The complexity of Plasmodium falciparum infections in children in western Kenya /

by Grills, Ardath White

The complexity of Plasmodium falciparum infections in children in western Kenya To investigate the allelic complexity of infection (COI) of Plasmodium falciparum infections in children living in Kisumu, western Kenya, samples from three studies conducted from June, 2003 through May, 2006 were analyzed: a longitudinal cohort, a phase 1 field trial and a phase 2 field trial. Samples from the studies were analyzed using nested PCR of the highly polymorphic msp1 block 2 to observe potential selective effects of the vaccine, a MSP1 formulation. The longitudinal cohort, used to determine the baseline COI, followed 60 children 1-4 years old for 13 months who donated scheduled samples monthly and additional samples when ill with clinical malaria. Results revealed a COI that was dependent on age, parasite density, illness, village location and bed net use. Nearly all infections were with multiple genotypes. Fluctuations of the three examined alleles of msp1, K1, MAD20 and RO33, were rapid and random within individual children, as well as the entire study group, indicating a highly diverse parasite population. Parasite density was found to be directly correlated with COI in those children with clinical illness. As the density increased, the contribution of the K1 allele proportionately increased while the contribution of the RO33 allele decreased. Presence of the invariable RO33 allele was also found to be mildly protective against clinical illness. For the first time, bed net use was found to decrease COI in 1-2 year old children who were both asymptomatic carriers of parasites and ill with clinical malaria; the RO33 allele was again most associated with the decrease in COI. In the phase 1 dose-escalation trial with 135 children, those - ii - participants who received the full vaccine dose had a decrease in COI following vaccine administration. In that group of children, the RO33 allele was identified in much greater prevalence following vaccine administration. Samples that were RO33 positive were also predominately chloroquine sensitive. The phase 2 vaccine trial with 400 participants is still currently blinded; initial analysis showed an increased COI in ill patients, a finding that contrasts with previous reports. Combined, the three studies provided evidence of the rapidly evolving immunity to malaria, even within the limited 1-4 year age range of the study participants. Ardath W. Grills Doctor of Philosophy, 2006 Thesis directed by: COL Christian F. Ockenhouse, MD Assistant Professor, Department of Medicine - iii - The complexity of Plasmodium falciparum infections in children in western Kenya by Ardath White Grills Dissertation submitted to the Faculty of the Emerging Infectious Diseases Program of the Uniformed Services University of the Health Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy September, 2006 - iv -