Malaria: Age, exposure and immunity
The acquisition of immunity to malaria by an individual depends on their age and the number of infectious mosquito bites they have received.
- Institut Pasteur, France
- Mahidol University, Thailand
- University of Oxford, United Kingdom
In a league table of infectious diseases, malaria would rank above all others in how often it causes infections and the number of parasites in infected hosts. In areas that are particularly favourable for malaria transmission, a single person can be infected more than 1,000 times per year (Smith et al., 2005). Each infection can potentially lead to a fatal episode of severe malaria that sees up to a trillion parasites circulating in the host’s blood.
Although every new infection boosts immunity to further infections, this comes at a high price: in some areas malaria can kill up to 5% of children before their fifth birthday (Streatfield et al., 2014). Adults become immune more quickly than children, but are also more likely to die from severe malaria (Baird, 1998). It would be useful, therefore, to be able to quantify the rate at which an individual acquires immunity to malaria, and how this depends on their age and exposure. Now, in eLife, Isabel Rodriguez-Barraquer of the University of California, San Francisco and colleagues in the US, Uganda and the UK report how they have developed a new model that sheds light on these relationships (Rodriguez-Barraquer et al., 2018).
Rodriguez-Barraquer et al. looked at data from 773 children aged between six months and 10 years old in three Ugandan villages. Each child was monitored for up to three years in an attempt to understand the relationships between their age, how often they were infected, the number of parasites in their blood, and the number of parasites required to cause symptoms of malaria. A child was considered to have developed a case of clinical malaria if they had a body temperature above 38°C, and if the density of parasites in their blood was high enough to be seen under a microscope. Alongside clinical follow-up, there was an accompanying effort to catch mosquitoes in the children’s houses. This allowed exposure to be measured in terms of the number of infectious mosquito bites the children received per year.
The villages had varying levels of malaria, with children experiencing an average of 22 bites and two cases of clinical malaria every year (Kamya et al., 2015). There was also a lot of variation in the number of cases per child, with one child experiencing 30 incidents of malaria over the course of the study.
Rodriguez-Barraquer et al. analysed data on two aspects of immunity – anti-parasite immunity (which reduces the number of parasites in the blood) and anti-disease immunity (which is the ability to tolerate a given parasite density without developing fever; Figure 1). They found that older children had fewer parasites than younger children, and that frequently infected children had fewer parasites than the less frequently infected. They also found that older children were less likely to develop fever than young children, and that frequently infected children were less likely to develop fever than the less frequently infected. These linear relationships agree with our current understanding of malaria immunity based on decades of epidemiological studies (Doolan et al., 2009).
Figure 1
The network of factors used by Rodriguez-Barraquer et al. to model immunity to malaria.
Malaria develops in stages (progression shown by green arrows). First, a mosquito bite can lead to a low-level infection (which can only be detected by techniques such as PCR). Rodriguez-Barraquer et al. focused on high-density infections, where there are enough parasites in the blood to be viewed using microscopy. These infections can lead to clinical malaria, which produces a fever. Two forms of immunity can inhibit the progression of the disease (red lines): anti-parasite immunity reduces the density of blood-stage infections, and anti-disease immunity reduces the temperature caused by a given parasite density. The plots show how each type of immunity varies with age (left) and exposure (right) in the model developed by Rodriguez-Barraquer et al. Exposure is measured in terms of the number of infectious mosquito bites per year, which is also known as the annual entomological inoculation rate (aEIR).
The researchers then investigated the nonlinear relationships between age, transmission and the acquisition of immunity. They found that children in the villages with the lowest rates of malaria transmission (who received an average of two infectious bites a year) developed immunity more efficiently than children in villages with moderate transmission rates (who received three times more bites). The average child coming to the health clinic in the low transmission village had both a lower parasite density and a lower body temperature than their counterpart from the moderate transmission village.
This is a counter-intuitive but statistically robust finding. If replicated elsewhere, it has important implications. Traditionally it has been assumed that as transmission rates decline, so does immunity, presenting an obstacle to malaria control (Rogier et al., 1999). However, the new analysis suggests a more complex pattern, which Rodriguez-Barraquer et al. suggest could be due to the lower genetic diversity found among parasites in low-transmission situations. This could mean that individuals may acquire immunity to infection more efficiently as malaria transmission is reduced, thus aiding control efforts. More work is needed to check if this association is causal and is free of selection bias. Selection bias could arise if the way children’s parents seek treatment varies for different transmission intensities.
The latest analysis also suggests future avenues of research. Asymptomatic infections, and those that do not reach sufficiently high density to be seen under a microscope, could be detected using PCR (polymerase chain reaction) techniques. Exposure could be measured more accurately by using genotyping to count the number of parasite clones circulating in the host (Mueller et al., 2012). Measurements of anti-malarial antibody responses can also be used as markers of both exposure to the disease and protection from it (França et al., 2017).
