An effective malaria vaccine is urgently needed, but progress toward this goal has been hindered by our limited understanding of the mechanisms underlying immunity to malaria and a lack of reliable in vitro correlates of protection. It has recently been shown that protective immunity to malaria can be achieved by experimental infection with viable sporozoites under cover of antimalarial drugs that eradicate blood-stage parasites but allow the pre-erythrocytic parasite stages to develop. This regimen induces CD4 T cells that produce IL-2, TNF?, and IFN? and results in sterile protection from homologous challenge that persists for at least 2 years. In the prior funding period, we tested the hypothesis that chemoprevention coupled with natural exposure to malaria could yield similar protection when given to children in a high endemnicity setting, leveraging a randomized trial of monthly dihydroartemisinin-piperaquine (DP) chemoprevention given to young children in Uganda. We found that children highly adherent to monthly DP exhibited sustained protection against naturally occurring malaria strains during one year of follow-up after the intervention ended. Children randomized to DP developed higher frequencies of malaria-specific CD4 T cells co-producing IL-2/TNF?, which were associated with prospective protection, and lower frequencies of CD4 cells co-producing IL10/IFN?, which were associated with increased risk. These data suggest that the functional quality of the CD4 T cell response is influenced by chemoprevention and is a critical determinant of protective immunity. In the renewal period, we wish to more fully characterize the functional, phenotypic, and transcriptional differences in T cell responses associated with protection by leveraging samples and data from a new trial, currently underway, in which pregnant women and their infants are randomized to receive monthly DP chemoprevention during pregnancy and the first 2 years of life. We will assess how chronic malaria antigen exposure impacts both CD4 T cells and V?2+ ?? T cells, a semi-innate lymphocyte population with intrinsic reactivity to malaria antigens. In the first aim, we will characterize CD4 T cell responses associated with protection from malaria in children receiving monthly DP chemoprevention, and determine how the phenotype, function, and transcriptional program of malaria-specific CD4 cells is impacted by chronic malaria antigen exposure. In the second aim, we will determine how malaria exposure impacts the V?9V?2 T cell population, including their frequency, differentiation status, clonotype composition, and expression of activating and inhibitory NK receptors (NKRs). We will also examine the impact of NKR expression on functional responsiveness to malaria antigens. In the third aim, we will measure associations between malaria-specific T cell responses (CD4 and V?9V?2) and protection from P. falciparum parasitemia and symptomatic malaria. These studies will address fundamental gaps in our understanding of the cellular and molecular mechanisms underlying protective immunity to malaria, and could provide a strong public health rationale for implementing malaria chemoprevention during pregnancy or early infancy.

Public Health Relevance

Malaria is a leading killer of children worldwide, but efforts to develop a preventive vaccine have failed due to our limited understanding of the immune response to infection. We will perform detailed longitudinal studies of the immune response to malaria in Ugandan infants participating in a chemoprevention trial, as well as cross- sectional studies of Ugandan adults and children from high and low malaria transmission settings. The resulting data will be analyzed to identify correlates of prospective protection from malaria, which can be used to guide malaria vaccine design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093615-07
Application #
9217550
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Wali, Tonu M
Project Start
2011-03-15
Project End
2021-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
7
Fiscal Year
2017
Total Cost
$658,721
Indirect Cost
$205,256
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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
Kakuru, Abel; Jagannathan, Prasanna; Muhindo, Mary K et al. (2016) Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. N Engl J Med 374:928-39
Farrington, Lila A; Jagannathan, Prasanna; McIntyre, Tara I et al. (2016) Frequent Malaria Drives Progressive Vδ2 T-Cell Loss, Dysfunction, and CD16 Up-regulation During Early Childhood. J Infect Dis 213:1483-90
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
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
Boyle, Michelle J; Jagannathan, Prasanna; Bowen, Katherine et al. (2015) Effector Phenotype of Plasmodium falciparum-Specific CD4+ T Cells Is Influenced by Both Age and Transmission Intensity in Naturally Exposed Populations. J Infect Dis 212:416-25
Jagannathan, Prasanna; Nankya, Felistas; Stoyanov, Cristina et al. (2015) IFNγ Responses to Pre-erythrocytic and Blood-stage Malaria Antigens Exhibit Differential Associations With Past Exposure and Subsequent Protection. J Infect Dis 211:1987-96
Boyle, Michelle J; Jagannathan, Prasanna; Farrington, Lila A et al. (2015) Decline of FoxP3+ Regulatory CD4 T Cells in Peripheral Blood of Children Heavily Exposed to Malaria. PLoS Pathog 11:e1005041
Sullivan, Richard T; Kim, Charles C; Fontana, Mary F et al. (2015) FCRL5 Delineates Functionally Impaired Memory B Cells Associated with Plasmodium falciparum Exposure. PLoS Pathog 11:e1004894

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