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 (TE/EM) and/or central memory (TCM) 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 TE/EM and TCM 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+ TE/EM cells and of CD4+ TCM 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+ TE/EM cells and of CD4+ TE/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 TE/EM and TCM cells are major producers of IL-2.

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

“…Selective depletion of different immune cell populations indicated that control of blood-stage infection is dependent on CD4 T cells, which can reduce parasitemia and promote host survival (3)(4)(5)(6)(7). The ability of Plasmodium-specific memory CD4 T cells to develop and be maintained in the host appears to be altered during malaria (8,9), and this phenomenon likely contributes to the lack of a long-term, sterilizing immunity.…”

Evaluation of the immune response to RTS,S/AS01 and RTS,S/AS02 adjuvanted vaccines

“…11 In that study, vaccine efficacy against malaria challenge was 50% with RTS,S/AS01 and 32% with RTS,S/ AS02, and significant correlations were found between protection against malaria challenge and both CS-specific antibody responses and CMI responses induced by the RTS,S vaccine. 7,11 CD4 + T cells predominantly expressed CD40L, a co-stimulatory ligand required for T cell help that also induces the differentiation of B cells, 18,19 and IL-2, a cytokine associated with memory T cells and T cell proliferation and differentiation. 20 There was also a strong association between the frequency of IL-2 producing CD4 + T cells and titers of CS-specific antibodies in the same individual, suggesting that IL-2 may contribute to protection by promoting both cellular and humoral responses.…”

“…20 There was also a strong association between the frequency of IL-2 producing CD4 + T cells and titers of CS-specific antibodies in the same individual, suggesting that IL-2 may contribute to protection by promoting both cellular and humoral responses. 7 Methods available at the time of the study, however, did not allow for a phenotypic analysis of the CS CD4 + T cell data. Induction of CD4 + T cells directed against P. falciparum CS protein by RTS,S adjuvanted formulations has been shown in clinical field trials in adults and children.…”

“…3,4 Anti-CS antibody titers and, to a lesser extent, CS-specific CD4 + T cells elicited by RTS,S have been identified as immunological markers associated with protection. [5][6][7] CS-specific CD4 + T cells induced by RTS,S produce a mixture of cytokines, such as interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. [7][8][9][10][11] In phase 2 clinical trials of adults and children, the RTS,S/AS01 formulation had an improved immunogenicity profile, in terms of humoral and cell-mediated immune (CMI) responses, and an equally favorable safety profile as compared with RTS,S/AS02.…”

“…[5][6][7] CS-specific CD4 + T cells induced by RTS,S produce a mixture of cytokines, such as interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. [7][8][9][10][11] In phase 2 clinical trials of adults and children, the RTS,S/AS01 formulation had an improved immunogenicity profile, in terms of humoral and cell-mediated immune (CMI) responses, and an equally favorable safety profile as compared with RTS,S/AS02. [11][12][13][14] The RTS,S/AS01 formulation was…”