Each year, malaria claims the lives of over a million individuals, mostly young children. An effective malaria vaccine is urgently needed, but progress toward this goal has been hindered by our limited understanding of the mechanisms underlying natural immunity to malaria and a lack of reliable in vitro correlates of protection. Data from both human and animal experiments offer hope that vaccine-mediated induction of immunity to malaria is achievable. Infection with irradiated sporozoites, which arrest development during the liver stage, confers sterile protective immunity in humans, suggesting an important role for the T cell response to pre-erythrocytic antigens. Importantly, studies in mice and more recently in humans demonstrate that similar protection is conferred by non-attenuated parasites when given under cover of chloroquine, which prevents blood stage malaria but does not impact the liver stage. Together these data indicate that limiting exposure to blood stage infection may actually enhance the development of immune responses to pre-erythrocytic stages, perhaps by avoiding the immunosuppressive mechanisms induced by parasitemia. The proposed study will leverage samples to be collected as part of a randomized clinical trial based in Tororo, Uganda that will compare the efficacy and safety of 3 promising malaria chemopreventive strategies with the current standard of no chemoprevention. This trial provides a unique opportunity to study the impact of chemoprevention, which uncouples liver-stage and blood-stage malaria, on the malaria-specific immune response to natural infection among infants in a high transmission setting. We will test the hypothesis that selective suppression of erythrocytic stage malaria by chemoprevention will enhance the development of highly functional T cell responses targeting pre-erythrocytic antigens and limit the induction of immunosuppressive mechanisms, and will thus foster the development of protective antimalarial immunity. In the first aim, we will prospectively evaluate the impact of potent chemoprevention on the development of the adaptive T cell response to P. falciparum during infancy. The frequency, breadth, and functional attributes of CD4 and CD8 T cells targeting pre-erythrocytic and erythrocytic stage P. falciparum antigens will be compared longitudinally between children randomized to receive chemoprevention vs. no intervention. In the second aim, we will assess the impact of recurrent parasitemia on the development of immune suppressor mechanisms and T cell dysfunction. We hypothesize that immune regulatory mechanisms, including Foxp3+ regulatory CD4 T cells, are induced by parasitemia and interfere with the establishment of effective, durable malaria-specific T cell responses that are necessary for protective immunity. In the third aim, we will determine whether malaria-specific T cell responses and/or immune suppressor mechanisms are associated with prospective protection from malaria following cessation of chemoprevention, following adjustment for epidemiologic covariates of exposure. These studies will greatly enhance our understanding of the acquisition of natural immunity to malaria in infancy.

Public Health Relevance

Malaria is a leading killer of children worldwide, but efforts to develop a preventive vaccine have failed due to our poor understanding of the immune response to infection by malaria parasites. We will perform detailed longitudinal studies of the immune response to malaria in Ugandan infants participating in a clinical trial of chemoprevention strategies. The immune responses of children receiving chemoprevention, which prevents blood-stage but not liver-stage malaria, will be compared to children who do not receive chemoprevention, and these immune parameters will be correlated with prospective protection from clinical malaria following cessation of chemoprevention

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Wali, Tonu M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
Zip Code
Odorizzi, Pamela M; Jagannathan, Prasanna; McIntyre, Tara I et al. (2018) In utero priming of highly functional effector T cell responses to human malaria. Sci Transl Med 10:
Prahl, Mary; Jagannathan, Prasanna; McIntyre, Tara I et al. (2017) Sex Disparity in Cord Blood FoxP3+ CD4 T Regulatory Cells in Infants Exposed to Malaria In Utero. Open Forum Infect Dis 4:ofx022
Jagannathan, Prasanna; Lutwama, Fredrick; Boyle, Michelle J et al. (2017) V?2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure. Sci Rep 7:11487
Farrington, Lila; Vance, Hilary; Rek, John et al. (2017) Both inflammatory and regulatory cytokine responses to malaria are blunted with increasing age in highly exposed children. Malar J 16:499
Boyle, Michelle J; Jagannathan, Prasanna; Bowen, Katherine et al. (2017) The Development of Plasmodium falciparum-Specific IL10 CD4 T Cells and Protection from Malaria in Children in an Area of High Malaria Transmission. Front Immunol 8:1329
Prahl, Mary; Jagannathan, Prasanna; McIntyre, Tara I et al. (2016) Timing of in utero malaria exposure influences fetal CD4 T cell regulatory versus effector differentiation. Malar J 15:497
Jagannathan, Prasanna; Bowen, Katherine; Nankya, Felistas et al. (2016) Effective Antimalarial Chemoprevention in Childhood Enhances the Quality of CD4+ T Cells and Limits Their Production of Immunoregulatory Interleukin 10. J Infect Dis 214:329-38
Sullivan, Richard T; Ssewanyana, Isaac; Wamala, Samuel et al. (2016) B cell sub-types following acute malaria and associations with clinical immunity. Malar J 15:139
Odorizzi, Pamela M; Feeney, Margaret E (2016) Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity. Trends Mol Med 22:877-888
Farrington, Lila A; Jagannathan, Prasanna; McIntyre, Tara I et al. (2016) Frequent Malaria Drives Progressive V?2 T-Cell Loss, Dysfunction, and CD16 Up-regulation During Early Childhood. J Infect Dis 213:1483-90

Showing the most recent 10 out of 17 publications