Malaria kills around 500,000 children every year. The disease occurs when an infected mosquito bites a human and passes on a Plasmodium parasite. One parasite in particular, Plasmodium falciparum, is responsible for most malaria-related deaths across the globe. A person can be infected by P. falciparum many times throughout their life. However, after children have had multiple infections, they become less likely to develop symptoms of malaria, such as high fever. In other words, they gradually acquire immunity.

This immunity to malaria can come in two forms: “anti-parasite immunity”, where the body fights the parasites and keeps their numbers low; and “anti-disease immunity”, where the body is more likely to tolerate an infection without developing a fever. To date, scientists do not fully understand how either kind of immunity arises in children. Is it because they have simply been exposed to more malaria? Or does being older and having a more mature immune system also help?

Now, Rodriguez-Barraquer et al. have followed more than 1,000 children living in places with high, moderate and low rates of malaria infection in Uganda. Over three years, regular blood samples were taken to see if the children were infected with P. falciparum. Mosquitoes were also collected from their houses to estimate how often the children were being bitten and infected. Using this information, Rodriguez-Barraquer et al. studied the different factors that affect how children develop anti-parasite and anti-disease immunity.

Both types of immunity develop differently in places with high, moderate and low rates of infection, so being infected multiple times is important. Yet, the findings also show that growing older itself contributes to the development of immunity regardless of how often a child is infected.

Children who get infected most often – in other words, those living in houses with the most mosquitoes – develop immunity faster than those who get infected at a moderate rate. Unexpectedly, however, children living in places with low rates of infection also develop immunity faster than those living in places with moderate rates.

Understanding how children acquire immunity to malaria is important for people trying to control the disease. These results suggest that reducing rates of infection to very low levels may not interfere with development of immunity and may even improve it. However, future research should see if these findings apply to other parts of the world as well, and, if so, why children develop immunity faster in places with lower rates of malaria infection.

The last decades have seen substantial declines in malaria transmission in sub-Saharan Africa that are largely attributable to increased access to effective control measures, including insecticide-treated bednets, indoor residual spraying of insecticide and artemisinin-based combination therapy (Bhatt et al., 2015; World Health Organization, 2016). In settings where transmission has been low, increased access to effective control interventions opens the possibility for malaria elimination. In highly endemic settings, however, there are concerns around the potential impact of failing to sustain interventions that reduce but do not stop transmission. Short-term decreases in malaria incidence due to reductions in transmission could be offset over time by reductions in population immunity to malaria resulting from lower exposure to parasites (Filipe et al., 2007; Smith et al., 2001; Snow et al., 1997).

Gradual acquisition of immunity against symptomatic malaria (also referred to as clinical immunity) is a key driver of the epidemiology of malaria in endemic settings, where the incidence of disease typically peaks in early childhood and then declines, while the prevalence of detectable asymptomatic parasitemia increases throughout childhood before declining in adulthood (Griffin et al., 2015; Reyburn et al., 2005; Okiro et al., 2009; Carneiro et al., 2010; Idro et al., 2006; Roca-Feltrer et al., 2010; Rodriguez-Barraquer et al., 2016). While these epidemiologic patterns have been described across the transmission spectrum, there are still many fundamental gaps in our understanding of the factors driving the development of immunity, and of the independent roles of age and repeated infection. One reason it has been challenging to study immunity to malaria is that there are currently no agreed upon reliable and quantifiable immune correlates of protection that can be measured in epidemiological studies (Valletta and Recker, 2017; Fowkes et al., 2010). In addition, there are few available datasets that include both detailed clinical data and independent metrics of exposure at the individual level.

Here, we use data from three parallel cohort studies conducted across the spectrum of malaria transmission in Uganda to model and quantify the development of immunity against symptomatic malaria as a function of transmission intensity and age. A key strength of these studies is that they involved detailed clinical and entomological surveillance of all study households. We focus on two specific types of immunity: anti-parasite immunity (i.e. the ability to control parasite densities upon infection) and anti-disease immunity (i.e. the ability to tolerate higher parasite infections without developing objective fever), as they have been described as independent components of clinical immunity (Struik and Riley, 2004).

