Self-Reactivities to the Non-Erythroid Alpha Spectrin Correlate with Cerebral Malaria in Gabonese Children

BACKGROUND: Hypergammaglobulinemia and polyclonal B-cell activation commonly occur in Plasmodium sp. infections. Some of the antibodies produced recognize self-components and are correlated with disease severity in P. falciparum malaria. However, it is not known whether some self-reactive antibodies produced during P. falciparum infection contribute to the events leading to cerebral malaria (CM). We show here a correlation between self-antibody responses to a human brain protein and high levels of circulating TNF alpha (TNFα), with the manifestation of CM in Gabonese children. METHODOLOGY: To study the role of self-reactive antibodies associated to the development of P. falciparum cerebral malaria, we used a combination of quantitative immunoblotting and multivariate analysis to analyse correlation between the reactivity of circulating IgG with a human brain protein extract and TNFα concentrations in cohorts of uninfected controls (UI) and P. falciparum-infected Gabonese children developing uncomplicated malaria (UM), severe non-cerebral malaria (SNCM), or CM. RESULTS/CONCLUSION: The repertoire of brain antigens recognized by plasma IgGs was more diverse in infected than in UI individuals. Anti-brain reactivity was significantly higher in the CM group than in the UM and SNCM groups. IgG self-reactivity to brain antigens was also correlated with plasma IgG levels and age. We found that 90% of CM patients displayed reactivity to a high-molecular mass band containing the spectrin non-erythroid alpha chain. Reactivity with this band was correlated with high TNFα concentrations in CM patients. These results strongly suggest that an antibody response to brain antigens induced by P. falciparum infection may be associated with pathogenic mechanisms in patients developing CM

West African donors have high percentages of activated cytokine producing T cells that are prone to apoptosis

Persistent immune activation has been suggested to affect the subset composition and activation status of peripheral blood cells. In this study we have compared peripheral blood mononuclear cells (PBMC) from a group of Ghanaians living in an area with high prevalence of malaria, mycobacteria, EBV and helmintic infections to a group of European counterparts. Our hypothesis was that persistent challenge with microorganisms is associated with increased production of cytokines and increased susceptibility of periphery cells to undergo apoptosis. We observed an increased frequency of activated T cells and a higher frequency of IL-4- but not IFN-γ-producing cells in the periphery of the Ghanaians. The IL-4 was produced mainly by CD4(+) cells, in contrast to IFN-γ which was produced equally by CD4(+), CD8(+) and TCR-γδ(+) cells. The frequencies of cytokine-producing cells were highly correlated to the frequencies of activated cells. Finally, cells from Ghanaians were more susceptible to activation-induced apoptosis. These results may explain why some epidemic diseases seem to have a different mode of transmission in Africa compared to the western world, and may thus be of importance when vaccine strategies are considered in Africa

MALVAC 2009 : progress and challenges in development of whole organism malaria vaccines for endemic countries, 3-4 June 2009, Dakar, Senegal

Research and development into whole organism malaria vaccines is progressing rapidly thanks to the major investments over recent years from several funders, and the commitment and interest of many leading researchers. Progress includes the discovery of potential new candidate vaccines and the start of the first phase 1/2a clinical trial of the radiation attenuated sporozoite approach for Plasmodium falciparum, under US Food and Drug Administration regulatory oversight. A group of leading scientists, clinical trialists and stakeholders, together with representatives of regulatory authorities including some from African countries, met recently to document the issues that will require detailed consideration to assess this promising approach. Questions related to scale-up, quality, purity and consistency of a manufacturing process using mosquitoes to generate a commercial product, and demonstration of the stability of attenuated sporozoites will need further work. Should a high level of efficacy be demonstrated in clinical challenge studies, it will become a priority to agree in which populations and age groups questions about strain-transcendence and duration of efficacy should be answered, and how clinical development can progress with an approach based on cryopreservation in liquid nitroge