Naturally acquired IgG responses to do not target the conserved termini of the malaria vaccine candidate Merozoite Surface Protein 2.

Introduction: Malaria remains a significant burden, and a fully protective vaccine against is critical for reducing morbidity and mortality. Antibody responses against the blood-stage antigen Merozoite Surface Protein 2 (MSP2) are associated with protection from malaria, but its extensive polymorphism is a barrier to its development as a vaccine candidate. New tools, such as long-read sequencing and accurate protein structure modelling allow us to study the genetic diversity and immune responses towards antigens from clinical isolates with unprecedented detail.

Antibody-Dependent Respiratory Burst against Merozoites in Individuals Living in an Area with Declining Malaria Transmission.

Malaria transmission intensity affects the development of naturally acquired immunity to malaria. An absolute correlate measure of protection against malaria is lacking. However, antibody-mediated functions against correlate with protection against malaria.

Persistent transmission of Plasmodium malariae and Plasmodium ovale species in an area of declining Plasmodium falciparum transmission in eastern Tanzania.

A reduction in the global burden of malaria over the past two decades has encouraged efforts for regional malaria elimination. Despite the need to target all Plasmodium species, current focus is mainly directed towards Plasmodium falciparum, and to a lesser extent P. vivax.

The Malaria-Protective Human Glycophorin Structural Variant DUP4 Shows Somatic Mosaicism and Association with Hemoglobin Levels.

Glycophorin A and glycophorin B are red blood cell surface proteins and are both receptors for the parasite Plasmodium falciparum, which is the principal cause of malaria in sub-Saharan Africa. DUP4 is a complex structural genomic variant that carries extra copies of a glycophorin A-glycophorin B fusion gene and has a dramatic effect on malaria risk by reducing the risk of severe malaria by up to 40%. Using fiber-FISH and Illumina sequencing, we validate the structural arrangement of the glycophorin locus in the DUP4 variant and reveal somatic variation in copy number of the glycophorin B-glycophorin A fusion gene.

Antibody acquisition models: A new tool for serological surveillance of malaria transmission intensity.

Serology has become an increasingly important tool for the surveillance of a wide range of infectious diseases. It has been particularly useful to monitor malaria transmission in elimination settings where existing metrics such as parasite prevalence and incidence of clinical cases are less sensitive. Seroconversion rates, based on antibody prevalence to Plasmodium falciparum asexual blood-stage antigens, provide estimates of transmission intensity that correlate with entomological inoculation rates but lack precision in settings where seroprevalence is still high.

Epidemiology of malaria in a village in the Rufiji River Delta, Tanzania: declining transmission over 25 years revealed by different parasitological metrics.

Background: Assessments of the epidemiology of malaria over time are needed to understand changes in transmission and guide control and elimination strategies.

Methods: A longitudinal population study was established in 1985 in Nyamisati village in the Rufiji River Delta, Tanzania. A physician and research team lived in the village 1984-2000.

Understanding the relationship between Plasmodium falciparum growth rate and multiplicity of infection.

Natural infections with Plasmodium falciparum are often composed of multiple concurrent genetically distinct parasite clones. Such multiclonal infections are more common in areas of high transmission, and the frequency of multiclonal infection also varies with age. A number of studies have suggested that multiclonal infection predicts the risk of subsequent clinical malaria.

Breadth of anti-merozoite antibody responses is associated with the genetic diversity of asymptomatic Plasmodium falciparum infections and protection against clinical malaria.

Background: Elucidating the mechanisms of naturally acquired immunity to Plasmodium falciparum infections would be highly valuable for malaria vaccine development. Asymptomatic multiclonal infections have been shown to predict protection from clinical malaria in a transmission-dependent manner, but the mechanisms underlying this are unclear. We assessed the breadth of antibody responses to several vaccine candidate merozoite antigens in relation to the infecting parasite population and clinical immunity.

CCL3L1 copy number and susceptibility to malaria.

Copy number variation can contribute to the variation observed in susceptibility to complex diseases. Here we present the first study to investigate copy number variation of the chemokine gene CCL3L1 with susceptibility to malaria. We present a family-based genetic analysis of a Tanzanian population (n=922), using parasite load, mean number of clinical infections of malaria and haemoglobin levels as phenotypes.

