RESUMO
BACKGROUND: The monoclonal antibody m102.4 is a potent, fully human antibody that neutralises Hendra and Nipah viruses in vitro and in vivo. We aimed to investigate the safety, tolerability, pharmacokinetics, and immunogenicity of m102.4 in healthy adults. METHODS: In this double-blind, placebo-controlled, single-centre, dose-escalation, phase 1 trial of m102.4, we randomly assigned healthy adults aged 18-50 years with a body-mass index of 18·0-35·0 kg/m2 to one of five cohorts. A sentinel pair for each cohort was randomly assigned to either m102.4 or placebo. The remaining participants in each cohort were randomly assigned (5:1) to receive m102.4 or placebo. Cohorts 1-4 received a single intravenous infusion of m102.4 at doses of 1 mg/kg (cohort 1), 3 mg/kg (cohort 2), 10 mg/kg (cohort 3), and 20 mg/kg (cohort 4), and were monitored for 113 days. Cohort 5 received two infusions of 20 mg/kg 72 h apart and were monitored for 123 days. The primary outcomes were safety and tolerability. Secondary outcomes were pharmacokinetics and immunogenicity. Analyses were completed according to protocol. The study was registered on the Australian New Zealand Clinical Trials Registry, ACTRN12615000395538. FINDINGS: Between March 27, 2015, and June 16, 2016, 40 (52%) of 77 healthy screened adults were enrolled in the study. Eight participants were assigned to each cohort (six received m102.4 and two received placebo). 86 treatment-emergent adverse events were reported, with similar rates between placebo and treatment groups. The most common treatment-related event was headache (12 [40%] of 30 participants in the combined m102.4 group, and three [30%] of ten participants in the pooled placebo group). No deaths or severe adverse events leading to study discontinuation occurred. Pharmacokinetics based on those receiving m102.4 (n=30) were linear, with a median half-life of 663·3 h (range 474·3-735·1) for cohort 1, 466·3 h (382·8-522·3) for cohort 2, 397·0 h (333·9-491·8) for cohort 3, and 466·7 h (351·0-889·6) for cohort 4. The elimination kinetics of those receiving repeated dosing (cohort 5) were similar to those of single-dose recipients (median elimination half-time 472·0 [385·6-592·0]). Anti-m102.4 antibodies were not detected at any time-point during the study. INTERPRETATION: Single and repeated dosing of m102.4 were well tolerated and safe, displayed linear pharmacokinetics, and showed no evidence of an immunogenic response. This study will inform future dosing regimens for m102.4 to achieve prolonged exposure for systemic efficacy to prevent and treat henipavirus infections. FUNDING: Queensland Department of Health, the National Health and Medical Research Council, and the National Hendra Virus Research Program.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Glicoproteínas/imunologia , Voluntários Saudáveis , Henipavirus/imunologia , Imunogenicidade da Vacina , Segurança , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/imunologia , Austrália , Método Duplo-Cego , Feminino , Cefaleia/etiologia , Humanos , Infusões Intravenosas , MasculinoRESUMO
BACKGROUNDInterventions that interrupt Plasmodium vivax transmission or eliminate dormant P. vivax liver-stage parasites will be essential for malaria elimination. Development of these interventions has been hindered by the lack of P. vivax in vitro culture and could be accelerated by a safe and reproducible clinical model in malaria-naive individuals.METHODSHealthy, malaria-naive adults were enrolled in 2 studies to assess the safety, infectivity, and transmissibility of a new P. vivax isolate. Participants (Study 1, n = 2; Study 2, n = 24) were inoculated with P. vivax-infected red blood cells to initiate infection, and were treated with artemether-lumefantrine (Study 1) or chloroquine (Study 2). Primary endpoints were safety and infectivity of the new isolate. In Study 2, transmission to mosquitoes was also evaluated using mosquito feeding assays, and sporozoite viability was assessed using in vitro cultured hepatocytes.RESULTSParasitemia and gametocytemia developed in all participants and was cleared by antimalarial treatment. Adverse events were mostly mild or moderate and none were serious. Sixty-nine percent of participants (11/16) were infectious to Anopheles mosquitoes at peak gametocytemia. Mosquito infection rates reached 97% following membrane feeding with gametocyte-enriched blood, and sporozoites developed into liver-stage schizonts in culture.CONCLUSIONWe have demonstrated the safe, reproducible, and efficient transmission of P. vivax gametocytes from humans to mosquitoes, and have established an experimental model that will accelerate the development of interventions targeting multiple stages of the P. vivax life cycle.TRIAL REGISTRATIONACTRN12614000930684 and ACTRN12616000174482.FUNDING(Australian) National Health and Medical Research Council Program Grant 1132975 (Study 1). Bill and Melinda Gates Foundation (OPP1111147) (Study 2).
