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Parasitology Jul 2013Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease,... (Review)
Review
Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.
Topics: Amidines; Animals; Antiprotozoal Agents; Humans; Intracellular Space; Microscopy, Electron, Transmission; Parasites; Pentamidine; Protozoan Infections; Ultrasonography
PubMed: 23561006
DOI: 10.1017/S0031182013000292 -
PLoS Medicine Jan 2010One of the criteria to objectively prioritize merozoite antigens for malaria vaccine development is the demonstration that naturally acquired antibodies are associated... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
One of the criteria to objectively prioritize merozoite antigens for malaria vaccine development is the demonstration that naturally acquired antibodies are associated with protection from malaria. However, published evidence of the protective effect of these antibodies is conflicting.
METHODS AND FINDINGS
We performed a systematic review with meta-analysis of prospective cohort studies examining the association between anti-merozoite immunoglobin (Ig) G responses and incidence of Plasmodium falciparum malaria. Two independent researchers searched six databases and identified 33 studies that met predefined inclusion and quality criteria, including a rigorous definition of symptomatic malaria. We found that only five studies were performed outside sub-Saharan Africa and that there was a deficiency in studies investigating antibodies to leading vaccine candidates merozoite surface protein (MSP)-1(42) and erythrocyte binding antigen (EBA)-175. Meta-analyses of most-studied antigens were conducted to obtain summary estimates of the association between antibodies and incidence of P. falciparum malaria. The largest effect was observed with IgG to MSP-3 C terminus and MSP-1(19) (responders versus nonresponders, 54%, 95% confidence interval [CI] [33%-68%] and 18% [4%-30%] relative reduction in risk, respectively) and there was evidence of a dose-response relationship. A tendency towards protective risk ratios (RR<1) was also observed for individual study estimates for apical membrane antigen (AMA)-1 and glutamate-rich protein (GLURP)-R0. Pooled estimates showed limited evidence of a protective effect for antibodies to MSP-1 N-terminal regions or MSP-1-EGF (epidermal growth factor-like modules). There was no significant evidence for the protective effect for MSP-2 (responders versus nonresponders pooled RR, MSP-2(FC27) 0.82, 95% CI 0.62-1.08, p = 0.16 and MSP-2(3D7) 0.92, 95% CI 0.75-1.13, p = 0.43). Heterogeneity, in terms of clinical and methodological diversity between studies, was an important issue in the meta-analysis of IgG responses to merozoite antigens.
CONCLUSIONS
These findings are valuable for advancing vaccine development by providing evidence supporting merozoite antigens as targets of protective immunity in humans, and to help identify antigens that confer protection from malaria. Further prospective cohort studies that include a larger number of lead antigens and populations outside Africa are greatly needed to ensure generalizability of results. The reporting of results needs to be standardized to maximize comparability of studies. We therefore propose a set of guidelines to facilitate the uniform reporting of malaria immuno-epidemiology observational studies. Please see later in the article for the Editors' Summary.
Topics: Antibodies, Protozoan; Antigens, Protozoan; Drug Design; Evidence-Based Medicine; Humans; Incidence; Malaria Vaccines; Malaria, Falciparum; Merozoites; Plasmodium falciparum; Protozoan Proteins
PubMed: 20098724
DOI: 10.1371/journal.pmed.1000218 -
The Cochrane Database of Systematic... Jul 2007Four types of malaria vaccine, SPf66 and MSP/RESA vaccines (against the asexual stages of the Plasmodium parasite) and CS-NANP and RTS,S vaccines (against the sporozoite... (Review)
Review
BACKGROUND
Four types of malaria vaccine, SPf66 and MSP/RESA vaccines (against the asexual stages of the Plasmodium parasite) and CS-NANP and RTS,S vaccines (against the sporozoite stages), have been tested in randomized controlled trials in endemic areas.
OBJECTIVES
To assess malaria vaccines against Plasmodium falciparum, P. vivax, P. malariae and P ovale in preventing infection, disease and death.
