Multicomponent vaccine for malaria providing long-lasting immune responses against plasmodia
Inventors
Schneerson, Rachel • Kubler-Kielb, Joanna • Robbins, John B. • Majadly, Fathy • Mocca, Christopher P. • Keith, Jerry • Biesova, Zuzana • Miller, Louis • Nussenzweig, Ruth • Liu, Darrell T.
Assignees
New York University NYU • US Department of Health and Human Services
Publication Number
US-8444996-B2
Publication Date
2013-05-21
Expiration Date
2029-10-01
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Abstract
Disclosed are immunogenic conjugates which elicit an immune response to Plasmodium proteins. In particular examples, the Plasmodium proteins include sexual stage surface proteins, circumsporozoite protein (CSP), or immunogenic portions of CSP. Also provided herein are immunogenic compositions including one or more of the disclosed immunogenic conjugates and a pharmaceutically acceptable carrier. Further provided is a method of eliciting an immune response to Plasmodium in a subject, comprising administering to the subject an immunogenic composition disclosed herein.
Core Innovation
The invention disclosed comprises immunogenic conjugates that elicit an immune response to Plasmodium proteins, specifically targeting sexual stage surface proteins such as P25, P28, P48/45, or P230, and the circumsporozoite protein (CSP) or immunogenic portions thereof. The conjugates are covalently linked proteins or peptides, with covalent linkages including non-peptide linkers like amide, hydrazone, or thioether, or peptide linkers with about one to twelve peptide bonds. These multicomponent conjugates can elicit immune responses to both sexual and asexual stages of Plasmodium, including species such as P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi.
The problem addressed by the invention is the global burden of malaria, which causes approximately 300 million cases per year and about one million deaths annually, mostly in young children. There is currently no effective vaccine, and the parasites are becoming increasingly resistant to antimalarial drugs. Infection involves both asexual and sexual stages of Plasmodium that are transmitted between humans and mosquitoes, and effective protection requires immune responses targeting multiple stages to reduce transmission and infection.
The disclosed immunogenic conjugates combine Plasmodium sexual stage surface proteins and CSP or portions thereof, including the major immunogenic repeat sequences of CSP such as NANP or variants NPNA, PNAN, and ANPN. The conjugates can include multiple copies of the sexual stage surface proteins linked to CSP or immunogenic repeats. The conjugates can also be linked to immunogenic carrier proteins other than Plasmodium proteins to enhance immune responses. The invention also includes immunogenic compositions comprising these conjugates with pharmaceutically acceptable carriers and methods of eliciting protective immune responses in subjects by administering the compositions.
Claims Coverage
The claims include one independent claim focused on a specific immunogenic conjugate and related method and composition claims.
Immunogenic conjugate of Plasmodium sexual stage surface proteins and circumsporozoite protein peptide
An immunogenic conjugate comprising at least two Plasmodium sexual stage surface proteins covalently linked to a peptide of Plasmodium circumsporozoite protein consisting of two or more NANP or NPNA repeats, which elicits an immune response to both the sexual stage proteins and the CSP peptide in a subject.
Specific sexual stage proteins included in the conjugate
The sexual stage surface protein comprises members selected from the group consisting of P25, P28, P48/45, or P230, including Pfs25 or Pvs25 variants.
Ratio of sexual stage surface protein to CSP peptide in the conjugate
The conjugate has a ratio of the sexual stage surface protein to the CSP peptide of greater than 1.0 to 1.0, enhancing immunogenicity.
Type of covalent linkage between proteins
The proteins are covalently linked through non-peptide linkages such as amide, hydrazone, thioether linkages, or a combination thereof.
Range of repeat units in the CSP peptide
The CSP peptide consists of two to eight NANP or NPNA repeats linked to the sexual stage surface proteins.
Pharmaceutical composition including the conjugate
A pharmaceutical composition comprises the immunogenic conjugate and a pharmaceutically acceptable carrier, optionally including an adjuvant.
Method of eliciting an immune response in a host
A method of eliciting an immune response to sexual and asexual stages of Plasmodium by administering the immunogenic conjugate to a host, optionally selecting the host for need of enhanced immunity.
The claims define a conjugate vaccine comprising multiple Plasmodium sexual stage surface proteins linked to CSP peptide repeats that elicit an immune response, pharmaceutical compositions containing such conjugates, and methods for vaccinating hosts against malaria.
Stated Advantages
The conjugates elicit long-lasting antibody responses to both sexual and asexual stages of Plasmodium.
Use of adjuvants such as aluminum hydroxide improves immune response to both components of the conjugates.
Pfs25 conjugates are more effective as carriers for CSP peptides compared to CSP monomers alone.
Conjugates containing two Pfs25 proteins linked to CSP repeats produce higher antibody titers and greater transmission-blocking activity.
The vaccine candidates can induce antibodies that reduce or block transmission of malaria from humans to mosquitoes.
Documented Applications
Vaccines for preventing or reducing infection with Plasmodium malaria parasites in humans and non-human primates.
Immunization of subjects at risk of or infected with malaria to induce protective immunity against sexual and asexual Plasmodium stages.
Pharmaceutical compositions comprising immunogenic conjugates for administration by various routes including subcutaneous, intramuscular, intravenous, oral, intranasal, or other conventional routes.
Use in transmission-blocking strategies by eliciting antibodies to sexual stage surface proteins that prevent parasite fertilization in the mosquito vector.
Preparation of immunogenic conjugates by chemical conjugation methods using specific linkers for use in vaccination protocols.
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