Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
Sci Transl Med. 2022 Jul 20;14(654):eabn1413. doi: 10.1126/scitranslmed.abn1413.
To combat the HIV epidemic and emerging threats such as SARS-CoV-2, immunization strategies are needed that elicit protection at mucosal portals of pathogen entry. Immunization directly through airway surfaces is effective in driving mucosal immunity, but poor vaccine uptake across the mucus and epithelial lining is a limitation. The major blood protein albumin is constitutively transcytosed bidirectionally across the airway epithelium through interactions with neonatal Fc receptors (FcRn). Exploiting this biology, here, we demonstrate a strategy of "albumin hitchhiking" to promote mucosal immunity using an intranasal vaccine consisting of protein immunogens modified with an amphiphilic albumin-binding polymer-lipid tail, forming amph-proteins. Amph-proteins persisted in the nasal mucosa of mice and nonhuman primates and exhibited increased uptake into the tissue in an FcRn-dependent manner, leading to enhanced germinal center responses in nasal-associated lymphoid tissue. Intranasal immunization with amph-conjugated HIV Env gp120 or SARS-CoV-2 receptor binding domain (RBD) proteins elicited 100- to 1000-fold higher antigen-specific IgG and IgA titers in the serum, upper and lower respiratory mucosa, and distal genitourinary mucosae of mice compared to unmodified protein. Amph-RBD immunization induced high titers of SARS-CoV-2-neutralizing antibodies in serum, nasal washes, and bronchoalveolar lavage. Furthermore, intranasal amph-protein immunization in rhesus macaques elicited 10-fold higher antigen-specific IgG and IgA responses in the serum and nasal mucosa compared to unmodified protein, supporting the translational potential of this approach. These results suggest that using amph-protein vaccines to deliver antigen across mucosal epithelia is a promising strategy to promote mucosal immunity against HIV, SARS-CoV-2, and other infectious diseases.
为了应对 HIV 疫情和 SARS-CoV-2 等新出现的威胁,我们需要制定免疫策略,以在病原体进入的黏膜门户处产生保护作用。直接通过气道表面进行免疫接种可有效地驱动黏膜免疫,但穿过黏液和上皮衬里的疫苗摄取不良是一个限制。主要的血液蛋白白蛋白通过与新生 Fc 受体(FcRn)的相互作用,双向构成性地穿过气道上皮细胞被转导。利用这种生物学特性,我们在这里展示了一种“白蛋白搭便车”策略,该策略使用一种鼻腔内疫苗来促进黏膜免疫,该疫苗由用两性亲和聚合物-脂质尾巴修饰的蛋白免疫原组成,形成两性蛋白(amph-proteins)。两性蛋白在小鼠和非人类灵长类动物的鼻黏膜中持续存在,并以 FcRn 依赖的方式增加组织摄取,从而导致鼻相关淋巴组织中的生发中心反应增强。鼻腔内免疫接种与两性-conjugated HIV Env gp120 或 SARS-CoV-2 受体结合域(RBD)蛋白,与未修饰的蛋白相比,可使血清、上呼吸道和下呼吸道黏膜以及远位生殖泌尿道黏膜中的抗原特异性 IgG 和 IgA 滴度分别提高 100 至 1000 倍。两性-RBD 免疫接种可诱导出高滴度的针对 SARS-CoV-2 的中和抗体,存在于血清、鼻腔冲洗液和支气管肺泡灌洗液中。此外,恒河猴的鼻腔内两性蛋白免疫接种可使血清和鼻黏膜中的抗原特异性 IgG 和 IgA 反应分别提高 10 倍,与未修饰的蛋白相比,这支持了该方法的转化潜力。这些结果表明,使用两性蛋白疫苗在黏膜上皮细胞中传递抗原是一种很有前途的策略,可以促进针对 HIV、SARS-CoV-2 和其他传染病的黏膜免疫。
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