SEARCH STRATEGY
We searched the Cochrane Infectious Diseases Group Specialized Register (April 2004), CENTRAL (The Cochrane Library Issue 2, 2004), MEDLINE (1966 to April 2004), EMBASE (1980 to April 2004), Science Citation Index (1981 to April 2004), and reference lists of articles. We also contacted organizations and researchers in the field.
SELECTION CRITERIA
Randomized controlled trials comparing vaccines against Plasmodium falciparum, P. vivax, P. malariae or P. ovale with placebo or routine antimalarial control measures in people of any age receiving a challenge malaria infection.
DATA COLLECTION AND ANALYSIS
Two reviewers independently assessed trial quality and extracted data.
MAIN RESULTS
Eighteen efficacy trials involving 10,971 participants were included. There were ten trials of SPf66 vaccine, four trials of CS-NANP vaccines, two trials of RTS,S vaccine, and two of MSP/RESA vaccine. Results with SPf66 in reducing new malaria infections (P. falciparum) were heterogeneous: it was not effective in four African trials (Peto odds ratio (OR) 0.96, 95% confidence interval (CI) 0.81 to 1.14), but in five trials outside Africa the number of first attacks was reduced (Peto OR 0.77, 95% CI 0.67 to 0.88). Trials to date have not indicated any serious adverse events with SPf66 vaccine. In three trials of CS-NANP vaccines, there was no evidence for protection by these vaccines against P. falciparum malaria (Peto OR 1.12, 95% CI 0.64 to 1.93). In a small trial in non-immune adults in the USA, RTS,S gave strong protection against experimental infection with P. falciparum. In a trial in an endemic area of the Gambia in semi-immune people, there was a reduction in clinical malaria episodes in the second year of follow up, corresponding to a vaccine efficacy of 66% (CI 14% to 85%). In a trial in Papua New Guinea, MSP/RESA had no protective effect against episodes of clinical malaria. There was evidence of an effect on parasite density, but this differed according to whether the participants had been pretreated with sulfadoxine/pyrimethamine or not. The prevalence of infections with the parasite subtype of MSP2 in the vaccine was reduced compared with the other subtype (Peto OR 0.35, CI 0.23 to 0.53).
AUTHORS' CONCLUSIONS
There is no evidence for protection by SPf66 vaccines against P. falciparum in Africa. There is a modest reduction in attacks of P. falciparum malaria following vaccination with SPf66 in other regions. Further research with SPf66 vaccines in South America or with new formulations of SPf66 may be justified. There was not enough evidence to evaluate the use of CS-NANP vaccines. The RTS,S vaccine showed promising result, as did the MSP/RESA vaccine, but it should include the other main allelic form of MSP2. The MSP/RESA trial demonstrated that chemotherapy during a vaccine trial may reduce vaccine efficacy, and trials should consider very carefully whether this practice is justified.
Topics: Adult; Antigens, Protozoan; Humans; Malaria; Malaria Vaccines; Malaria, Falciparum; Protozoan Proteins; Randomized Controlled Trials as Topic; Recombinant Proteins; Vaccines, Synthetic
PubMed: 17636596
DOI: 10.1002/14651858.CD000129.pub2 -
The Cochrane Database of Systematic... Oct 2006A malaria vaccine is needed because of the heavy burden of mortality and morbidity due to this disease. This review describes the results of trials of blood... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A malaria vaccine is needed because of the heavy burden of mortality and morbidity due to this disease. This review describes the results of trials of blood (asexual)-stage vaccines. Several are under development, but only one (MSP/RESA, also known as Combination B) has been tested in randomized controlled trials.
OBJECTIVES
To assess the effect of blood-stage malaria vaccines in preventing infection, disease, and death.
SEARCH STRATEGY
In March 2006, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2006, Issue 1), MEDLINE, EMBASE, LILACS, and the Science Citation Index. We also searched conference proceedings and reference lists of articles, and contacted organizations and researchers in the field.