Assuntos
Combinação Arteméter e Lumefantrina/administração & dosagem , Cloroquina/administração & dosagem , Malária Vivax , Plasmodium vivax/metabolismo , Adolescente , Adulto , Animais , Anopheles , Feminino , Humanos , Malária Vivax/tratamento farmacológico , Malária Vivax/metabolismo , Malária Vivax/transmissão , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Projetos PilotoRESUMO
Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum-induced blood-stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on day 0 and received a single oral dose of artefenomel and DSM265 on day 7. Cohort 1 (n = 8) received 200 mg artefenomel plus 100 mg DSM265, and cohort 2 (n = 5) received 200 mg artefenomel plus 50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel-DSM265 plasma concentrations. There were no treatment-related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to those of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log10 parasite reduction ratios over 48 h [PRR48] of 2.80 for cohort 1 and 2.71 for cohort 2; parasite clearance half-lives of 5.17 h for cohort 1 and 5.33 h for cohort 2). Recrudescence occurred in 5/8 subjects in cohort 1 between days 19 and 28 and in 5/5 subjects in cohort 2 between days 15 and 22. Low-level gametocytemia (1 to 330 female gametocytes/ml) was detected in all subjects from day 14. The results of this single-dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria. (This study has been registered at ClinicalTrials.gov under identifier NCT02389348.).
Assuntos
Adamantano/análogos & derivados , Antimaláricos/administração & dosagem , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Peróxidos/administração & dosagem , Pirimidinas/administração & dosagem , Triazóis/administração & dosagem , Adamantano/administração & dosagem , Adamantano/farmacocinética , Administração Oral , Adulto , Antimaláricos/farmacocinética , Combinação de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Parasitemia/metabolismo , Parasitemia/parasitologia , Peróxidos/farmacocinética , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/farmacocinética , Triazóis/farmacocinética , Adulto JovemRESUMO
DSM265 is a novel antimalarial drug in clinical development that acts as a selective inhibitor of Plasmodium dihydroorotate dehydrogenase. In a previous phase 1b study, a single 150-mg dose of DSM265 showed partial efficacy against experimentally induced blood-stage Plasmodium falciparum malaria (IBSM). Pharmacokinetic/pharmacodynamic modeling predicted a human efficacious dose of 340 mg. The primary objectives of the current study were to determine the safety and efficacy of a single oral 400-mg dose of DSM265 against P. falciparum in the IBSM model. Eight healthy participants were inoculated intravenously with 2,800 parasites and treated with DSM265 7 days later. Unexpectedly, one participant did not develop parasitemia during the study. All other participants developed parasitemia, with the complete clearance of asexual parasites occurring following DSM265 treatment. All seven subjects also became gametocytemic. The secondary objectives were to investigate the gametocytocidal and transmission-blocking activity of a second 400-mg dose of DSM265, which was administered 23 days after inoculation. Gametocytes were not cleared by the second dose of DSM265, and transmission-blocking activity could not be determined due to low gametocyte densities. Three DSM265-related adverse events occurred, including a cutaneous rash in one subject on the day of the second DSM265 dose. The results obtained in this study support the prediction of the efficacious dose of DSM265 and provide further evidence that DSM265 is generally safe and well tolerated. In addition, this study confirms preclinical data indicating that DSM265 permits the development and maturation of gametocytes and does not clear mature circulating gametocytes. (This study has been registered at ClinicalTrials.gov under identifier NCT02573857.).
Assuntos
Antimaláricos/farmacologia , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/fisiologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Animais , Anopheles , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Masculino , Mosquitos Vetores , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto JovemRESUMO
OBJECTIVES: If patients are to reap the benefits of continued drug development, an understanding of why healthy participants take part in phase I clinical trials is imperative. The current study aimed to explore the nature of these underlying motivations which may, in turn, improve the overall participant experience and assist in the development of more effective recruitment and retention strategies. DESIGN: This study used a qualitative design based on the theory of planned behaviour. Specifically, it explored healthy participants' underlying behavioural, control and normative beliefs which influence their participation in phase I clinical trials. SETTING: This study took place at a company that specialises in conducting phase I and phase II clinical trials in the Australian state of Queensland. PARTICIPANTS: Participants (n=31) were either currently undergoing a phase I clinical trial or had previously taken part in a phase I clinical trial. RESULTS: Results showed that the motivations were varied and not solely centred on financial gains. Reported advantages of participation included altruism, while inconvenience was most often reported as a disadvantage. Friends were reported as those most likely to approve, while one's mother was reported as most likely to disapprove. Having a suitable time frame/flexible scheduling and feeling comfortable taking part in the trial were both the most commonly reported facilitators, while inflexible scheduling/time commitment was the most commonly reported barrier. CONCLUSIONS: Practical implications included the need for organisations involved in clinical trials to be mindful of inflexible scheduling and exploring the possibility of making educational materials available to family members who may be concerned about the risks associated with participation. Overall, it is anticipated that the results of this study will improve the understanding of factors that influence phase I clinical trial participation which may, ultimately, help develop new therapeutics to improve patient health.
