Vaccine Platforms Combining Circumsporozoite Protein and Potent Immune Modulators, rEA or EAT-2, Paradoxically Result in Opposing Immune Responses

Malaria greatly impacts the health and wellbeing of over half of the world's population. Promising malaria vaccine candidates have attempted to induce adaptive immune responses to Circumsporozoite (CS) protein. Despite the inclusion of potent adjuvants, these vaccines have limited protective efficacy. Conventional recombinant adenovirus (rAd) based vaccines expressing CS protein can induce CS protein specific immune responses, but these are essentially equivalent to those generated after use of the CS protein subunit based vaccines. In this study we combined the use of rAds expressing CS protein along with rAds expressing novel innate immune response modulating proteins in an attempt to significantly improve the induction of CS protein specific cell mediated immune (CMI) responses.BALB/cJ mice were co-vaccinated with a rAd vectors expressing CS protein simultaneous with a rAd expressing either TLR agonist (rEA) or SLAM receptors adaptor protein (EAT-2). Paradoxically, expression of the TLR agonist uncovered a potent immunosuppressive activity inherent to the combined expression of the CS protein and rEA. Fortunately, use of the rAd vaccine expressing EAT-2 circumvented CS protein's suppressive activity, and generated a fivefold increase in the number of CS protein responsive, IFNγ secreting splenocytes, as well as increased the breadth of T cells responsive to peptides present in the CS protein. These improvements were positively correlated with the induction of a fourfold improvement in CS protein specific CTL functional activity in vivo.Our results emphasize the need for caution when incorporating CS protein into malaria vaccine platforms expressing or containing other immunostimulatory compounds, as the immunological outcomes may be unanticipated and/or counter-productive. However, expressing the SLAM receptors derived signaling adaptor EAT-2 at the same time of vaccination with CS protein can overcome these concerns, as well as significantly improve the induction of malaria antigen specific adaptive immune responses in vivo

The role of diet in the aetiopathogenesis of inflammatory bowel disease

Crohn’s disease and ulcerative colitis, collectively known as IBD, are chronic inflammatory disorders of the gastrointestinal tract. Although the aetiopathogenesis of IBD is largely unknown, it is widely thought that diet has a crucial role in the development and progression of IBD. Indeed, epidemiological and genetic association studies have identified a number of promising dietary and genetic risk factors for IBD. These preliminary studies have led to major interest in investigating the complex interaction between diet, host genetics, the gut microbiota and immune function in the pathogenesis of IBD. In this Review, we discuss the recent epidemiological, gene–environment interaction, microbiome and animal studies that have explored the relationship between diet and the risk of IBD. In addition, we highlight the limitations of these prior studies, in part by explaining their contradictory findings, and review future directions

Nucleic acid-based infectious and pseudoinfectious flavivirus vaccines

The genus Flavivirus contains a number of important pathogens of humans including yellow fever virus (YFV), dengue virus (DENV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), and West Nile virus (WNV). Despite causing significant morbidity and mortality worldwide, commercially available vaccines only exist for YFV (live-attenuated), TBEV, and JEV (inactivated). Flavivirus vaccine research has been driven by the need for cheap, safe, thermally stable, and efficacious preparations amenable to use in developing nations. The creation of infectious cDNA clones of various flaviviruses has led to the development of genetically engineered, nucleic acid-delivered, attenuated live vaccine candidates. These provide effective immunity from a single immunisation, however share the same safety concerns as traditional live-attenuated vaccines. The generation of large internal deletions in the capsid gene of flavivirus genomes create; a vaccine that secretes large amounts of immunogenic prM/E particles from;elf-replicating RNA but does not form a spreading infection. Packaging of these capsid-deleted RNAs into virus-like particles (VLPs) using a cell line that produces capsid gene from another expression vector creates a pseudo-infectious vaccine that elicits a highly efficient immune response from a single dose and is safer than infectious virus. However, production of these VLPs is cumbersome and the resulting product is heat labile. Providing the capsid gene in trans from another promoter but within the same plasmid DNA as the capsid-deleted viral genome creates a DNA vaccine capable of producing VLPs in vivo. Uptake of this plasmid DNA results in the generation of self-replicating, capsid-deleted RNA and the capsid protein in the same cell, leading to production of secreted single-round infectious particles (SRIPs). These SRIPs then deliver capsid-deleted RNA to adjacent cells where it replicates to produce more prM/E particles. As functional capsid cannot be produced in SRIP-infected cells, further spread does not occur. SRIP-producing DNA was shown to be highly effective in mice and horses and provides an easier to manufacture and thermally stable alternative to other vaccine candidates currently being developed