Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to provide a rational basis for the development of a pre-erythrocytic malaria vaccine we have aimed at: (a) elucidating the mechanisms of protection, and (b) identifying vaccine formulations that best elicit protection in experimental animals and humans. Based on earlier successful immunization of experimental animals with irradiated sporozoites, human volunteers were exposed to the bites of large numbers of Plasmodium falciparum or P. vivax infected irradiated mosquitoes. The result of this vaccine trial demonstrated for the first time that a pre-erythrocytic vaccine, administered to humans, can result in their complete resistance to malaria infection. However, since infected irradiated mosquitoes are unavailable for large scale vaccination, the alternative is to develop subunit vaccines. The human trials using irradiated sporozoites provided valuable information on the human immune responses to pre-erythrocytic stages and studies on mice an excellent experimental model to characterize protective immune mechanisms. The circumsporozoite protein, the first pre-erythrocytic antigen identified, is present in all malaria species, displaying a similar structure, with a central region of repeats, and two conserved regions, essential for parasite development. Most pre-erythrocytic vaccine candidates are based on the CS protein, expressed in various cell lines, microorganisms, and recently the corresponding DNA. We and others have identified CS-specific B and T cell epitopes, recognized by the rodent and human immune systems, and used them for the development of synthetic vaccines. We used synthetic peptide vaccines, multiple antigen peptides and polyoximes, for immunization, first in experimental animals, and recently in two human safety and immunogenicity trials. We also report here on our work on T cell mediated immunity, particularly the protection of mice immunized with viral vectors expressing CS-specific cytotoxic CD8+ T cell epitopes, and the striking booster effect of recombinant vaccinia virus. To what degree CD8+ T cells, and/or other T cells specific for sporozoites and/or liver stage epitopes, contribute to pre-erythrocytic protective immunity in humans, remains to be determined.
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PMID:Pre-erythrocytic malaria vaccine: mechanisms of protective immunity and human vaccine trials. 1069 92

We characterized the immunogenicity of the hybrid Ty-virus-like carrying the CD8(+) T cell epitope (SYVPSAEQI) of the circumsporozoite (CS) protein of Plasmodium yoelii (TyCS-VLP), a rodent malaria parasite. Balb/c mice were immunized with hybrid TyCS-VLP, and their CS-specific CD8(+) T cell response was quantitatively evaluated with the ELISPOT assay, based on the enumeration of epitope specific gamma-interferon secreting CD8(+) T cell. A single immunization with the TyCS-VLP by a variety of routes and doses indicated that the maximal response occurred in mice, which were immunized with 50 micrograms of these particles, administered via intramuscular. Combined immunization of mice with this TyCS-VLP followed by recombinant vaccinia virus expressing the entire P. yoelii CS protein (VacPyCS) or irradiated sporozoites, induced high levels of IFN-gamma-producing cells. The immunization regime, priming with TyCS-VLP and boosting with VacPyCS generated a potent protective immune response, which strongly inhibited P. yoelii liver stages development and protected 62% of the mice against a subsequent live P. yoelii sporozoite challenge.
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PMID:Immunogenicity of Ty-VLP bearing a CD8(+) T cell epitope of the CS protein of P. yoelii: enhanced memory response by boosting with recombinant vaccinia virus. 1069 35

CD8(+) cytolytic T lymphocytes (CTL) play a fundamental role in the clearance of malaria parasites from the liver in mouse models. In humans, however, only low levels of parasite-specific CD8(+) T lymphocytes have been observed in individuals living in endemic areas. In the present study, we identified high levels of circulating CD8(+) T lymphocytes specific for a previously described HLA-A2-restricted CTL epitope of the circumsporozoite (CS) protein of Plasmodium falciparum in an adult living in Burkina Faso, as evidenced by IFN-gamma ELISPOT assay and MHC-tetramer technology. After cloning by limiting dilution culture, T cell recognition of natural CS variants of P. falciparum was studied. The results demonstrate that naturally occurring variations drastically affect residues critical for T cell recognition as only two out of nine sequences analyzed were efficiently recognized by the CTL clones. These clones were also used to analyze T cell recognition of the endogenously presented cognate antigen. We observed efficient antigen recognition of both HLA-A*0201-transfected murine antigen presenting cells and liver cells from HLA-A*0201/K(b)-transgenic mice upon infection with recombinant vaccinia virus encoding the CS protein (WR-CS). More importantly, we demonstrate for the first time efficient recognition of WR-CS-infected human liver cells.
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PMID:Generation and characterization of malaria-specific human CD8(+) lymphocyte clones: effect of natural polymorphism on T cell recognition and endogenous cognate antigen presentationby liver cells. 1109 22

