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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A good CD8+ response is required for immunity to many intracellular pathogens. Traditional antigen delivery using isolated sub-units or killed pathogens and adjuvant stimulates strong antibody responses but weak T-cell reactivity. Attenuated vaccines are usually more effective. The prime-boost delivery system based on immunisation with a naked DNA antigen-gene construct followed by boosting with an attenuated vaccinia virus expressing the same antigen is proving to be a powerful way to stimulate antigen-specific CD8 responses. Success using single epitopes is possible in malaria and we believe this approach holds much promise for other apicomplexan parasites such as Theileria spp.
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PMID:Prime-boost: the way forward for recombinant vaccines against apicomplexan parasites. A Theileria perspective. 1205 10

The persistence of immunity to malaria induced in mice by a heterologous DNA priming and poxvirus boosting regimen was characterized. Mice were immunized by priming with DNA vaccine plasmids encoding the Plasmodium yoelii circumsporozoite protein (PyCSP) and murine granulocyte-macrophage colony-stimulating factor and boosting with recombinant vaccinia encoding PyCSP. BALB/c mice immunized with either high-dose (100 microg of p PyCSP plus 30 microg of pGM-CSF) or low-dose (1 microg of p PyCSP plus 1 microg of pGM-CSF DNA) priming were protected against challenge with 50 P. yoelii sporozoites. Protection 2 weeks after immunization was 70 to 100%, persisted at this level for at least 20 weeks, and declined to 30 to 40% by 28 weeks. Eight of eight mice protected at 20 weeks were still protected when rechallenged at 40 weeks. The antigen (Ag)-specific effector CD8(+)-T-cell population present 2 weeks after boosting had ex vivo Ag-specific cytolytic activity, expressed both gamma interferon (IFN-gamma) and tumor necrosis factor alpha, and constituted 12 to 20% of splenic CD8(+) T cells. In contrast, the memory CD8(+)-Ag-specific-cell population at 28 weeks lacked cytolytic activity and constituted only 6% of splenic CD8(+) T cells, but at the single-cell level it produced significantly higher levels of IFN-gamma than the effectors. High levels of Ag- or parasite-specific antibodies present 2 weeks after boosting had declined three- to sevenfold by 28 weeks. Low-dose priming was similarly immunogenic and as protective as high-dose priming against a 50-, but not a 250-, sporozoite challenge. These results demonstrate that a heterologous priming and boosting vaccination can provide lasting protection against malaria in this model system.
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PMID:Persistence of protective immunity to malaria induced by DNA priming and poxvirus boosting: characterization of effector and memory CD8(+)-T-cell populations. 1206 88

Potent and safe vaccinia virus vectors inducing cell-mediated immunity are needed for clinical use. Replicating vaccinia viruses generally induce strong cell-mediated immunity; however, they may have severe adverse effects. As a vector for clinical use, we assessed the defective vaccinia virus system, in which deletion of an essential gene blocks viral replication, resulting in an infectious virus that does not multiply in the host. The vaccinia virus Lister/Elstree strain, used during worldwide smallpox eradication, was chosen as the parental virus. The immunogenicity and safety of the defective vaccinia virus Lister were evaluated without and with the inserted human p53 gene as a model and compared to parallel constructs based on modified vaccinia virus Ankara (MVA), the present "gold standard" of recombinant vaccinia viruses in clinical development. The defective viruses induced an efficient Th1-type immune response. Antibody and cytotoxic-T-cell responses were comparable to those induced by MVA. Safety of the defective Lister constructs could be demonstrated in vitro in cell culture as well as in vivo in immunodeficient SCID mice. Similar to MVA, the defective viruses were tolerated at doses four orders of magnitude higher than those of the wild-type Lister strain. While current nonreplicating vectors are produced mainly in primary chicken cells, defective vaccinia virus is produced in a permanent safety-tested cell line. Vaccines based on this system have the additional advantage of enhanced product safety. Therefore, a vector system was made which promises to be a valuable tool not only for immunotherapy for diseases such as cancer, human immunodeficiency virus infection, or malaria but also as a basis for a safer smallpox vaccine.
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PMID:Immunogenicity and safety of defective vaccinia virus lister: comparison with modified vaccinia virus Ankara. 1209 85

