title: Protective immunity induced with the RTS,S/AS vaccine is associated with IL-2 and TNF-α producing effector and central memory CD4 T cells.
abstract: A phase 2a RTS,S/AS malaria vaccine trial, conducted previously at the Walter Reed Army Institute of Research, conferred sterile immunity against a primary challenge with infectious sporozoites in 40% of the 80 subjects enrolled in the study. The frequency of Plasmodium falciparum circumsporozoite protein (CSP)-specific CD4(+) T cells was significantly higher in protected subjects as compared to non-protected subjects. Intrigued by these unique vaccine-related correlates of protection, in the present study we asked whether RTS,S also induced effector/effector memory (T(E/EM)) and/or central memory (T(CM)) CD4(+) T cells and whether one or both of these sub-populations is the primary source of cytokine production. We showed for the first time that PBMC from malaria-non-exposed RTS,S-immunized subjects contain both T(E/EM) and T(CM) cells that generate strong IL-2 responses following re-stimulation in vitro with CSP peptides. Moreover, both the frequencies and the total numbers of IL-2-producing CD4(+) T(E/EM) cells and of CD4(+) T(CM) cells from protected subjects were significantly higher than those from non-protected subjects. We also demonstrated for the first time that there is a strong association between the frequency of CSP peptide-reactive CD4(+) T cells producing IL-2 and the titers of CSP-specific antibodies in the same individual, suggesting that IL-2 may be acting as a growth factor for follicular Th cells and/or B cells. The frequencies of CSP peptide-reactive, TNF-α-producing CD4(+) T(E/EM) cells and of CD4(+) T(E/EM) cells secreting both IL-2 and TNF-α were also shown to be higher in protected vs. non-protected individuals. We have, therefore, demonstrated that in addition to TNF-α, IL-2 is also a significant contributing factor to RTS,S/AS vaccine induced immunity and that both T(E/EM) and T(CM) cells are major producers of IL-2.
authors.affiliation: Division of Malaria Vaccine Development, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Lumsden
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwenk
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Rein
authors.forename: Philippe
authors.initials: P
authors.lastname: Moris
authors.forename: Michel
authors.initials: M
authors.lastname: Janssens
authors.forename: Opokua
authors.initials: O
authors.lastname: Ofori-Anyinam
authors.forename: Joe
authors.initials: J
authors.lastname: Cohen
authors.forename: Kent E
authors.initials: KE
authors.lastname: Kester
authors.forename: D Gray
authors.initials: DG
authors.lastname: Heppner
authors.forename: Urszula
authors.initials: U
authors.lastname: Krzych
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D017780:Malaria Vaccines / Q000276:immunology* / Q000627:therapeutic use; D008297:Male; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D017780:Malaria Vaccines; D014409:Tumor Necrosis Factor-alpha