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

TLDR

The study investigated whether RTS,S vaccination induces effector/effector memory and/or central memory CD4+ T cells as the primary source of cytokine production. PBMCs from RTS,S‑immunized, malaria‑naïve subjects were re‑stimulated with CSP peptides in vitro to quantify IL‑2–producing effector/effector memory and central memory CD4+ T cells. RTS,S vaccination elicited IL‑2–producing effector/effector memory and central memory CD4+ T cells that were more frequent and abundant in protected individuals, and IL‑2 levels correlated with CSP‑specific antibody titers, indicating that IL‑2 and TNF‑α from these cells contribute to vaccine‑induced protection.

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.