Determination of the Processes Driving the Acquisition of Immunity to Malaria Using a Mathematical Transmission Model

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. Whilst it is clear that natural immunity to malaria infection develops in those living in malaria-endemic regions of the world, the precise way in which it is acquired and the duration of immune memory are less-well-understood. We used a mathematical model that mimics malaria transmission between humans and mosquitoes in endemic settings to explore what epidemiological data, and in particular the prevalence of malaria in different aged individuals, can tell us about how immunity might develop. We explored three different parts of the transmission cycle at which immunity could act: 1) reducing the likelihood that an infected person develops symptomatic disease; 2) increasing the rate at which infection is cleared, and 3) increasing the duration of low-level (subpatent) infections that would continue to boost the immune system and hence protect against further disease. Our results show that the first two mechanisms together give rise to patterns of malaria by age group that are consistent with those observed in different malaria endemic settings in Africa. Our model also suggests that immunity to symptomatic disease lasts for at least five years, develops faster if there are higher levels of infection in the population, and increases with age. On the other hand, our model suggests that immunity that helps to clear infection lasts longer (20 years or more), develops later in life, and does not depend on the amount of transmission in the population.