Compositions and methods for the prevention and treatment of...

Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...

Reexamination Certificate

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C424S168100, C435S006120, C435S007100, C435S252100, C435S252300, C435S253100, C435S320100, C435S325000

Reexamination Certificate

active

06350456

ABSTRACT:

TECHNICAL FIELD
The present invention relates generally to compositions for the prevention and treatment of tuberculosis. The invention is more particularly related to compositions comprising at least two
Mycobacterium tuberculosis
antigens, and the use of such compositions for treating and vaccinating against
Mycobacterium tuberculosis
infection.
BACKGROUND OF THE INVENTION
Tuberculosis is a chronic, infectious disease, that is generally caused by infection with
Mycobacterium tuberculosis
. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If left untreated, serious complications and death typically result.
Although tuberculosis can generally be controlled using extended antibiotic therapy, such treatment is not sufficient to prevent the spread of the disease. Infected individuals may be asymptomatic, but contagious, for some time. In addition, although compliance with the treatment regimen is critical, patient behavior is difficult to monitor. Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistance.
Inhibiting the spread of tuberculosis requires effective vaccination and accurate, early diagnosis of the disease. Currently, vaccination with live bacteria is the most efficient method for inducing protective immunity. The most common Mycobacterium employed for this purpose is Bacillus Calmette-Guerin (BCG), an avirulent strain of
Mycobacterium bovis
. However, the safety and efficacy of BCG is a source of controversy and some countries, such as the United States, do not vaccinate the general public. Diagnosis is commonly achieved using a skin test, which involves intradermal exposure to tuberculin PPD (protein-purified derivative). Antigen-specific T cell responses result in measurable induration at the injection site by 48-72 hours after injection, which indicates exposure to Mycobacterial antigens. Sensitivity and specificity have, however, been a problem with this test, and individuals vaccinated with BCG cannot be distinguished from infected individuals.
While macrophages have been shown to act as the principal effectors of
M. tuberculosis
immunity, T cells are the predominant inducers of such immunity. The essential role of T cells in protection against
M. tuberculosis
infection is illustrated by the frequent occurrence of
M. tuberculosis
in AIDS patients, due to the depletion of CD4+ T cells associated with human immunodeficiency virus (HIV) infection. Mycobacterium-reactive CD4+ T cells have been shown to be potent producers of gamma-interferon (IFN-&ggr;), which, in turn, has been shown to trigger the anti-mycobacterial effects of macrophages in mice. While the role of IFN-&ggr; in humans is less clear, studies have shown that 1,25-dihydroxy-vitamin D3, either alone or in combination with IFN-&ggr; or tumor necrosis factor-alpha, activates human macrophages to inhibit
M. tuberculosis
infection. Furthermore, it is known that IFN-&ggr; stimulates human macrophages to make 1,25-dihydroxy-vitamin D3. Similarly, IL-12 has been shown to play a role in stimulating resistance to
M. tuberculosis
infection. For a review of the immunology of
M. tuberculosis
infection see Chan and Kaufmann in
Tuberculosis: Pathogenesis, Protection and Control
, Bloom (ed.), ASM Press, Washington, D.C., 1994.
Accordingly, there is a need in the art for improved compositions and methods for preventing and treating tuberculosis.
SUMMARY OF THE INVENTION
Briefly stated, this invention provides compositions and methods for preventing and treating
M. tuberculosis
infection. In one aspect, pharmaceutical compositions are provided that comprise a physiologically acceptable carrier and either (a) a first polypeptide and a second polypeptide, or (b) a fusion protein including a first polypeptide and a second polypeptide, wherein each of the polypeptides comprises an immunogenic portion of a
M. tuberculosis
antigen or a variant thereof. In specific embodiments, the first polypeptide comprises an immunogenic portion of a
M. tuberculosis
antigen having an amino acid sequence selected from the group consisting of sequences provided in SEQ ID NO: 91, 107, 109, 111 and variants thereof, and the second polypeptide comprises an immunogenic portion of a
M. tuberculosis
antigen having an amino acid sequence selected from the group consisting of sequences provided in SEQ ID NO: 79, 88, 115, 117, 118, 119 and variants thereof. In one preferred embodiment, the first polypeptide comprises an amino acid sequence of SEQ ID NO:107 and the second polypeptide comprises an amino acid sequence of SEQ ID NO:115. In another preferred embodiment, the first polypeptide comprises an amino acid sequence of SEQ ID NO:107 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 79.
Within other aspects, the present invention provides pharmaceutical compositions that comprise a physiologically acceptable carrier and either (a) a first DNA molecule and a second DNA molecule, or (b) a DNA fusion molecule comprising a first DNA molecule and a second DNA molecule, wherein each of the DNA molecules encodes an immunogenic portion of a
M. tuberculosis
antigen or a variant thereof. In specific embodiments, the first DNA molecule comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 33, 106, 108, 110 and variants thereof, and the second DNA molecule comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 17, 46, 112, 116 and variants thereof. In one preferred embodiment, the first DNA molecule comprises a nucleotide sequence of SEQ ID NO:107 and the second DNA molecule comprises a nucleotide sequence of SEQ ID NO:115. In another preferred embodiment, the first DNA molecule comprises a nucleotide sequence of SEQ ID NO:107 and the second DNA molecule comprises a nucleotide sequence of SEQ ID NO: 17.
The invention also provides vaccines comprising an immune response enhancer and either (a) a first polypeptide and a second polypeptide, or (b) a fusion protein including a first polypeptide and a second polypeptide, wherein each of the polypeptides comprises an immunogenic portion of a
M. tuberculosis
antigen or a variant thereof. In specific embodiments, the first polypeptide comprises an immunogenic portion of a
M. tuberculosis
antigen having an amino acid sequence selected from the group consisting of sequences provided in SEQ ID NO: 91, 107, 109, 111 and variants thereof, and the second polypeptide comprises an immunogenic portion of a
M. tuberculosis
antigen having an amino acid sequence selected from the group consisting of sequences provided in SEQ ID NO: 79, 88, 115, 117, 118, 119 and variants thereof. In one preferred embodiment of this aspect of the present invention, the first polypeptide comprises an amino acid sequence of SEQ ID NO:107 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 115. In another preferred embodiment, the first polypeptide comprises an amino acid sequence of SEQ ID NO:107 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 79.
In a related aspect, the present invention provides vaccines comprising an immune response enhancer and either (a) a first DNA molecule and a second DNA molecule, or (b) a DNA fusion molecule comprising a first DNA molecule and a second DNA molecule, wherein each of the DNA molecules encodes an immunogenic portion of a
M. tuberculosis
antigen or a variant thereof. In specific embodiments, the first DNA molecule comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:33, 106, 108, 1 10 and variants thereof, and the second DNA molecule comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:

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