Intranasal administration of adenoviral vaccines expressing SARS-CoV-2 spike protein improves vaccine immunity in mouse models.
Intranasal administration of adenoviral vaccines expressing SARS-CoV-2 spike protein improves vaccine immunity in mouse models.
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DOI：
10.1016/j.vaccine.2023.04.020
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发表时间：
2023-05-11
期刊：
影响因子：
5.5
通讯作者：
Saksela, Kalle
中科院分区：
文献类型：
--
作者：
Freitag, Tobias L.;Fagerlund, Riku;Karam, Nihay Laham;Leppanen, Veli-Matti;Ugurlu, Hasan;Kant, Ravi;Makinen, Petri;Tawfek, Ahmed;Jha, Sawan Kumar;Strandin, Tomas;Leskinen, Katarzyna;Hepojoki, Jussi;Kesti, Tapio;Kareinen, Lauri;Kuivanen, Suvi;Koivulehto, Emma;Sormunen, Aino;Laidinen, Svetlana;Khattab, Ayman;Saavalainen, Paivi;Meri, Seppo;Kipar, Anja;Sironen, Tarja;Vapalahti, Olli;Alitalo, Kari;Yla-Herttuala, Seppo;Saksela, Kalle
正在进行的SARS-CoV-2大流行得到了控制，但没有被公共卫生措施和大规模疫苗接种战略所阻止，这些措施完全依赖于肌内疫苗。鼻内疫苗可以引发或募集能够预防感染的呼吸道上皮粘膜免疫细胞。在这里，我们报告了一个全面的系列研究，这一概念使用各种小鼠模型，包括HLA II类人源化转基因株。我们发现，单次鼻内（i.n.）表达SARS-CoV-2刺突蛋白的受体结合结构域（Ad 5-RBD）或完整胞外域（Ad 5-S）的血清型5腺病毒载体的剂量有效诱导i）血清和支气管肺泡灌洗液（BAL）抗刺突伊加和IgG，ii）血清和BAL中稳健的SARS-CoV-2中和活性，iii）严格的刺突导向的辅助性T细胞1/细胞毒性T细胞免疫，和iv）保护小鼠免受SARS-CoV-2 β变体的攻击。肌内（i.m.）Ad 5-RBD或Ad 5-S施用不诱导血清或BAL伊加，并且导致血清中较低的中和滴度。此外，由肌内mRNA疫苗诱导的先前免疫可以通过i. n. Ad 5-S增强剂值得注意的是，在i.m.但不是I. N。在一些实施方案中，疫苗载体在施用后没有全身性扩散，这表明缺乏疫苗载体的全身性扩散，这与血栓性血小板减少症的风险相关。与其他遗传上相同的HLA-DQ 6小鼠不同，在HLA-DQ 8小鼠中，Ad 5-RBD疫苗劣于Ad 5-S，表明RBD片段不含有足够的辅助T细胞表位集合以构成最佳疫苗抗原。我们的数据增加了以前有希望的临床前结果鼻内SARS-CoV-2疫苗接种，并支持这种方法的潜力，以引起粘膜免疫，防止传播的SARS-CoV-2。
The ongoing SARS-CoV-2 pandemic is controlled but not halted by public health measures and mass vaccination strategies which have exclusively relied on intramuscular vaccines. Intranasal vaccines can prime or recruit to the respiratory epithelium mucosal immune cells capable of preventing infection. Here we report a comprehensive series of studies on this concept using various mouse models, including HLA class II-humanized transgenic strains. We found that a single intranasal (i.n.) dose of serotype-5 adenoviral vectors expressing either the receptor binding domain (Ad5-RBD) or the complete ectodomain (Ad5-S) of the SARS-CoV-2 spike protein was effective in inducing i) serum and bronchoalveolar lavage (BAL) anti-spike IgA and IgG, ii) robust SARS-CoV-2-neutralizing activity in the serum and BAL, iii) rigorous spike-directed T helper 1 cell/cytotoxic T cell immunity, and iv) protection of mice from a challenge with the SARS-CoV-2 beta variant. Intramuscular (i.m.) Ad5-RBD or Ad5-S administration did not induce serum or BAL IgA, and resulted in lower neutralizing titers in the serum. Moreover, prior immunity induced by an intramuscular mRNA vaccine could be potently enhanced and modulated towards a mucosal IgA response by an i.n. Ad5-S booster. Notably, Ad5 DNA was found in the liver or spleen after i.m. but not i.n. administration, indicating a lack of systemic spread of the vaccine vector, which has been associated with a risk of thrombotic thrombocytopenia. Unlike in otherwise genetically identical HLA-DQ6 mice, in HLA-DQ8 mice Ad5-RBD vaccine was inferior to Ad5-S, suggesting that the RBD fragment does not contain a sufficient collection of helper-T cell epitopes to constitute an optimal vaccine antigen. Our data add to previous promising preclinical results on intranasal SARS-CoV-2 vaccination and support the potential of this approach to elicit mucosal immunity for preventing transmission of SARS-CoV-2.
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