Plasmodium falciparum sporozoite and liver stage antigens
Inventors
Aguiar, Joao • Limbach, Keith • Sedegah, Martha • Richie, Thomas
Assignees
US Department of Navy • Henry M Jackson Foundation for Advancedment of Military Medicine Inc
Publication Number
US-9694062-B2
Publication Date
2017-07-04
Expiration Date
2034-03-19
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Abstract
The invention provides novel malaria polypeptides expressed at the pre-erythrocytic stage of the malaria life-cycle. The antigens can be utilized to induce an immune response against malaria in a mammal by administering the antigens in vaccine formulations or expressing the antigens in DNA or other nucleic acid expression systems delivered as a vaccine formulation.
Core Innovation
The invention provides novel Plasmodium falciparum polypeptides expressed at the pre-erythrocytic stage of the malaria life-cycle. These antigens can be used to induce an immune response against malaria in mammals via vaccine formulations or nucleic acid expression systems such as DNA vaccines.
The identified polypeptides were selected based on criteria relevant to protection against malaria and can be utilized individually or in combination within immunogenic compositions. They may be administered as purified proteins or expressed in vivo from vectors like DNA plasmids or viral systems, including adenoviral vectors.
The problem addressed is the lack of an efficacious FDA-approved malaria vaccine, compounded by the complex life-cycle of Plasmodium falciparum, the scarcity of promising antigens despite sequencing its genome, and the emergence of drug-resistant strains. Existing vaccine candidates have failed to induce high-grade protection, but immunization with radiation-attenuated sporozoites demonstrates that protective immunity targeting multiple sporozoite and liver stage antigens is achievable.
Claims Coverage
The patent contains multiple inventive features focused on immunogenic compositions and methods for inducing immune responses against malaria, primarily involving specific polypeptides and vector expression systems.
Immunogenic composition comprising vector expression systems
An immunogenic composition comprising a vector expression system encoding separate polypeptides with amino acid sequences of SEQ ID NOs: 6 and 10, wherein the vector expression system is a DNA plasmid or a replicating or nonreplicating viral vector.
Encoding polypeptides by specific nucleic acid sequences
The polypeptides in the composition are encoded by the nucleic acid sequences of SEQ ID NOs. 5 or 9 inserted into the suitable vector expression system.
Method of inducing immune response using immunogenic composition
A method to induce an immune response against malaria in a mammal by administering the immunogenic composition containing the specified polypeptides expressed by suitable plasmid or viral vectors.
Prime-boost immunization regimen incorporating polypeptides
The induction method comprises one or more priming and boosting immunizations with immunologically effective amounts of polypeptides expressed by suitable DNA plasmid or various replicating or nonreplicating viral vectors from defined vector systems.
Use of diverse viral vector systems in expression
The suitable viral vectors include DNA plasmid, alphavirus (and replicons), adenovirus, poxvirus, adeno-associated virus, cytomegalovirus, canine distemper virus, yellow fever virus, retrovirus, and RNA or DNA replicons, including specific poxvirus selections such as cowpox, canarypox, vaccinia, modified vaccinia Ankara, or fowlpox.
Incorporation of additional polypeptides in vector system
The vector expression system may also comprise nucleic acid sequences encoding polypeptides with amino acid sequences of SEQ ID NO. 14 and additional polypeptides selected from SEQ ID NOs: 2, 4, 8, and 12, with corresponding nucleic acid sequences.
Expanded immunization compositions comprising multiple polypeptides
The immunogenic compositions and methods may include nucleic acid sequences encoding one or more polypeptides selected from SEQ ID NOs. 2, 4, 8, 12, and 14, expressed by suitable vector systems to induce immune responses.
The claims collectively cover immunogenic compositions containing specific Plasmodium falciparum polypeptides expressed by DNA plasmid or viral vectors, along with methods for inducing immune responses in mammals, employing prime-boost regimens and multiple types of vector expression systems.
Stated Advantages
The proteins are recognized by human antibodies and T-cells from volunteers immunized with irradiated sporozoite vaccine, indicating their relevance in natural protective immune responses against malaria.
The combination of multiple polypeptides can elicit additive or enhanced protective immunity, demonstrated in murine models with orthologous P. yoelii proteins.
The proteins induce both humoral and T-cell mediated immune responses, including class I HLA-restricted T-cell epitopes important for immunity.
The immunogenic compositions can be delivered by various vector systems for in vivo expression, enabling flexible vaccine design and prime-boost immunization strategies.
Documented Applications
Use of novel Plasmodium falciparum pre-erythrocytic stage proteins as subunit immunogens or expressed from nucleic acid vectors for vaccination against malaria in mammals, including humans.
Development of DNA or viral vector-based vaccines expressing the identified polypeptides to induce protective immune responses against malaria.
Use in prime-boost immunization regimens comprising sequential administration of DNA plasmid and viral vector-based vaccines encoding malaria antigens.
Application of identified P. falciparum antigens orthologous to P. yoelii proteins shown to confer protection in murine challenge models, supporting their use in human malaria vaccine candidates.
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