The long term goals of the proposed work are to understand how anti-malaria antibodies and T-cell and B-cell memory contribute to protection against asexual blood stage Plasmodium falciparum and the impact of vector interventions that are now decreasing malaria transmission in Africa on immune memory and malaria susceptibility. Our previous research in western Kenya has been concerned with elucidating the mechanisms underlying age-related naturally acquired immunity, with a focus on antibody and T-cell responses to the 42 kDa C-terminal region of Merozoite Surface Protein 1. This earlier work was done when malaria transmission was higher than at present and before a clinical trial of MSP1 in Kenyan children showed no efficacy. Accordingly, our research strategy has been modified to address the impact of reduced malaria exposure on acquired immunity and stalled progress toward development of a blood stage vaccine.
The Specific Aims are to: 1: Identify a repertoire of merozoite invasion ligands important in protection against parasitemia and clinical malaria. Antibodies from well characterized historic cohorts of children and adults (2000-09) will be used to identify merozoite proteins credentialed as biologically significant by their established role for progression of merozoites through the erythrocyte cycle (MSP1, AMA1, EBA175, EBA140, Reticulocyte-binding homolog (Rh) proteins, SERA5) and other targets that are (presently) not well characterized (6-cys proteins, MSP6, MSP7). 2: Examine how T-cell memory to credentialed merozoite antigens contributes to age-related malaria immunity. CD4 T-cell memory subsets and cytokines implicated to have a protective role (IFN-() and counter- regulatory function on IFN-( (IL-10, TGF-?) from historic and new (2012-14) child and adult cohorts will be evaluated and compared. 3: Evaluate the relationship of B-cell memory to the development and maintenance of acquired immunity. The frequency of circulating Ag-specific memory B-cells will be quantified and correlated with the magnitude and durability of antibody responses, incident parasitemia, and clinical malaria. These responses will be evaluated in the context of B-cell memory phenotypes stratified according to age and clinical malaria status. Measurable outcomes from this research will identify and validate new malaria antigens as vaccine candidates and contribute to understanding the mechanisms and impact of decreasing transmission on the age profile and durability of naturally acquired immunity against malaria.

Public Health Relevance

This research will advance understanding of how decreasing malaria transmission in Africa impacts the strength and durability of acquired immunity that has historically resulted in protection against malaria morbidity by late childhood and credential novel merozoite proteins as potential vaccine targets.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Rao, Malla R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
Schrum, Jacob E; Crabtree, Juliet N; Dobbs, Katherine R et al. (2018) Cutting Edge: Plasmodium falciparum Induces Trained Innate Immunity. J Immunol 200:1243-1248
Dobbs, Katherine R; Embury, Paula; Vulule, John et al. (2017) Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria. JCI Insight 2:
Dent, Arlene E; Malhotra, Indu; Wang, Xuelie et al. (2016) Contrasting Patterns of Serologic and Functional Antibody Dynamics to Plasmodium falciparum Antigens in a Kenyan Birth Cohort. Clin Vaccine Immunol 23:104-16
Drew, Damien R; Wilson, Danny W; Elliott, Salenna R et al. (2016) A novel approach to identifying patterns of human invasion-inhibitory antibodies guides the design of malaria vaccines incorporating polymorphic antigens. BMC Med 14:144
Pinkevych, Mykola; Chelimo, Kiprotich; Vulule, John et al. (2015) Time-to-infection by Plasmodium falciparum is largely determined by random factors. BMC Med 13:19
Noland, Gregory S; Jansen, Paul; Vulule, John M et al. (2015) Effect of transmission intensity and age on subclass antibody responses to Plasmodium falciparum pre-erythrocytic and blood-stage antigens. Acta Trop 142:47-56
Dent, Arlene E; Nakajima, Rie; Liang, Li et al. (2015) Plasmodium falciparum Protein Microarray Antibody Profiles Correlate With Protection From Symptomatic Malaria in Kenya. J Infect Dis 212:1429-38
Pinkevych, Mykola; Petravic, Janka; Chelimo, Kiprotich et al. (2014) Decreased growth rate of P. falciparum blood stage parasitemia with age in a holoendemic population. J Infect Dis 209:1136-43
Pinkevych, Mykola; Petravic, Janka; Chelimo, Kiprotich et al. (2013) Density-dependent blood stage Plasmodium falciparum suppresses malaria super-infection in a malaria holoendemic population. Am J Trop Med Hyg 89:850-6
Pinkevych, Mykola; Petravic, Janka; Chelimo, Kiprotich et al. (2012) The dynamics of naturally acquired immunity to Plasmodium falciparum infection. PLoS Comput Biol 8:e1002729

Showing the most recent 10 out of 12 publications