Malaria vaccine

Abstract: Malaria is a major killer of children worldwide and the strongest known force for evolutionary selection in the recent history of the human genome. The past decade has seen growing evidence of ethnic differences in susceptibility to malaria and of the diverse genetic adaptations to malaria that have arisen in different populations: epidemiological confirmation of the hypotheses that G6PD deficiency, α + thalassemia, and hemoglobin C protect against malaria mortality; the application of novel haplotype-based techniques demonstrating that malaria-protective genes have been subject to recent positive selection; the first genetic linkage maps of resistance to malaria in experimental murine models; and a growing number of reported associations with resistance and susceptibility to human malaria, particularly in genes involved in immunity, inflammation, and cell adhesion. The challenge for the next decade is to build the global epidemiological infrastructure required for statistically robust genomewide association analysis, as a way of discovering novel mechanisms of protective immunity that can be used in the development of an effective malaria vaccine.

Abstract: Background The candidate vaccines against malaria are poorly immunogenic and thus have been ineffective in preventing infection. We developed a vaccine based on the circumsporozoite protein of Plasmodium falciparum that incorporates adjuvants selected to enhance the immune response. Methods The antigen consists of a hybrid in which the circumsporozoite protein fused to hepatitis B surface antigen (HBsAg) is expressed together with unfused HBsAg. We evaluated three formulations of this antigen in an unblinded trial in 46 subjects who had never been exposed to malaria. Results Two of the vaccine formulations were highly immunogenic. Four subjects had adverse systemic reactions that may have resulted from the intensity of the immune response after the second dose, which led us to reduce the third dose. Twenty-two vaccinated subjects and six unimmunized controls underwent a challenge consisting of bites from mosquitoes infected with P. falciparum. Malaria developed in all six control subjects, seven of eight ...

Abstract: Summary Background Development of an effective malaria vaccine could greatly contribute to disease control RTS,S/AS02A is a pre-erythrocytic vaccine candidate based on Plasmodium falciparum circumsporozoite surface antigen We aimed to assess vaccine efficacy, immunogenicity, and safety in young African children Methods We did a double-blind, phase IIb, randomised controlled trial in Mozambique in 2022 children aged 1–4 years The study included two cohorts of children living in two separate areas which underwent different follow-up schemes Participants were randomly allocated three doses of either RTS,S/AS02A candidate malaria vaccine or control vaccines The primary endpoint, determined in cohort 1 (n=1605), was time to first clinical episode of P falciparum malaria (axillary temperature ≥37·5°C and P falciparum asexual parasitaemia >2500 per μL) over a 6-month surveillance period Efficacy for prevention of new infections was determined in cohort 2 (n=417) Analysis was per protocol Findings 115 children in cohort 1 and 50 in cohort 2 did not receive all three doses and were excluded from the per-protocol analysis Vaccine efficacy for the first clinical episodes was 29·9% (95% CI 11·0–44·8; p=0·004) At the end of the 6-month observation period, prevalence of P falciparum infection was 37% lower in the RTS,S/AS02A group compared with the control group (11·9% vs 18·9%; p=0·0003) Vaccine efficacy for severe malaria was 57·7% (95% CI 16·2–80·6; p=0·019) In cohort 2, vaccine efficacy for extending time to first infection was 45·0% (31·4–55·9; p Interpretation The RTS,S/AS02A vaccine was safe, well tolerated, and immunogenic Our results show development of an effective vaccine against malaria is feasible

Abstract: A Brief History of Malaria and Discovery of the Parasite's Life Cycle The Current Global Malaria Situation Gametocytes and Sexual Development Sporogonic Development in the Mosquito Engineering Resistance to Malaria Parasite Development in Mosquitoes Invasion of Vertebrate Cells: Hepatocytes Invasion of Vertebrate Cells: Erythrocytes Ultrastructure of Asexual Stages Carbohydrate Metabolism of Asexual Stages Hemoglobin Processing and the Metabolism of Amino Acids, Heme and Iron Malarial Lipids Purine and Pyrimidine Metabolism of Asexual Stages Malaria Parasite DNA The Plasmodium rRNA Genes Membrane Transport in the Malaria-Infected Erythrocyte The Genetic Structure of Malaria Parasite Populations Genome Discovery and Malaria Research: Current Status and Promise Extrachromosomal DNA: the Mitochondrion Extrachromosomal DNA: Plastid DNA Evolutionary Relationships of Human Malaria Parasites Introduction to the Modes of Action of and Mechanisms of Resistance to Anitmalarials The Molecular Basis of Resistance to the Sulfones, Sulfamides, and Dihydrofolate Reductase Inhibitors Chloroquine: Modes of Actions and Resistance and the Activity of Chloroquine Analogs From Quinine to Qinghaosu: Historical Perspectives Mitochondrial Physiology as a Target for Atovaquone and Other Antimalarials Malaria Pathophysiology Rosetting of Malaria-Infected Erythrocytes Animal Models: Rodents Animal Models: Primates Host Genetic Factors in Resistance to Malaria Acquired Immunity to Sexual Stages Acquired Immunity to Asexual Blood Stages Acquired Immunity to Sporozoites Immunity to Liver Stages Using DNA-Based Vaccine Technology and the Malaria Genome Project to Overcome Obstacles to Malaria Vaccine Development.

Abstract: BACKGROUND An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 is being conducted in seven African countries. METHODS From March 2009 through January 2011, we enrolled 15,460 children in two age categories--6 to 12 weeks of age and 5 to 17 months of age--for vaccination with either RTS,S/AS01 or a non-malaria comparator vaccine. The primary end point of the analysis was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6000 children 5 to 17 months of age at enrollment who received all three doses of vaccine according to protocol. After 250 children had an episode of severe malaria, we evaluated vaccine efficacy against severe malaria in both age categories. RESULTS In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64). CONCLUSIONS The RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619 .).