Hitchhiking Across the Mucosa

Many pathogens, ranging from HIV to SARS-CoV-2, are transmitted through mucosal surfaces and are thought to require a ‘frontline’ immune response in the mucosa as well as ‘backup’ defense in the blood for effective protection. Yet, traditional parenteral vaccines that are administered by subcutaneous or intramuscular injection typically elicit poor mucosal immunity. While vaccination at mucosal surfaces is known to activate mucosal immunity, development of mucosal vaccines has long been plagued by poor uptake and delivery of vaccine components across mucosal barriers, resulting in weak immune responses. As a result, only a small number of mucosal vaccines have reached the clinic, most of which are based on live attenuated pathogens that naturally infect mucosal surfaces, which cannot be used by transplant patients and others who are immunocompromised. Thus, development of technologies to overcome barriers to mucosal delivery while meeting safety and efficacy requirements of prophylactic vaccines remains an urgent unmet need. 

While mucosal barriers are very good at keeping most vaccine components out, the endogenous protein albumin is known to be very good at getting in. Albumin, a major blood protein also present in mucosal fluids that functions in vivo as a fatty acid transporter, is constitutively transcytosed across mucosal barriers by interactions with the neonatal Fc receptor (FcRn) expressed on mucosal epithelial cells. We are developing intranasal amphiphile vaccines that exploit this biology by 'hitchhiking' on albumin across mucosal barriers for more efficient uptake into the underlying nasal-associated lymphoid tissue (NALT). 'Amph vaccines', consisting of immunogens conjugated to an albumin-binding amphiphilic tail, exhibit enhanced FcRn-dependent uptake into the nasal mucosal tissue leading to enhanced germinal center responses in the NALT. Compared to soluble protein antigens or parenterally administered antigens, intranasal amph vaccines prime significant systemic and mucosal humoral immune responses across multiple mucosal tissues. We are working on continued development of this vaccine platform against a range of mucosally-transmitted pathogens, correlating vaccine design parameters with mucosal uptake and functional immune protection. Employing amph-vaccines to deliver antigen across the mucosal epithelium is a promising strategy to promote mucosally-transmitted pathogens such as HIV, SARS-CoV-2, influenza, and cytomegalovirus (CMV).

[1] Intranasal vaccine uptake is typically impeded by rapid mucociliary clearance, degradation in the mucosal layer, and lack of diffusive uptake across mucosal epithelium. Amph vaccines use endogenous albumin, which is trancytosed across mucosal epithelium by binding the neonatal Fc receptor (FcRn), as a chaperone to hitchhike across mucosal barriers for uptake into the underlying nasal-associated lymphoid tissue (NALT) in order to activate 'frontline' mucosal immune protection.

[2] 'Albumin hitchhiking' enables enhanced retention of amph vaccines in the nasal passage (B), efficient FcRn-mediated uptake into nasal epithelium and underlying submucosa (C), and activation of germinal center (GC) B cells in the NALT (D). (Adapted from Hartwell et al. Science Translational Medicine, 2022.)

Supporting publications:

Hartwell BL, Melo MB, Xiao P, Lemnios AA, Li N, Chang JYH, Yu J, Gebre MS, Chang A, Maiorino L, Carter C, Moyer TJ, Dalvie NC, Rodriguez-Aponte SA, Rodrigues KA, Silva M, Suh H, Adams J, Fontenot J, Love JC, Barouch DH, Villinger F, Ruprecht RM, Irvine DJ. “Intranasal vaccination with lipid-conjugated immunogens promotes antigen transmucosal uptake to drive mucosal and systemic immunity.” Science Translational Medicine. 2022 Jul 20;14(654):eabn1413. DOI: 10.1126/scitranslmed.abn1413.

Szoka FC Jr. “A hitchhiker's guide to mucosal and systemic immunity.” Science Translational Medicine. 2022 Jul 20;14(654):eadc8697. doi: 10.1126/scitranslmed.adc8697.

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