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Biomedical subjects

A Saul

Publications and source records attributed to A Saul.

At least 37 records · Page 2Linked to original sources
PubMed2000

Effect of vaccination with 3 recombinant asexual-stage malaria antigens on initial growth rates of Plasmodium falciparum in non-immune volunteers.

A placebo controlled, randomised, double blind trial was conducted in human volunteers to test a mixture of three recombinant Plasmodium falciparum blood stage antigens for its ability to reduce the initial growth rates of parasites. The vaccine contained recombinant MSP2 (3D7 allele), a portion of MSP1 (190LCS.T3) and part of the RESA antigen (C terminal 771 amino acids) in the Montanide ISA 720 adjuvant (SEPPIC). Twelve volunteers received two doses of the vaccine, 6 weeks apart. The five participants in the placebo group received an equivalent volume of the adjuvant emulsion using the same schedule. Antibody responses were low, as has been reported in earlier studies with this combination, while T cell responses were stronger. All the volunteers were challenged with approximately 140 ring infected red cells of the 3D7 cloned line, 4 weeks after the second dose. Parasitaemia was determined once daily from day 4 using a sensitive and quantitative PCR assay. All the volunteers were infected and were treated on day 8, before any developed symptoms. There was no significant difference in initial parasite growth rates between the verum and placebo groups, nor was there any significant correlation between parasite growth rates and any of the measured immunological responses. These results suggest that the formulation tested in this trial did not generate immune responses that were strong enough to reduce parasite growth in naive volunteers.

Adult↗
PubMed2000

Twin study of adolescent genetic susceptibility to mosquito bites using ordinal and comparative rating data.

Ordinal and comparative rating measures of mosquito attraction and mosquito bite frequency and symptoms were administered in a self-report questionnaire format to a sample of 197 monozygotic and 326 dizygotic Australian adolescent twin pairs at age 12 between 1992 and 1999, in order to investigate the environmental and possibly genetic determinants of variation between individuals. Repeat measures were obtained from the twin pairs at age 14. Ordinal variable measures, although providing some support for genetic effects on mosquito susceptibility, were affected by low repeatability. However, analysis of a comparative rating variable "compared with your twin, who is bitten by mosquitoes more often?" indicated a strong genetic influence on frequency of being bitten by mosquitoes, with no significant differences observed between males and females. Comparative rating questionnaire items are a potentially valuable tool for complementing and improving the results obtained from more conventional absolute measures.

Adolescent↗
PubMed2000

Anti-malarial effect of histone deacetylation inhibitors and mammalian tumour cytodifferentiating agents.

The histones of Plasmodium falciparum represent a potential new target for anti-malarial compounds. A naturally occurring compound, apicidin, has recently been shown to inhibit the in vitro growth of P. falciparum. Apicidin was shown to hyperacetylate histones, suggesting that its mode of action is through histone deacetylase inhibition. We have tested the ability of known histone deacetylase inhibitors, mammalian tumour suppressor compounds, and cytodifferentiating agents to inhibit the in vitro growth of a drug sensitive and resistant strain of P. falciparum. Seven of the tested compounds had microM IC50 values, and trichostatin A, a histone deacetylation inhibitor and cytodifferentiating agent, was active at low nM concentrations. One compound, suberic acid bisdimethylamide, which selectively arrests tumour cells as opposed to normal mammalian cells, had an in vivo cytostatic effect against the acute murine malaria Plasmodium berghei, and one round of treatment with the compound failed to select for resistant mutations. These results suggest a promising role for histone deacetylase inhibitors and cytodifferentiating agents as antimalarial drug candidates.

Acetamides↗
PubMed2000

Malaria vaccines.

Although the possibility of a live attenuated malaria vaccine has been considered, current malaria vaccine development activities are dominated by attempts to develop a subunit vaccine. Hence, it is entirely appropriate that a session of the Molecular Approaches to Malaria conference, Lorne, Australia, 2-5 February 2000, was devoted to vaccine development. The oral presentations in this session and the relevant poster presentations are outlined here by Robin Anders and Allan Saul.

Animals↗
PubMed2000

Functional conservation of the malaria vaccine antigen MSP-119across distantly related Plasmodium species.