Assuntos
Ensaios Clínicos Fase I como Assunto , Voluntários Saudáveis/psicologia , Motivação , Adulto , Idoso , Altruísmo , Feminino , Grupos Focais , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Queensland , Remuneração , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Group A streptococcus (GAS) is a serious human pathogen that affects people of different ages and socio-economic levels. Although vaccination is potentially one of the most effective methods to control GAS infection and its sequelae, few prototype vaccines have been investigated in humans. In this study, we report the safety and immunogenicity of a novel acetylated peptide-protein conjugate vaccine candidate MJ8VAX (J8-DT), when delivered intramuscularly to healthy adults. METHODS: A randomized, double-blinded, controlled Phase I clinical trial was conducted in 10 healthy adult participants. Participants were randomized 4:1 to receive the vaccine candidate (N = 8) or placebo (N = 2). A single dose of the vaccine candidate (MJ8VAX), contained 50 µg of peptide conjugate (J8-DT) adsorbed onto aluminium hydroxide and re-suspended in PBS in a total volume of 0.5 mL. Safety of the vaccine candidate was assessed by monitoring local and systemic adverse reactions following intramuscular administration. The immunogenicity of the vaccine was assessed by measuring the levels of peptide (anti-J8) and toxoid carrier (anti-DT)-specific antibodies in serum samples. RESULTS: No serious adverse events were reported over 12 months of study. A total of 13 adverse events (AEs) were recorded, two of which were assessed to be associated with the vaccine. Both were mild in severity. No local reactogenicity was recorded in any of the participants. MJ8VAX was shown to be immunogenic, with increase in vaccine-specific antibodies in the participants who received the vaccine. The maximum level of vaccine-specific antibodies was detected at 28 days post immunization. The level of these antibodies decreased with time during follow-up. Participants who received the vaccine also had a corresponding increase in anti-DT serum antibodies. CONCLUSIONS: Intramuscular administration of MJ8VAX was demonstrated to be safe and immunogenic. The presence of DT in the vaccine formulation resulted in a boost in the level of anti-DT antibodies. TRIAL REGISTRATION: ACTRN12613000030774.
Assuntos
Infecções Estreptocócicas/tratamento farmacológico , Vacinas Estreptocócicas/administração & dosagem , Vacinação/efeitos adversos , Vacinas Conjugadas/administração & dosagem , Adolescente , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Vacinas Estreptocócicas/efeitos adversos , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/patogenicidade , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/imunologiaRESUMO
BACKGROUND: Drugs and vaccines that can interrupt the transmission of Plasmodium falciparum will be important for malaria control and elimination. However, models for early clinical evaluation of candidate transmission-blocking interventions are currently unavailable. Here, we describe a new model for evaluating malaria transmission from humans to Anopheles mosquitoes using controlled human malaria infection (CHMI). METHODS: Seventeen healthy malaria-naive volunteers underwent CHMI by intravenous inoculation of P. falciparum-infected erythrocytes to initiate blood-stage infection. Seven to eight days after inoculation, participants received piperaquine (480 mg) to attenuate asexual parasite replication while allowing gametocytes to develop and mature. Primary end points were development of gametocytemia, the transmissibility of gametocytes from humans to mosquitoes, and the safety and tolerability of the CHMI transmission model. To investigate in vivo gametocytocidal drug activity in this model, participants were either given an experimental antimalarial, artefenomel (500 mg), or a known gametocytocidal drug, primaquine (15 mg), or remained untreated during the period of gametocyte carriage. RESULTS: Male and female gametocytes were detected in all participants, and transmission to mosquitoes was achieved from 8 of 11 (73%) participants evaluated. Compared with results in untreated controls (n = 7), primaquine (15 mg, n = 5) significantly reduced gametocyte burden (P = 0.01), while artefenomel (500 mg, n = 4) had no effect. Adverse events (AEs) were mostly mild or moderate. Three AEs were assessed as severe - fatigue, elevated alanine aminotransferase, and elevated aspartate aminotransferase - and were attributed to malaria infection. Transaminase elevations were transient, asymptomatic, and resolved without intervention. CONCLUSION: We report the safe and reproducible induction of P. falciparum gametocytes in healthy malaria-naive volunteers at densities infectious to mosquitoes, thereby demonstrating the potential for evaluating transmission-blocking interventions in this model. TRIAL REGISTRATION: ClinicalTrials.gov NCT02431637 and NCT02431650. FUNDING: Bill & Melinda Gates Foundation.