SELECTION CRITERIA
Randomized controlled trials comparing blood-stage vaccines (other than SPf66) against P. falciparum, P. vivax, P. malariae, or P. ovale with placebo, control vaccine, or routine antimalarial control measures in people of any age receiving a challenge malaria infection.
DATA COLLECTION AND ANALYSIS
Both authors independently assessed trial quality and extracted data. Results for dichotomous data were expressed as relative risks (RR) with 95% confidence intervals (CI).
MAIN RESULTS
Five trials of MSP/RESA vaccine with 217 participants were included; all five reported on safety, and two on efficacy. No severe or systemic adverse effects were reported at doses of 13 to 15 microg of each antigen (39 to 45 microg total). One small efficacy trial with 17 non-immune participants with blood-stage parasites showed no reduction or delay in parasite growth rates after artificial challenge. In the second efficacy trial in 120 children aged five to nine years in Papua New Guinea, episodes of clinical malaria were not reduced, but MSP/RESA significantly reduced parasite density only in children who had not been pretreated with an antimalarial drug (sulfadoxine-pyrimethamine). Infections with the 3D7 parasite subtype of MSP2 (the variant included in the vaccine) were reduced (RR 0.38, 95% CI 0.26 to 0.57; 719 participants) while those with the other main subtype, FC27, were not (720 participants).
AUTHORS' CONCLUSIONS
The MSP/RESA (Combination B) vaccine shows promise as a way to reduce the severity of malaria episodes, but the effect of the vaccine is MSP2 variant-specific. Pretreatment for malaria during a vaccine trial makes the results difficult to interpret, particularly with the relatively small sample sizes of early trials. The results show that blood-stage vaccines may play a role and merit further development.
Topics: Antigens, Protozoan; Humans; Malaria; Malaria Vaccines; Merozoites; Protozoan Proteins; Randomized Controlled Trials as Topic; Vaccines, Combined
PubMed: 17054281
DOI: 10.1002/14651858.CD006199 -
The Cochrane Database of Systematic... Oct 2006Vaccines against all stages of the malaria parasite are in development, mainly for Plasmodium falciparum, which causes the most serious form of malaria. Pre-erythrocytic... (Review)
Review
BACKGROUND
Vaccines against all stages of the malaria parasite are in development, mainly for Plasmodium falciparum, which causes the most serious form of malaria. Pre-erythrocytic vaccines act to prevent or delay a malaria attack by attacking the sporozoite and liver stages before the parasite reaches the bloodstream.
OBJECTIVES
To assess the efficacy and safety of pre-erythrocytic malaria vaccines against any type of human malaria.
SEARCH STRATEGY
In March 2006, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2006, Issue 1), MEDLINE, EMBASE, LILACS, and the Science Citation Index. We also searched conference proceedings and reference lists of articles, and contacted organizations and researchers in the field.
SELECTION CRITERIA
Randomized controlled trials comparing pre-erythrocytic vaccines with placebo, control vaccine, or routine antimalarial control measures in people of any age receiving an artificial challenge or natural exposure to malaria infection.
DATA COLLECTION AND ANALYSIS
Both authors independently assessed trial quality and extracted data. Results of meta-analyses were expressed as relative risks with 95% confidence intervals (CI) using an intention-to-treat analysis.
MAIN RESULTS
Nine safety and efficacy trials, and two safety trials, with over 3000 participants were included. In semi-immune children, RTS,S vaccine reduced clinical episodes of malaria by 26% (95% CI 13% to 37%) and severe malaria by 58% (95% CI 15% to 79%) for up to 18 months. Prevalence of parasitaemia was also reduced by 26% (95% CI 11% to 38%) at six months after immunization. RTS,S also reduced clinical malaria episodes by 63% (95% CI 18% to 83%) in semi-immune adult men in the second year of follow up after a booster dose. No severe adverse events were judged to be related to RTS,S vaccine, although the frequencies of injection site pain, swelling, arm motion limitation, headache, and malaise were increased in the vaccine groups. There was no evidence for effect of the CS-NANP vaccines (307 participants, 3 trials), CS102 peptide vaccine (14 participants, 1 trial), or the ME-TRAP vaccine (372 participants, 1 trial).
