Induction in Humans of CD8+ and CD4+ T Cell and Antibody Responses by Sequential Immunization with Malaria DNA and Recombinant Protein

Abstract

Vaccine-induced protection against diseases like malaria, AIDS, and cancer may require induction of Ag-specific CD8+ and CD4+ T cell and Ab responses in the same individual. In humans, a recombinant Plasmodium falciparum circumsporozoite protein (PfCSP) candidate vaccine, RTS,S/adjuvant system number 2A (AS02A), induces T cells and Abs, but no measurable CD8+ T cells by CTL or short-term (ex vivo) IFN-γ ELISPOT assays, and partial short-term protection. P. falciparum DNA vaccines elicit CD8+ T cells by these assays, but no protection. We report that sequential immunization with a PfCSP DNA vaccine and RTS,S/AS02A induced PfCSP-specific Abs and Th1 CD4+ T cells, and CD8+ cytotoxic and Tc1 T cells. Depending upon the immunization regime, CD4+ T cells were involved in both the induction and production phases of PfCSP-specific IFN-γ responses, whereas, CD8+ T cells were involved only in the production phase. IFN-γ mRNA up-regulation was detected in both CD45RA− (CD45RO+) and CD45RA+CD4+ and CD8+ T cell populations after stimulation with PfCSP peptides. This finding suggests CD45RA+ cells function as effector T cells. The induction in humans of the three primary Ag-specific adaptive immune responses establishes a strategy for developing immunization regimens against diseases in desperate need of vaccines.

Development, Characterization and Immunogenicity of a Multi-Stage, MultivalentPlasmodium falciparumVaccine Antigen (FALVAC-1A) Expressed inEscherichia coli

“…14 Recently a number of multi-antigen vaccines have entered development. [10][11][12]15 Multi-antigen vaccines are intended to induce immunity to several antigens on a given parasite stage, or against different stages of malaria, and thus to increase the chances of preventing infection and/or disease. Another advantage is the ability to include combinations of epitopes intended to work together to minimize the inherent genetic restrictions of human immune responses, while maximizing human reactivity to genetically diverse P. falciparum populations.…”

Gene therapy progress and prospects: the skin – easily accessible, but still far away

“…Nevertheless, sequential immunization with malaria DNA followed by boosting with recombinant protein has led to the induction of CD8+ and CD4+ T cell and antibody responses in human volunteers. 44 The CD8+ T cells of the CD45RA (naïve) phenotype seemed to act as effector T cells. Thus, this immunization strategy has proven the concept of DNA priming and protein boosting in humans.…”

PATH Malaria Vaccine Initiative (MVI): Perspectives on the status of malaria vaccine development

“…5,7,8 High-titer anti-CSP antibodies have been associated with protection in the controlled challenge model and in semi-immune adults in field studies, 5, 9, 10 but not in African children. 11 Polyfunctional CD4+ T cells have been positively linked to protection from infection in the challenge model in both the presence and absence of high titers of anti-CSP antibodies.…”