Plasmodium falciparum line-dependent association of in vitro growth-inhibitory activity and risk of malaria.

Plasmodium falciparum's ability to invade erythrocytes is essential for its survival within the human host. Immune mechanisms that impair this ability are therefore expected to contribute to immunity against the parasite. Plasma of humans who are naturally exposed to malaria has been shown to have growth-inhibitory activity (GIA) in vitro.

Extensive dynamics of Plasmodium falciparum densities, stages and genotyping profiles.

Background: Individuals living in areas of high malaria transmission often have different Plasmodium falciparum clones detected in the peripheral blood over time. The aim of this study was to assess the dynamics of asymptomatic P. falciparum infections in a few hours intervals.

Genetics of susceptibility to malaria related phenotypes.

Previous studies have established a genetic component for susceptibility to malaria. Here we use a pedigree based approach, and transmission disequilibrium testing (TDT), to identify immune response genes that influence susceptibility to Plasmodium falciparum malarial phenotypes (parasite density and frequency of clinical episodes) in a Tanzanian population. Evidence for association was observed between markers in the TNF gene cluster and both the malarial phenotypes.

Allelic dimorphism-associated restriction of recombination in Plasmodium falciparum msp1.

Allelic dimorphism is a characteristic feature of the Plasmodium falciparum msp1 gene encoding the merozoite surface protein 1, a strong malaria vaccine candidate. Meiotic recombination is a major mechanism for the generation of msp1 allelic diversity. Potential recombination sites have previously been mapped to specific regions within msp1 (a 5' 1-kb region and a 3' 0.

High frequency of recombination-driven allelic diversity and temporal variation of Plasmodium falciparum msp1 in Tanzania.

A major mechanism for the generation allelic diversity in the Plasmodium falciparum msp1 gene is meiotic recombination in the Anopheles mosquito. The frequency of recombination events is dependent on the intensity of transmission. Herein we investigate the frequency of recombination-driven allelic diversity and temporal variation of msp1 in Rufiji, eastern coastal Tanzania, where malaria transmission is intense.

Immunogenetic control of antibody responsiveness in a malaria endemic area.

This study builds upon the established genetic control of antimalarial immune responses and prior association studies by using a family-based approach, transmission disequilibrium testing, to identify immune response genes that influence antibody responses to Plasmodium falciparum infection in an endemic Tanzanian population. Candidate polymorphisms are within the interleukin-1 (IL-1) gene cluster, the IL-10 promoter, Major histocompatibility complex class II and III, the 5q31-q33 region, and the T-Cell Receptor beta variable region. There was a significant association between the IL1RN alleles and total IgE.

Multiclonal asymptomatic Plasmodium falciparum infections predict a reduced risk of malaria disease in a Tanzanian population.

Protective immunity to malaria is acquired after repeated exposure to the polymorphic Plasmodium falciparum parasite. Whether the number of concurrent antigenically diverse clones in asymptomatic infections predicts the risk of subsequent clinical malaria needs further understanding. We assessed the diversity of P.

Elevated anti-malarial IgE in asymptomatic individuals is associated with reduced risk for subsequent clinical malaria.

Immunological characteristics were assessed for prospective risk of clinical malaria in a longitudinally followed population in a holoendemic area of Tanzania. Baseline characteristics including crude Plasmodium falciparum extract-specific IgE and IgG; total IgE; and parasitological indices, e.g.

Unique TCR beta-subunit variable gene haplotypes in Africans.

This study investigated polymorphisms of genes in two regions of the T-cell antigen receptor beta-subunit (TCRB) locus, including BV9S2P, and BV6S7 in a 5' linkage group, and BV8S3, BV24S1, BV25S1, BV18S1, BV2S1, BV15S1 and BV3S1 in a 3' linkage group. These loci have been genotyped in individuals from five regions in Africa, including The Gambia, Nigeria, Cameroon, Tanzania, and Zambia, and in individuals from northern Britain, northern India, and Papua New Guinea (PNG). In the 3' linkage group, 11 unique haplotypes were identified in the combined African populations; two equally frequent haplotypes represent the majority of African chromosomes.