AUTHORS' CONCLUSIONS
RTS,S vaccine was effective in preventing a significant number of clinical malaria episodes, including good protection against severe malaria in children for 18 months. No severe adverse events were attributable to the vaccine. Progression of this vaccine towards licensing is justified while efforts to increase its efficacy continue. The other vaccines do not look promising and further research is a priority.
Topics: Adult; Antigens, Protozoan; Child; Humans; Malaria; Malaria Vaccines; Protozoan Proteins; Vaccines, DNA
PubMed: 17054280
DOI: 10.1002/14651858.CD006198 -
The Cochrane Database of Systematic... Apr 2006A malaria vaccine is badly needed. SPf66 was one of the earliest vaccines developed. It is a synthetic peptide vaccine containing antigens from the blood stages of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A malaria vaccine is badly needed. SPf66 was one of the earliest vaccines developed. It is a synthetic peptide vaccine containing antigens from the blood stages of malaria linked together with an antigen from the sporozoite stage, and is targeted mainly against the blood (asexual) stages.
OBJECTIVES
To assess the effect of SPf66 malaria vaccines against Plasmodium falciparum, P. vivax, P. malariae, and P. ovale in preventing infection, disease, and death.
SEARCH STRATEGY
We searched the Cochrane Infectious Diseases Group Specialized Register (September 2005), CENTRAL (The Cochrane Library 2005, Issue 3), MEDLINE (1966 to September 2005), EMBASE (1980 to September 2005), LILACS (1982 to September 2005), Science Citation Index (1981 to September 2005), and reference lists of articles. We also contacted organizations and researchers in the field.
SELECTION CRITERIA
Randomized and quasi-randomized controlled trials comparing SPf66 vaccine with placebo or routine antimalarial control measures in people of any age receiving an artificial challenge or natural exposure to malaria infection (any species).
DATA COLLECTION AND ANALYSIS
Two people independently assessed trial quality and extracted data, including adverse events. Results were expressed as relative risks (RR) with 95% confidence intervals (CI).
MAIN RESULTS
Ten efficacy trials of SPf66 involving 9698 participants were included. Results with SPf66 in reducing new episodes of P. falciparum malaria were heterogeneous: it was not effective in four African trials (RR 0.98, 95% CI 0.90 to 1.07; 2371 participants) or in one Asian trial (RR 1.06, 95% CI 0.90 to 1.25; 1221 participants). In four trials in South America the number of first attacks with P. falciparum was reduced by 28% (RR 0.72, 95% CI 0.63 to 0.82; 3807 participants). It did not reduce episodes of P. vivax malaria or admission to hospital with severe malaria. Trials have not indicated any serious adverse events with SPf66 vaccine.
AUTHORS' CONCLUSIONS
There is no evidence for protection by SPf66 vaccines against P. falciparum in Africa. There is a modest reduction in attacks of P. falciparum malaria following vaccination with SPf66 in South America. There is no justification for further trials of SPf66 in its current formulation. Further research with SPf66 vaccines in South America or with new formulations of SPf66 may be justified.
Topics: Humans; Malaria; Malaria Vaccines; Protozoan Proteins; Randomized Controlled Trials as Topic; Recombinant Proteins; Vaccines, Synthetic
PubMed: 16625647
DOI: 10.1002/14651858.CD005966 -
Health Technology Assessment... 1998
Comparative Study Review
Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Calcium Channel Blockers; Cerebrovascular Disorders; Clinical Trials as Topic; Coronary Artery Bypass; Coronary Care Units; Databases, Bibliographic; Eligibility Determination; Female; Humans; Information Storage and Retrieval; MEDLINE; Malaria; Malaria Vaccines; Male; Models, Statistical; Patient Participation; Random Allocation; Randomized Controlled Trials as Topic; Reproducibility of Results; Research Design; Risk Assessment; Survival Rate; United States
PubMed: 9793791
DOI: No ID Found