An RBD-Fc mucosal vaccine provides variant-proof protection against SARS-CoV-2 in mice and hamsters.

IF 6.9 1区 医学 Q1 IMMUNOLOGY
Yanjun Zhang, Yan Wu, Meng-Qian Zhang, Haiyue Rao, Zhaoyong Zhang, Xiangyue He, Yiwen Liang, Raoqing Guo, Yaochang Yuan, Jing Sun, Helen M E Duyvesteyn, Elizabeth E Fry, David I Stuart, Jingxian Zhao, XiaoYan Pan, Shu-Lin Liu, Jincun Zhao, Jiandong Huo
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Abstract

Current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are effective against severe disease and death, but do not prevent viral infections, probably due to the limited mucosal immunity induced by intramuscular administration of the vaccine. Fusion of SARS-CoV-2 subunit immunogens with a human IgG Fc backbone can be used as a mucosal vaccine but its effectiveness in delivery in animal models, and its immunogenicity and the vaccine-induced protection against viral infections requires further studies. Here we investigate a bivalent RBD-Fc vaccine that includes the spike receptor-binding domains (RBDs) of the ancestral and BQ.1.1 variant of SARS-CoV-2. Ex vivo fluorescent imaging demonstrates that this vaccine can be effectively delivered to the lungs of mice through intranasal administration, with enhancement of retention in the nasal cavity and lung parenchyma. In mice, the vaccine elicited potent and broad-spectrum antibody responses against different variants including KP.3 which could persist for at least 3 months after booster. Importantly, it was able to induce RBD-specific mucosal IgA responses. Further, heterologous intranasal immunisation with adeno-vectored Chadv1 and RBD-Fc elicited both potent neutralising antibody and T cell responses. Immunised BALB/c and K18-hACE2-transgenic mice were also protected against viral challenge of XBB.1 and viral transmission was effectively limited in hamsters through intranasal immunisation. This work thus demonstrates the potential of RBD-Fc antigens as mucosal vaccines for prevention of breakthrough infections and onward transmission. Moreover, Fc-fusion proteins can be used as an effective mucosal vaccine strategy which can be used either alone or in combination with other vaccine technology to constitute heterologous immunisations, enabling strong protection against SARS-CoV-2 and other respiratory viruses.

一种RBD-Fc粘膜疫苗可在小鼠和仓鼠中提供抗SARS-CoV-2变异体保护。
目前的严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)疫苗对严重疾病和死亡有效,但不能预防病毒感染,可能是由于肌肉注射疫苗诱导的粘膜免疫有限。SARS-CoV-2亚单位免疫原与人IgG Fc骨干融合可作为粘膜疫苗,但其在动物模型中的传递有效性、免疫原性和疫苗诱导的病毒感染保护作用有待进一步研究。在这里,我们研究了一种二价RBD-Fc疫苗,该疫苗包括SARS-CoV-2祖先和BQ.1.1变体的刺突受体结合域(rbd)。体外荧光成像显示,该疫苗可以通过鼻内给药有效地递送到小鼠肺部,并增强在鼻腔和肺实质的滞留。在小鼠中,疫苗引发了针对包括KP.3在内的不同变体的强效广谱抗体反应,这种反应在加强后至少持续3个月。重要的是,它能够诱导rbd特异性粘膜IgA反应。此外,用腺载体Chadv1和RBD-Fc进行异源鼻内免疫,可引起有效的中和抗体和T细胞反应。经免疫的BALB/c和k18 - hace2转基因小鼠也能抵抗xbb - 1的病毒攻击,并且通过鼻内免疫有效地限制了病毒在仓鼠中的传播。因此,这项工作证明了RBD-Fc抗原作为预防突破性感染和进一步传播的粘膜疫苗的潜力。此外,fc融合蛋白可作为一种有效的粘膜疫苗策略,可单独使用或与其他疫苗技术联合使用,构成异源免疫,从而对SARS-CoV-2和其他呼吸道病毒具有强大的保护作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
NPJ Vaccines
NPJ Vaccines Immunology and Microbiology-Immunology
CiteScore
11.90
自引率
4.30%
发文量
146
审稿时长
11 weeks
期刊介绍: Online-only and open access, npj Vaccines is dedicated to highlighting the most important scientific advances in vaccine research and development.
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