Assuntos
Adamantano/análogos & derivados , Antimaláricos/administração & dosagem , Malária Falciparum , Modelos Biológicos , Peróxidos/administração & dosagem , Plasmodium falciparum , Primaquina/administração & dosagem , Adamantano/administração & dosagem , Adolescente , Adulto , Animais , Culicidae/parasitologia , Eritrócitos/parasitologia , Feminino , Humanos , Malária Falciparum/prevenção & controle , Malária Falciparum/transmissão , Masculino , Pessoa de Meia-Idade , Quinolinas/administração & dosagemRESUMO
Most vaccinations are performed by intramuscular injection with a needle and syringe. However, this method is not ideal due to limitations, such as the risk of needle-stick injury, the requirement for trained personnel to give injections and the need to reconstitute lyophilized vaccines. Therefore, we tested an alternative delivery technology that overcomes the problems with needle and syringe. The Nanopatch™ is an array of 10,000 silicon micro-projections per cm2 that can be dry-coated with vaccine for skin delivery. The high number and density of micro-projections means that high velocity application is required to achieve consistent skin penetration. Before clinically testing a vaccine Nanopatch, this study tests the safety, tolerability and acceptability/utility of uncoated and excipient-coated Nanopatches in healthy adults. Nanopatches were applied to skin of the upper arm and volar forearm and left in contact with the skin for two minutes before removal. The application sites were assessed for local skin response over 28â¯days. Acceptability interviews were also performed. No unexpected adverse events directly related to the Nanopatch application were reported. All applications of the Nanopatch resulted in an expected erythema response which faded between days 3 and 7. In some subjects, some skin discolouration was visible for several days or up to 3â¯weeks after application. The majority (83%) of subjects reported a preference for the Nanopatch compared to the needle and syringe and found the application process to be simple and acceptable. On a pain scale from 0 to 10, 78% of applications were scored "0" (no pain) with the average scores for less than 1. The results from this study demonstrate the feasibility of the Nanopatch to improve vaccination by showing that application of the product without vaccine to human skin is safe, tolerable and preferred to needle and syringe administration. Clinical trial registry ID: ACTRN1261500083549.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Excipientes/química , Nanoestruturas/efeitos adversos , Nanoestruturas/química , Silício/química , Adulto , Sistemas de Liberação de Medicamentos/efeitos adversos , Excipientes/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nanoestruturas/administração & dosagem , Sujeitos da Pesquisa , Silício/administração & dosagem , Silício/efeitos adversos , Pele/efeitos dos fármacos , Vacinas/administração & dosagem , Adulto JovemRESUMO
Testate amoeba-derived transfer functions are frequently used in peatland palaeohydrological studies and involve the development of training sets from surficial peats. However, within acrotelmic peats, considerable vertical variation in assemblage composition can occur, particularly along Sphagnum stems, which may limit the representation of the associated 'contemporary' testate amoeba samples as analogues for the peatland surface. This paper presents contiguous testate amoeba assemblage data from nine monoliths collected from different peatland microforms (hummock, hollow, lawn) in three Sphagnum dominated ombrotrophic peatlands in Ontario and Quebec, eastern Canada. The aim is to: (i) gain a greater understanding of the vertical distribution of xerophilous/hygrophilous taxa along Sphagnum stems; (ii) determine the vertical extent of live/encysted taxa along this gradient; and (iii) assess the significance of this distribution on surface sampling protocols. The results show that testate amoeba communities in the uppermost acrotelmic peat layers display considerable variability. This may reflect a complex interplay of abiotic and biotic controls, including moisture, temperature, light and other characteristics, food availability, and mineral particle availability for test construction. These findings underline the complexity of testate amoeba community structure and highlight the importance of analysing both living and dead Sphagnum stem sections when developing calibration sets.
Assuntos
Amoeba/fisiologia , Biodiversidade , Solo/parasitologia , Amoeba/classificação , Hidrologia , Paleontologia , Dinâmica Populacional , Sphagnopsida/parasitologia , Áreas AlagadasRESUMO
BACKGROUND: DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity. METHODS: Healthy participants aged 18-55 years were enrolled in a two-part study: part 1, a single ascending dose (25-1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2). FINDINGS: In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (Cmax) ranged between 1310 ng/mL and 34â800 ng/mL and was reached in a median time (tmax) between 1·5 h and 4 h, with a mean elimination half-life between 86 h and 118 h. In part 2, the log10 parasite reduction ratio at 48 h in the DSM265 (150 mg) group was 1·55 (95% CI 1·42-1·67) and in the mefloquine (10 mg/kg) group was 2·34 (2·17-2·52), corresponding to a parasite clearance half-life of 9·4 h (8·7-10·2) and 6·2 h (5·7-6·7), respectively. The median minimum inhibitory concentration of DSM265 in blood was estimated as 1040 ng/mL (range 552-1500), resulting in a predicted single efficacious dose of 340 mg. Parasite clearance was significantly faster in participants who received mefloquine than in participants who received DSM265 (p<0·0001). INTERPRETATION: The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment. FUNDING: Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.