The C-terminal region of Plasmodium falciparum merozoite surface protein 1 (MSP-119) is at present a leading malaria vaccine candidate. Antibodies against the epidermal growth factor-like domains of MSP-1 19are associated with immunity to P. falciparum and active immunization with recombinant forms of the molecule protect against malaria challenge in various experimental systems. These findings, with the knowledge that epidermal growth factor-like domains in other molecules have essential binding functions, indicate the importance of this protein in merozoite invasion of red blood cells. Despite extensive molecular epidemiological investigations, only limited sequence polymorphism has been identified in P. falciparum MSP-119 (refs. 9-11). This indicates its sequence is functionally constrained, and is used in support of the use of MSP-119 as a vaccine. Here, we have successfully complemented the function of most of P. falciparum MSP-119 with the corresponding but highly divergent sequence from the rodent parasite P. chabaudi. The results indicate that the role of MSP-119 in red blood cell invasion is conserved across distantly related Plasmodium species and show that the sequence of P. falciparum MSP-119 is not constrained by function.

Amino Acid Sequence↗
PubMed2000

Recombinant chimeric proteins generated from conserved regions of Plasmodium falciparum merozoite surface protein 2 generate antiparasite humoral responses in mice.

The merozoite surface protein 2 of P. falciparum is highly polymorphic in nature, but has regions of almost complete conservation at its N- and C-termini. We produced a chimeric recombinant protein comprising these regions only (hereafter termed NC). Mice immunized with the NC antigen produce antibodies at levels comparable to those immunized with 1624, a full-length recombinant protein representing MSP2 from P. falciparum. Antisera raised against NC recognized P. falciparum schizonts by IFA and a P. falciparum protein of Mr 45 kDa by Western blot. However, antibody specificities were observed to differ between anti-NC and anti-1624 sera, and this resulted in differences in parasite recognition, despite similar levels of antibodies having been produced. The response to the NC antigen was also shown to be restricted in some mice (H2-d), but this was overcome by including appropriate T-cell help, which was accomplished by creating recombinant protein chimeras that contained NC and T-helper epitopes from Tetanus toxoid, or MSP119 from P. berghei.

Adolescent↗
PubMed2000

Aedes notoscriptus (Diptera: Culicidae) survival and dispersal estimated by mark-release-recapture in Brisbane, Queensland, Australia.

The survival and dispersal of adult Aedes notoscriptus (Skuse) were estimated in Brisbane, Queensland, Australia, where this species has been identified as a vector of Ross River and Barmah Forest viruses and shown to be orally susceptible to dengue virus types 1-4. Standard mark-release-recapture methods were used. Before the field study, laboratory trials showed that marking Ae. notoscriptus with fluorescent powder had no effect on survivorship. Female recapture rates of 10.6 and 2.3% over an 8-d period were achieved for two cohorts of marked Ae. notoscriptus released at the same field site. No males were recaptured over the 8-d period. The probability of daily survival was calculated using the Saul model as 0.77 and 0.79 for blue- and pink-marked females, respectively. For blue- and pink-marked females, the mean distance traveled was 105.2 and 179.9 m, and the maximum distance traveled was 195 and 238 m, respectively. The results indicate that protected harborage sites and shade influenced the distribution of Ae. notoscriptus within the study site.

Aedes↗
PubMed2000

Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site.

Atovaquone is the major active component of the new antimalarial drug Malarone. Considerable evidence suggests that malaria parasites become resistant to atovaquone quickly if atovaquone is used as a sole agent. The mechanism by which the parasite develops resistance to atovaquone is not yet fully understood. Atovaquone has been shown to inhibit the cytochrome bc(1) (CYT bc(1)) complex of the electron transport chain of malaria parasites. Here we report point mutations in Plasmodium falciparum CYT b that are associated with atovaquone resistance. Single or double amino acid mutations were detected from parasites that originated from a cloned line and survived various concentrations of atovaquone in vitro. A single amino acid mutation was detected in parasites isolated from a recrudescent patient following atovaquone treatment. These mutations are associated with a 25- to 9,354-fold range reduction in parasite susceptibility to atovaquone. Molecular modeling showed that amino acid mutations associated with atovaquone resistance are clustered around a putative atovaquone-binding site. Mutations in these positions are consistent with a reduced binding affinity of atovaquone for malaria parasite CYT b.

