[93] During infection, because of bacterial lysis, multiple pathogen hsp will be visible

to the host in parallel. The identity of cargo proteins will depend upon the family and type of hsp chaperone.[40] The meningococcal stress protein MSP63, a member of the hsp60 family, has been shown in man to be immunogenic during natural meningococcal infection.[94] I-BET-762 ic50 Genes encoding hsp, including DnaK, GroEL, GroES, DnaJ, GrpE and ClpB, were shown by transcriptional profiling to be up-regulated several fold in N. meningitidis in human blood during bacteraemia.[95] The similarity of pathogen-derived hsp to human hsp raises the hypothetical possibility of enhanced self recognition induced by vaccines enriched for pathogen hsp. Theoretically, this could occur as a consequence of the presentation of host proteins to DC by vaccine-derived hsp and the induction of autoimmune responses induced by the vaccine hsp. The potential for antibodies produced in mice against TGF-beta inhibitor plant

hsp70 to cross-react, either with murine hsp70 or human hsp70, has been investigated and found to be absent despite the significant structural similarities between the three isoforms.[86] Significantly, as a consequence of the manufacturing process, hsp are present in many marketed vaccines against infectious diseases, notably in whole cell vaccines and vaccines derived from cell extracts. The extensive, safe use of vaccines containing hsp therefore provides compelling evidence against safety concerns. For example, whole cell vaccines are used widely and possess acceptable safety profiles.[96] Antibodies to hsp65 were found in sera from children vaccinated

with DTP (diphtheria, tetanus, pertussis) vaccine administered extensively in Europe and the USA.[97] Antibodies against BCG hsp develop naturally in infants in 6–12 months, even without BCG vaccination.[98] The safety of human exposure to N. meningitidis hsp was obtained from administration of marketed vaccines that contain hsp.[99] Such vaccines have been used since the 1980s and the safety records are excellent. From the pioneering work of Benjamin Jesty and subsequent developments Nitroxoline from Edward Jenner to the present day, vaccines have delivered and continue to deliver significant improvements to global health. Smallpox is eradicated, polio has been controlled and the frequency of childhood diseases such as measles has reduced. However, the most successful vaccines have been against diseases where the causal pathogen does not have major anti-immune defence mechanisms. Many pathogens, including hepatitis C and human immunodeficiency viruses, M. tuberculosis, Helicobacter pylori and Plasmodium falciparum have evolved complex immune evasion strategies and probably require high level effector T-cell activation for their eradication. So far, these pathogens have proved intractable to existing vaccination strategies.