely prevent infection and transmission, likely due to insufficient immunity in the upper respiratory tract. Here, we compare intramuscular and intranasal administration of a live, replication-deficient modified vaccinia virus Ankara (MVA)–based Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike (S) vaccine to raise protective immune responses in the K18-hACE2 mouse model. Using a recombinant MVA expressing firefly luciferase for tracking, live imaging revealed luminescence of the respiratory tract of mice within 6 h and persisting for 3 d following intranasal inoculation, whereas luminescence remained at the site of intramuscular vaccination. Intramuscular vaccination induced S-binding–Immunoglobulin G (IgG) and neutralizing antibodies in the lungs, whereas intranasal vaccination also induced Immunoglobulin A (IgA) and higher levels of antigen-specific CD3 + CD8 + IFN-γ + T cells. Similarly, IgG and neutralizing antibodies were present in the blood of mice immunized intranasally and intramuscularly, but IgA was detected only after intranasal inoculation. Intranasal boosting increased IgA after intranasal or intramuscular priming. While intramuscular vaccination prevented morbidity and cleared SARS-CoV-2 from the respiratory tract within several days after challenge, intranasal vaccination was more effective as neither infectious virus nor viral messenger (m)RNAs were detected in the nasal turbinates or lungs as early as 2 d after challenge, indicating prevention or rapid elimination of SARS-CoV-2 infection. Additionally, we determined that neutralizing antibody persisted for more than 6 mo and that serum induced to the Wuhan S protein neutralized pseudoviruses expressing the S proteins of variants, although with less potency, particularly for Beta and Omicron.

中文翻译：

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鼻内接种基于 MVA 的疫苗可诱导 IgA 并保护 hACE2 小鼠的呼吸道免受 SARS-CoV-2 感染

目前的疫苗已经大大降低了 COVID-19 大流行的严重程度，尽管它们不能完全防止感染和传播，这可能是由于上呼吸道免疫力不足所致。在这里，我们比较了基于复制缺陷型改良痘苗病毒安卡拉 (MVA) 的严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 刺突 (S) 活疫苗的肌内和鼻内给药，以提高 K18 的保护性免疫反应-hACE2 小鼠模型。使用表达萤火虫荧光素酶的重组 MVA 进行跟踪，活体成像显示小鼠呼吸道在 6 小时内发光，并在鼻内接种后持续 3 天，而发光则保留在肌内接种部位。+CD8+干扰素γ+T 细胞。同样，IgG 和中和抗体存在于鼻内和肌内免疫小鼠的血液中，但 IgA 仅在鼻内接种后检测到。在鼻内或肌内引发后，鼻内加强增加了 IgA。虽然肌内接种疫苗可预防发病并在攻击后几天内从呼吸道清除 SARS-CoV-2，但鼻内接种疫苗更有效，因为早在 2 d 攻击后，表明预防或快速消除 SARS-CoV-2 感染。此外，我们确定中和抗体持续超过 6 个月，并且诱导武汉 S 蛋白的血清中和了表达变体 S 蛋白的假病毒，