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

Twenty malaria-naive volunteers received a recombinant Plasmodium falciparum malaria vaccine (RTS,S) containing 19 NANP repeats and the carboxy terminus (amino acids 210-398) of the circumsporozoite (CS) antigen coexpressed in yeast with hepatitis B surface antigen. Ten received vaccine adjuvanted with alum, and 10 received vaccine adjuvanted with alum plus 3-deacylated monophosphoryl lipid A (MPL). Both formulations were well tolerated and immunogenic. MPL enhanced CS antibody levels (measured by ELISA, immunofluorescence, and inhibition of sporozoite invasion assays). After sporozoite challenge, 6 of 6 in the alum group and 6 of 8 in the alum-MPL group developed patent malaria. Protected subjects had higher levels of CS antibody titers on day of challenge than did nonprotected subjects. After immunization, 1 protected subject had increased cytotoxic T lymphocyte activity against CS and recall of memory T cell responses to RTS,S and selected CS.
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PMID:Safety, immunogenicity, and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein-hepatitis B surface antigen subunit vaccine. 776 95

After the first in vitro cultivation of Plasmodium falciparum 21 years ago, the prospect of anti-malarial vaccination arose many hopes, but, in the end, it so far has mainly given rise to doubts and disappointments. Technically, the problem is particularly difficult. Plasmodium falciparum has a very complex antigenic structure with several hundreds, if not several thousands, of different epitopes for each of the four main evolutive stages of the parasite (sporozoites, merozoites, gametocytes, ookinetes) which correspond to different phase of the infection and could be a target for vaccination. Many of these epitopes are stage-specific and some of them vary from one strain to another. Adjuvants also play a major role and can qualitatively modify the type of immune response. The immune mechanisms also differ according to the final goal: anti-Plasmodium infection or anti-disease vaccine. Over the last few years, the first clinical assays have been carried out with the Spf66 vaccine, a synthetic complex protein directed against sporozoites and merozoites. In adults and children, the first results in South America and in East Africa were modest but encouraging. Unfortunately they were not confirmed by further studies in West Africa and South-East Asia. Two new types of vaccines are under preliminary clinical evaluation. One is directed against ookinetes of Plasmodium falciparum (Pfs25 and Pfs28) and can stop the transmission from the mosquito. The other is an anti-sporozoite vaccine with a new immunogen (RTS,S) in which the circumsporozoite protein is fused to the hepatitis B surface antigen and can protect against infestation. New prospects and improvements are offered by the technique of DNA vaccines and will probably also result from better knowledge of cellular and molecular biology of the parasite which is being extensively studied (genomic structure). If new promising perspectives exist, it is particularly important to be careful to avoid such disappointments as those caused, in the past, by a too-optimistic and over-publicized presentation of some preliminary results. It is now certain that one or several malaria-vaccines will be available, but no one can seriously say when, for whom and how. In any case, it is unrealistic to hope that vaccine(s) alone will be able to eradicate such an epidemiologically complex disease as malaria. It is probable that only the coordinated use of all the techniques available (anti-vectorial protection and fight, chemoprophylaxis and chemotherapy, vaccination) will lead to success.
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PMID:[Vaccination against malaria. Disappointments and hopes]. 955 23

Encapsulation of soluble protein antigens in liposomes was previously shown to result in processing of antigen via the major histocompatibility complex class I pathway, as evidenced by costaining of the trans-Golgi region of murine bone marrow-derived macrophages (BMs) by fluorophore-labeled liposomal antigen and by a trans-Golgi-specific fluorescent lipid. Evidence is presented here that free or liposome-encapsulated RTS,S, a particulate malaria antigen consisting of hepatitis B particles coexpressed with epitopes from the Plasmodium falciparum circumsporozoite protein, also was localized in the trans-Golgi after incubation with BMs, suggesting processing by the class I pathway. An in vivo cytotoxic T-lymphocyte (CTL) response was detected, however, only after immunization with RTS,S encapsulated in liposomes containing lipid A and not after immunization with free RTS,S or with RTS,S encapsulated in liposomes lacking lipid A. Therefore, intracellular delivery of antigen containing CTL epitopes to the Golgi of BMs does not necessarily result in a CTL response in vivo unless an additional adjuvant, such as liposomes containing lipid A, is utilized. Encapsulation of RTS,S in liposomes containing monophosphoryl lipid A (MPL) resulted in a dose-dependent enhancement of the NANP-specific immunoglobulin G (IgG) antibody response compared to that of free RTS,S. The IgG1 and IgG2a subclasses predominated after immunization with RTS,S encapsulated in liposomes containing MPL. These results demonstrate that encapsulation of a lipid-containing particulate antigen, such as RTS, S, in liposomes containing lipid A can enhance both humoral and cellular immune responses.
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PMID:Liposomes containing lipid A serve as an adjuvant for induction of antibody and cytotoxic T-cell responses against RTS,S malaria antigen. 959 60

The malaria sporozoite vaccine candidate RTS,S, formulated with an oil-in-water emulsion plus the immunostimulants monophosphoryl lipid A and the saponin derivative QS21 (vaccine 3), recently showed superior efficacy over two other experimental formulations. Immunized volunteers were followed to determine the duration of protective immune responses. Antibody levels decreased to between one-third and one-half of peak values 6 months after the last dose of vaccine. T cell proliferation and interferon-gamma production in vitro were observed in response to RTS,S or hepatitis B surface antigen. Seven previously protected volunteers received sporozoite challenge, and 2 remained protected (1/1 for vaccine 1, 0/1 for vaccine 2, and 1/5 for vaccine 3). The prepatent period was 10.8 days for the control group and 13.2 days for the vaccinees (P < .01). Immune responses did not correlate with protection. Further optimization in vaccine composition and/or immunization schedule will be required to induce longer-lasting protective immunity.
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PMID:Long-term efficacy and immune responses following immunization with the RTS,S malaria vaccine. 980 46