The three cohorts enrolled a total of 1021 children aged 6 months to 10 years from 331 randomly chosen households across the three study sites. This analysis was limited to data from 773 children who experienced at least one patent P. falciparum infection between August 2011 and November 2014. Table 1 summarizes the general characteristics of the participants included in this analysis.

Participants living in Nagongera experienced the highest incidences of symptomatic malaria (median 2.6 episodes per person year), followed by those living in Kihihi (median 1.6 episodes per person year) and Walukuba (median 0.6 episodes per person year) (Table 1 and Figure 1). These incidences were consistent with results from monthly entomological surveys conducted in all cohort households, with significantly higher annual entomological inoculation rates (aEIR) recorded in Nagongera (median 51 infectious bites per year, range 10–582) as compared to Kihihi (median 8 infectious bites per year, range 4–47) and Walukuba (median 2 infectious bites per year, range 1–8). Interestingly, prevalence of asymptomatic parasitemia did not follow this same relationship; the prevalence of asymptomatic parasitemia was highest in Nagongera, and prevalences in the lower transmission sites were similar.

Figure 1

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aEIR as a metric of individual exposure

To assess whether entomological metrics were a good indicator of individual exposure to P. falciparum, we correlated the measured annual EIRs (aEIR) for each household (Figure 2a) with estimates of the average individual hazard of infection (Figure 2b). Individual hazards were estimated by fitting time-to-event models to the incidence data from each site. We found a significant correlation between these two independent metrics of exposure across sites (R² = 0.47, p<0.001). aEIR explained less of the variance between individuals within each site: Nagongera (R² = 0.03, p=0.004); Kihihi (R² = 0.12, p<0.001); Walukuba (0.01, p=0.05).

Figure 2

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Anti-parasite immunity

Parasite densities developed upon infection decreased with increasing age in all settings and for both symptomatic (passive detection) and asymptomatic (detected during routine visits) infections. Despite the large variability in parasite densities recorded within and between individuals, this trend is evident in the raw data (Figure 3a). A trend toward lower parasite densities was also observed among individuals living in settings with higher aEIRs (Nagongera), as compared to settings with lower aEIR (Kihihi and Walukuba).

Figure 3

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We considered multiple candidate models to describe the association between parasite density, age and aEIR (Appendix 1). Models allowing smooth (non-linear) relationships with aEIR best fit the data. Models allowing for two-way interactions between age and aEIR also outperformed models that did not include interactions.

In moderate and high transmission settings (households with aEIR >5), increasing age and increasing exposure were independently and linearly associated with decreases in the parasite densities (Table 2). On average, parasite densities decreased by a factor of 0.76 (95%CI 0.75–0.77) for each additional year of age and by a factor of 0.73 (95%CI 0.70–0.76) for each two-fold increase in the aEIR. The relationship was less evident for the lower transmission households (aEIR <5). In these settings, there continued to be a decreasing (although smaller) association with age, but the expected parasite densities at any given age were equal or lower to those observed in the higher exposure (aEIR >10) settings.

Table 2

	All data	aEIR ≥ 5 (n = 5047)	aEIR < 5 (n = 593)
Anti-parasite immunity	Fold change in parasite density (95% CI)
Age (years)	0.78 (0.77, 0.79)	0.76 (0.75, 0.77)	0.87 (0.83, 0.90)
Log2 aEIR	0.82 (0.79, 0.84)	0.73 (0.69, 0.77)	1.92 (1.69, 2.15)
Anti-disease immunity*	Change in objective temperature C (95% CI)
Age (years)	−0.07 (–0.06, –0.08)	−0.08 (–0.07, –0.1)	−0.04 (–0.07, –0.01)
Log2 aEIR	−0.02 (–0.04, 0.0)	−0.07 (–0.05, –0.1)	0.27 (0.11, 0.44)
Overall immunity against symptomatic malaria	Odds ratio of symptomatic disease (95% CI)
Age (years)	0.78 (0.75, 0.82)	0.77 (0.74, 0.80)	0.90 (0.83, 0.99)
Log2 aEIR	0.91 (0.74, 1.13)	0.62 (0.48, 0.80)	3.83 (1.39, 10.6)

1. *Model adjusted as well for Log parasite density.

