title: Evaluation of immune responses to a Plasmodium vivax CSP-based recombinant protein vaccine candidate in combination with second-generation adjuvants in mice.
abstract: Plasmodium vivax is the major cause of malaria outside of sub-Saharan Africa and causes morbidity and results in significant economic impact in developing countries. In order to produce a P. vivax vaccine for global use, we have previously reported the development of VMP001, based on the circumsporozoite protein (CSP) of P. vivax. Our interest is to evaluate second-generation vaccine formulations to identify novel combinations of adjuvants capable of inducing strong, long-lasting immune responses. In this study, groups of C57BL/6J mice were immunized subcutaneously three times with VMP001 emulsified with synthetic TLR4 (GLA) or TLR7/8 (R848) agonist in stable emulsion (SE), a combination of the TLR4 and TLR7/8 agonists, or SE alone. Sera and splenocytes were tested for the presence of antigen-specific humoral and cellular responses, respectively. All groups of mice generated high titers of anti-P. vivax IgG antibodies as detected by ELISA and immunofluorescence assay. GLA-SE promoted a shift in the antibody response to a Th1 profile, as demonstrated by the change in IgG2c/IgG1 ratio. In addition, GLA-SE induced a strong cellular immune response characterized by multi-functional, antigen-specific CD4(+) T cells secreting IL-2, TNF and IFN-γ. In contrast, mice immunized with SE or R848-SE produced low numbers of antigen-specific CD4(+) T cells, and these T cells secreted IL-2 and TNF, but not IFN-γ. Finally, R848-SE did not enhance the immune response compared to GLA-SE alone. Based on these results, we conclude that the combination of VMP001 and GLA-SE is highly immunogenic in mice and may serve as a potential second-generation vaccine candidate against vivax malaria.
authors.affiliation: Malaria Vaccine Branch United States, Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Lumsden
authors.forename: Saule
authors.initials: S
authors.lastname: Nurmukhambetova
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Klein
authors.forename: Jetsumon
authors.initials: J
authors.lastname: Sattabongkot
authors.forename: Jason W
authors.initials: JW
authors.lastname: Bennett
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bertholet
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Fox
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.forename: Randall F
authors.initials: RF
authors.lastname: Howard
authors.forename: Mark E
authors.initials: ME
authors.lastname: Polhemus
authors.forename: Anjali
authors.initials: A
authors.lastname: Yadava
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004655:Emulsions / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D007074:Immunoglobulin G / Q000097:blood; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010966:Plasmodium vivax / Q000276:immunology*; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D004655:Emulsions; D007074:Immunoglobulin G; D007376:Interleukin-2; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014614:Vaccines, Synthetic; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma