Recombinant polypeptide construct comprising Plasmodium falciparum circumsporozoite protein HLA class I restricted T-cell epitopes
Inventors
Sedegah, Martha • Richie, Thomas
Assignees
Publication Number
US-9645147-B2
Publication Date
2017-05-09
Expiration Date
2033-11-01
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Abstract
The invention relates to a recombinant polypeptide construct comprising epitopes from Plasmodium falciparum protein circumsporozoite protein (CSP). The epitopes contain HLA class I binding motifs and stimulate an anti-malaria CD8+T-cell response. The polypeptides can be incorporated into immunogenic formulations against malaria. Additionally, the antigens are useful for facilitating evaluation of immunogenicity of candidate malaria vaccines.
Core Innovation
The invention relates to recombinant polypeptide constructs comprising HLA class I binding motifs containing epitopes from Plasmodium falciparum circumsporozoite protein (CSP) that stimulate an anti-malaria CD8+ T-cell response. These polypeptides can be included in immunogenic compositions against malaria, produced by recombinant DNA techniques, and expressed via suitable expression systems such as viral or DNA plasmid vectors. The polypeptides may be administered in multiple doses to a mammal to induce an immunogenic response.
The problem being solved is the lack of FDA-approved vaccines for malaria in the context of the complex malaria lifecycle and the emergence of drug-resistant Plasmodium strains. Despite sequencing the P. falciparum genome, vaccine development has been hampered by the paucity of promising antigens, particularly antigens that consistently elicit CD8+ T cell responses which are thought crucial for liver stage immunity. The RTS,S vaccine induces antibodies and CD4+ T cell responses but does not consistently induce CD8+ T cell responses, limiting its efficacy.
The invention addresses this by identifying and isolating specific polypeptides from CSP containing HLA-restricted CD8+ T cell epitopes. Utilizing computational algorithms such as NetMHC to predict binding affinities, combined with assays from clinical trial volunteers immunized with adenovector vaccines expressing CSP, the invention defines multiple minimal epitopes recognized by CD8+ T cells. These epitopes cover a broad range of HLA alleles and supertypes, enabling coverage of genetically diverse populations. The recombinant polypeptide constructs comprising these epitopes can be used as components of vaccines or as antigens in immunogenic formulations to stimulate protective cell-mediated immunity against malaria.
Claims Coverage
The patent includes one independent claim covering a recombinant polypeptide construct and multiple dependent claims covering methods of inducing immune responses and administration strategies.
Recombinant polypeptide construct comprising multiple HLA class I restricted T-cell epitopes
A recombinant polypeptide construct comprising the amino acid sequences SEQ ID Nos. 5, 6, and 7, and one or more amino acid sequences from SEQ ID Nos. 1, 2, 3, 4, 8, 9, 10, and 11, each containing a T-cell epitope isolated from Plasmodium falciparum circumsporozoite protein, linked directly or via polypeptide spacer sequences that do not contain T-cell epitopes, where the construct is expressed from a DNA or viral expression system.
Spacer sequences linking epitopes
The spacer sequences linking the amino acid epitopes in the recombinant polypeptide construct are amino acid sequences of 1 to 10 amino acids in length and do not contain T-cell epitopes.
Methods of inducing immune response using the recombinant polypeptide construct
Methods of inducing an immune response in a mammal against Plasmodium falciparum by administering one or more doses of the recombinant polypeptide construct, including as priming and/or boosting immunizations.
Use of DNA or viral expression vectors for expressing the recombinant polypeptide construct
The recombinant polypeptide construct is expressed from a DNA or viral expression vector selected from DNA plasmid, alphavirus replicon, adenovirus, poxvirus, adeno-associated virus, cytomegalovirus, canine distemper virus, yellow fever virus, and retrovirus.
Immunization regimens involving alphavirus and non-alphavirus vectors
Priming immunization using alphavirus vectors and boosting using non-alphavirus vectors such as poxvirus, adenovirus, adeno-associated virus, or retrovirus.
Specific alphavirus and poxvirus selections
The alphavirus replicons can be RNA replicon, DNA replicon, or alphavirus replicon particles derived from Venezuelan Equine Encephalitis Virus, Semliki Forest Virus, or Sindbis Virus; the poxvirus can be cowpox, canarypox, vaccinia, modified vaccinia Ankara, or fowlpox.
The claims cover a recombinant polypeptide construct comprising defined CSP-derived HLA class I restricted CD8+ T-cell epitopes linked directly or via spacer sequences, expressed from various DNA or viral vectors, and methods of using these compositions for vaccination against malaria employing various immunization strategies to induce cellular immunity.
Stated Advantages
The identified epitopes are restricted by multiple HLA supertypes, allowing broad population coverage for immune responses.
The recombinant polypeptide constructs elicit CD8+ T-cell responses essential for immunity against liver stage malaria parasites.
Use in vaccine formulations enhances stimulation of cell-mediated immunity, potentially improving protection beyond antibody and CD4+ T cell focused vaccines.
The polypeptides facilitate evaluation of immunogenicity of candidate malaria vaccines.
Documented Applications
Incorporation of the recombinant polypeptides into immunogenic compositions or vaccines to induce protective cellular immunity against Plasmodium falciparum malaria.
Use of the recombinant polypeptide constructs expressed from DNA plasmid or viral vectors including adenovirus, poxvirus, alphavirus replicons, and others for vaccination protocols involving priming and boosting immunizations.
Use in methods to evaluate immune responses against malaria vaccine candidates by exposing human lymphocytes to the recombinant polypeptides and measuring CD8+ T cell responses.
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