Figures 4a and 5a present the predicted parasite densities, as a function of age and aEIR, according to the best fitting model. While an individual aged 1 year exposed to an aEIR of 10 is expected to develop a parasite density of 14,610 parasites/μL (95% CI 5924–36,031 parasites/μL) upon infection, the expected parasite density goes down to 3237 parasites/μL (95% CI 1381–7586 parasites/μL) by age 10 years. In contrast, the expected parasite density in an individual living in a setting with aEIR of 150 will be similar at age 1 year (13,071 parasites/μL (95% CI 5256–32,503 parasites/μL)), but significantly lower by age 10 years (999 parasites/μL (95% CI 398–2508 parasites/μL)).

Figure 4

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Figure 5 with 13 supplements see all

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To test whether the observed associations with age could be explained by the cumulative exposure over a life time, we also fit models where, instead of adjusting for the aEIR, we adjusted for the cumulative number of infectious bites (i.e. the product of age and aEIR) (Figure 5—figure supplement 2). Results from these models are consistent with a smaller, yet independent effect of age on the development of anti-parasite immunity; for any given level of cumulative exposure, each additional year of life was associated with decreases in parasite densities by a factor of 0.82 (95%CI 0.81–0.85).

Anti-disease immunity

We define anti-disease immunity as the ability to tolerate a given parasite density without developing objective fever. Thus, we were interested in modeling temperatures recorded at specific parasite densities, as a function of age and aEIR. Consistent with models characterizing anti-parasite immunity, models including smooth effects and interactions fitted the data significantly better than simpler models.

As expected, we found a strong association between parasite densities and objective temperature (Figure 6—figure supplement 1). Increases in parasite densities above 1000 parasites/μL were associated with higher expected temperatures across ages and transmission settings. In addition, we found a negative association between objective temperature at a given parasite density and age (Figures 3b, 4b and 6). In moderate and high transmission settings (aEIR >5), the objective temperature at a given parasite density decreased on average by 0.08°C (95% CI 0.07–0.10°C) for each additional year of life (Table 2). Thus, while the expected temperature for a child aged 1 year living in a setting with aEIR of 10 with a parasite density of 40,000 would be 38.8°C (95% CI 38.5–39.2°C), the expected temperature would decrease to 37.6°C (95% CI 37.3–38.0°C) if the same child experienced the infection at age 10 years (Figures 4b and 6). This association was similar even when adjusting for cumulative exposure and for the differences in incidence of non-malarial fever across age-groups (Figure 5—figure supplement 5).

Figure 6 with 2 supplements see all

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Similar to the anti-parasite immunity results described above, the observed association between exposure level and anti-disease immunity was less evident than the association with age (Figures 3b, 4b and 6). For moderate and high transmission settings (aEIR 5 to 300), there was a linear negative association between objective temperature at a given parasite density and aEIR. The objective temperature decreased by 0.07°C (95% CI 0.05–0.10°C) for each two-fold increase in aEIR. However, the relationship did not follow this trend for lower transmission settings (Table 2). Children living in the lowest transmission settings (aEIR 1 to 5) appeared to tolerate higher parasite densities than children living in moderate transmission settings (aEIR 5 to 10).