Assuntos
Antimaláricos/administração & dosagem , Mefloquina/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Triazóis/administração & dosagem , Triazóis/farmacocinética , Adolescente , Adulto , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Austrália , Di-Hidro-Orotato Desidrogenase , Método Duplo-Cego , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Humanos , Malária Falciparum/tratamento farmacológico , Pessoa de Meia-Idade , Nova Zelândia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Plasmodium falciparum , Pirimidinas/uso terapêutico , Triazóis/uso terapêuticoRESUMO
BACKGROUND: Interventions to interrupt transmission of malaria from humans to mosquitoes represent an appealing approach to assist malaria elimination. A limitation has been the lack of systems to test the efficacy of such interventions before proceeding to efficacy trials in the field. We have previously demonstrated the feasibility of induced blood stage malaria (IBSM) infection with Plasmodium vivax. In this study, we report further validation of the IBSM model, and its evaluation for assessment of transmission of P. vivax to Anopheles stephensi mosquitoes. METHODS: Six healthy subjects (three cohorts, n = 2 per cohort) were infected with P. vivax by inoculation with parasitized erythrocytes. Parasite growth was monitored by quantitative PCR, and gametocytemia by quantitative reverse transcriptase PCR (qRT-PCR) for the mRNA pvs25. Parasite multiplication rate (PMR) and size of inoculum were calculated by linear regression. Mosquito transmission studies were undertaken by direct and membrane feeding assays over 3 days prior to commencement of antimalarial treatment, and midguts of blood fed mosquitoes dissected and checked for presence of oocysts after 7-9 days. RESULTS: The clinical course and parasitemia were consistent across cohorts, with all subjects developing mild to moderate symptoms of malaria. No serious adverse events were reported. Asymptomatic elevated liver function tests were detected in four of six subjects; these resolved without treatment. Direct feeding of mosquitoes was well tolerated. The estimated PMR was 9.9 fold per cycle. Low prevalence of mosquito infection was observed (1.8%; n = 32/1801) from both direct (4.5%; n = 20/411) and membrane (0.9%; n = 12/1360) feeds. CONCLUSION: The P. vivax IBSM model proved safe and reliable. The clinical course and PMR were reproducible when compared with the previous study using this model. The IBSM model presented in this report shows promise as a system to test transmission-blocking interventions. Further work is required to validate transmission and increase its prevalence. TRIAL REGISTRATION: Anzctr.org.au ACTRN12613001008718.
Assuntos
Anopheles/parasitologia , Malária Vivax/parasitologia , Malária Vivax/transmissão , Mosquitos Vetores/parasitologia , Animais , Anopheles/fisiologia , Modelos Animais de Doenças , Eritrócitos/parasitologia , Voluntários Saudáveis , Experimentação Humana , Humanos , Malária Vivax/tratamento farmacológico , Mosquitos Vetores/fisiologia , Oocistos , Parasitemia , Reprodutibilidade dos TestesRESUMO
Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ(-/-) (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems. In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 µg/ml and 1.8 µg/ml in the NSG and IBSM models, respectively, aligning with 1.8 µg/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations. (This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.).
Assuntos
Antimaláricos/farmacocinética , Malária Falciparum/tratamento farmacológico , Mefloquina/farmacocinética , Plasmodium falciparum/efeitos dos fármacos , Adulto , Animais , Antimaláricos/sangue , Antimaláricos/farmacologia , Estudos de Coortes , Modelos Animais de Doenças , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Feminino , Voluntários Saudáveis , Humanos , Concentração Inibidora 50 , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Masculino , Mefloquina/sangue , Mefloquina/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Plasmodium falciparum/crescimento & desenvolvimentoRESUMO
BACKGROUND: Piperaquine, coformulated with dihydroartemisinin, is a component of a widely used artemisinin combination therapy. There is a paucity of data on its antimalarial activity as a single agent. Such data, if available, would inform selection of new coformulations. METHODS: We undertook a study in healthy subjects, using the induced blood stage malaria (IBSM) model to test the antimalarial activity of single doses of piperaquine (960, 640, and 480 mg) in 3 cohorts. In a pilot study in the third cohort, gametocyte clearance following administration of 15 mg, or 45 mg or no primaquine was investigated. RESULTS: Parasite clearance over the 48-hour period after piperaquine administration was more rapid in the 960 mg cohort, compared with the 640 mg cohort (parasite reduction ratio, 2951 [95% confidence interval {CI}, 1520-5728] vs 586 [95% CI, 351-978]; P < .001). All 24 subjects developed gametocytemia as determined by pfs25 transcripts. Clearance of pfs25 was significantly faster in those receiving primaquine than in those not receiving primaquine (P < .001). CONCLUSIONS: Piperaquine possesses rapid parasite-clearing activity, but monotherapy is followed by the appearance of gametocytemia, which could facilitate the spread of malaria. This new information should be taken into account when developing future antimalarial coformulations. CLINICAL TRIALS REGISTRATION: ACTRN12613000565741.
