Hybrid hepadnavirus cores carrying multiple malaria parasite epitopes
Inventors
Milich, David R. • WHITACRE, David C.
Assignees
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Publication Number
US-11235045-B2
Publication Date
2022-02-01
Expiration Date
Abstract
The present disclosure relates to rodent hepadnavirus core antigens including one or more B cell and T cell epitopes of a malaria parasite antigen. More specifically, the present disclosure relates to hybrid woodchuck hepadnavirus core antigens that have been modified to diminish the antibody response to the core antigen so as to enhance the antibody response to fragments of malaria antigen(s) included therein.
Core Innovation
The invention relates to an antigenic composition comprising a hybrid woodchuck hepadnavirus core antigen. The hybrid core antigen is a fusion protein that comprises a malaria antigen and a woodchuck hepadnavirus core antigen, where the woodchuck hepadnavirus core antigen is a modified woodchuck hepadnavirus core antigen comprising the amino acid sequence of SEQ ID NO:14 with a serine at position 61.
The malaria antigen comprises a B cell domain and a T cell domain, with length constraints of 20 to 60 amino acids for the B cell domain and 30 to 120 amino acids for the T cell domain. In the fusion protein, the B cell domain is inserted at position 78 and the T cell domain is inserted at position 188 as numbered according to SEQ ID NO:1. The fusion protein is capable of assembling as a hybrid virus-like particle (VLP).
The disclosure designs hybrid rodent woodchuck hepadnavirus core antigen constructs to display malaria B-cell and T-cell epitopes on self-assembling hybrid VLPs while diminishing anti-carrier antibody responses to bias immunity toward malaria insert epitopes.
The documented disclosure further characterizes and exemplifies that hybrid constructs that include malaria B-cell epitopes and carrier modifications assemble into hybrid VLPs and are used to evaluate antigenicity and immune response outcomes.
Claims Coverage
The partial content contains one independent claim. It is supported by dependent claims that refine domain content, insertion architecture, and stated immunological outcomes, and that also include a related screening method.
Hybrid fusion woodchuck hepadnavirus core antigen assembling as hybrid VLP
A fusion protein comprising a malaria antigen and a woodchuck hepadnavirus core antigen, where the woodchuck hepadnavirus core antigen is a modified woodchuck hepadnavirus core antigen comprising the amino acid sequence of SEQ ID NO:14 with a serine at position 61, and the fusion protein is capable of assembling as a hybrid virus-like particle (VLP).
Malaria antigen with defined B cell and T cell domains inserted at specific positions
The malaria antigen comprises a B cell domain of from 20 to 60 amino acids in length and a T cell domain of from 30 to 120 amino acids in length, with the B cell domain inserted at position 78 and the T cell domain inserted at position 188 as numbered according to SEQ ID NO:1.
Overall, the claimed coverage centers on a malaria antigen–woodchuck hepadnavirus core fusion protein with defined B-cell and T-cell domains inserted at specified positions and capable of assembling into hybrid VLPs.
Stated Advantages
Diminish anti-carrier (core) antibody responses to bias immunity toward malaria insert epitopes.
Hybrid constructs displaying malaria B-cell epitopes on WHcAg VLPs drive strong liver protection and sterile blood-stage immunity.
Adding CS-specific T-cell domains enhances efficacy.
Modifying or redirecting other malaria epitopes affects immunogenicity and protection.
Documented Applications
A method screens anti-malaria antigen antibodies by measuring binding to a hybrid woodchuck hepadnavirus core antigen containing the malaria antigen and comparing it with binding to a woodchuck hepadnavirus core antigen lacking the malaria antigen, determining specificity based on binding to the hybrid but not the core devoid of the malaria antigen.
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