As an alternative way to characterize anti-disease immunity, we used our best fitting model to predict the fever threshold, defined as the minimum parasite density associated with objective fever (temperature >38°C), across levels of age and aEIR (Figure 5b). This quantity is often referred to as the ‘pyrogenic density’. Results from this analysis show that, for settings with moderate and high transmission (aEIR >5), the fever threshold increases both with age and increasing exposure. Thus, while a 1-year-old child living in a setting with aEIR of 10 presenting with a parasite density as low as 3747 parasites/μL (95% CI 777–11,129 parasites/μL) will be expected to be febrile, children older than 6 years of age exposed to very high transmission (aEIR 150) might be afebrile even with parasite densities higher than 60,000 parasites/μL.

Overall immunity against symptomatic malaria

Finally, to characterize the association between age and aEIR on the overall risk of developing symptomatic malaria upon infection (i.e. the combined effect of anti-parasite and anti-disease immunity), we fit a series of models where the outcome of each independent microscopically detectable infection (i.e. symptomatic malaria or asymptomatic parasitemia) was modeled as a function of age and aEIR. Models allowing smooth relationships, with or without two-way interactions, fit the data equally well.

Results from this analysis are consistent with results from the anti-parasite and anti-disease models (Figure 7). While young children living in low transmission settings (aEIR = 5) develop symptomatic malaria in most their infections, the probability that an infection results in symptomatic malaria decreases as a function of age and exposure. The expected probability of symptomatic disease for a child aged 1 year living in a setting with aEIR of 50 is 0.92 (95% CI 0.79–0.97), but it decreases to 0.51 (95% CI 0.29–0.73) by age 10 years.

Figure 7 with 1 supplement see all

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Our findings illustrate how anti-parasite and anti-disease immunity develop gradually and in parallel, complementing each other in reducing the probability of experiencing symptomatic disease upon infection with P. falciparum. While anti-parasite immunity acts to restrict the parasite densities that develop upon each subsequent infection, anti-disease immunity increases the tolerance to high parasite densities. Thus, older children are less likely to develop symptomatic malaria upon infection both because they tolerate parasite densities better without developing fever, and because they are less likely to develop high parasite densities.

Our results indicate independent effects of age on the acquisition of both anti-parasite and anti-disease immunity. These independent age effects may reflect maturation of the immune system as well as other physiological changes that decrease the propensity to fever (Struik and Riley, 2004; Baird, 1998). Furthermore, our findings are consistent with independent effects of transmission intensity on the acquisition of these two types of immunity. While the results obtained for moderate and high transmission settings (aEIR >5) are consistent and expected, and suggest that immunity develops faster in settings where individuals get infected by P. falciparum more often, the results obtained for the lowest transmission settings are harder to reconcile. These results were largely driven by observations collected in the Walukuba site, and as such it is possible that site-specific characteristics may have driven them. Walukuba was previously a relatively high transmission rural area, but substantial decreases in transmission intensity have been observed since 2011, likely due to urbanization. While our sensitivity analyses suggested that differences in the prevalence of three well characterized host-genetic polymorphisms between sites do not explain these discrepant results, it is still possible that other unmeasured site-specific characteristics may have driven them. Lower complexity of infection coupled with lower parasite diversity in Walukuba, for example, could cause this difference, as developing an effective immune response against fewer parasite strains may be much easier than developing immunity against a more diverse pool (Hviid, 1998; Bull et al., 1998). Testing this hypothesis would require careful characterization of the complexity and diversity of infections in each of our cohort settings.

While site-specific characteristics may underlie the observed high levels of clinical immunity against malaria in the low transmission setting, it is also possible that this finding reflects biologically relevant differences in how immunity against malaria develops. For example, it has been hypothesized that immunity may develop optimally in individuals that are exposed at a low rate, and that more frequent infections may interfere with the development of robust immune responses (Wipasa et al., 2010; Langhorne et al., 2008). Answering this question will require further detailed studies across transmission settings, with careful characterization of both exposure and infection outcomes.