Assuntos
Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Gametogênese/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Plasmodium falciparum/isolamento & purificação , Quinolinas/uso terapêutico , Adolescente , Adulto , Austrália , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Plasmodium falciparum/efeitos dos fármacos , Adulto JovemRESUMO
AIM: To examine if fasting affects serum bilirubin levels in clinically healthy males and females. METHODS: We used retrospective data from phase I clinical trials where blood was collected in either a fed or fasting state at screening and predosing time points and analysed for total bilirubin levels as per standard clinical procedures. Participants were clinically healthy males (n=105) or females (n=30) aged 18-48 inclusive who participated in a phase I clinical trial in 2012 or 2013. RESULTS: We found a statistically significant increase in total serum bilirubin levels in fasting males as compared with non-fasting males. The fasting time correlated positively with increased bilirubin levels. The age of the healthy males did not correlate with their fasting bilirubin level. We found no correlation between fasting and bilirubin levels in clinically normal females. CONCLUSIONS: The recruitment and screening of volunteers for a clinical trial is a time-consuming and expensive process. This study clearly demonstrates that testing for serum bilirubin should be conducted on non-fasting male subjects. If fasting is required, then participants should not be excluded from a trial based on an elevated serum bilirubin that is deemed non-clinically significant.
Assuntos
Bilirrubina/sangue , Jejum/sangue , Adolescente , Adulto , Biomarcadores/sangue , Ensaios Clínicos Fase I como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Valores de Referência , Estudos Retrospectivos , Fatores Sexuais , Regulação para Cima , Adulto JovemRESUMO
BACKGROUND: Major impediments to development of vaccines and drugs for Plasmodium vivax malaria are the inability to culture this species and the extreme difficulty in undertaking clinical research by experimental infection. METHODS: A parasite bank was collected from a 49-year-old woman with P. vivax infection, characterized, and used in an experimental infection study. RESULTS: The donor made a full recovery from malaria after collection of a parasite bank, which tested negative for agents screened for in blood donations. DNA sequence analysis of the isolate indicated that it was clonal. Two subjects inoculated with the isolate became polymerase chain reaction positive on days 8 and 9, with onset of symptoms and positive blood smears on day 14, when they were treated with artemether-lumefantrine, with rapid clinical and parasitologic response. Transcripts of the parasite gene pvs25 that is expressed in gametocytes, the life cycle stage infectious to mosquitoes, were first detected on days 11 and 12. CONCLUSIONS: This experimental system results in in vivo parasite growth, probably infectious to mosquitoes. It offers the opportunity to undertake studies previously impossible in P. vivax that will facilitate a better understanding of the pathology of vivax malaria and development of antimalarial drugs and vaccines. Trial Registration. ANZCTR: 12612001096842.
Assuntos
Voluntários Saudáveis , Estágios do Ciclo de Vida , Malária Vivax/parasitologia , Plasmodium vivax/crescimento & desenvolvimento , Animais , Resistência a Medicamentos/genética , Feminino , Genótipo , Humanos , Malária Vivax/diagnóstico , Malária Vivax/tratamento farmacológico , Pessoa de Meia-Idade , Parasitemia/diagnóstico , Parasitemia/parasitologia , Plasmodium vivax/genética , Polimorfismo GenéticoRESUMO
BACKGROUND: Critical to the development of new drugs for treatment of malaria is the capacity to safely evaluate their activity in human subjects. The approach that has been most commonly used is testing in subjects with natural malaria infection, a methodology that may expose symptomatic subjects to the risk of ineffective treatment. Here we describe the development and pilot testing of a system to undertake experimental infection using blood stage Plasmodium falciparum parasites (BSP). The objectives of the study were to assess the feasibility and safety of induced BSP infection as a method for assessment of efficacy of new drug candidates for the treatment of P. falciparum infection. METHODS AND FINDINGS: A prospective, unblinded, Phase IIa trial was undertaken in 19 healthy, malaria-naïve, male adult volunteers who were infected with BSP and followed with careful clinical and laboratory observation, including a sensitive, quantitative malaria PCR assay. Volunteers were randomly allocated to treatment with either of two licensed antimalarial drug combinations, artemether-lumefantrine (A/L) or atovaquone-proguanil (A/P). In the first cohort (nâ=â6) where volunteers received â¼360 BSP, none reached the target parasitemia of 1,000 before the day designated for antimalarial treatment (day 6). In the second and third cohorts, 13 volunteers received 1,800 BSP, with all reaching the target parasitemia before receiving treatment (A/L, nâ=â6; A/P, nâ=â7) The study demonstrated safety in the 19 volunteers tested, and a significant difference in the clearance kinetics of parasitemia between the drugs in the 13 evaluable subjects, with mean parasite reduction ratios of 759 for A/L and 17 for A/P (95% CI 120-4786 and 7-40 respectively; p<0.01). CONCLUSIONS: This system offers a flexible and safe approach to testing the in vivo activity of novel antimalarials. TRIAL REGISTRATION: ClinicalTrials.gov NCT01055002.