Amino Acid Sequence↗
PubMed2000

Interaction of HLA and age on levels of antibody to Plasmodium falciparum rhoptry-associated proteins 1 and 2.

The Plasmodium falciparum rhoptry-associated proteins 1 and 2 (RAP1 and RAP2) are candidate antigens for a subunit malaria vaccine. The design of the study, which looks at the acquisition of immunity to malaria from childhood to old age, has allowed us to document the interaction of HLA and age on levels of antibody to specific malarial antigens. Antibodies reach maximum levels to RAP1 after the age of 15 but to RAP2 only after the age of 30. The effect of HLA-DRB1 and -DQB1 and age on levels of antibody to rRAP1 and rRAP2 was analyzed with a multiple regression model in which all HLA alleles and age were independent variables. DQB1*0301 and -*03032 showed an age-dependent association with levels of antibody to rRAP1, being significant in children 5 to 15 years (P < 0.001) but not in individuals over 15 years of age. DRB1*03011 showed an age-dependent association with antibody levels to rRAP2; however, this association was in adults over the age of 30 years (P < 0.01) but not in individuals under the age of 30 years. No associations were detected between DRB1 alleles and RAP1 antibody levels or between DQB1 alleles and RAP2 antibody levels. Thus, not only the HLA allele but also the age at which an interaction is manifested varies for different malarial antigens. The interaction may influence either the rate of acquisition of antibody or the final level of antibody acquired by adults.

Adolescent↗
PubMed2000

Ribosomal DNA sequence markers differentiate two species of the Anopheles maculatus (Diptera: Culicidae) complex in the Philippines.

The Anopheles maculatus Theobald complex includes important vectors of malaria. Based on chromosomal and morphological evidence, two species in this complex occur in the Philippines. Because separation of these species, An. dispar Rattanarithikul & Harbach and An. greeni Rattanarithikul & Harbach, is problematic due to the difficulty or unreliability of the identification methods currently available, we sought a molecular technique for identifying these two species. We sequenced two regions of nuclear ribosomal DNA; the second internal transcribed spacer (ITS2) and the third domain (D3) of the 28S gene, from An. maculatus sensu lato (s.l.) collected throughout the Philippines. Two sequence groups were identified that corresponded morphologically to An. dispar and An. greeni. Four percent of the 318-320 bp ITS2 and 2.5% of the 367 bp D3 differed between the two species. No evidence of intraspecific variation in sequences was found. From the sequence data, we developed a more reliable and easier method for identifying An. dispar and An. greeni, based on a HaeII restriction fragment-length polymorphism in a polymerase chain reaction amplified fragment of ITS2. This method will facilitate future vector studies, which will be necessary, as previous data collected on An. maculatus s.l. in the Philippines is unreliable given the multispecies nature of this taxon.

Animals↗
PubMed2000

Efficacy of vaccines containing rhoptry-associated proteins RAP1 and RAP2 of Plasmodium falciparum in Saimiri boliviensis monkeys.

A vaccine trial was conducted with rhoptry-associated proteins 1 and 2 (RAP1 and RAP2) of Plasmodium falciparum in Saimiri boliviensis monkeys to compare the ability of parasite-derived (PfRAP1 and 2) and recombinant proteins (rRAP1 and 2) to induce protective immune responses and to find adjuvants suitable for use in humans. Eight groups of 6 monkeys each were immunized with parasite-derived or recombinant RAP1 and 2 with Freund's complete adjuvant (FCA) followed by Freund's incomplete adjuvant (FIA), Montanide ISA720 adjuvant, or CRL1005 adjuvant. Recombinant RAP1 and RAP2 were also administered separately, with Montanide ISA720. After 3 immunizations, monkeys were challenged by iv inoculation of 50,000 parasites of the Uganda Palo Alto strain of P. falciparum. Of the animals vaccinated using FCA/FIA, 1 of 6 control monkeys, 3 of 6 immunized with PfRAP1 and 2, and 2 of 6 with rRAP1 and 2 did not require drug treatment. Of the monkeys vaccinated with Montanide ISA720 adjuvant, 0 of the 6 control monkeys, 2 of 6 immunized with RAP1 and 2, 1 of 6 immunized with rRAP1, and 4 of 6 immunized with RAP2 did not require drug treatment. Two of 6 monkeys immunized with PfRAP1 and 2 with CRL1005 did not require treatment. All groups receiving RAP1, RAP2, or both had a significant decrease in initial parasite multiplication rates and there was a significant negative correlation between anti-RAP2 antibody and multiplication rates. Animals were rechallenged with the homologous parasite 126 days after the first challenge. Of the monkeys that did not require drug treatment after the first challenge, none developed detectable parasitemia following rechallenge.

