Adenoviral vector-based malaria vaccines
Inventors
Bruder, Joseph T. • King, C. Richter • Richie, Thomas • Limbach, Keith • Doolan, Denise Louise
Assignees
Publication Number
US-9254316-B2
Publication Date
2016-02-09
Expiration Date
2033-05-09
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The invention provides a method of inducing an immune response against malaria in a mammal. The method comprises intramuscularly administering to a mammal a composition comprising a pharmaceutically acceptable carrier and either or both of (a) a first adenoviral vector comprising a nucleic acid sequence encoding a P. falciparum circumsporozoite protein (CSP) operably linked to a human CMV promoter, and/or (b) a second adenoviral vector comprising a nucleic acid sequence encoding a P. falciparum apical membrane antigen 1 (AMA-1) antigen operably linked to a human CMV promoter.
Core Innovation
The invention provides a method of inducing an immune response against malaria in a mammal by intramuscularly administering a composition comprising a pharmaceutically acceptable carrier and one or both of two adenoviral vectors. The first adenoviral vector comprises a nucleic acid sequence encoding a Plasmodium falciparum circumsporozoite protein (CSP) operably linked to a human CMV promoter, and the second adenoviral vector comprises a nucleic acid sequence encoding a Plasmodium falciparum apical membrane antigen 1 (AMA-1) antigen operably linked to a human CMV promoter. These adenoviral vectors are replication-deficient and designed to express the respective antigens in the mammal to induce an immune response against malaria.
Malaria poses a severe health challenge globally, infecting millions and causing significant mortality, particularly in sub-Saharan Africa, and among military personnel deployed in endemic regions. Existing preventive measures like drugs and insect repellants face limitations due to resistance, side effects, and compliance issues. Despite extensive efforts, development of an effective malaria vaccine has been challenging, largely due to difficulty in eliciting strong and durable immune responses in humans. The invention addresses this need for improved methods that deliver malaria antigens effectively to prevent onset or subsequent infections.
The approach utilizes recombinant adenoviral vector technology, particularly replication-deficient adenoviruses with deletions in essential genome regions, enabling safe and efficient antigen delivery. These adenoviral vectors can be engineered with modifications to optimize immune responses and expression persistence, including codon optimization of antigen genes and use of specific promoters like the human CMV immediate-early promoter. The method supports vaccination regimens involving administration of one or both vectors, alone or in combination, to induce humoral and/or cell-mediated immunity against malaria.
Claims Coverage
The claims define a method for inducing an immune response against malaria involving priming and boosting steps using specific nucleic acid vectors and compositions. Main inventive features concern the composition, adenoviral vector characteristics, administration method, and antigen encoding sequences.
Use of a priming plasmid encoding malaria antigens
Administering a priming composition comprising a plasmid encoding P. falciparum circumsporozoite protein (CSP), or an immunogenic portion thereof, and/or P. falciparum apical membrane antigen 1 (AMA-1) antigen, or an immunogenic portion thereof.
Intramuscular administration of adenoviral vector compositions encoding P. falciparum antigens
Administering a composition intramuscularly comprising a pharmaceutically acceptable carrier and either or both of (1) a first adenoviral vector encoding P. falciparum CSP under a human CMV promoter and (2) a second adenoviral vector encoding P. falciparum AMA-1 antigen under a human CMV promoter, in amounts from about 1×10^6 to about 1×10^12 particle units (pu), inducing expression of the antigens to stimulate immunity.
Inclusion of both adenoviral vectors in defined dosage ranges
The composition comprises both first and second adenoviral vectors in ranges about 5×10^9 to about 5×10^10 pu or about 1×10^10 to about 1×10^11 pu, with specific embodiments including approximately 1×10^10 pu or 5×10^10 pu of each vector.
Use of replication-deficient adenoviral vectors with E1 and E4 region deletions
Each adenoviral vector is replication-deficient, requiring complementation of E1 and E4 regions for propagation, lacking the entire E1 region and at least a portion of the E4 region, with the antigen-encoding nucleic acid sequences inserted into the deleted E1 region.
Codon optimization of antigen-encoding nucleic acid sequences
The nucleic acid sequences encoding P. falciparum CSP and AMA-1 antigen comprise codons expressed more frequently in mammals than in Plasmodium, enhancing expression in the mammalian host; exemplary sequences include SEQ ID NO: 10 for CSP and SEQ ID NO: 16 for AMA-1.
Flexibility in administration regimen and subject
The composition can be administered once or twice to a mammal, wherein the mammal is a human.
The claims collectively cover a vaccination method using a priming plasmid and intramuscular administration of replication-deficient adenoviral vectors encoding optimized sequences of P. falciparum CSP and/or AMA-1 antigens in defined dosages to induce an immune response against malaria.
Stated Advantages
Induces potent and broad immune responses against multiple malaria antigens.
Offers a cost-effective alternative to multiple vaccine administrations by providing multivalent immunity.
Employs adenoviral vectors that efficiently express antigens in vivo to overcome limitations of traditional malaria vaccines.
Allows modulation of immune response persistence and reduces host inflammatory reactions through vector genome modifications.
Enables vaccination prior to malaria exposure, decreasing dependency on preventive drugs and associated compliance issues.
Documented Applications
Inducing immune responses against malaria by vaccinating mammals, particularly humans, using adenoviral vectors encoding P. falciparum CSP and AMA-1 antigens.
Use as a vaccination method for military personnel or individuals in malaria-endemic regions to reduce infection rates and disease burden.
Combining the adenoviral vector administration with priming compositions or boosting regimens involving plasmids or other gene transfer vectors to enhance immunity.
Clinical application in humans demonstrated via planned Phase 1/2a trials to assess safety, immunogenicity, and protective efficacy against P. falciparum sporozoite challenge.
Interested in licensing this patent?