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Vaccines comprising tb 10.4

Inactive Publication Date: 2010-01-21
STATENS SERUM INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0003]An immunogenic composition and vaccine for mammalian use with a low dose of an antigen comprising TB 10.4 fused to a polypeptide of the antigen 85-complex (Ag85, compo

Problems solved by technology

However, progress in this field has been delayed by the lack of adjuvants that induce a strong cell-mediated immune (CMI) response.

Method used

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  • Vaccines comprising tb 10.4
  • Vaccines comprising tb 10.4
  • Vaccines comprising tb 10.4

Examples

Experimental program
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Effect test

example 1

Immune Response Induced After Immunization with Ag85B-TB10.4 Fusion Protein in IC31® Adjuvant

[0052]The immunogenicity of Ag85B-TB10.4 fusion protein delivered in IC31® adjuvant was analyzed, including whether both components of the fusion protein were recognized by the immune system after immunization.

[0053]PBMC's isolated from groups of mice vaccinated with different doses of H4 in IC31® adjuvant and a saline control group were stimulated with either 1 or 5 μg / ml of Ag85B, TB10.4 or CFP10 (a Mycobacterium tuberculosis-specific antigen). After 72 hours the concentration of cell released IFN-γ was determined by ELISA. PBMC's were isolated 1 week after third vaccination and were pooled from five mice per group. Values in FIGS. 1A-1D represent the means of triplicate and SEM's are indicated by bars.

[0054]Groups of mice were immunized with Ag85B-TB10.4 fusion protein in IC31® adjuvant. As negative control, a group of mice received the adjuvant alone (data not shown). To examine antigen ...

example 2

Vaccination with Ag85B-TB10.4 Fusion Protein in IC31®Adjuvant Induces Polyfunctional CD4+T Cells

[0057]The phenotype of the T cells induced by immunizing with Ag85B-TB10.4 fusion protein in IC31® adjuvant was analyzed. In particular, the ability of this vaccine to induce polyfunctional (IFN-γ+IL-2+TNF-α+) CD4+T cells was determined as these have been shown to correlate with protective immunity against infections such as Leishmania major and to form the basis for a long lived memory response.

[0058]Ag85B and TB10.4 specific T cells are poly-functional. Production of IFN-γ, TNF-α and IL-2 was assessed following antigenic stimulation of PBMC's and spleenocytes 2 weeks post-vaccination by flow cytometry.

[0059]PBMC's from Ag85B-TB10.4 fusion protein in IC31® adjuvant vaccinated mice were stimulated in vitro with Ag85B or TB10.4 fusion protein and analyzed by flow cytometry for expression of CD4, CD8, IFN-γ, TNF-α, and IL-2. The results show that immunizing with Ag85B-TB10.4 fusion protein ...

example 3

Protective Efficacy of Ag85B-TB10.4 Fusion Protein and IC31® Adjuvant in a Mouse M. tuberculosis Infection Model

[0060]The protective efficacy of Ag85B-TB10.4 fusion protein in IC31® adjuvant was examined, including whether the dose dependency regarding the immunogenicity of the vaccine was also reflected in the protective efficacy of the vaccine.

[0061]In two independent experiments (A and B) groups of mice were vaccinated with three different doses of H4 formulated in IC31® adjuvant and compared to saline and BCG-vaccinated controls.

[0062]Mice were vaccinated three times at two weeks interval with Ag85B-TB10.4 fusion protein in IC31® adjuvant. As a positive control for protection, a group of mice were immunized once with BCG.

[0063]Ten weeks after the first vaccination, the mice were challenged by the aerosol route with virulent M. tuberculosis Erdman. Six weeks post challenge, the mice were sacrificed and the numbers [bacterial burden (CFU)] were determined in the lungs. As observed...

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Abstract

Vaccination with the combination of Ag85B-TB10.4 and IC31® adjuvant generated a high amount of polyfunctional CD4+T cells expressing high levels of IFN-γ, TNF-α, and IL-2. This in turn led to significant protection against infection with M. tuberculosis in the mouse aerosol challenge model of tuberculosis. Both the immunogenicity of the vaccine and its ability to protect against TB infection was highly dependent on the antigen dose. Thus, whereas the standard antigen dose of 5 μg, as well as 15 μg, did not induce significant protection against M. tuberculosis, reducing the dose to 0.5 μg increased both the immunogenicity of the vaccine as well as its protective efficacy to a level comparable to that observed in BCG vaccinated mice. Thus, the IC31® adjuvant, with the specified antigen dose, can induce a strong protective Th1 response against M. tuberculosis.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 USC 119(e) of prior U.S. Provisional Patent Application No. 61 / 085,973, filed Aug. 4, 2008, which is incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]The global effort to develop a more effective Mycobacterium tuberculosis (M. tuberculosis) vaccine than the currently used Bacillus of Calmette and Guerin (BCG) vaccine involves different strategies such as live attenuated vaccines (Horwitz, et al., 2000), virally vectored M. tuberculosis vaccines (McShane, et al., 2004), and subunit vaccines (Olsen, et al., 2001 and Skeiky, et al., 2004). The subunit approach holds a number of advantages, such as increased safety and stability as well as the demonstrated ability to boost prior BCG vaccination (Brandt, et al., 2004; Dietrich, et al., 2006). In addition, as subunit vaccines appear not to be influenced by environmental mycobacteria, this type of vaccine may be of particular use in t...

Claims

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Application Information

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IPC IPC(8): A61K39/04A61K38/16C07K14/35A61P37/02
CPCA61K39/04A61K2039/55561A61K2039/55516A61K2039/545A61K39/39A61K2300/00A61P31/06A61P37/02A61P37/04
Inventor DIETRICH, JESAAGAARD, CLAUSANDERSEN, PETER
Owner STATENS SERUM INST
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