Harnessing a mRNA Platform Against Salmonellae

Abstract

Salmonella enterica serotypes are the cause of gastroenteritis outbreaks in developed countries but also have a considerable burden, especially on young children, in developing countries in the form of more severe diseases, namely typhoid fever, paratyphoid fever, and invasive non typhoidal diseases. The widespread use of antibiotics has mitigated the still high mortality rate of these diseases, but also contributed to the emergence of multidrug resistant strains. Concurrently, there is a realization that the available vaccines do not meet the current needs of strain coverage as they are against Salmonella enterica typhi alone. In the last decade, several conserved immunogenic Salmonella proteins have been identified as conferring partial protection in the typhimurium mouse models of typhoid fever. Because no one protein will likely be sufficient, we evaluate the possibility of a polyvalent vaccine by leveraging a mRNA vaccine platform that is well suited for the combination of multiple antigens and has proven effective in inducing T cell responses and neutralizing antibodies against viral pathogens. Here, we try the mRNA approach for a bacterial pathogen. We first show that it is possible to express both secreted and membrane bound Salmonella antigens in mammalian cells, albeit to varying degrees. To explore the immunogenicity of mRNA-encoded bacterial antigens, mice were immunized with selected mRNA constructs encapsulated in biodegradable lipid nanoparticles or recombinant protein as a comparator, and splenic T cells and sera were probed for antigen-specific responses. Certain constructs were strong T cell antigens while for others serum antibodies could also be detected; a phenomenon possibly dependent on distinct cellular retention patterns in vivo. Together, the data indicate that immunization with mRNA-encoded bacterial antigens can trigger both humoral and cellular responses. Whether these responses confer protection remains to be tested.