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

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-alpha-producing CD4(+) T-E/EM cells and of CD4(+) T-E/EM cells secreting both IL-2 and TNF-alpha were also shown to be higher in protected vs. non-protected individuals. We have, therefore, demonstrated that in addition to TNF-alpha, 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.