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The dynamics of naturally acquired immunity to Plasmodium falciparum infection.

Pinkevych M, Petravic J, Chelimo K, Kazura JW, Moormann AM, Davenport MP - PLoS Comput. Biol. (2012)

Bottom Line: Here we analyse the dynamics of Plasmodium falciparum malaria infection after treatment in a cohort of 197 healthy study participants of different ages in order to model naturally acquired immunity.We find that both delayed time-to-infection and reductions in asymptomatic parasitaemias in older age groups can be explained by immunity that reduces the growth of blood stage as opposed to liver stage parasites.We found that this mechanism would require at least two components - a rapidly acting strain-specific component, as well as a slowly acquired cross-reactive or general immunity to all strains.

View Article: PubMed Central - PubMed

Affiliation: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.

ABSTRACT
Severe malaria occurs predominantly in young children and immunity to clinical disease is associated with cumulative exposure in holoendemic settings. The relative contribution of immunity against various stages of the parasite life cycle that results in controlling infection and limiting disease is not well understood. Here we analyse the dynamics of Plasmodium falciparum malaria infection after treatment in a cohort of 197 healthy study participants of different ages in order to model naturally acquired immunity. We find that both delayed time-to-infection and reductions in asymptomatic parasitaemias in older age groups can be explained by immunity that reduces the growth of blood stage as opposed to liver stage parasites. We found that this mechanism would require at least two components - a rapidly acting strain-specific component, as well as a slowly acquired cross-reactive or general immunity to all strains. Analysis and modelling of malaria infection dynamics and naturally acquired immunity with age provides important insights into what mechanisms of immune control may be harnessed by malaria vaccine strategists.

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The dynamics of reinfection.Panel A. The rates of reinfection in the clinical cohort are shown for each age group over time. The proportion uninfected is shown as a ‘survival curve’ for each age group. Patients were censored if they had missing values or were treated prior to reinfection. Blue triangle and blue line - C1, green diamond and green line - C2, orange square and orange line - C3, red circle and red line - A. Panel B. Schematic illustration of parasite growth in blood. Infection commences with an infected bite, followed by a liver stage of one week. Once the blood stage commences, rapid parasite growth (high PMR) will lead to early detection on infection. Factors that slow parasite growth in the blood will delay the time until detection. Panel C. Exponential fit to field study data for group C1.
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pcbi-1002729-g001: The dynamics of reinfection.Panel A. The rates of reinfection in the clinical cohort are shown for each age group over time. The proportion uninfected is shown as a ‘survival curve’ for each age group. Patients were censored if they had missing values or were treated prior to reinfection. Blue triangle and blue line - C1, green diamond and green line - C2, orange square and orange line - C3, red circle and red line - A. Panel B. Schematic illustration of parasite growth in blood. Infection commences with an infected bite, followed by a liver stage of one week. Once the blood stage commences, rapid parasite growth (high PMR) will lead to early detection on infection. Factors that slow parasite growth in the blood will delay the time until detection. Panel C. Exponential fit to field study data for group C1.

Mentions: The details of cohort study have been described elsewhere [3]. Briefly, upon entry into the study (day 0) study participants (n = 201) were treated with Coartem®, which is expected to eradicate blood stage infection but is not effective against liver stage parasites [11]. Therefore, if a study participant was parasitaemic at week two post-treatment, this was considered an emerging liver stage infection and they were eliminated from further study. After treatment, blood smears were monitored weekly for 11 weeks by examination of thick and thin blood smears using light microscopy for the presence of Pf-malaria parasites. In addition, if weekly samples were not collected after week two post-treatment, then the study participant was eliminated; thus leaving 197 remaining for analysis. The cohort was divided into four age groups based on the immuno-epidemiology of malaria; C1 (children 1–4 years old (y.o.) were the least likely to have developed anti-malarial immunity and thus most susceptible to rapid infection; C2 (5–9 y.o.) have begun to develop partially protective immunity though may have limited strain-specific immunity; C3 (10–14 y.o.) have developed anti-malarial immunity that should begin to contain a broader repertoire of strain-specific immunity due to cumulative exposure; and A (adults>15 y.o.) who have developed anti-malarial immunity that decreases the rate of infection, parasite growth and provides coverage across many strains. Fig. 1A shows the infection curves for each age group over the 11 weeks of the study.


