The parasite Trypanosoma cruzi is the causative agent of Chagas disease, a potentially life-threatening infection that represents a major health problem in Latin America. Several characteristics of this protozoan contribute to the lack of an effective vaccine, among them: its silent invasion mechanism, T. cruzi antigen redundancy and immunodominance without protection. Taking into account these issues, we engineered Traspain, a chimeric antigen tailored to present a multivalent display of domains from key parasitic molecules, combined with stimulation of the STING pathway by c-di-AMP as a novel prophylactic strategy. This formulation proved to be effective for the priming of functional humoral responses and pathogen-specific CD8+ and CD4+ T cells, compatible with a Th1/Th17 bias. Interestingly, vaccine effectiveness assessed across the course of infection, showed a reduction in parasite load and chronic inflammation in different proof of concept assays. In conclusion, this approach represents a promising tool against parasitic chronic infections.

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The need for more effective influenza vaccines is highlighted by the emergence of novel influenza strains, which can lead to new pandemics. There is a growing population of susceptible subjects at risk for severe complications of influenza, such as the elderly who are only in part protected by current licensed seasonal vaccines. One strategy for improving seasonal and pandemic vaccines takes advantage of adjuvants to boost and modulate evoked immune responses. In this study, we examined the capacity of the recently described adjuvant cyclic di-adenosine monophosphate (c-di-AMP) to serve as an adjuvant for improved mucosal influenza vaccines, and induce effective protection against influenza H5N1. In detail, c-di-AMP promoted (i) effective local and systemic humoral immune responses, including protective hemagglutination inhibition titers, (ii) effective cellular responses, including multifunctional T cell activity, (iii) induction of long-lasting immunity, and (iv) protection against viral challenge. Furthermore, we demonstrated the dose-sparing capacity of the adjuvant as well as the ability to evoke cross-clade protective immune responses. Overall, our results suggest that c-di-AMP contributes to the generation of a protective cell-mediated immune response required for efficacious vaccination against influenza, which supports the further development of c-di-AMP as an adjuvant for seasonal and pandemic influenza mucosal vaccines.

In vaccine development, activating the immune system is the major challenge. In this perspective, transcutaneous immunization (TCI) offers an attractive approach due to the presence of abundant antigen presenting cells (APCs) such as Langerhans cells and dendritic cells. In particular transfollicular vaccination aims to deliver antigens to the abundant perifollicular APCs without compromising the SC barrier function. The present work clearly demonstrates the potential of transfollicular immunization as an approach to deliver antigens across intact skin following co-administration of nanoparticles with an adjuvant on intact skin as well as stimulating and modulating efficient humoral and cellular immune response according to the specific clinical needs. Conflict of interest:Claus Prior presentations:Parts of this study were presented on international conferences as listed below. There is no conflict of copy rights with these abstracts or proceedings.

Transfollicular antigen delivery through the intact skin is an interesting new avenue for needle-free vaccination. The aim of this work was to evaluate the potential of surfactant based inverse micellar sugar glass nanoparticles (IMSG NPs) as a delivery system for such purpose. To this end, we evaluated the strength and type of immune response elicited after administration of IMSG NPs containing the model antigen ovalbumin (OVA) by intranasal, transfollicular or intradermal route. Furthermore, we explored the possibility of improving the immune response elicited by co-encapsulating the adjuvant bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di-AMP) and OVA within one particulate carrier system. The study showed enhanced stability and encapsulation efficacy of the antigen when encapsulated in IMSG NPs in comparison to polylactic-co-glycolic acid (PLGA) and chitosan-PLGA NPs. Moreover, by transfollicular delivery, IMSG NPs showed enhanced follicular uptake in comparison to OVA solution or OVA-loaded chitosan-PLGA NPs. While the immune response stimulated after intranasal administration was negligible, significant humoral and cellular responses were observed after immunization via transfollicular and intradermal route. This holds particularly true when OVA and c-di-AMP were co-encapsulated in IMSG NPs, as compared to OVA±c-di-AMP solution or OVA-loaded IMSG NPs without adjuvantation. The results of this study underscore not only the potential of transfollicular vaccination, but also the need for optimized nanocarriers and adjuvants.