Cholera toxin, mucosal immunity and development of mucosal vaccines and immunotherapies
Members: Carl-Fredrik Flach (postdoc, Ph.D.), Michael Lebens (scientist, Ph.D.), Anna Lundgren (shared postdoc, Ph.D.), Jia-Bin Sun (scientist, Ph.D.), Sukanya Raghavan (scientist, Ph.D.), Margareta Blomquist (research technician), Annelie Ekman (research technician, M.D.), Susanne Källgård (research engineer), Madeleine Löfqvist (research technician), Stefan Karlsson (PhD student)
The mucosal immune system comprises ca 80% of all immunocytes and has developed effective, as yet incompletely understood means for protecting both against mucosal infections and harmful immune responses to ingested or inhaled antigens. There is currently great interest internationally in developing mucosal vaccines against many important microbial pathogens. Mucosally induced tolerance also is a promising form of immunomodulation for treating certain autoimmune diseases and allergies. Our research addresses these closely interlinked areas by studies in which cholera toxin or cholera toxin derivatives are often used as antigens, vectors or immunomodulating agents:
1. Mucosal immunity research aiming at improved ways of mucosal vaccination and immune response steering. We will continue animal research to further define mucosal regulatory mechanisms determining the outcome -- immunity or tolerance -- of local antigen exposure and to develop ways of steering and maximizing the immune response in the desired direction. Specifically, we will continue our efforts to define the role of different subsets of mucosally induced antigen presenting cells (APC) for induction of immunity or tolerance, compare immunization by different mucosal routes focusing on oral and sublingual antigen delivery, and continue our development of mucosal adjuvants including the recently described promising CTB-CpG and dmLT adjuvants.
2. Continued research towards the development of oral vaccines against gastrointestinal infections. We have developed an internationally widely registered oral vaccine (Dukoral®) against cholera with efficacy also against diarrhea caused by enterotoxigenic E.coli (ETEC); this is the only original vaccine developed in Scandinavia. The further specific vaccine development objectives are: (1) To develop a simplified and cheaper, yet hopefully even further efficacious oral vaccine against Vibrio cholerae using a single inactivated V. cholerae O1 strain engineered to express both the Inaba and Ogawa serotype antigens and also containing periplasmic CTB or adjuvant-active mutation-detoxified CT ; (2) To contribute to the development of a specific vaccine against ETEC diarrhea, the most common cause of diarrheal illness in both children in developing countries and in travelers – joint project with A-M Svennerholm et al., ETVAX AB and PATH Vaccine Solutions (USA); and (3) to advance the understanding and develop means of steering the balance between immune protection and immunopathology in experimental H. pylori infection and immunization as a basis for vaccine development.
3. Research to develop therapeutic vaccines based on oral tolerance induction, including the further development of a promising “vaccine” in the treatment of Behcet’s disease. We have developed a novel concept for mucosal tolerance induction based on the use of recombinantly produced CTB fused chemically or genetically to a relevant antigen/tolerogen. This has given very promising results in the prevention and treatment in animal models of autoimmune diseases (e.g. MS-like encephalomyelitis, RA-like arthritis, diabetes and uveitis); IgE- and DTH-mediated allergies; and infection immunopathology (e.g. schistosomiasis). This novel treatment principle has also recently been tested clinically with promising results in patients with Behcet’s disease. Based on this we will now (1) Further develop selected CTB-based fusion proteins for potential immune therapy in Behcet’s disease, diabetes and arteriosclerosis; (2) In animals and humans further define immunological correlates to positive treatment effects; and (3) Further develop our recent findings that B cells are important APCs for inducing tolerance and that B cells that are “vaccinated” in vitro with CTB-linked antigens and then transferred to autologous or syngeneic recipients can effectively induce regulatory T cells and prevent autoimmune disease .