The dynamics of naturally acquired immunity to Plasmodium falciparum infection.

Pinkevych M, Petravic J, Chelimo K, Kazura JW, Moormann AM, Davenport MP - PLoS Comput. Biol. (2012)

The dynamics of reinfection.Panel A. The rates of reinfection in the clinical cohort are shown for each age group over time. The proportion uninfected is shown as a ‘survival curve’ for each age group. Patients were censored if they had missing values or were treated prior to reinfection. Blue triangle and blue line - C1, green diamond and green line - C2, orange square and orange line - C3, red circle and red line - A. Panel B. Schematic illustration of parasite growth in blood. Infection commences with an infected bite, followed by a liver stage of one week. Once the blood stage commences, rapid parasite growth (high PMR) will lead to early detection on infection. Factors that slow parasite growth in the blood will delay the time until detection. Panel C. Exponential fit to field study data for group C1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475668&req=5

pcbi-1002729-g001: The dynamics of reinfection.Panel A. The rates of reinfection in the clinical cohort are shown for each age group over time. The proportion uninfected is shown as a ‘survival curve’ for each age group. Patients were censored if they had missing values or were treated prior to reinfection. Blue triangle and blue line - C1, green diamond and green line - C2, orange square and orange line - C3, red circle and red line - A. Panel B. Schematic illustration of parasite growth in blood. Infection commences with an infected bite, followed by a liver stage of one week. Once the blood stage commences, rapid parasite growth (high PMR) will lead to early detection on infection. Factors that slow parasite growth in the blood will delay the time until detection. Panel C. Exponential fit to field study data for group C1.
Mentions: The details of cohort study have been described elsewhere [3]. Briefly, upon entry into the study (day 0) study participants (n = 201) were treated with Coartem®, which is expected to eradicate blood stage infection but is not effective against liver stage parasites [11]. Therefore, if a study participant was parasitaemic at week two post-treatment, this was considered an emerging liver stage infection and they were eliminated from further study. After treatment, blood smears were monitored weekly for 11 weeks by examination of thick and thin blood smears using light microscopy for the presence of Pf-malaria parasites. In addition, if weekly samples were not collected after week two post-treatment, then the study participant was eliminated; thus leaving 197 remaining for analysis. The cohort was divided into four age groups based on the immuno-epidemiology of malaria; C1 (children 1–4 years old (y.o.) were the least likely to have developed anti-malarial immunity and thus most susceptible to rapid infection; C2 (5–9 y.o.) have begun to develop partially protective immunity though may have limited strain-specific immunity; C3 (10–14 y.o.) have developed anti-malarial immunity that should begin to contain a broader repertoire of strain-specific immunity due to cumulative exposure; and A (adults>15 y.o.) who have developed anti-malarial immunity that decreases the rate of infection, parasite growth and provides coverage across many strains. Fig. 1A shows the infection curves for each age group over the 11 weeks of the study.

Bottom Line: Here we analyse the dynamics of Plasmodium falciparum malaria infection after treatment in a cohort of 197 healthy study participants of different ages in order to model naturally acquired immunity.We find that both delayed time-to-infection and reductions in asymptomatic parasitaemias in older age groups can be explained by immunity that reduces the growth of blood stage as opposed to liver stage parasites.We found that this mechanism would require at least two components - a rapidly acting strain-specific component, as well as a slowly acquired cross-reactive or general immunity to all strains.

View Article: PubMed Central - PubMed

Affiliation: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.

ABSTRACT
Severe malaria occurs predominantly in young children and immunity to clinical disease is associated with cumulative exposure in holoendemic settings. The relative contribution of immunity against various stages of the parasite life cycle that results in controlling infection and limiting disease is not well understood. Here we analyse the dynamics of Plasmodium falciparum malaria infection after treatment in a cohort of 197 healthy study participants of different ages in order to model naturally acquired immunity. We find that both delayed time-to-infection and reductions in asymptomatic parasitaemias in older age groups can be explained by immunity that reduces the growth of blood stage as opposed to liver stage parasites. We found that this mechanism would require at least two components - a rapidly acting strain-specific component, as well as a slowly acquired cross-reactive or general immunity to all strains. Analysis and modelling of malaria infection dynamics and naturally acquired immunity with age provides important insights into what mechanisms of immune control may be harnessed by malaria vaccine strategists.

Show MeSH
Related in: MedlinePlus