Levels of immunity are not just dependent on age and exposure, but also on the cumulative number of episodes of clinical malaria that an individual has experienced (Rodriguez-Barraquer et al., 2016). Other data sources may shed light on this problem. An ideal target would be to identify combinations of immune responses that allow immunity to be quantified independently of age and exposure to the malaria parasites.
References
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Acquired immunity to malariaClinical Microbiology Reviews 22:13–36.https://doi.org/10.1128/CMR.00025-08
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Malaria transmission, infection, and disease at three sites with varied transmission intensity in Uganda: implications for malaria controlAmerican Journal of Tropical Medicine and Hygiene 92:903–912.https://doi.org/10.4269/ajtmh.14-0312
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Quantifying heterogeneous malaria exposure and clinical protection in a cohort of Ugandan childrenJournal of Infectious Diseases 214:1072–1080.https://doi.org/10.1093/infdis/jiw301
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Plasmodium falciparum clinical malaria: lessons from longitudinal studies in SenegalParassitologia 41:255–259.
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- Version of Record published: August 21, 2018 (version 1)
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© 2018, White et al.
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Malaria: Age, exposure and immunity
eLife 7:e40150.
https://doi.org/10.7554/eLife.40150
Further reading
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- Epidemiology and Global Health
Background:
The Zanzibar archipelago of Tanzania has become a low-transmission area for Plasmodium falciparum. Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania and continued local transmission.
Methods:
To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 282 P. falciparum isolates collected across Zanzibar and in Bagamoyo district on the coastal mainland from 2016 to 2018.
Results:
Overall, parasite populations on the coastal mainland and Zanzibar archipelago remain highly related. However, parasite isolates from Zanzibar exhibit population microstructure due to the rapid decay of parasite relatedness over very short distances. This, along with highly related pairs within shehias, suggests ongoing low-level local transmission. We also identified highly related parasites across shehias that reflect human mobility on the main island of Unguja and identified a cluster of highly related parasites, suggestive of an outbreak, in the Micheweni district on Pemba island. Parasites in asymptomatic infections demonstrated higher complexity of infection than those in symptomatic infections, but have similar core genomes.
Conclusions:
Our data support importation as a main source of genetic diversity and contribution to the parasite population in Zanzibar, but they also show local outbreak clusters where targeted interventions are essential to block local transmission. These results highlight the need for preventive measures against imported malaria and enhanced control measures in areas that remain receptive to malaria reemergence due to susceptible hosts and competent vectors.
Funding:
This research was funded by the National Institutes of Health, grants R01AI121558, R01AI137395, R01AI155730, F30AI143172, and K24AI134990. Funding was also contributed from the Swedish Research Council, Erling-Persson Family Foundation, and the Yang Fund. RV acknowledges funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 program supported by the European Union. RV also acknowledges funding by Community Jameel.
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Background: Few national-level studies have evaluated the impact of 'hybrid' immunity (vaccination coupled with recovery from infection) from the Omicron variants of SARS-CoV-2.
Methods: From May 2020 to December 2022, we conducted serial assessments (each of ~4000-9000 adults) examining SARS-CoV-2 antibodies within a mostly representative Canadian cohort drawn from a national online polling platform. Adults, most of whom were vaccinated, reported viral test-confirmed infections and mailed self-collected dried blood spots to a central lab. Samples underwent highly sensitive and specific antibody assays to spike and nucleocapsid protein antigens, the latter triggered only by infection. We estimated cumulative SARS-CoV-2 incidence prior to the Omicron period and during the BA.1/1.1 and BA.2/5 waves. We assessed changes in antibody levels and in age-specific active immunity levels.
Results: Spike levels were higher in infected than in uninfected adults, regardless of vaccination doses. Among adults vaccinated at least thrice and infected more than six months earlier, spike levels fell notably and continuously for the nine months post-vaccination. By contrast, among adults infected within six months, spike levels declined gradually. Declines were similar by sex, age group, and ethnicity. Recent vaccination attenuated declines in spike levels from older infections. In a convenience sample, spike antibody and cellular responses were correlated. Near the end of 2022, about 35% of adults above age 60 had their last vaccine dose more than six months ago, and about 25% remained uninfected. The cumulative incidence of SARS-CoV-2 infection rose from 13% (95% CI 11-14%) before omicron to 78% (76-80%) by December 2022, equating to 25 million infected adults cumulatively. However, the COVID-19 weekly death rate during the BA.2/5 waves was less than half of that during the BA.1/1.1 wave, implying a protective role for hybrid immunity.
Conclusions: Strategies to maintain population-level hybrid immunity require up-to-date vaccination coverage, including among those recovering from infection. Population-based, self-collected dried blood spots are a practicable biological surveillance platform.
Funding: Funding was provided by the COVID-19 Immunity Task Force, Canadian Institutes of Health Research, Pfizer Global Medical Grants, and St. Michael's Hospital Foundation. PJ and ACG are funded by the Canada Research Chairs Program.
