A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

Background: Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens. Methods: In a single centre, open-label randomised tr

Demonstration of the Blood-Stage Plasmodium falciparum Controlled Human Malaria Infection Model to Assess Efficacy of the P. falciparum Apical Membrane Antigen 1 Vaccine, FMP2.1/AS01

We study whether the relationship between the state unemployment rate at the time of conception and infant health, infant mortality and maternal characteristics in the United States has changed over the years 1980-2004. We use microdata on births and deaths for years 1980-2004 and find that the relationship between the state unemployment rate at the time of conception and infant mortality and birthweight changes over time and is stronger for blacks than whites. For years 1980-1989 increases in the state unemployment rate are associated with a decline in infant mortality among blacks, an effect driven by mortality from gestational development and birth weight, and complications of placenta while in utero. In contrast, state economic conditions are unrelated to black infant mortality in years 1990-2004 and white infant mortality in any period, although effects vary by cause of death. We explore potential mechanisms for our findings and, including mothers younger than 18 in the analysis, uncover evidence of age-related maternal selection in response to the business cycle. In particular, in years 1980-1989 an increase in the unemployment rate at the time of conception is associated with fewer babies born to young mothers. The magnitude and direction of the relationship between business cycles and infant mortality differs by race and period. Age-related selection into motherhood in response to the business cycle is a possible explanation for this changing relationship

Meta-analysis of Parkinson's Disease: Identification of a Novel Locus, RIT2

OBJECTIVE: Genome-wide association (GWAS) methods have identified genes contributing to Parkinson disease (PD); we sought to identify additional genes associated with PD susceptibility. METHODS: A two stage design was used. First, individual level genotypic data from five recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 SNPs were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls). RESULTS: Genome-wide significance was reached for SNPs in SNCA (rs356165, G: odds ratio (OR)=1.37; p=9.3 × 10(−21)), MAPT (rs242559, C: OR=0.78; p=1.5 × 10(−10)), GAK/DGKQ (rs11248051, T:OR=1.35; p=8.2 × 10(−9)/ rs11248060, T: OR=1.35; p=2.0×10(−9)), and the HLA region (rs3129882, A: OR=0.83; p=1.2 × 10(−8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K OR=1.71; p=5 × 10(−8) Combined Sample) (N370 OR=3.08; p=7 × 10(−5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5 × 10(−5) Discovery Sample; p=1.52 × 10(−7) Replication sample; p=2 × 10(−10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes. INTERPRETATION: We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than one risk allele within SNCA and GBA

Meta-analysis of Parkinson's Disease: Identification of a novel locus, RIT2

OBJECTIVE: Genome-wide association (GWAS) methods have identified genes contributing to Parkinson disease (PD); we sought to identify additional genes associated with PD susceptibility. METHODS: A two stage design was used. First, individual level genotypic data from five recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 SNPs were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls). RESULTS: Genome-wide significance was reached for SNPs in SNCA (rs356165, G: odds ratio (OR)=1.37; p=9.3 × 10(−21)), MAPT (rs242559, C: OR=0.78; p=1.5 × 10(−10)), GAK/DGKQ (rs11248051, T:OR=1.35; p=8.2 × 10(−9)/ rs11248060, T: OR=1.35; p=2.0×10(−9)), and the HLA region (rs3129882, A: OR=0.83; p=1.2 × 10(−8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K OR=1.71; p=5 × 10(−8) Combined Sample) (N370 OR=3.08; p=7 × 10(−5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5 × 10(−5) Discovery Sample; p=1.52 × 10(−7) Replication sample; p=2 × 10(−10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes. INTERPRETATION: We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than one risk allele within SNCA and GBA

Demonstration of the blood-stage controlled human malaria infection model to assess efficacy of the Plasmodium falciparum AMA1 vaccine FMP2.1/AS01

 Mosquito-bite controlled human malaria infection (CHMI) models have been widely used to assess efficacy of pre-erythrocytic vaccine candidates in small proof-of-concept Phase IIa clinical trials. Efficacy testing of blood-stage vaccines, however, has generally relied on larger-scale Phase IIb field trials in endemic populations. We report the use of a blood-stage Plasmodium falciparum CHMI model to assess blood-stage vaccine candidates using impact on the parasite multiplication rate (PMR) as the primary efficacy endpoint. Fifteen healthy UK adult volunteers were vaccinated with FMP2.1, a protein vaccine, based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1), and formulated in AS01. Twelve vaccinees, and fifteen infectivity controls, subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time PCR, and PMR was modelled from these data. The FMP2.1/AS01 vaccine elicited anti-AMA1 T cell and serum antibody responses. Purified IgG showed functional growth inhibition activity against P. falciparum in vitro. There were no vaccine- or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR. FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers, and will accelerate proof-of-concept testing of future blood-stage malaria vaccine candidates. NCT02044198