We tested a cytokine-enhanced, multiantigen, DNA priming and poxvirus boosting vaccine regimen for prevention of malaria in the Plasmodium knowlesi-rhesus macaque model system. Animals were primed with a mixture of DNA plasmids encoding two preerythrocytic-stage proteins and two erythrocytic-stage proteins from P. knowlesi and combinations of the cytokines granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor alpha and were boosted with a mixture of four recombinant, attenuated vaccinia virus strains encoding the four P. knowlesi antigens. Two weeks after boosting, the geometric mean immunofluorescence titers in the immunized groups against sporozoites and infected erythrocytes ranged from 160 to 8,096 and from 1,810 to 5,120, respectively. The geometric mean anti-P. knowlesi circumsporozoite protein (PkCSP) titers ranged from 1,761 to 24,242. Peripheral blood mononuclear cells (PBMC) from the immunized monkeys produced gamma interferon (IFN-gamma) in response to incubation with pooled peptides from the PkCSP at frequencies of 10 to 571 spot-forming cells/10(6) PBMC. Following challenge with 100 infectious P. knowlesi sporozoites, 2 of 11 immunized monkeys were sterilely protected, and 7 of the 9 infected monkeys resolved their parasitemias spontaneously. In contrast, all four controls became infected and required treatment for overwhelming parasitemia. Early protection was strongly associated with IFN-gamma responses against a pool of peptides from the preerythrocytic-stage antigen, PkCSP. These findings demonstrate that a multistage, multiantigen, DNA priming and poxvirus boosting vaccine regimen can protect nonhuman primates from an otherwise lethal malaria sporozoite challenge.
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PMID:Protection of rhesus macaques against lethal Plasmodium knowlesi malaria by a heterologous DNA priming and poxvirus boosting immunization regimen. 1211 42

The demonstration of the i) acquired protective immunity in adults living in endemic areas, ii) cure of malaria patients with passive transfer of specific immunoglobulins, and iii) protection conferred by vaccination with sporozoites attenuated by radiation, justifies the search for a malaria vaccine. Given the improbability that a vaccine directed against a single antigen will be completely protective, the preferred option is to combine several antigens of different stages of the parasite in a multi-component multi-stage vaccine which is likely to protect both the travellers and the populations living in endemic areas. Potential manufacturing technologies include recombinant proteins, synthetic peptides and DNA vaccines, the relevant genes encoding malaria antigens being inserted into a plasmid or a live vector such as vaccinia or poxvirus. A number of human trials using different antigens and technologies have been carried out in the last ten years. Three vaccines have undergone safety and efficacy testing in the field. SPf66, comprising a linear polymerised synthetic peptide with several distinct epitopes, has been extensively evaluated in different epidemiological settings. The efficacy overall was 23%, but was only 2% in African infants, the most susceptible group. The circumsporozoite recombinant protein fused with the antigen S of the hepatitis B virus and formulated in a potent adjuvant (RTS,S) led to a high, but short-term, level of protection against infection and disease in Gambian adults. The first pure asexual blood-stage vaccine comprising three antigens of the merozoite stage (MSP1&2 and RESA, Combination B) had an efficacy of 62% in reducing parasite density in Papua New Guinean children. A malaria vaccine that can reduce the burden of disease in the most affected populations is thus an achievable goal, and each trial provides additional knowledge about mechanisms of protection as well as about new vaccine technology.
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PMID:Malaria vaccines: from the laboratory to the field. 1247 90

A series of phase I clinical studies were conducted to evaluate the safety of plasmid DNA and modified vaccinia virus Ankara malaria vaccines. The vaccines each encoded a polyepitope string fused to whole Plasmodium falciparum TRAP antigen. Forty-three healthy adult volunteers received the vaccines alone or in DNA/MVA prime-boost combinations. The DNA vaccine was administered either intramuscularly by needle or intradermally by a needleless delivery device. The MVA vaccine was administered intradermally by needle. The vaccines were well-tolerated by all three routes and in various DNA/MVA immunisation regimes. There were no severe or serious adverse events.
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PMID:Safety of DNA and modified vaccinia virus Ankara vaccines against liver-stage P. falciparum malaria in non-immune volunteers. 1270 89

