LAUSR

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. Description Modifying protein antigens with an amphiphile tail promotes uptake in nasal mucosa and amplifies immune responses after intranasal immunization. Winning by a nose Despite the fact that many viruses initially enter the body through mucosal surfaces, most vaccines are administered by nonmucosal routes. This is, in part, due to historically poor development of immune responses after mucosal immunization. To address this, Hartwell et al. developed lipid-conjugated immunogens, called amph-proteins, and administered them intranasally to mice and nonhuman primates; these vaccines, which used the neonatal Fc receptor to mediate transmucosal uptake, elicited immune responses at both local and distal mucosal sites. These data support further development of amph-protein–based intranasal vaccines for immunogens such as the SARS-CoV-2 receptor binding domain and the HIV envelope protein, among others.