title: Protection and polyfunctional T cells induced by Ag85B-TB10.4/IC31 against Mycobacterium tuberculosis is highly dependent on the antigen dose.
abstract: BACKGROUND
  Previously we have shown that Ag85B-TB10.4 is a highly efficient vaccine against tuberculosis when delivered in a Th1 inducing adjuvant based on cationic liposomes. Another Th1 inducing adjuvant, which has shown a very promising profile in both preclinical and clinical trials, is IC31. In this study, we examined the potential of Ag85B-TB10.4 delivered in the adjuvant IC31 for the ability to induce protection against infection with Mycobacterium tuberculosis. In addition, we examined if the antigen dose could influence the phenotype of the induced T cells.
  
  
  RESULTS
  We found that vaccination with the combination of Ag85B-TB10.4 and IC31 resulted in high numbers of polyfunctional CD4 T cells co-expressing IL-2, IFN-gamma and TNF-alpha. This correlated with protection against subsequent challenge with M.tb in the mouse TB model. Importantly, our results also showed that both the vaccine induced T cell response, and the protective efficacy, was highly dependent on the antigen dose. Thus, whereas antigen doses of 5 and 15 microg did not induce significant protection against M.tb, reducing the dose to 0.5 microg selectively increased the number of polyfunctional T cells and induced a strong protection against infection with M.tb. The influence of antigen dose was also observed in the guinea pig model of aerosol infection with M.tb. In this model a 2.5 fold increase in the antigen dose reduced the protection against infection with M.tb to the level observed in non-vaccinated animals.
  
  
  CONCLUSIONS
  Small changes in the antigen dose can greatly influence the induction of specific T cell subpopulations and the dose is therefore a crucial factor when testing new vaccines. However, the adjuvant IC31 can, with the optimal dose of Ag85B-TB10.4, induce strong protection against Mycobacterium tuberculosis. This vaccine has now entered clinical trials.
authors.affiliation: Department of Infectious Disease Immunology, Statens Serum Institute, Copenhagen, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Aagaard
authors.forename: Truc Thi Kim Thanh
authors.initials: TT
authors.lastname: Hoang
authors.forename: Angelo
authors.initials: A
authors.lastname: Izzo
authors.forename: Rolf
authors.initials: R
authors.lastname: Billeskov
authors.forename: JoLynn
authors.initials: J
authors.lastname: Troudt
authors.forename: Kim
authors.initials: K
authors.lastname: Arnett
authors.forename: Andrew
authors.initials: A
authors.lastname: Keyser
authors.forename: Tara
authors.initials: T
authors.lastname: Elvang
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.forename: Jes
authors.initials: J
authors.lastname: Dietrich
mesh_terms: D000217:Acyltransferases / Q000737:chemistry*; D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry*; D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology; D004338:Drug Combinations; D005260:Female; D006168:Guinea Pigs; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D014376:Tuberculosis / Q000382:microbiology / Q000517:prevention & control; D032581:Tuberculosis Vaccines / Q000737:chemistry
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D004338:Drug Combinations; C544002:IC31 adjuvant; D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; C501710:TB10.4 antigen, Mycobacterium tuberculosis; D032581:Tuberculosis Vaccines; D007371:Interferon-gamma; D000217:Acyltransferases; C121433:antigen 85B, Mycobacterium tuberculosis