Protection and Polyfunctional T Cells Induced by Ag85B-TB10.4/IC31® against Mycobacterium tuberculosis Is Highly Dependent on the Antigen Dose

Abstract

BackgroundPreviously 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.Methods and FindingsWe 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-γ and TNF-α. 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 µg did not induce significant protection against M.tb, reducing the dose to 0.5 µg 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/SignificanceSmall 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.

Evaluation of the Safety and Immunogenicity of Two Antigen Concentrations of the Mtb72F/AS02ACandidate Tuberculosis Vaccine in Purified Protein Derivative-Negative Adults

“…Earlier work showed that the MVA85a TB vaccine candidate was immunogenic in PPD-negative British adults and that the magnitude of the IFN-␥ enzyme-linked immunospot assay response was positively influenced by BCG priming (26). Our results are promising, since studies in mouse models showed that induction of polyfunctional T cells correlated with protection against tuberculosis (1,19) and that assessment in humans of T-cell polyfunctionality might allow more accurate identification of a protective T-cell population (9). Moreover, it is generally accepted that the induction of cellular Th1 immune responses is associated with protection against TB (36).…”

Difference in TB10.4 T‐cell epitope recognition following immunization with recombinant TB10.4, BCG or infection with Mycobacterium tuberculosis

“…It should be noted that although in a recent study we showed that vaccines formulated in IC31 improved their efficacy when Ag dose was reduced to 0.5 mg/animal [18]; in this study we used the CAF01 adjuvant, where the optimal dose for TB10.4 was found to be 5 mg/animal (and changing the dose did not affect the epitope pattern (data not shown).…”

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

“…Many different approaches, such as recombinant vaccinia viruses (9), adjuvanted subunit vaccines (10), or genetically modified BCG variants (11), are currently in clinical trials. At the same time, there is a growing interest in characterizing relevant T cell epitopes for incorporation into vaccination strategies, mainly focusing on proteinaceous targets, including the immunodominant early secretory antigenic target, , and its dimerization partner culture filtrate protein, CFP10; different isoforms of Ag 85 (13); and more recently also dormant-phase Ags, such as TB10.4 (14). However, it is increasingly recognized that unconventional epitopes may also play a role in the antimycobacterial immune response.…”