Mucosal adjuvants and anti-infection and anti-immunopathology vaccines based on cholera toxin, cholera toxin B subunit and CpG DNA

Abstract

The mucosal immune system consists of an integrated network of lymphoid cells that work in concert with innate host factors to promote host defence. Mucosal immunization can be used both to protect the mucosal surfaces against colonization and invasion by microbial pathogens and to provide a means for immunological treatment of selected autoimmune, allergic or infectious-immunopathological disorders through the induction of antigen-specific tolerance. The development of mucosal vaccines, whether for prevention of infectious diseases or for oral tolerance immunotherapy, requires efficient antigen delivery and adjuvant systems. Significant progress has recently been made to generate partly or wholly detoxified derivatives of cholera toxin (including the completely nontoxic cholera toxin B subunit) and the closely related Escherichia coli heat-labile enterotoxin, with retained adjuvant activity. Cholera toxin B subunit is a protective component of a widely registered oral vaccine against cholera, and has proven to be a promising vector for either giving rise to anti-infective immunity or for inducing peripheral anti-inflammatory tolerance to chemically or genetically linked foreign antigens administered mucosally. Promising advances have also recently been made in the design of efficient mucosal adjuvants based on bacterial DNA that contains CpG-motifs and various imidazoquinoline compounds binding to different Toll-like receptors on mucosal antigen-presenting cells.

Dendritic cell targeting ofBacillus anthracisprotective antigen expressed byLactobacillus acidophilusprotects mice from lethal challenge

“…To date, there are significant efforts and interest in the development of mucosal vaccines against various microbes and notable pioneering accomplishments using lactic acid bacteria as live vectors for oral delivery (21,36,37). Accordingly, one scientific consensus is that the next generation of vaccines should ideally be given orally in single doses.…”

“…It was previously shown that some recombinant lactic acid bacteria vaccine candidates induced elevated levels of antigen-specific secretory IgA (6), the predominant Ig class at mucosal surfaces (21). Moreover, one feature of this class of IgA is that it resists proteases rendering these antibodies critical for mucosal immunity.…”

“…Accordingly, a robust and highly specialized innate, as well as adaptive, mucosal immune system protects the mucosal membrane from pathogens (e.g., Salmonella) (19,20). Although the mucosal site normally tolerates associated commensal microbiota, specific immunity is constantly induced against invading pathogens in mucosa-associated lymphoid tissues (MALT) through the homing specificity of activated effector lymphocytes (21,22). Professional antigen presenting DCs have been identified in numerous tissue compartments, including the lamina propria (LP), the subepithelium, a T cell-rich zone of lymphoid tissue associated with the mucosa, and draining lymph nodes (23,24).…”

Cancer immunotherapy based on recombinant Salmonella enterica serovar Typhimurium aroA strains secreting prostate-specific antigen and cholera toxin subunit B

“…Although not significant, this delayed effect is well compatible to the innate cellular response which was measured in the ELISPOT assay and has already been described for CtxB or Salmonella alone. 15,46 Furthermore, also the PSA-secreting strain achieved significant protection at day 14, which indicates that also this strain induced a Tcell response which was below the detection threshold. In contrast, the strain separately expressing CtxB and PSA Figure 3 ELISPOT analysis of PPSA 18-specific cellular responses.…”

“…The native CtxB is one of the best studied and most effective experimental mucosal adjuvants known today. 15,16 In addition, this protein is a highly efficient carrier molecule for chemically or genetically conjugated antigens for eliciting mucosal and systemic antibody responses, as well as mucosal tolerance for prophylactic vaccines against autoimmune diseases. [17][18][19] To test the hypothesis that CtxB can enhance the antitumor efficacy of a cancer vaccine, several plasmids, encoding different combinations between PSA and CtxB, were generated.…”