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Determination of the processes driving the acquisition of immunity to malaria using a mathematical transmission model.

Filipe JA, Riley EM, Drakeley CJ, Sutherland CJ, Ghani AC - PLoS Comput. Biol. (2007)

Bottom Line: The results were compared to age patterns of parasite prevalence and clinical disease in endemic settings in northeastern Tanzania and The Gambia.Two types of immune function were required to reproduce the epidemiological age-prevalence curves seen in the empirical data; a form of clinical immunity that reduces susceptibility to clinical disease and develops with age and exposure (with half-life of the order of five years or more) and a form of anti-parasite immunity which results in more rapid clearance of parasitaemia, is acquired later in life and is longer lasting (half-life of >20 y).The development of anti-parasite immunity better reproduced observed epidemiological patterns if it was dominated by age-dependent physiological processes rather than by the magnitude of exposure (provided some exposure occurs).

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.

ABSTRACT
Acquisition of partially protective immunity is a dominant feature of the epidemiology of malaria among exposed individuals. The processes that determine the acquisition of immunity to clinical disease and to asymptomatic carriage of malaria parasites are poorly understood, in part because of a lack of validated immunological markers of protection. Using mathematical models, we seek to better understand the processes that determine observed epidemiological patterns. We have developed an age-structured mathematical model of malaria transmission in which acquired immunity can act in three ways ("immunity functions"): reducing the probability of clinical disease, speeding the clearance of parasites, and increasing tolerance to subpatent infections. Each immunity function was allowed to vary in efficacy depending on both age and malaria transmission intensity. The results were compared to age patterns of parasite prevalence and clinical disease in endemic settings in northeastern Tanzania and The Gambia. Two types of immune function were required to reproduce the epidemiological age-prevalence curves seen in the empirical data; a form of clinical immunity that reduces susceptibility to clinical disease and develops with age and exposure (with half-life of the order of five years or more) and a form of anti-parasite immunity which results in more rapid clearance of parasitaemia, is acquired later in life and is longer lasting (half-life of >20 y). The development of anti-parasite immunity better reproduced observed epidemiological patterns if it was dominated by age-dependent physiological processes rather than by the magnitude of exposure (provided some exposure occurs). Tolerance to subpatent infections was not required to explain the empirical data. The model comprising immunity to clinical disease which develops early in life and is exposure-dependent, and anti-parasite immunity which develops later in life and is not dependent on the magnitude of exposure, appears to best reproduce the pattern of parasite prevalence and clinical disease by age in different malaria transmission settings. Understanding the effector mechanisms underlying these two immune functions will assist in the design of transmission-reducing interventions against malaria.

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Sensitivity of the Relationship between Parasitaemia, Clinical Disease, and Age to Assumptions about the Duration of Acquired Immunity(A,B) Sensitivity to the duration of the immune response that reduces susceptibility to clinical disease where dS is the half-life; (A) shows the relationship between parasitaemia and age, and (B) shows the proportion of people predicted by the model to be symptomatic cases, have asymptomatic infections, and be parasitaemic (i.e., have patent infections) for different values of dS. Subpatent infections are not shown. For dS less than 5 y, the model predicts too high a proportion of all infections to be symptomatic cases rather than asymptomatic (B).(C,D) Sensitivity to the duration of the immune response that increases clearance of detectable parasites where dA is the half-life; (C) shows the relationship between parasitaemia and age, and (D) shows the proportion of people predicted by the model to be symptomatic cases, asymptomatic infections, and parasitaemic for different values of dA. For dA less than approximately 20 y, the model predicts that high levels of parasitaemia will persist into adulthood (C). Results are presented for an annual EIR of 110 ibppy. Similar patterns are obtained for lower EIR values.
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pcbi-0030255-g005: Sensitivity of the Relationship between Parasitaemia, Clinical Disease, and Age to Assumptions about the Duration of Acquired Immunity(A,B) Sensitivity to the duration of the immune response that reduces susceptibility to clinical disease where dS is the half-life; (A) shows the relationship between parasitaemia and age, and (B) shows the proportion of people predicted by the model to be symptomatic cases, have asymptomatic infections, and be parasitaemic (i.e., have patent infections) for different values of dS. Subpatent infections are not shown. For dS less than 5 y, the model predicts too high a proportion of all infections to be symptomatic cases rather than asymptomatic (B).(C,D) Sensitivity to the duration of the immune response that increases clearance of detectable parasites where dA is the half-life; (C) shows the relationship between parasitaemia and age, and (D) shows the proportion of people predicted by the model to be symptomatic cases, asymptomatic infections, and parasitaemic for different values of dA. For dA less than approximately 20 y, the model predicts that high levels of parasitaemia will persist into adulthood (C). Results are presented for an annual EIR of 110 ibppy. Similar patterns are obtained for lower EIR values.

Mentions: Reducing the half-life for the duration of clinical immunity below 5 y results in a sharp increase in the proportion of all infections that are symptomatic cases and, in addition, results in less-pronounced age-prevalence peaks which begin to deviate from those observed in data. Increasing the duration of clinical immunity does not substantially change age-prevalence patterns but does have an impact on the proportion of infections that are symptomatic cases (Figure 5A and 5B).


