Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan; Department of Biological Science and Technology, Tokyo University of Science, Tokyo, Japan.
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan; Department of Biological Science and Technology, Tokyo University of Science, Tokyo, Japan.
Vaccine. 2022 Sep 29;40(41):5892-5903. doi: 10.1016/j.vaccine.2022.08.049. Epub 2022 Aug 26.
To control the coronavirus disease 2019 (COVID-19) pandemic, there is a need to develop vaccines to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. One candidate is a nasal vaccine capable of inducing secretory IgA antibodies in the mucosa of the upper respiratory tract, the initial site of infection. However, regarding the development of COVID-19 vaccines, there is concern about the potential risk of inducing lung eosinophilic immunopathology as a vaccine-associated enhanced respiratory disease as a result of the T helper 2 (Th2)-dominant adaptive immune response. In this study, we investigated the protective effect against virus infection induced by intranasal vaccination of recombinant trimeric spike protein derived from SARS-CoV-2 adjuvanted with CpG oligonucleotides, ODN2006, in mouse model. The intranasal vaccine combined with ODN2006 successfully induced not only systemic spike-specific IgG antibodies, but also secretory IgA antibodies in the nasal mucosa. Secretory IgA antibodies showed high protective ability against SARS-CoV-2 variants (Alpha, Beta and Gamma variants) compared to IgG antibodies in the serum. The nasal vaccine of this formulation induced a high number of IFN-γ-secreting cells in the draining cervical lymph nodes and a lower spike-specific IgG1/IgG2a ratio compared to that of subcutaneous vaccination with alum as a typical Th2 adjuvant. These features are consistent with the induction of the Th1 adaptive immune response. In addition, mice intranasally vaccinated with ODN2006 showed less lung eosinophilic immunopathology after viral challenge than mice subcutaneously vaccinated with alum adjuvant. Our findings indicate that intranasal vaccine adjuvanted with ODN2006 could be a candidate that can prevent the infection of antigenically different variant viruses, reducing the risk of vaccine-associated enhanced respiratory disease.
为了控制 2019 年冠状病毒病（COVID-19）大流行，需要开发疫苗来预防严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）变体的感染。一种候选疫苗是鼻内疫苗，能够在上呼吸道粘膜中诱导分泌型 IgA 抗体，这是感染的初始部位。然而，在 COVID-19 疫苗的开发方面，人们担心由于辅助性 T 细胞 2（Th2）优势适应性免疫反应，鼻内疫苗接种可能会导致与疫苗相关的增强性呼吸道疾病，从而引发肺部嗜酸性免疫病理学。在这项研究中，我们研究了鼻腔内接种与 CpG 寡核苷酸 ODN2006 佐剂的 SARS-CoV-2 重组三聚体刺突蛋白鼻内疫苗在小鼠模型中对病毒感染的保护作用。鼻内疫苗与 ODN2006 联合成功诱导了不仅系统特异性 IgG 抗体，而且还诱导了鼻黏膜分泌型 IgA 抗体。与血清中的 IgG 抗体相比，分泌型 IgA 抗体对 SARS-CoV-2 变体（Alpha、Beta 和 Gamma 变体）具有更高的保护能力。与作为典型 Th2 佐剂的铝佐剂皮下接种相比，该制剂的鼻内疫苗在引流颈淋巴结中诱导了更多的 IFN-γ 分泌细胞，并且 Spike 特异性 IgG1/IgG2a 比值较低。这些特征与 Th1 适应性免疫反应的诱导一致。此外，与铝佐剂皮下接种相比，用 ODN2006 鼻腔内接种的小鼠在病毒攻击后肺部嗜酸性免疫病理学的程度较低。我们的研究结果表明，用 ODN2006 佐剂的鼻内疫苗可能是一种候选疫苗，可预防抗原不同的变体病毒感染，降低与疫苗相关的增强性呼吸道疾病的风险。
