Malaria immunogen and methods for using same
Inventors
Chackerian, Bryce • Peabody, David S. • Petrovsky, Nikolai • Jelinkova, Lucia • Zavala, Fidel
Assignees
Vaxine Pty Ltd • VAXINE Pty Ltd • Johns Hopkins University • UNM Rainforest Innovations
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Publication Number
US-12161710-B2
Publication Date
2024-12-10
Expiration Date
Abstract
An immunogen useful for treating malaria generally includes an immunogenic carrier and an antigenic malaria circumsporozoite protein (CSP) peptide that includes the peptide NPDPNANPNVDPNAN (amino acids 5-19 of SEQ ID NO:1) linked to the immunogenic carrier. The immunogen may be administered to a subject having or at risk of having malaria.
Core Innovation
The invention relates to an immunogen for malaria immunization in which a Qβ bacteriophage virus-like particle (VLP) functions as an immunogenic carrier. The VLP displays an antigenic malaria circumsporozoite protein (CSP) junction region peptide comprising NPDPNANPNVDPNAN (amino acids 5–19 of SEQ ID NO:1) linked to the immunogenic carrier, including embodiments that use SMPH cross-linker for the linkage.
The disclosed immunogen optionally includes an additional antigenic CSP peptide linked to the Qβ bacteriophage VLP. Variant CSP peptide sequences are identified as antigenic CSP peptide variants corresponding to SEQ ID NOs:5–9, and linker peptides are also described for VLP display. The document further describes immunogenic compositions that comprise the immunogen together with one or more adjuvants, including delta inulin polysaccharide-based ADVAX, and specifically ADVAX-3 and ADVAX-4.
The document reports that CIS43 VLPs elicit strong, long-lived anti-CSP antibodies in mice and macaques and reduce liver-stage parasite burden after intravenous and mosquito challenges. The anti-CSP antibody responses include increased antibody titers and antibody avidity index (AI) when adjuvanted with ADVAX, and infection inhibition is reported as non-sterilizing.
Claims Coverage
The document provides two independent claims covering an immunogen comprising a Qβ bacteriophage VLP linked to a specific CSP junction region peptide, and a method of treating malaria by administering that immunogen. Across the dependent claims, the coverage further refines linkage chemistry, adds an additional CSP peptide, restricts allowable CSP sequences to specified SEQ ID NOs, and optionally adds adjuvants including delta inulin polysaccharide and additional prophylactic or therapeutic agents.
Qβ bacteriophage VLP-linked CSP junction region peptide immunogen
An immunogen comprising an immunogenic carrier comprising a Qβ bacteriophage virus-like particle (VLP) and an antigenic malaria circumsporozoite protein (CSP) junction region peptide comprising NPDPNANPNVDPNAN (amino acids 5–19 of SEQ ID NO:1) linked to the immunogenic carrier.
SMPH-mediated linkage of CSP peptide to Qβ VLP
The immunogen where the immunogenic carrier is linked to the CSP peptide via a succinimidyl-6-[β-maleimidopropionamido]hexanoate (SMPH) cross-linker molecule.
Additional linked antigenic CSP peptide with specified SEQ ID variants
An immunogen of the carrier-linked CSP design further comprising a second antigenic CSP peptide attached to the immunogenic carrier, wherein the second antigenic CSP peptide has an amino acid sequence corresponding to SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9.
Immunogenic composition including adjuvant
An immunogenic composition comprising the immunogen of the Qβ VLP-linked CSP design and at least one adjuvant.
Delta inulin polysaccharide adjuvant for the immunogenic composition
The immunogenic composition in which the adjuvant is a delta inulin polysaccharide.
Therapeutically effective administration of the Qβ VLP-linked CSP immunogen to treat malaria
A method of treating malaria in an individual comprising administering a therapeutically effective amount of an immunogen to the individual, wherein the immunogen comprises an immunogenic carrier comprising a Qβ bacteriophage virus-like particle (VLP) and an antigenic malaria CSP junction region peptide comprising NPDPNANPNVDPNAN (amino acids 5–19 of SEQ ID NO:1) linked to the immunogenic carrier.
Therapeutic method with an additional linked antigenic CSP peptide
The method wherein the immunogen further includes a second antigenic CSP peptide linked to the immunogenic carrier.
Therapeutic method with second CSP peptide restricted to SEQ ID variants
The method wherein the second antigenic CSP peptide comprises an amino acid sequence corresponding to SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9.
Therapeutic method combined with an additional prophylactic agent
The method further comprising administering at least one additional prophylactic agent to the individual for treating malaria.
Therapeutic method combined with an additional therapeutic agent
The method further comprising administering at least one additional therapeutic agent to the individual for treating malaria.
Overall, the claim coverage centers on a Qβ bacteriophage VLP immunogenic carrier linked to a defined CSP junction region peptide sequence (amino acids 5–19 of SEQ ID NO:1), with dependent coverage specifying SMPH linkage, optional inclusion of an additional CSP peptide restricted to SEQ ID NOs:5–9, optional formulation with adjuvants including delta inulin polysaccharide, and method coverage for treating malaria via therapeutically effective administration, including optional combination with additional prophylactic and/or therapeutic agents.
Stated Advantages
Elicits strong, long-lived anti-CSP antibodies in mice and macaques.
Reduces liver-stage parasite burden after intravenous and mosquito challenges.
When adjuvanted with ADVAX, boosts antibody titers and antibody avidity (AI).
Enhances inhibition of infection (non-sterilizing).
Documented Applications
Prophylactic and therapeutic administration of a malaria immunogen comprising a Qβ bacteriophage VLP displaying a CSP junction region peptide (and optional CSP variants) with adjuvants such as ADVAX.
Treatment of malaria in an individual by administering a therapeutically effective amount of the Qβ VLP-linked CSP immunogen.
Evaluation in mice and macaques, including reduction of liver-stage parasite burden after intravenous challenge and after mosquito challenge (Anopheles stephensi).
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