title: IgG2 antibodies against a clinical grade Plasmodium falciparum CSP vaccine antigen associate with protection against transgenic sporozoite challenge in mice.
abstract: The availability of a highly purified and well characterized circumsporozoite protein (CSP) is essential to improve upon the partial success of recombinant CSP-based malaria vaccine candidates. Soluble, near full-length, Plasmodium falciparum CSP vaccine antigen (CS/D) was produced in E. coli under bio-production conditions that comply with current Good Manufacturing Practices (cGMP). A mouse immunogenicity study was conducted using a stable oil-in-water emulsion (SE) of CS/D in combination with the Toll-Like Receptor 4 (TLR4) agonist Glucopyranosyl Lipid A (GLA/SE), or one of two TLR7/8 agonists: R848 (un-conjugated) or 3M-051 (covalently conjugated). Compared to Alum and SE, GLA/SE induced higher CS/D specific antibody response in Balb/c mice. Subclass analysis showed higher IgG2:IgG1 ratio of GLA/SE induced antibodies as compared to Alum and SE. TLR synergy was not observed when soluble R848 was mixed with GLA/SE. Antibody response of 3M051 formulations in Balb/c was similar to GLA/SE, except for the higher IgG2:IgG1 ratio and a trend towards higher T cell responses in 3M051 containing groups. However, no synergistic enhancement of antibody and T cell response was evident when 3M051 conjugate was mixed with GLA/SE. In C57Bl/6 mice, CS/D adjuvanted with 3M051/SE or GLA/SE induced higher CSP repeat specific titers compared to SE. While, 3M051 induced antibodies had high IgG2c:IgG1 ratio, GLA/SE promoted high levels of both IgG1 and IgG2c. GLA/SE also induced more potent T-cell responses compared to SE in two independent C57/BL6 vaccination studies, suggesting a balanced and productive T(H1)/T(H2) response. GLA and 3M-051 similarly enhanced the protective efficacy of CS/D against challenge with a transgenic P. berghei parasite and most importantly, high levels of cytophilic IgG2 antibodies were associated with protection in this model. Our data indicated that the cGMP-grade, soluble CS/D antigen combined with the TLR4-containing adjuvant GLA/SE warrants further evaluation for protective responses in humans.
authors.affiliation: Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Schwenk
authors.affiliation: Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
authors.forename: Margot
authors.initials: M
authors.lastname: DeBot
authors.affiliation: Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Porter
authors.affiliation: Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nikki
authors.affiliation: Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rein
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Spaccapelo
authors.affiliation: Imperial College London, London, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Crisanti
authors.affiliation: 3M Drug Delivery Systems, St. Paul, MN, United States of America.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Wightman
authors.affiliation: Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.affiliation: Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000913:Antibodies, Protozoan / Q000276:immunology*; D000953:Antigens, Protozoan / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D051940:B7-2 Antigen / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D007109:Immunity; D007074:Immunoglobulin G / Q000276:immunology*; D008024:Ligands; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology*; D051193:Toll-Like Receptors / Q000819:agonists; D014611:Vaccination
chemical_list: D000911:Antibodies, Monoclonal; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D051940:B7-2 Antigen; D007074:Immunoglobulin G; D008024:Ligands; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D051193:Toll-Like Receptors; C041595:circumsporozoite protein, Protozoan