Methods for vaccinating against malaria
Inventors
Hoffman, Stephen L. • Wang, Ruobing • Epstein, Judith E. • Cohen, Joseph D.
Assignees
GlaxoSmithKline Biologicals SA • US Department of Navy
Publication Number
US-8232255-B2
Publication Date
2012-07-31
Expiration Date
2023-10-22
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Abstract
The invention pertains to methods for protecting against malaria infection by vaccination. The method of the invention involves priming an anti-malaria immune response with a DNA-based vaccine and boosting that response with a protein-based a vaccine. The method of the invention also relates to broadening the resulting immune response by boosting with a protein-based vaccine.
Core Innovation
The invention relates to methods for protecting against malaria infection by vaccination, wherein an anti-malaria immune response is first primed with a DNA-based vaccine encoding at least one malaria antigen, and subsequently boosted with a protein-based vaccine comprising at least one malarial antigen having at least one epitope in common with that of the priming vaccine. This prime/boost strategy was developed to overcome the limitations of prior malaria vaccines that failed to induce a sustained and broad immune response involving CD8+ T cells, CD4+ T cells, and antibodies.
The problem addressed by the invention arises from the complexity of the human immune response to Plasmodium falciparum and the multi-stage life cycle of the parasite, which expresses stage-specific proteins. DNA vaccines known to induce cell-mediated immune responses including CD8+ cytotoxic T lymphocytes have proved suboptimal in humans, while protein-based vaccines such as RTS,S elicit strong antibody and CD4+ T cell responses but fail to induce CD8+ T cell responses. Neither approach alone established a durable and comprehensive protective immune response.
The invention solves this problem by combining two heterologous vaccines in a prime/boost regimen, with the DNA vaccine priming a CD8+ T cell response and the protein-based vaccine boosting and broadening T cell and antibody responses. Notably, the protein vaccine is capable of boosting CD8+ T cell responses—a surprising effect since such protein vaccines were previously considered ineffective at stimulating CD8+ T cells. This strategy broadens the immune response by inducing both CD4+ Th1 and CD8+ Tc1 IFN-γ-producing T cells and expands the repertoire of epitopes recognized by CD8+ T cells, which were not originally primed by the DNA vaccine alone.
Claims Coverage
The patent includes one independent claim focusing on a prime-boost vaccination method against malaria in humans.
Prime and boost vaccination method using circumsporozoite protein encoding polynucleotide and polypeptide
A method for eliciting an immune response against malaria-causing pathogens in humans comprising priming with a priming composition containing at least one polynucleotide encoding all or substantially all of the circumsporozoite protein (PfCSP), followed by boosting with a composition comprising at least one polypeptide comprising substantially all or a fragment of the circumsporozoite protein to boost the primed immune response.
Priming of CD8+ T cells and broadening of immune response by boosting
The priming composition primes CD8+ T cells while the boosting composition recalls and broadens the primed CD8+ T cell response, resulting in the generation of anti-malaria CD8+ T cells, anti-malaria CD4+ T cells, and anti-malaria antibodies.
Dosages and administration routes
Priming doses range from 0.01 μg to 50 mg, boosting doses range from 1 μg to 100 μg; administration methods include intramuscular (IM), intravenous (IV), intradermal (ID), subcutaneous, mucosal, recombinant bacteria or virus delivery, and gene gun.
Specific vaccine compositions
The priming composition comprises PfCSP, the boosting composition comprises RTS,S, a hybrid protein containing at least 160 amino acids of the C-terminal portion of the CS protein fused to hepatitis B surface antigen (HBsAg), optionally with a Th1-inducing adjuvant.
Target pathogen and antigen specificity
The method is applicable to P. falciparum and involves vaccines sharing at least one epitope of the circumsporozoite protein to induce comprehensive immune responses including CTLs.
The claim covers a heterologous prime-boost vaccination method against malaria, wherein priming with a DNA vaccine encoding the circumsporozoite protein primes CD8+ T cells, and subsequent boosting with a protein-based vaccine such as RTS,S broadens and recalls CD8+ and CD4+ T cell responses and induces protective antibodies.
Stated Advantages
The combined heterologous prime-boost vaccination activates both cellular and humoral arms of the immune system, inducing CD8+ T cells, CD4+ T cells, and antibodies against malaria, which neither vaccine alone achieved.
Protein-based vaccines, previously considered ineffective at stimulating CD8+ T cell responses, can boost and broaden CD8+ T cell responses when used after DNA priming, a surprising and novel finding.
The prime-boost strategy broadens the immune response by inducing a broader repertoire of IFN-γ-producing T cells and by expanding the range of epitopes recognized by CD8+ T cells beyond those initially primed by the DNA vaccine.
The method produces long-lived memory T cell responses, enhancing the durability of protection against malaria.
Priming with DNA vaccine directs and balances the immune response towards malaria antigens even in individuals with pre-existing antibodies to HBsAg, overcoming immunodominance of the carrier antigen in the protein vaccine.
Documented Applications
Preventing malaria infection by vaccination in humans, including providing partial, enhanced, or full protection from P. falciparum.
Reducing the chance of developing malaria infection or illness severity when infected.
Reducing parasite concentration and mortality associated with malaria.
Vaccination in populations previously exposed or naïve to malaria-causing pathogens, including use in endemic regions.
Use as a pharmaceutical kit comprising priming and boosting vaccines for malaria prevention.
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