ASTMH 2016, Robert Mitchell: "Skin scarification with Plasmodium falciparum CS peptide vaccines using synthetic TLR agonist adjuvants elicits chemokine/cytokine patterns that correlate with induction of sporozoite neutralizing antibodies"
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Title: "Skin scarification with Plasmodium falciparum CS peptide vaccines using synthetic TLR agonist adjuvants elicits chemokine/cytokine patterns that correlate with induction of sporozoite neutralizing antibodies"
Speaker: Robert Mitchell, New York University School of Medicine, USA
Session information: Scientific Session 34: Malaria: Vaccines - Diverse Approaches
Monday, 14 November, 1:45 - 3:30pm, Marriott - Marquis C
Sterile immunity can be elicited by immunization with sporozoites, however, the production, storage and administration of whole parasite vaccines present numerous logistical hurdles. Vaccination by skin scarification (SS), as used for mass immunization during the Smallpox Eradication Programme, may more closely mimic the natural route of sporozoite inoculation by mosquito bite. We investigated SS immunization using synthetic peptides containing minimal T and B cell epitopes of P. falciparum CS protein combined with TLR agonists as adjuvants. In a murine model, SS immunization with CS peptide in the oil emulsion AddaVax containing TLR-7/8 and -9 agonists, but not AddaVax without TLR agonists, elicited high levels of systemic sporozoite neutralizing antibody, Th1- type CD4+ T cells and resistance to challenge by bites of mosquitoes infected with transgenic rodent parasites expressing P. falciparum CS repeats. Immunogenicity of SS delivered vaccine was demonstrated with either branched or linear peptide containing minimal T and B cell epitopes, indicating that induction of sporozoite neutralizing antibody was not dependent on antigen form. Standard serological assays for measuring the magnitude, fine specificity or affinity of anti-repeat antibodies were not predictive of the differences in levels of sporozoite neutralizing antibodies detected in functional assays based on transgenic parasites. To determine the immunological mechanisms relevant to the initiation of the enhanced levels of sporozoite neutralizing antibodies, we examined a panel of cytokines and chemokines elicited by SS using various TLR agonists alone and in combination. Cellular sources of these cytokines/chemokines were examined by immunohistology and flow cytometry using fluorescent reporter cells including Langerhan cells and dendritic cells. Patterns of chemokines/cytokines were detected in serum at early time points that correlated with enhanced immunogenicity of SS delivered vaccines.