There are several limitations to this study. With a study design including routine visits every 3 months, we are likely to have missed several asymptomatic infections, particularly in the moderate and high transmission settings. Moreover, since infections were detected using microscopy, we were unable to detect sub-patent infections, and we lack knowledge about the genetic complexity of each infection. While it is possible that the expected values modeled here (expected parasite density and fever threshold) were biased by these sources of measurement error, sensitivity analyses suggest that the relationships observed were robust. Secondly, while we found an independent association between the average household aEIR and both anti-parasite and anti-disease immunity, it is not clear that this is the most relevant metric of exposure for the development of clinical immunity to malaria. Alternative metrics such as the number of discrete infections, the number of ‘strains’ seen or the total parasite-positive time might be more relevant, but require the collection of additional data, including more frequent sampling. Finally, while this study provides very detailed insight into how two types of clinical immunity to malaria develop in endemic settings as a function of age and repeated exposure, it says nothing about the duration of immunity.

Prior studies have tried to model the processes driving acquisition of clinical immunity against malaria. However, these models have been generally informed by aggregated epidemiological data (age-incidence and age-prevalence) which limits their capacity to isolate the contributions of age and repeated exposure (Filipe et al., 2007; Griffin et al., 2015, 2014). Our results quantify how anti-parasite and anti-disease immunity develop in children across the malaria transmission spectrum, and they support strong independent effect of age and a perhaps paradoxical effect of exposure. The methods proposed here to model anti-parasite and anti-disease immunity may also provide a framework to select individuals with immune and non-immune phenotypes for evaluations of immune correlates of protection.

All the data used for these analyses as well as the R code used to reproduce the main study findings are available at https://github.com/isabelrodbar/immunity (copy archived at https://github.com/elifesciences-publications/immunity). Complete data from the 3 cohort studies are available at the CliEpiDB website (https://clinepidb.org/ce/app/record/dataset/DS_0ad509829e).

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Author details

1. Isabel Rodriguez-Barraquer

   Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   For correspondence

   isabel.rodriguez-barraquer@ucsf.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6784-1021

2. Emmanuel Arinaitwe

   Infectious Diseases Research Collaboration, Kampala, Uganda

   Contribution

   Investigation, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

3. Prasanna Jagannathan

   Department of Medicine, Stanford University, Stanford, United States

   Contribution

   Formal analysis, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6305-758X

4. Moses R Kamya

   Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda

   Contribution

   Supervision, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

5. Phillip J Rosenthal

   Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, United States

   Contribution

   Conceptualization, Funding acquisition, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

6. John Rek

   Infectious Diseases Research Collaboration, Kampala, Uganda

   Contribution

   Supervision, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

7. Grant Dorsey

   Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, United States

   Contribution

   Conceptualization, Funding acquisition, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

8. Joaniter Nankabirwa

   Infectious Diseases Research Collaboration, Kampala, Uganda

   Contribution

   Investigation, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

9. Sarah G Staedke

   London School of Hygiene and Tropical Medicine, London, United Kingdom

   Contribution

   Supervision, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

10. Maxwell Kilama

    Infectious Diseases Research Collaboration, Kampala, Uganda

    Contribution

    Data curation, Investigation, Writing—review and editing

    Competing interests

    No competing interests declared

11. Chris Drakeley

    London School of Hygiene and Tropical Medicine, London, United Kingdom

    Contribution

    Conceptualization, Funding acquisition, Investigation, Writing—review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-4863-075X

12. Isaac Ssewanyana

    Infectious Diseases Research Collaboration, Kampala, Uganda

    Contribution

    Investigation, Writing—review and editing

    Competing interests

    No competing interests declared

13. David L Smith

    Institute of Health Metrics and Evaluation, University of Washington, Seattle, United States

    Contribution

    Conceptualization, Formal analysis, Writing—original draft

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-4367-3849

14. Bryan Greenhouse

    Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, United States

    Contribution

    Conceptualization, Formal analysis, Funding acquisition, Methodology, Writing—original draft, Writing—review and editing

    Competing interests

    No competing interests declared

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