Abstract
Identification of correlates of protection for infectious diseases including malaria is a major challenge and has become one of the main obstacles in developing effective vaccines. We investigated protection against liver-stage malaria conferred by vaccination with adenoviral and Modified Vaccinia Ankara (MVA) vectors expressing pre-erythrocytic malaria antigens. By classifying CD8
+
T cells into effector (T
E
), effector/memory (T
EM
) and central memory (T
CM
) subsets using CD62L and CD127 markers, we found striking differences in T cell memory generation. While MVA induced accelerated T
CM
generation, which could be efficiently boosted by subsequent adenoviral administration, it failed to protect against malaria. In contrast, adenoviral (Ad) vectors, which permit persistent antigen delivery, elicit a prolonged T
E
and T
EM
response that requires long intervals for an efficient boost. A preferential T
EM
phenotype was maintained in liver, blood and spleen following Ad/MVA prime-boost regimens and animals were protected against malaria sporozoite challenge. Blood CD8
+
T
EM
cells correlated with protection against malaria liver-stage infection, assessed by estimation of number of parasites emerging from the liver into the blood. The protective ability of antigen-specific T
EM
cells was confirmed by transfer experiments into naive recipient mice. Thus, we identify persistent CD8 T
EM
populations as essential for vaccine-induced pre-erythrocytic protection against malaria, a finding that has important implications for logical vaccine design.