For over 100 years, vaccines have been one of the most effective medical interventions for reducing infectious disease, and are estimated to save millions of lives globally each year. Nevertheless, many diseases are not yet preventable by vaccination. This large unmet medical need demands further research and the development of novel vaccines with high efficacy and safety. Compared to the 19th and early 20th century vaccines that were made of killed, inactivated, or live-attenuated pathogens, modern vaccines containing isolated, highly purified antigenic protein subunits are safer but tend to induce lower levels of protective immunity. One strategy to overcome the latter is to design antigen nanoparticles: assemblies of polypeptides that present multiple copies of subunit antigens in well-ordered arrays with defined orientations that can potentially mimic the repetitiveness, geometry, size, and shape of the natural host-pathogen surface interactions. Such nanoparticles offer a collective strength of multiple binding sites (avidity) and can provide improved antigen stability and immunogenicity. Several exciting advances have emerged lately, including preclinical evidence that this strategy may be applicable for the development of innovative new vaccines, for example, protecting against influenza, human immunodeficiency virus, and respiratory syncytial virus. Here, we provide a concise review of a critical selection of data that demonstrate the potential of this field. In addition, we highlight how the use of self-assembling protein nanoparticles can be effectively combined with the emerging discipline of structural vaccinology for maximum impact in the rational design of vaccine antigens.

Summary. Background: Endothelial cell protein C receptor (EPCR) binds protein C through its c-carboxyglutamic acid (Gla) domain and enhances its thrombin-thrombomodulin complex-dependent activation. So far, only protein C/ activated protein C has been shown to interact with EPCR. Factor VII (FVII), the coagulation trigger upon tissue factor (TF) interaction, is a serine protease whose Gla domain is highly homologous to the Gla domain of protein C. Objectives: To characterize the binding of FVII/FVIIa to EPCR and its functional consequences. Methods and results:We demonstrated by surface plasmon resonance (SPR) that FVII/FVIIa binds to EPCR through its Gla domain. At therapeutic concentrations, FVIIa reduced the activation of protein C by 40%. Soluble EPCR (sEPCR) was also able to prolong dose-dependently the clotting time induced by the FVIIa-TF complex. SPR and amidolytic experiments showed that FVIIa is able to interact simultaneously with TF and EPCR, thus ruling out the possibility that the effect of EPCR on clotting time was due to the inhibition of the binding between FVIIa and TF. sEPCR inhibited dose-dependently the activation of FX by the FVIIa-TF complex. Notably, blocking the binding site of EPCR on the endothelial surface increased the generation of FXa 2-fold. Conclusions: EPCR binds to FVII/ FVIIa and inhibits the procoagulant activity of the FVIIa-TF complex.

Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved αβ T-cell lineage that express a semi-invariant T-cell receptor (TCR) restricted to the MHC related-1 (MR1) protein. MAIT cells are dependent upon MR1 expression and exposure to microbes for their development and stimulation, yet these cells can exhibit microbial-independent stimulation when responding to MR1 from different species. We have used this microbial-independent, crossspecies reactivity of MAIT cells to define the molecular basis of MAIT-TCR/MR1 engagement and present here a 2.85 Å complex structure of a human MAIT-TCR bound to bovine MR1. The MR1 binding groove is similar in backbone structure to classical peptide-presenting MHC class I molecules (MHCp), yet is partially occluded by large aromatic residues that form cavities suitable for small ligand presentation. The docking of the MAIT-TCR on MR1 is perpendicular to the MR1 surface and straddles the MR1 α1 and α2 helices, similar to classical αβ TCR engagement of MHCp. However, the MAIT-TCR contacts are dominated by the α-chain, focused on the MR1 α2 helix. TCR β-chain contacts are mostly through the variable CDR3β loop that is positioned proximal to the CDR3α loop directly over the MR1 open groove. The elucidation of the MAIT TCR/ MR1 complex structure explains how the semi-invariant MAIT-TCR engages the nonpolymorphic MR1 protein, and sheds light onto ligand discrimination by this cell type. Importantly, this structure also provides a critical link in our understanding of the evolution of αβ T-cell recognition of MHC and MHC-like ligands.M ucosal-associated invariant T (MAIT) cells are a highly conserved T-cell subset found in most mammalian species (1-4). In humans, they can constitute up to 10% of circulating double-negative T cells, although they are much less frequent in mice (1,5,6). Most MAIT cells lack expression of the CD4 or CD8 coreceptors, although many MAIT cells express the αα form of the CD8 coreceptor (1). In humans, these cells are found at moderate frequency in the intestine and represent up to ∼50% of T cells in the liver (7). The cells exhibit an effector-memory phenotype and express the CD161 receptor (6). Their presence as mature effector cells in the periphery is dependent on B cells and the gut commensal flora (6, 8). Stimulated human MAIT cells can express both proinflammatory cytokines (IFN-γ, TNF-α, and IL-17) and cytolytic effectors (granzyme B) (7, 9, 10). MAIT cells are known best for their reactivity against various microorganisms from both bacterial and fungal origin (9, 10). These microorganisms include several important human pathogens, such as Mycobacterium tuberculosis, Salmonella typhimurium, and Staphylococcus aureus. Indeed, a significant proportion of the nonclassically restricted responding T cells in M. tuberculosisinfected individuals were determined to be of the MAIT lineage (9). MAIT cells have also demonstrated autoreactivity and have been associated with various autoimmune disorders (11, 12); they have also been found in both k...

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