Immunogenic compositions comprising Mycobacterium tuberculosis polypeptides and fusions thereof
Inventors
Reed, Steven G. • Coler, Rhea N. • Ireton, Gregory C. • Bertholet, Sylvie
Assignees
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Publication Number
US-11897922-B2
Publication Date
2024-02-13
Expiration Date
Abstract
The present invention relates to compositions and fusion proteins containing at least two Mycobacterium sp.) antigens, and polynucleotides encoding such compositions and fusion proteins. The invention also relates to methods for their use in the treatment, prevention and/or diagnosis of tuberculosis infections.
Core Innovation
The invention provides immunogenic Mycobacterium tuberculosis compositions and methods for stimulating an immune response by administering to a subject an effective amount of a composition comprising two or more Mycobacterium tuberculosis antigens. The antigens include Rv3478, Rv3619, Rv2389, and Rv1886, or corresponding antigens comprising amino acid sequences having at least 90% sequence identity to those sequences.
A central feature is that the two or more antigens are covalently linked in the form of a fusion polypeptide. The disclosed concept includes multicomponent fusion proteins made from multiple selected M. tuberculosis antigens, including identity-constrained variants, with further narrowing that can include higher identity thresholds and specific fusion polypeptides such as ID91.
The disclosed compositions are presented together with immunostimulants/adjuvants and are directed to eliciting protective immune responses characterized as Th1-biased, including humoral and cell-mediated immunity. The document supports the disclosed immunogenic and protective outcomes with readouts such as IFN-gamma, TNF, and IgG isotypes, and with example protection after aerosol challenge with outcomes described in terms of lung bacterial burden reduction.
Claims Coverage
The independent claim recites a method for stimulating an immune response, with coverage centered on a fusion polypeptide that covalently links two or more specified M. tuberculosis antigens or 90% identity variants. Dependent claims further refine antigen identity thresholds, specify a particular fusion polypeptide, and narrow the covalent linkage arrangement and optional immunostimulant selection.
Covalently linked fusion of specified M. tuberculosis antigens
Administering an effective amount of a composition comprising two or more Mycobacterium tuberculosis antigens, wherein the antigens comprise Rv3478 (SEQ ID NO:41), Rv3619 (SEQ ID NO:46), Rv2389 (SEQ ID NO:21), and Rv1886 (SEQ ID NO:145) or antigens with at least 90% sequence identity to those sequences; wherein the two or more antigens are covalently linked in the form of a fusion polypeptide.
Higher sequence identity constraints for selected antigens
Defining that the method includes antigens comprising amino acid sequences with at least 99% sequence identity to SEQ ID NO:21 and SEQ ID NO:145.
Specific fusion polypeptide identity constraint (ID91)
Defining that the method includes a fusion polypeptide identified as ID91 that comprises the amino acid sequence of SEQ ID NO:236 or a sequence with at least 90% identity to SEQ ID NO:236.
Direct covalent linking of the antigens
Defining that the two or more antigens are directly linked.
Immunostimulant selected from a defined set
Defining that an immunostimulant is chosen from a defined group of listed immunostimulant agents, or combinations thereof.
Immunostimulant as GLA
Defining that the immunostimulant used is GLA.
Overall claim coverage centers on stimulating an immune response by administering a covalently linked fusion polypeptide composed of multiple specified M. tuberculosis antigens or 90% identity variants, with dependent refinements that include higher antigen identity thresholds, a specified fusion polypeptide with sequence identity constraints, direct covalent linking, and optional selection of an immunostimulant from a defined list including GLA.
Stated Advantages
Th1-biased recall responses are reported, including IFN-gamma and TNF.
Immunization reduces lung bacterial burden after aerosol challenge with H37Rv.
Protection is stated to approach or be partially comparable to BCG.
Fusion-protein formulations confer protection.
Ad5-ID83 is stated to induce IFN-gamma recall and partially reduce CFU with only two doses.
Recombinant antigen panels with higher sensitivity/specificity for TB serum reactivity are described for serodiagnostic utility.
An immunotherapy concept is described combining antibiotic therapy with Rv1813/Rv2608/Rv3620 plus GLA-SE to extend survival in established infection.
Elicits protective immune responses characterized as Th1-biased protective immune responses.
Generates immunogenic readouts including IFN-gamma, TNF, and IgG isotypes, as described in example results.
Documented Applications
Stimulation of an immune response using compositions of covalently linked Mycobacterium tuberculosis antigens in fusion polypeptides, evaluated with human PPD+ PBMC and mouse splenocytes.
Immunization in C57BL/6 mice followed by aerosol challenge with H37Rv, with evaluation of lung bacterial burden reduction.
Serological diagnosis using recombinant antigen panels selected for higher sensitivity/specificity for TB serum reactivity, including TB sputum-positive serum and healthy control serum.
An immunotherapy concept combining antibiotic therapy with Rv1813/Rv2608/Rv3620 plus GLA-SE to extend survival in established infection.
Vaccine/prevention use through administration of an immunogenic composition to stimulate an immune response in a subject.
Diagnostic uses through diagnostic methods/kits to detect antibody- and/or T-cell responses for TB infection using antigen or fusion polypeptides, optionally with monoclonal antibodies.
Assessment of protective performance after aerosol challenge, with described readouts including lung bacterial burden reduction.
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