Objectives The upper respiratory tract is the major entry site for Streptococcus pyogenes and influenza virus. Vaccine strategies that activate mucosal immunity could significantly reduce morbidity and mortality because of these pathogens. The severity of influenza is significantly greater if a streptococcal infection occurs during the viraemic period and generally viral infections complicated by a subsequent bacterial infection are known as super‐infections. We describe an innovative vaccine strategy against influenza virus: S . pyogenes super‐infection. Moreover, we provide the first description of a liposomal multi‐pathogen‐based platform that enables the incorporation of both viral and bacterial antigens into a vaccine and constitutes a transformative development. Methods Specifically, we have explored a vaccination strategy with biocompatible liposomes that express conserved streptococcal and influenza A virus B‐cell epitopes on their surface and contain encapsulated diphtheria toxoid as a source of T‐cell help. The vaccine is adjuvanted by inclusion of the synthetic analogue of monophosphoryl lipid A, 3D‐PHAD. Results We observe that this vaccine construct induces an Immunoglobulin A (IgA) response in both mice and ferrets. Vaccination reduces viral load in ferrets from influenza challenge and protects mice from both pathogens. Notably, vaccination significantly reduces both mortality and morbidity associated with a super‐infection. Conclusion The vaccine design is modular and could be adapted to include B‐cell epitopes from other mucosal pathogens where an IgA response is required for protection.

Highlights An HA-based vaccine candidate, created by DNA shuffling (HA-113), can be immunogenic when the recombinant antigen is expressed by PIV5 (PIV5-113). Immunity induced by the PIV5-113 vaccine can protect mice against infection with 4 of 5 parental HAs used to create the vaccine. Immunity induced by PIV5-113 can protect pigs against infection with an influenza virus isolate that is known to be infectious in pigs.

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Mechanisms of autoimmunity are varied and complex, resulting from the failure of multiple layers of immune tolerance mechanisms. Failures occur in the thymus and bone marrow during lymphocyte development, in the secondary lymphoid organs during activation, and finally at the site of autoimmunity. We will discuss mechanistic insights into autoimmune processes in the periphery. The diverse nature of the cellular composition, milieu, and structure of the target tissue introduces the potential for differing mechanisms of activation and tolerance that are environmentally dependent. Live imaging in autoimmunity provides the ability to analyze immune cell dynamics within the complex environment where disease occurs, including immune cell interactions with each other and the tissue. In depth research imaging the secondary lymphoid organs and tissue target sites, particularly in models of multiple sclerosis (MS) and type 1 diabetes (T1D), have revealed mechanisms of T cell activation and tolerance, immune cell trafficking to the autoimmune disease site, and immune cell function and regulation at the autoimmune site. Preservation of the intact tissue for imaging has been key to many of the findings that resulted from these studies. These findings have informed our knowledge of T cell activation, regulation, and function which is relevant to health, tumors, and autoimmunity.