CD8+ T cells have been implicated as critical effector cells in protection against the pre-erythrocytic stage of malaria in mice and humans following irradiated sporozoite immunization. Immunization experiments in animal models by several investigators have suggested different strategies for vaccination against malaria and many of the targets from liver stage malaria antigens have been shown to be immunogenic and to protect mice from the sporozoite challenge. Several prime/boost protocols with replicating vectors, such as vaccinia/influenza, with non-replicating vectors, such as recombinant particles derived from yeast transposon (Ty-particles) and modified vaccinia virus Ankara, and DNA, significantly enhanced CD8+ T cell immunogenicity and also the protective efficacy against the circumsporosoite protein of Plasmodium berghei and P. yeti. Based on these experimental results the development of a CD8+ T cell inducing vaccine has moved forward from epitope identification to planning stages of safety and immunogenicity trials of candidate vaccines.
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PMID:Protective CD8+ T cell responses against the pre-erythrocytic stages of malaria parasites: an overview. 1128

A main goal of the industrialized world is the development of effective vaccines to control infectious diseases with major health and socio-economic impact. Current understanding of the immune response triggered during infection with pathogens causing malaria, hepatitis C and AIDS emphasizes the importance of cytotoxic T lymphocytes (CTLs) in combating these infections. This has led to the development of new vaccination strategies, some of which are in phase I/II clinical trials. Promising strategies of vaccination are based on highly attenuated viral vectors, such as Vaccinia virus (VV) in combination with heterologous like vectors naked DNA, referred to as priming/booster vaccination. While these immunization schedules increased the production of specific CTLs, there is a need to further expand the CD8+T cell population to control an infection. Among molecules that play a significant role in the modulation of the CTL response is the cytokine IL-12. Immunoregulation by IL-12 is of central importance in cell-mediated immunity (CMI) against those pathogens and tumors that are controlled by cell-mediated mechanisms, supported by Thl cells. The use of this cytokine in combination with highly immunogenic VV-derived vectors is a promising system for development of future vaccination schedules. In this review, we summarize recent data on the use of IL-12 in vaccination procedures, as well as undesired side-effects of the cytokine that can be overcome by accurate use of dose, route and time-window administration of IL-12 encoding vectors. Results described here indicate that VV IL-12-mediated enhancement of the specific CMI response against a model antigen HIV-1 env was time- and dose-dependent and that the antigen and the cytokine could be expresed from two different rVVs modulating the doses of the vectors and allowing for enhancement of a specific CMI response. Moreover, the use of IL-12 during DNA prime/VV boost regimens enhanced the specific anti-HIV-1 env cellular response 20 times compared to that generated after a single rVVenv inoculation. Variables such as: a) dose of the cytokine applied, b) time of its administration and c) routes of inoculation play a critical role in the final outcome of the response. The findings presented here can be extended to other antigens, suggesting that immunomodulatory cytokines can be useful in the development of the future vaccines against numerous infectious diseases and tumors.
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PMID:Towards a new generation of vaccines: the cytokine IL-12 as an adjuvant to enhance cellular immune responses to pathogens during prime-booster vaccination regimens. 1133 21

Vaccination has been one of the most successful and cost-effective health interventions ever employed. One disease (smallpox) has been eradicated, another (poliomyelitis) should disappear early in the new millennium and a third (measles) should follow shortly after. Conventional vaccines usually depend on one of three development processes, attenuation of virulent organisms (by passage in cell culture and/or experimental animals), killing of virulent organisms (by chemical inactivation) or the purification of immunogenic molecules (either proteins or carbohydrates) from whole organisms. These traditional processes, although serendipitous and poorly understood, have produced effective pharmaceutical products which give excellent protection against diseases such as smallpox, rabies, measles, yellow fever, tetanus and diphtheria. In spite of these successes however, the application of these protocols have failed to produce safe and efficacious vaccines against other infectious diseases which kill or maim tens of millions of people every year. The most important of these are malaria, AIDS, herpes, dengue fever and some forms of viral hepatitis. Consequently, fundamentally new technologies are required to tackle these important infections. One of the most promising has been the development of genetically modified viruses. This process normally involves taking a proven safe and efficacious vaccine virus, such as vaccinia or adenovirus, and modifying its genome to include genes coding for immunogenic proteins from other viruses such as HIV or measles. This review will describe the generation of such novel vaccine vectors and compare their advantages and shortcomings. In addition the literature describing their use as experimental vaccines will also be reviewed.
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PMID:Genetically modified viruses: vaccines by design. 1148 48

