Intranasal vaccination with lipid-conjugated immunogens promotes antigen transmucosal uptake to drive mucosal and systemic immunity

Abstract

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.

An FcRn-targeted mucosal vaccine against SARS-CoV-2 infection and transmission

“…FcRn bounds S-Fc in acidic pH conditions. A slightly acidic pH in the respiratory tract 27 is expected to facilitate FcRn to retain antigens in airway mucosal surfaces and transfer them across the airway barrier, as shown by our previous studies 28,29 and others 30 . The local Ab immune responses can represent a primary barrier of immune defense against viral infections of the respiratory tract, characterized by the presence of sIgA in the nasal mucosa or IgG in the BAL 10 .…”

Targeted modulation of immune cells and tissues using engineered biomaterials

“…6a). Similar to the backpacking approach, protein or peptide antigens linked to PEG-lipids (amph-vaccines) associate with albumin in the airway fluid and 'hitchhike' through the mucus across the epithelial barrier in an FcRn-dependent manner 28,143 . Peptide amph-vaccines that were administered into the lungs primed robust lung tissue-resident memory T cells that enhanced vaccine protection against respiratory viral or tumour challenge 28 .…”

“…Peptide amph-vaccines that were administered into the lungs primed robust lung tissue-resident memory T cells that enhanced vaccine protection against respiratory viral or tumour challenge 28 . Alternatively, intranasal administration of protein amph-vaccines amplified germinal centre responses in the NALT, promoting higher mucosal antibody titres in both mice (100-1,000-fold increase) and non-human primates (10-fold increase), compared with unmodified proteins 143 .…”

Biomaterials for intranasal and inhaled vaccine delivery

“…Alternatively, self-assembling peptides, consisting of a CD8 + T cell epitope fused to a β-sheet nanofiber assembly domain, have been used as inhaled vaccines where immunogenicity can be increased by tuning material properties, such as shape, size, charge and surface composition 8 . Peptide-based amphiphilic antigen immunoconjugates, termed immunogens, that self-assemble into nanoscale micelles have also proven useful for mucosal vaccination 9 . When delivered intranasally, these immunogen nanoparticles are efficiently trafficked to Check for updates nasal-associated lymphoid tissue (NALT), leading to an IgG and IgA immune response, which persist in the nose and other mucosal tissues, such as the vaginal and gastrointestinal tracts.…”