Statens Serum Institut

Jes Dietrich

Peter Andersen

Claus Aagaard

Carina Vingsbo Lundberg

Truc Thi Kim Than Hoang

Claus Aagard

The present invention discloses a vaccine or immunogenic composition that can be administered to latently infected individuals to prevent reactivation of latent tuberculosis infection caused by species of the tuberculosis complex microorganisms (), The invention is based on a number ofderived proteins and protein fragments which are constitutively expressed in different stages of the infection. The invention is directed to the use of these polypeptides, immunologically active fragments thereof and the genes encoding them for immunological compositions such as vaccines.

Tuberculosis TB vaccine to prevent reactivation

Vaccination with the combination of Ag85B-TB10.4 and IC31&#xae; adjuvant generated a high amount of polyfunctional CD4T cells expressing high levels of IFN-&#x3b3;, TNF-&#x3b1;, 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 &#x3bc;g, as well as 15 &#x3bc;g, did not induce significant protection against M. tuberculosis, reducing the dose to 0.5 &#x3bc;g 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&#xae; adjuvant, with the specified antigen dose, can induce a strong protective Th1 response against M. tuberculosis.

Vaccines comprising TB10.4

The present invention discloses a vaccine or immunogenic composition that can be administered to latently infected individuals to prevent reactivation of latent tuberculosis infection caused by species of the tuberculosis complex microorganisms (). The invention is base on a number ofderived proteins and protein fragments which are constitutively expressed in different stages of the infection. The invention is directed to the use of these polypeptides, immunologically active fragments thereof and the genes encoding them for immunological compositions such as vaccines.

Vaccination with the combination of Ag85B-TB10.4 and IC31&#xae; adjuvant generated a high amount of polyfunctional CD4T cells expressing high levels of IFN-&#x3b3;, TNF-&#x3b1;, and IL-2. This in turn led to significant protection against infection within 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 &#x3bc;g, as well as 15 &#x3bc;g, did not induce significant protection against, reducing the dose to 0.5 &#x3bc;g 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&#xae; adjuvant, with the specified antigen dose, can induce a strong protective Th1 response against

A convenient way of inducing a broad recognition of dominant and subdominant responses to epitopes of any given antigen of importance for prophylaxis or treatment of a chronic disease is provided. The method involves by immunizing with pools of overlapping fragments (synthetic peptides, e.g., 10-30 mers with 2-20 aa overlap) of the desired antigen in appropriate adjuvants. The T cell repertoire is primed to include not only the immunodominant epitope recognized when the intact molecule is used for immunization and induced by the chronic infection itself, but induce a much broader and balanced response to a number of the subdominant epitopes as well. The vaccination with peptide mix induces a T-cell response that includes response to subdominant epitopes is important for protection against chronic disease that on their own induces a response focused only on immunodominant epitopes. The major advantage of the present invention is that it requires no prior knowledge of the precise localization and identity of the subdominant epitopes and their recognition in a human population, but expands the T-cell repertoire and thereby the total number of epitopes recognized by specific T cells primed by vaccination from a few immunodominant epitopes to a multiple of epitopes.

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Copenhagen, Denmark

Jes Dietrich