Two chimpanzees were vaccinated intramuscularly against malaria using plasmid DNA expressing the pre-erythrocytic antigens thrombospondin related adhesion protein (PfTRAP) and liver stage specific antigen-1 (PfLSA-1) of Plasmodium falciparum together with GM-CSF protein. A recombinant modified vaccinia virus Ankara (MVA) expressing PfTRAP was injected intramuscularly 6 weeks later to boost the immune response. This sequence of antigen delivery induced a specific and long-lasting T cell and antibody response to PfTRAP as detected by ELISPOT assay and ELISA. Antibody responses were detected after four DNA injections, and were boosted by injection of recombinant MVA expressing PfTRAP. Interferon-gamma secreting antigen-specific T cells were detected in both animals, but only after boosting with recombinant MVA. By screening a panel of PfTRAP-derived peptides, an epitope was identified that was recognized by cytotoxic T lymphocytes in one of the chimpanzees studied. T cells specific for this epitope were present in PBMCs and liver-infiltrating lymphocytes at a frequency of between 1 in 200 and 1 in 500. The high immunogenicity of this prime-boost regimen in chimpanzees supports further assessment of this delivery strategy for the induction of protection against P. falciparum malaria in humans.
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PMID:A prime-boost immunisation regimen using DNA followed by recombinant modified vaccinia virus Ankara induces strong cellular immune responses against the Plasmodium falciparum TRAP antigen in chimpanzees. 1153 6

We report that complete protection against malaria and total inhibition of liver stage development and parasitemia was obtained in 100% of BALB/c mice primed with a replication-defective recombinant adenovirus expressing the circumsporozoite (CS) protein of Plasmodium yoelii (AdPyCS), followed by a booster with an attenuated recombinant vaccinia virus, expressing the same malaria antigen, VacPyCS. We found increased levels of activated CS-specific CD8(+) and CD4(+) T cells, higher anti-sporozoite antibody titers, and greater protection in these mice, when the time between priming and boosting with these two viral vectors was extended from 2 to 8 or more weeks. Most importantly, by using this immunization regimen, the protection of the immunized mice was found to be long-lasting, namely complete resistance to infection of all animals 3 1/2 months after priming. These results indicate that immunization with AdPyCS generates highly effective memory T and B cells that can be recalled long after priming by boosting with VacPyCS.
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PMID:Complete, long-lasting protection against malaria of mice primed and boosted with two distinct viral vectors expressing the same plasmodial antigen. 1155 79

A generic approach to inducing high level CD8+ T cell responses would be of value for prophylactic and therapeutic immunisation against several infectious diseases. However, it has been very difficult to achieve such immune responses using available vaccination strategies. Malaria is one of several diseases against which a new generation of better CD8+ T cell-inducing vaccines might be useful and is unusual in that it allows assessment of vaccine efficacy in small numbers of volunteers in carefully controlled challenge studies. Here we review the identification of a heterologous prime-boost regime using DNA priming and recombinant modified vaccinia Ankara (MVA) boosting that induces high level T cell responses in both mice and non-human primates. Clinical trials to determine whether this prime-boost approach is immunogenic in humans are in progress.
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PMID:DNA-based vaccines for malaria: a heterologous prime-boost immunisation strategy. 1171 17

Since the rhesus is often used as a "gatekeeper" model for the evaluation of malaria and simian immunodeficiency virus (SIV)/HIV vaccines, the identification of strategies to enhance the activation of rhesus T cells would potentially aid in the generation of more potent vaccines directed against these infectious agents. Several molecules normally found on the surface of professional human APCs are capable of providing the second signals critical for T cell activation: B7-1 (CD80), ICAM-1 (CD54), and LFA-3 (CD58). With the exception of B7, T cell costimulatory molecules in the rhesus have not been identified. We have recently designed and characterized both recombinant vaccinia and recombinant avipox vectors containing the transgenes for a triad of human T cell costimulatory molecules (B7-1, ICAM-1, LFA-3; designated TRICOM). Here, we demonstrate the enhanced activation of rhesus T cells stimulated with rhesus APCs infected with TRICOM vectors in the presence of signal 1. Infection with TRICOM vectors led to significant improvement of APC capabilities in terms of reduction of the amount of signal 1 needed to activate naive T cells, and reduction in the amount of APCs required to activate T cells using a constant amount of signal 1. Antibody blocking studies demonstrated that each of the three costimulatory molecule transgenes contributed to the enhanced proliferation of T cells. TRICOM-enhanced T cell activation was shown to correspond to increases in type 1 cytokines and a reduced level of apoptosis. TRICOM-infected autologous B cells from rhesus immunized with either an SIV vaccine or a malaria vaccine stimulated significantly greater levels of IFN-gamma in response to specific peptide than stimulation with uninfected autologous B cells or B cells infected with wild-type vector. The ability to augment immune responses using poxvirus-based vaccines containing multiple costimulatory molecule transgenes can now be addressed in the rhesus macaque model.
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PMID:Enhanced activation of rhesus T cells by vectors encoding a triad of costimulatory molecules (B7-1, ICAM-1, LFA-3). 1173 38


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