Assuntos
Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Saúde , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Plasmodium falciparum/crescimento & desenvolvimento , Adolescente , Adulto , Animais , Humanos , Masculino , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Projetos Piloto , Plasmodium falciparum/efeitos dos fármacos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: In a previous Phase 1/2b malaria vaccine trial testing the 3D7 isoform of the malaria vaccine candidate Merozoite surface protein 2 (MSP2), parasite densities in children were reduced by 62%. However, breakthrough parasitemias were disproportionately of the alternate dimorphic form of MSP2, the FC27 genotype. We therefore undertook a dose-escalating, double-blinded, placebo-controlled Phase 1 trial in healthy, malaria-naïve adults of MSP2-C1, a vaccine containing recombinant forms of the two families of msp2 alleles, 3D7 and FC27 (EcMSP2-3D7 and EcMSP2-FC27), formulated in equal amounts with Montanide® ISA 720 as a water-in-oil emulsion. METHODOLOGY/PRINCIPAL FINDINGS: The trial was designed to include three dose cohorts (10, 40, and 80 µg), each with twelve subjects receiving the vaccine and three control subjects receiving Montanide® ISA 720 adjuvant emulsion alone, in a schedule of three doses at 12-week intervals. Due to unexpected local reactogenicity and concern regarding vaccine stability, the trial was terminated after the second immunisation of the cohort receiving the 40 µg dose; no subjects received the 80 µg dose. Immunization induced significant IgG responses to both isoforms of MSP2 in the 10 µg and 40 µg dose cohorts, with antibody levels by ELISA higher in the 40 µg cohort. Vaccine-induced antibodies recognised native protein by Western blots of parasite protein extracts and by immunofluorescence microscopy. Although the induced anti-MSP2 antibodies did not directly inhibit parasite growth in vitro, IgG from the majority of individuals tested caused significant antibody-dependent cellular inhibition (ADCI) of parasite growth. CONCLUSIONS/SIGNIFICANCE: As the majority of subjects vaccinated with MSP2-C1 developed an antibody responses to both forms of MSP2, and that these antibodies mediated ADCI provide further support for MSP2 as a malaria vaccine candidate. However, in view of the reactogenicity of this formulation, further clinical development of MSP2-C1 will require formulation of MSP2 in an alternative adjuvant. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry 12607000552482.
Assuntos
Antígenos de Protozoários/química , Antígenos de Protozoários/imunologia , Estágios do Ciclo de Vida/imunologia , Vacinas Antimaláricas/química , Vacinas Antimaláricas/imunologia , Manitol/análogos & derivados , Ácidos Oleicos/química , Plasmodium falciparum/imunologia , Proteínas de Protozoários/química , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Animais , Anticorpos/imunologia , Antígenos de Protozoários/efeitos adversos , Química Farmacêutica , Estudos de Coortes , Relação Dose-Resposta Imunológica , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Vacinas Antimaláricas/efeitos adversos , Manitol/química , Plasmodium falciparum/crescimento & desenvolvimento , Isoformas de Proteínas/efeitos adversos , Isoformas de Proteínas/química , Isoformas de Proteínas/imunologia , Proteínas de Protozoários/efeitos adversos , Adulto JovemRESUMO
A randomized, double-blind, study was conducted to evaluate the safety, tolerability and immunogenicity of a live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) co-administered with live attenuated yellow fever vaccine (YF-17D strain; Stamaril®, Sanofi Pasteur) or administered successively. Participants (n = 108) were randomized to receive: YF followed by JE-CV 30 days later, JE followed by YF 30 days later, or the co-administration of JE and YF followed or preceded by placebo 30 days later or earlier. Placebo was used in a double-dummy fashion to ensure masking. Neutralizing antibody titers against JE-CV, YF-17D and selected wild-type JE strains was determined using a 50% serum-dilution plaque reduction neutralization test. Seroconversion was defined as the appearance of a neutralizing antibody titer above the assay cut-off post-immunization when not present pre-injection at day 0, or a least a four-fold rise in neutralizing antibody titer measured before the pre-injection day 0 and later post vaccination samples. There were no serious adverse events. Most adverse events (AEs) after JE vaccination were mild to moderate in intensity, and similar to those reported following YF vaccination. Seroconversion to JE-CV was 100% and 91% in the JE/YF and YF/JE sequential vaccination groups, respectively, compared with 96% in the co-administration group. All participants seroconverted to YF vaccine and retained neutralizing titers above the assay cut-off at month six. Neutralizing antibodies against JE vaccine were detected in 82-100% of participants at month six. These results suggest that both vaccines may be successfully co-administered simultaneously or 30 days apart.