Adjuvants, Immunologic↗
PubMed2000

Treatment of uncomplicated Plasmodium falciparum malaria in Myanmar: a clinical decision analysis.

This study was undertaken to compare cost-effectiveness of three drug regimes for treatment of uncomplicated falciparum malaria in Myanmar. The alternative regimens in this study were chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and mefloquine (MFQ) along with their therapeutic efficacy in Myanmar. The study was performed by modeling a clinical decision tree based on a hypothetical 1,000 adult uncomplicated falciparum malaria cases. Key variables were (i) three drug regimes: CQ, SP and MFQ, (ii) three categories of therapeutic efficacy of each drug: adequate clinical response (ACR), early treatment failure (ETF) and late treatment failure (LTF) according to the 1996 WHO protocol, and (iii) compliance with each drug. In structuring the model, necessary assumptions were made. The cost effectiveness was measured as cost per case cured and cost per case prevented death related to the provided drug, from the provider's perspective. According to the present price and therapeutic efficacy, SP is the most cost effective drug for a case cured in all three categories of efficacy (US$ 0.12 per case cured in ACR, US$ 0.38 per case cured in ETF and US$ 0.54 per case cured in LTF). For a case prevented death, CQ is most cost effective in all three categories (US$ 0.58 per case prevented death in the ACR, US$ 2.14 per case prevented death in the ETF and US$ 2.51 per case prevented death in the LTF). The lowest cost effective regimen is MFQ for both indicators of effectiveness at the present price and therapeutic efficacy. A sensitivity analysis was performed for sensitive values.

Antimalarials↗
PubMed2000

Modeling factors influencing malaria incidence in Myanmar.

This is a documentary study to determine factors influencing malaria incidence in Myanmar. The period of study covered was from 1989 to 1998 using time series data. Multiple regression analysis was performed on the dependent variable, yearly incidence of malaria in Myanmar, with hypothesized independent variables including variables related to epidemiology, demography, service and socioeconomic status. Malaria incidence was inversely associated with the government budget for malaria control at the 5% level and with the case fatality rate of malaria at the 10% level. Other variables: yearly gross domestic product, yearly proportion of Plasmodium falciparum cases and yearly DDT use of spraying displayed expected signs but were not statistically significant.

Animals↗
PubMed1999

Human phase I vaccine trials of 3 recombinant asexual stage malaria antigens with Montanide ISA720 adjuvant.

Two phase I vaccine trials were conducted to test the immunogenicity and safety of a vaccine containing three recombinant malaria antigens from the asexual stage of Plasmodium falciparum. The three antigens are a fragment of MSP1 (190LCS.T3); MSP2 and a portion of RESA and were formulated in Montanide ISA720 adjuvant. These trials investigated the dose response of each antigen for eliciting both antibody and T-cell responses and the immunogenicity of a mixture of the antigens compared with the antigens injected separately. All three antigens elicited both antibody and T-cell responses. Strong T-cell responses were observed with 190LCS.T3 and RESA with stimulation indices exceeding 100 for peripheral blood leucocytes in some individuals. The antibody responses were generally weak. The human antibody responses observed with MSP2 in Montanide ISA720 were not significantly different from those obtained in an earlier trial which used MSP2 with alum as the adjuvant. No antigenic competition was observed: volunteers receiving a mixture of antigens had similar responses to those receiving the three antigens at separate sites. Tenderness and pain at the injection site were common over the first few days following immunization. In some volunteers, especially those receiving the highest doses tested, there was a delayed reaction at the injection site with pain and swelling occurring approximately 10 days after injection.

Adjuvants, Immunologic↗