Poly(I:C) is an effective adjuvant for antibody and multi-functional CD4+ T cell responses to Plasmodium falciparum circumsporozoite protein (CSP) and αDEC-CSP in non human primates

Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
Vaccine (Impact Factor: 3.62). 10/2010; 28(45):7256-66. DOI: 10.1016/j.vaccine.2010.08.098
Source: PubMed


Development of a fully effective vaccine against the pre-erythrocytic stage of malaria infection will likely require induction of both humoral and cellular immune responses. Protein based vaccines can elicit such broad-based immunity depending on the adjuvant and how the protein is formulated. Here to assess these variables, non human primates (NHP) were immunized three times with Plasmodium falciparum (Pf) circumsporozoite protein (CSP) or CSP cloned into MG38, a monoclonal antibody that targets DEC-205 (αDEC-CSP), an endocytic receptor on dendritic cells (DCs). Both vaccines were administered with or without poly(I:C) as adjuvant. Following three immunizations, the magnitude and quality of cytokine secreting CD4+ T cells were comparable between CSP+poly(I:C) and αDEC-CSP+poly(I:C) groups with both regimens eliciting multi-functional cytokine responses. However, NHP immunized with CSP+poly(I:C) had significantly higher serum titers of CSP-specific IgG antibodies and indirect immunofluorescent antibody (IFA) titers against Pf sporozoites. Furthermore, sera from both CSP or αDEC-CSP+poly(I:C) immunized animals limited sporozoite invasion of a hepatocyte cell line (HC04) in vitro. To determine whether CSP-specific responses could be enhanced, all NHP primed with CSP or αDEC-CSP+poly(I:C) were boosted with a single dose of 150,000 irradiated Pf sporozoites (PfSPZ) intravenously. Remarkably, boosting had no effect on the CSP-specific immunity. Finally, immunization with CSP+poly-ICLC reduced malaria parasite burden in the liver in an experimental mouse model. Taken together, these data showing that poly(I:C) is an effective adjuvant for inducing potent antibody and Th1 immunity with CSP based vaccines offers a potential alternative to the existing protein based pre-erythrocytic vaccines.

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    • "While most adjuvants can induce antibody responses, generation of CD8+ T-cell immunity has proved particularly difficult (122). Immunization studies in non-human primates showed that Poly ICLC which stimulate multiple PPRs (TLR3, RIG-I, and MDA-5) and TLR7/8 agonists are currently the most potent known adjuvants for induction of T helper 1 and CD8+ T-cell responses (123–126). Poly ICLC and TLR7/8 agonist are the only TLR ligands capable of inducing both IL-12 and type I interferon, which are required for efficient cross-priming (53, 70, 114, 118). In mice, multiple cell types need to be stimulated for the production of IL-12 and type I interferon. "
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    • "Previous studies utilizing polyIC or polyICLC as an adjuvant have used dose levels several logs higher than those described in our report. In murine vaccination models, dose levels of 50 µg (administered subcutaneously) were administered with a malaria vaccine [33], [53]. A liposome-encapsulated form of polyICLC was also tested with intranasal administration in mice, wherein a dose of 20 µg of polyICLC increased the efficacy of an H5N1 vaccine [54]. "
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    • "Poly(I:C) could increase Th1 cytokines and type I IFNs by activating innate immunity through TLR3 and some other molecules mediating signal transduction. Then, DC maturation and B cell activation are induced [25]. Potent CD4+ T cell and humoral immune responses can thus be induced. "
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