In animals, effective immune responses against malignancies and against several infectious pathogens, including malaria, are mediated by T cells. Here we show that a heterologous prime-boost vaccination regime of DNA either intramuscularly or epidermally, followed by intradermal recombinant modified vaccinia virus Ankara (MVA), induces high frequencies of interferon (IFN)-gamma-secreting, antigen-specific T-cell responses in humans to a pre-erythrocytic malaria antigen, thrombospondin-related adhesion protein (TRAP). These responses are five- to tenfold higher than the T-cell responses induced by the DNA vaccine or recombinant MVA vaccine alone, and produce partial protection manifest as delayed parasitemia after sporozoite challenge with a different strain of Plasmodium falciparum. Such heterologous prime-boost immunization approaches may provide a basis for preventative and therapeutic vaccination in humans.
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PMID:Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans. 1277 54

The present study is an investigation of the safety and immunogenicity of DNA and modified vaccinia virus Ankara (MVA) candidate vaccines, each encoding the malaria DNA sequence multiple epitope-thrombospondin related adhesion protein (ME-TRAP), against Plasmodium falciparum. DNA ME-TRAP and MVA ME-TRAP are safe and immunogenic for effector and memory T cell induction. MVA ME-TRAP, with or without prior DNA ME-TRAP immunization, was more immunogenic and more cross-reactive in malaria-exposed individuals than in malaria-naive individuals, a finding suggesting that recombinant MVA vaccines are particularly promising for the development of a malaria vaccine for exposed populations. Both CD4(+) and CD8(+) T cells were induced by these vaccines.
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PMID:Safety and immunogenicity of DNA/modified vaccinia virus ankara malaria vaccination in African adults. 1455 95

We immunized mice with an attenuated (cold-adapted) influenza virus followed by an attenuated vaccinia virus (modified vaccinia virus Ankara), both expressing a CD8(+)-T-cell epitope derived from malaria sporozoites. This vaccination regimen elicited high levels of protection against malaria. This is the first time that the vaccine efficacy of a recombinant cold-adapted influenza virus vector expressing a foreign antigen has been evaluated.
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PMID:Induction of protective immunity against malaria by priming-boosting immunization with recombinant cold-adapted influenza and modified vaccinia Ankara viruses expressing a CD8+-T-cell epitope derived from the circumsporozoite protein of Plasmodium yoelii. 1455 72

To generate broadly protective T cell responses more similar to those acquired after vaccination with radiation-attenuated Plasmodium falciparum sporozoites, we have constructed candidate subunit malaria vaccines expressing six preerythrocytic antigens linked together to produce a 3240-aa-long polyprotein (L3SEPTL). This polyprotein was expressed by a plasmid DNA vaccine vector (DNA) and by two attenuated poxvirus vectors, modified vaccinia virus Ankara (MVA) and fowlpox virus of the FP9 strain. MVAL3SEPTL boosted anti-thrombospondin-related adhesive protein (anti-TRAP) and anti-liver stage antigen 1 (anti-LSA1) CD8(+) T cell responses when primed by single antigen TRAP- or LSA1-expressing DNAs, respectively, but not by DNA-L3SEPTL. However, prime boost regimes involving two heterologous viral vectors expressing L3SEPTL induced a strong cellular response directed against an LSA1 peptide located in the C-terminal region of the polyprotein. Peptide-specific T cells secreted IFN-gamma and were cytotoxic. IFN-gamma-secreting T cells specific for each of the six antigens were induced after vaccination with L3SEPTL, supporting the use of polyprotein inserts to induce multispecific T cells against P. falciparum. The use of polyprotein constructs in nonreplicating poxviruses should broaden the target antigen range of vaccine-induced immunity and increase the number of potential epitopes available for immunogenetically diverse human populations.
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PMID:A Plasmodium falciparum candidate vaccine based on a six-antigen polyprotein encoded by recombinant poxviruses. 1469 97


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