title: Phase I trial of an alhydrogel adjuvanted hepatitis B core virus-like particle containing epitopes of Plasmodium falciparum circumsporozoite protein.
abstract: The objectives of this non-randomized, non-blinded, dose-escalating Phase I clinical trial were to assess the safety, reactogenicity and immunogenicity of ICC-1132 formulated with Alhydrogel (aluminum hydroxide) in 51 healthy, malaria-naive adults aged 18 to 45 years. ICC-1132 (Malariavax) is a recombinant, virus-like particle malaria vaccine comprised of hepatitis core antigen engineered to express the central repeat regions from Plasmodium falciparum circumsporozoite protein containing an immunodominant B [(NANP)(3)] epitope, an HLA-restricted CD4 (NANPNVDPNANP) epitope and a universal T cell epitope (T*) (amino acids 326-345, NF54 isolate). We assessed an Alhydrogel (aluminum hydroxide)-adjuvanted vaccine formulation at three ICC-1132 dose levels, each injected intramuscularly (1.0 mL) on study days 0, 56 and 168. A saline vaccine formulation was found to be unstable after prolonged storage and this formulation was subsequently removed from the study. Thirty-two volunteers were followed for one year. Local and systemic adverse clinical events were measured and immune responses to P. falciparum and hepatitis B virus core antigens were determined utilizing the following assays: IgG and IgM ELISA, indirect immunofluorescence against P. falciparum sporozoites, circumsporozoite precipitin (CSP) and transgenic sporozoite neutralization assays. Cellular responses were measured by proliferation and IL-2 assays. Local and systemic reactions were similarly mild and well tolerated between dose cohorts. Depending on the ICC-1132 vaccine concentration, 95 to 100% of volunteers developed antibody responses to the ICC-1132 immunogen and HBc after two injections; however, only 29-75% and 29-63% of volunteers, respectively, developed malaria-specific responses measured by the malaria repeat synthetic peptide ELISA and IFA; 2 of 8 volunteers had positive reactions in the CSP assay. Maximal transgenic sporozoite neutralization assay inhibition was 54%. Forty-seven to seventy-five percent demonstrated T cell proliferation in response to ICC-1132 or to recombinant circumsporozoite protein (rCS) NF-54 isolate. This candidate malaria vaccine was well tolerated, but the vaccine formulation was poorly immunogenic. The vaccine may benefit from a more powerful adjuvant to improve immunogenicity.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00587249.
authors.affiliation: Department of Medicine and Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Aric L
authors.initials: AL
authors.lastname: Gregson
authors.forename: Giane
authors.initials: G
authors.lastname: Oliveira
authors.forename: Caroline
authors.initials: C
authors.lastname: Othoro
authors.forename: J Mauricio
authors.initials: JM
authors.lastname: Calvo-Calle
authors.forename: George B
authors.initials: GB
authors.lastname: Thorton
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nardin
authors.forename: Robert
authors.initials: R
authors.lastname: Edelman
mesh_terms: D000293:Adolescent; D000328:Adult; D000536:Aluminum Hydroxide; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000917:Antibody Formation; D049109:Cell Proliferation; D000939:Epitopes / Q000627:therapeutic use; D006512:Hepatitis B Core Antigens; D006801:Humans; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000276:immunology; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000737:chemistry / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016896:Treatment Outcome; D014771:Virion
chemical_list: D000913:Antibodies, Protozoan; D000939:Epitopes; D006512:Hepatitis B Core Antigens; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan; D000536:Aluminum Hydroxide