Quantification of anti-parasite and anti-disease immunity to malaria as a function of age and exposure
- University of California, San Francisco, United States
- Infectious Diseases Research Collaboration, Uganda
- Stanford University, United States
- Makerere University College of Health Sciences, Uganda
- Infectious Diseases Resarch Collaboration, Uganda
- London School of Hygiene and Tropical Medicine, United Kingdom
- University of Washington, United States
Abstract
Fundamental gaps remain in our understanding of how immunity to malaria develops. We used detailed clinical and entomological data from parallel cohort studies conducted across the malaria transmission spectrum in Uganda to quantify the development of immunity against symptomatic P. falciparum as a function of age and transmission intensity. We focus on: anti-parasite immunity (i.e; ability to control parasite densities) and anti-disease immunity (i.e; ability to tolerate higher parasite densities without fever). Our findings suggest a strong effect of age on both types of immunity, not explained by cumulative-exposure. They also show an independent effect of exposure, where children living in moderate/high transmission settings develop immunity faster as transmission increases. Surprisingly, children in the lowest transmission setting appear to develop immunity more efficiently than those living in moderate transmission settings. Anti-parasite and anti-disease immunity develop in parallel, reducing the probability of experiencing symptomatic malaria upon each subsequent P. falciparum infection.
Data availability
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. Complete data from the 3 cohort studies are available at the CliEpiDB website (https://clinepidb.org/ce/app/record/dataset/DS_0ad509829e).
Article and author information
Author details
Isabel Rodriguez-Barraquer
Prasanna Jagannathan
Funding
National Institutes of Health (2U19AI089674)
- Isabel Rodriguez-Barraquer
- Emmanuel Arinaitwe
- Prasanna Jagannathan
- Moses R Kamya
- Phillip J Rosenthal
- John Rek
- Grant Dorsey
- Joaniter Nankabirwa
- Sarah G Staedke
- Maxwell Kilama
- Chris Drakeley
- Isaac Ssewanyana
- David L Smith
- Bryan Greenhouse
Bill and Melinda Gates Foundation (OPP1110495)
- David L Smith
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ben Cooper, Mahidol Oxford Tropical Medicine Research Unit, Thailand
Ethics
Human subjects: The study protocol was reviewed and approved by the Makerere University School of Medicine Research and Ethics Committee (Identification numbers 2011-149 and 2011-167, the Uganda National Council for Science and Technology, , the London School of Hygiene and Tropical Medicine Ethics Committee (Identification numbers 5943 and 5944), the Durham University School of Biological and Biomedical Sciences Ethics Committee (PRISM Entomology Uganda), and the University of California, San Francisco, Committee on Human Research (Identification numbers 11-05539 and 11-05995) and the Uganda National Council for Science and Technology (Identification numbers HS350 and HS-1019).. All parents/guardians were asked to provide written informed consent at the time of enrollment.
Version history
- Received: February 10, 2018
- Accepted: July 15, 2018
- Accepted Manuscript published: July 25, 2018 (version 1)
- Version of Record published: August 21, 2018 (version 2)
Copyright
© 2018, Rodriguez-Barraquer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Quantification of anti-parasite and anti-disease immunity to malaria as a function of age and exposure
eLife 7:e35832.
https://doi.org/10.7554/eLife.35832
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.