Determination of the processes driving the acquisition of immunity to malaria using a mathematical transmission model.

Filipe JA, Riley EM, Drakeley CJ, Sutherland CJ, Ghani AC - PLoS Comput. Biol. (2007)

Sensitivity of the Relationship between Parasitaemia, Clinical Disease, and Age to Assumptions about the Duration of Acquired Immunity(A,B) Sensitivity to the duration of the immune response that reduces susceptibility to clinical disease where dS is the half-life; (A) shows the relationship between parasitaemia and age, and (B) shows the proportion of people predicted by the model to be symptomatic cases, have asymptomatic infections, and be parasitaemic (i.e., have patent infections) for different values of dS. Subpatent infections are not shown. For dS less than 5 y, the model predicts too high a proportion of all infections to be symptomatic cases rather than asymptomatic (B).(C,D) Sensitivity to the duration of the immune response that increases clearance of detectable parasites where dA is the half-life; (C) shows the relationship between parasitaemia and age, and (D) shows the proportion of people predicted by the model to be symptomatic cases, asymptomatic infections, and parasitaemic for different values of dA. For dA less than approximately 20 y, the model predicts that high levels of parasitaemia will persist into adulthood (C). Results are presented for an annual EIR of 110 ibppy. Similar patterns are obtained for lower EIR values.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2230683&req=5

pcbi-0030255-g005: Sensitivity of the Relationship between Parasitaemia, Clinical Disease, and Age to Assumptions about the Duration of Acquired Immunity(A,B) Sensitivity to the duration of the immune response that reduces susceptibility to clinical disease where dS is the half-life; (A) shows the relationship between parasitaemia and age, and (B) shows the proportion of people predicted by the model to be symptomatic cases, have asymptomatic infections, and be parasitaemic (i.e., have patent infections) for different values of dS. Subpatent infections are not shown. For dS less than 5 y, the model predicts too high a proportion of all infections to be symptomatic cases rather than asymptomatic (B).(C,D) Sensitivity to the duration of the immune response that increases clearance of detectable parasites where dA is the half-life; (C) shows the relationship between parasitaemia and age, and (D) shows the proportion of people predicted by the model to be symptomatic cases, asymptomatic infections, and parasitaemic for different values of dA. For dA less than approximately 20 y, the model predicts that high levels of parasitaemia will persist into adulthood (C). Results are presented for an annual EIR of 110 ibppy. Similar patterns are obtained for lower EIR values.
Mentions: Reducing the half-life for the duration of clinical immunity below 5 y results in a sharp increase in the proportion of all infections that are symptomatic cases and, in addition, results in less-pronounced age-prevalence peaks which begin to deviate from those observed in data. Increasing the duration of clinical immunity does not substantially change age-prevalence patterns but does have an impact on the proportion of infections that are symptomatic cases (Figure 5A and 5B).

Bottom Line: The results were compared to age patterns of parasite prevalence and clinical disease in endemic settings in northeastern Tanzania and The Gambia.Two types of immune function were required to reproduce the epidemiological age-prevalence curves seen in the empirical data; a form of clinical immunity that reduces susceptibility to clinical disease and develops with age and exposure (with half-life of the order of five years or more) and a form of anti-parasite immunity which results in more rapid clearance of parasitaemia, is acquired later in life and is longer lasting (half-life of >20 y).The development of anti-parasite immunity better reproduced observed epidemiological patterns if it was dominated by age-dependent physiological processes rather than by the magnitude of exposure (provided some exposure occurs).

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.

ABSTRACT
Acquisition of partially protective immunity is a dominant feature of the epidemiology of malaria among exposed individuals. The processes that determine the acquisition of immunity to clinical disease and to asymptomatic carriage of malaria parasites are poorly understood, in part because of a lack of validated immunological markers of protection. Using mathematical models, we seek to better understand the processes that determine observed epidemiological patterns. We have developed an age-structured mathematical model of malaria transmission in which acquired immunity can act in three ways ("immunity functions"): reducing the probability of clinical disease, speeding the clearance of parasites, and increasing tolerance to subpatent infections. Each immunity function was allowed to vary in efficacy depending on both age and malaria transmission intensity. The results were compared to age patterns of parasite prevalence and clinical disease in endemic settings in northeastern Tanzania and The Gambia. Two types of immune function were required to reproduce the epidemiological age-prevalence curves seen in the empirical data; a form of clinical immunity that reduces susceptibility to clinical disease and develops with age and exposure (with half-life of the order of five years or more) and a form of anti-parasite immunity which results in more rapid clearance of parasitaemia, is acquired later in life and is longer lasting (half-life of >20 y). The development of anti-parasite immunity better reproduced observed epidemiological patterns if it was dominated by age-dependent physiological processes rather than by the magnitude of exposure (provided some exposure occurs). Tolerance to subpatent infections was not required to explain the empirical data. The model comprising immunity to clinical disease which develops early in life and is exposure-dependent, and anti-parasite immunity which develops later in life and is not dependent on the magnitude of exposure, appears to best reproduce the pattern of parasite prevalence and clinical disease by age in different malaria transmission settings. Understanding the effector mechanisms underlying these two immune functions will assist in the design of transmission-reducing interventions against malaria.

Show MeSH
Related in: MedlinePlus