title: 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.
abstract: 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.
authors.affiliation: Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Tewari
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Flynn
authors.forename: Silvia B
authors.initials: SB
authors.lastname: Boscardin
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kastenmueller
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.forename: Charles A
authors.initials: CA
authors.lastname: Anderson
authors.forename: Velmurugan
authors.initials: V
authors.lastname: Soundarapandian
authors.forename: Adriana
authors.initials: A
authors.lastname: Ahumada
authors.forename: Tibor
authors.initials: T
authors.lastname: Keler
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hoffman
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000276:immunology; D008253:Macaca mulatta; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum / Q000276:immunology; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D034101:Sporozoites / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma; D011070:Poly I-C