A seven-year study on the effect of the pre-erythrocytic malaria vaccine candidate RTS,S/AS01 E on blood stage immunity in young Kenyan children.

Background: RTS,S/AS01 E, the most advanced malaria vaccine confers partial immunity. The vaccine-induced pre-erythrocytic immunity reduces exposure to blood-stage parasites, delaying acquisition of antibodies to blood-stage antigens.  However, the duration of this effect is unknown. Methods: We measured, by enzyme-linked immunosorbent assay, IgG-antibodies to 4 Plasmodium falciparum blood-stage antigens (AMA1, MSP1 42, EBA175, and MSP3) on 314 children randomized to receive RTS,S/AS01 E or Rabies vaccine at 5 - 17 months of age in a phase 2b trial in Kenya, and thereafter participated in a 7-year study of the duration of vaccine immunity. Results: Antibody levels to MSP1 42, AMA1 and EBA175 were slightly lower among the RTS,S/AS01 E recipients, relative to the Rabies-control vaccinees, during the first 48 months of surveillance. Irrespective of vaccine arm, antibody levels to merozoite antigens were positively associated with the risk for malaria. However, this was only apparent at high levels for EBA175 and AMA1 and was not evident after adjusting for heterogeneity in malaria-exposure. Among children with asymptomatic parasitaemia, antibody levels were associated with reduced clinical malaria. Conclusions: The reduction in levels of antibodies to blood-stage antigens induced by vaccination with RTS,S/AS01 E can last for several years. In absence of asymptomatic infection, anti-merozoite antibody levels were unreliable correlates of clinical immunity

Malaria exposure drives both cognate and bystander human B cells to adopt an atypical phenotype

Atypical memory B cells (aMBCs) are found in elevated numbers in individuals exposed to malaria. A key question is whether malaria induces aMBCs as a result of exposure to Ag, or non-Ag-specific mechanisms. We identified Plasmodium and bystander tetanus toxoid (TT) specific B cells in individuals from areas of previous and persistent exposure to malaria using tetramers. Malaria-specific B cells were more likely to be aMBCs than TT-specific B cells. However, TT-specific B cells from individuals with continuous exposure to malaria were more likely to be aMBCs than TT-specific B cells in individuals from areas where transmission has ceased. Finally, sequences of BCRs specific for a blood stage malaria-Ag were more highly mutated than sequences from TT-specific BCRs and under strong negative selection, indicative of ongoing antigenic pressure. Our data suggest both persistent Ag exposure and the inflammatory environment shape the B-cell response to malaria and bystander Ags

Some Computational Aspects of the Branch and Bound Method for Integer Programs

66 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1982.Different heuristics for the branch and bound method are tested on capital budgeting type integer programming problems. The standard up and down penalties are compared with Tomlin's improved penalties. The use of the 'priority order' derived from the objective coefficients is also examined. A new heuristic--"the nearer integer rule"--is introduced that reduces the time taken to find the optimal solution.The "pseudo-costs" of Benichou et. al. are examined and it is shown that there is no good basis for their use. The "BP Criterion" is compared to the "best-bound" rule for node selection and found to be inferior. A 'correction' for the depth of a node is suggested to improve the best-bound rule.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Relationships of antibody levels and avidities with age.

<p>Antibody levels and avidity indices for each antigen are plotted against age. Linear regression lines are shown, as are the associated R squared and P values.</p

Prospective association between antibody levels and avidities at baseline with the risk of malaria during 10-months follow up.

<p>Summary of a multivariable Cox and Poisson Regression models for both Antibody levels and avidities, controlling for age, baseline parasitaemia and exposure index. AI, avidity index; IRR, Incidence Risk Ratio.</p

Characteristics of the study subjects.

*<p>Previous episodes only refer those clinical malaria episodes that occurred before May 2009, the sampling date.</p

Multivariable analysis of association between EI, age and cross sectional parasitaemia with antibody levels and avidities.

<p>Data was analysed by multivariable linear regression.</p

Antibody levels but not avidities were elevated in the presence of asymptomatic parasitaemia.

<p>Antibody levels (top panel) and avidities (lower panel) for children with (open symbols) and without (filled symbols) asymptomatic <i>P. falciparum</i> parasitaemia as determined by use of blood-films at sampling. Horizontal bars are medians. Statistical significance of differences was determined by Wilcoxon rank-sum test.</p

10-year longitudinal study of malaria in children: insights into acquisition and maintenance of naturally acquired immunity

Background: Studies of long-term malaria cohorts have provided essential insights into how Plasmodium falciparum interacts with humans, and influences the development of antimalarial immunity. Immunity to malaria is acquired gradually after multiple infections, some of which present with clinical symptoms. However, there is considerable variation in the number of clinical episodes experienced by children of the same age within the same cohort. Understanding this variation in clinical symptoms and how it relates to the development of naturally acquired immunity is crucial in identifying how and when some children stop experiencing further malaria episodes. Where variability in clinical episodes may result from different rates of acquisition of immunity, or from variable exposure to the parasite. Methods: Using data from a longitudinal cohort of children residing in an area of moderate P. falciparum transmission in Kilifi district, Kenya, we fitted cumulative episode curves as monotonic-increasing splines, to 56 children under surveillance for malaria from the age of 5 to 15. Results: There was large variability in the accumulation of numbers of clinical malaria episodes experienced by the children, despite being of similar age and living in the same general location. One group of children from a particular sub-region of the cohort stopped accumulating clinical malaria episodes earlier than other children in the study. Despite lack of further clinical episodes of malaria, these children had higher asymptomatic parasite densities and higher antibody titres to a panel of P. falciparum blood-stage antigens. Conclusions: This suggests development of clinical immunity rather than lack of exposure to the parasite, and supports the view that this immunity to malaria disease is maintained by a greater exposure to P. falciparum, and thus higher parasite burdens. Our study illustrates the complexity of anti-malaria immunity and underscores the need for analyses which can sufficiently reflect the heterogeneity within endemic populations

Individual-level variations in malaria susceptibility and acquisition of clinical protection

After decades of research, our understanding of when and why individuals infected with Plasmodium falciparum develop clinical malaria is still limited. Correlates of immune protection are often sought through prospective cohort studies, where measured host factors are correlated against the incidence of clinical disease over a set period of time. However, robustly inferring individual-level protection from these population-level findings has proved difficult due to small effect sizes and high levels of variance underlying such data. In order to better understand the nature of these inter-individual variations, we analysed the long-term malaria epidemiology of children ≤12 years old growing up under seasonal exposure to the parasite in the sub-location of Junju, Kenya. Despite the cohort’s limited geographic expanse (ca. 3km x 10km), our data reveal a high degree of spatial and temporal variability in malaria prevalence and incidence rates, causing individuals to experience varying levels of exposure to the parasite at different times during their life. Analysing individual-level infection histories further reveal an unexpectedly high variability in the rate at which children experience clinical malaria episodes. Besides exposure to the parasite, measured as disease prevalence in the surrounding area, we find that the birth time of year has an independent effect on the individual’s risk of experiencing a clinical episode. Furthermore, our analyses reveal that those children with a history of an above average number of episodes are more likely to experience further episodes during the upcoming transmission season. These findings are indicative of phenotypic differences in the rates by which children acquire clinical protection to malaria and offer important insights into the natural variability underlying malaria epidemiology