Assuntos
Encefalite Japonesa/prevenção & controle , Vacinas contra Encefalite Japonesa/administração & dosagem , Vacinas contra Encefalite Japonesa/imunologia , Vacinação/métodos , Vacina contra Febre Amarela/administração & dosagem , Vacina contra Febre Amarela/imunologia , Febre Amarela/prevenção & controle , Adolescente , Adulto , Anticorpos Neutralizantes , Anticorpos Antivirais/sangue , Método Duplo-Cego , Feminino , Humanos , Vacinas contra Encefalite Japonesa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Placebos/administração & dosagem , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/efeitos adversos , Vacinas Combinadas/imunologia , Ensaio de Placa Viral , Vacina contra Febre Amarela/efeitos adversos , Adulto JovemRESUMO
A Phase 1 trial was conducted in malaria-naïve adults to evaluate the recombinant protein vaccine apical membrane antigen 1-Combination 1 (AMA1-C1) formulated in Montanide ISA 720 (SEPPIC, France), a water-in-oil adjuvant. Vaccinations were halted early due to a formulation issue unrelated to stability or potency. Twenty-four subjects (12 in each group) were enrolled and received 5 or 20 microg protein at 0 and 3 months and four subjects were enrolled and received one vaccination of 80 microg protein. After first vaccination, nearly all subjects experienced mild to moderate local reactions and six experienced delayed local reactions occurring at Day 9 or later. After the second vaccination, three subjects experienced transient grade 3 (severe) local reactions; the remainder experienced grade 1 or 2 local reactions. All related systemic reactogenicity was grade 1 or 2, except one instance of grade 3 malaise. Anti-AMA1-C1 antibody responses were dose dependent and seen following each vaccination, with mean antibody levels 2-3 fold higher in the 20 microg group compared to the 5 microg group at most time points. In vitro growth-inhibitory activity was a function of the anti-AMA1 antibody titer. AMA1-C1 formulated in ISA 720 is immunogenic in malaria-naïve Australian adults. It is reasonably tolerated, though some transient, severe, and late local reactions are seen.
Assuntos
Adjuvantes Imunológicos/efeitos adversos , Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Manitol/análogos & derivados , Proteínas de Membrana/imunologia , Ácidos Oleicos/efeitos adversos , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/administração & dosagem , Austrália , Relação Dose-Resposta Imunológica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Imunização Secundária/métodos , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/prevenção & controle , Masculino , Manitol/administração & dosagem , Manitol/efeitos adversos , Proteínas de Membrana/administração & dosagem , Pessoa de Meia-Idade , Ácidos Oleicos/administração & dosagem , Proteínas de Protozoários/administração & dosagem , Adulto JovemRESUMO
"Andrea," an 18-year-old college freshman, walked into her first fraternity party with a few of her sorority sisters. As she walked through the crowded house, one of the fraternity boys handed the girls large plastic cups. Another boy circulated through the crowd, filling up the cups of all guests from two pitchers of beer. When he filled Andrea's cup, he smiled and was polite and charming. She thought his act of filling her cup was kind and gentlemanly, and was flattered by his attention. She didn't notice he used a different pitcher for her than he had for her friends. She and her friends continued to mill through the crowd, sipping their beer. About 20 minutes later, Andrea suddenly had trouble focusing her vision. She felt disoriented and "drunk" even though she had only consumed a third of her beer. She started feeling nauseated, and tried to find her friends. The polite boy who had poured her beer asked her if she was all right, and offered to take her up to his room so she could rest. She followed him, grateful to be able to lie down. Forty-five minutes later, her concerned friends searched the house for Andrea. They found her upstairs passed out in a bedroom, lying on her side; she had vomited and her clothes were disheveled. Suspecting only alcohol intoxication; they picked her up, and walked her out of the party. After Andrea slept for about two hours, she woke up and told her friends something wasn't right. She had only drunk a small amount of her beer, and had no recollection after she walked up the stairs with the boy. She burst into tears, stating she feels some vaginal discomfort, and is afraid she may have been raped. Her friends looked at each other, thinking, "How did this happen and what are we supposed to do?"