The RTS,S/SBAS2 vaccine confers sterile protection against Plasmodium falciparum sporozoite challenge. The mechanisms underlying this are of great interest, yet little is known about the immune effector mechanisms induced by this vaccine. The immune responses induced by RTS,S/SBAS2 were characterized in 10 malaria-naive volunteers. Several epitopes in the circumsporozoite protein (CSP) were identified as targets of cultured interferon (IFN)-gamma-secreting CD4+ T cells. RTS,S-specific IFN-gamma-secreting effector T cells were induced in 8 subjects; this ex vivo response mapped to a single peptide in Th2R. CSP-specific CD8+ cytotoxic T lymphocytes were not detected. RTS, S-specific IFN-gamma production was universal, whereas interleukin-4 and -5 production was rare. RTS,S-specific lymphoproliferative responses and antibodies to CSP were strongly induced in all volunteers. Responses waned with time but were boostable. Thus, RTS, S/SBAS2 is a potent inducer of Th1-type cellular and humoral immunity. These results highlight possible immune mechanisms of protection and have important implications for vaccine design in general.
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PMID:Potent induction of focused Th1-type cellular and humoral immune responses by RTS,S/SBAS2, a recombinant Plasmodium falciparum malaria vaccine. 1051 29

RTS,S is a novel pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein (CSP) of Plasmodium falciparum linked to hepatitis B surface antigen (HBs) and combined with a novel adjuvant system (SBAS2). We have conducted a Phase I trial with three doses of this vaccine given at 0, 1, and 6 months to 20 semi-immune, adult, male volunteers in The Gambia to assess its safety and immunogenicity. Eighteen of the 20 volunteers completed the study. There were no clinically significant local or systemic adverse events following each vaccination. Hematologic and biochemical indices before and two weeks after each vaccination showed no evidence of toxicity. Antibody titers to both CSP and HBs showed a significant increase after vaccination; these were the largest after the third dose. We conclude that the RTS,S/SBAS2 vaccine induces no significant toxicity in this semi-immune population and produces significant increases in antibody titers to CSP.
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PMID:A phase I safety and immunogenicity trial with the candidate malaria vaccine RTS,S/SBAS2 in semi-immune adults in The Gambia. 1067 60

A safe and effective malaria vaccine will greatly facilitate efforts to control the global spread of malaria. This paper discusses the conceptual framework for developing malaria vaccines and some of the difficulties that the various approaches face. It emphasizes the role of pre-erythrocytic malaria vaccines, which are designed to protect against malaria infection, rather than simply prevent clinical disease. It describes recent encouraging results in human subjects with the RTS,S vaccine, a promising pre-erythrocytic malaria vaccine candidate.
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PMID:Malaria vaccines: triumphs or tribulations? 1069 93

After initial successful evaluation of the circumsporozoite-based vaccine RTS,S/SBAS2, developed by SmithKline Beecham Biologicals with the Walter Reed Army Institute of Research, protective efficacy of several regimens against Plasmodium falciparum challenge was determined. A controlled phase 1/2a study evaluated 1 or 2 standard doses of RTS,S/SBAS2 in 2 groups whose members received open-label therapy and 3 immunizations in blinded groups who received standard, one-half, or one-fifth doses. RTS,S/SBAS2 was safe and immunogenic in all groups. Of the 41 vaccinees and 23 control subjects who underwent sporozoite challenge, malaria developed in 7 of 10 who received 1 dose, in 7 of 14 who received 2 doses, in 3 of 6 who received 3 standard doses, in 3 of 7 who received 3 one-half doses, in 3 of 4 who received 3 one-fifth doses, and in 22 of 23 control subjects. Overall protective efficacy of RTS,S/SBAS2 was 41% (95% confidence interval, 22%-56%; P=.0006). This and previous studies have shown that 2 or 3 doses of RTS,S/SBAS2 protect against challenge with P. falciparum sporozoites.
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PMID:Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum malaria. 1117 Sep 91

William Harvey wrote about malaria, snake bite and rabies, three diseases now having their greatest impact in tropical developing countries. Global malarial mortality has not declined for 50 years. The most effective control measure would be a vaccine. Temporary immunity in humans, through hundreds of bites by irradiated infected mosquitoes, was achieved in the 1970s. A promising current strategy is effector T-cell vaccination directed at infected hepatocytes. RTS,S/(SB)ASO2, an adjuvanted fusion protein, produced transient protection in 70% of vaccines. Prime (DNA vaccine) boost (poxvirus recombinant) is particularly immunogenic. Pyrethroid-treated bed nets reduce childhood mortality and deplete the mosquito population, interrupting transmission. Chlorproguanil-dapsone is more effective than pyrimethamine-sulfadoxine in treating uncomplicated chloroquine-resistant malaria. Artemisinin derivatives are as effective as quinine in severe disease. Snake bite is an underestimated and neglected cause of morbidity and mortality in rural communities in tropical countries. Sutherland's pressure-immobilisation technique is recommended first-aid for victims of neurotoxic elapid snakes. Rabies post-exposure prophylaxis, using new generation cell culture vaccines, is now feasible in developing countries, employing an economical 8-site intradermal regimen. This Harveian Oration, the first in 350 years to be devoted to tropical medicine, emphasises the importance of this speciality in the twenty-first century.
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PMID:'To search and studdy out the secrett of tropical diseases by way of experiment'. 1179 90

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


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