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.

Trial registration: ClinicalTrials.gov NCT00587249.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. The T1(B)3 repeat epitopes, NANPDVDP(NANP)3, are inserted between amino acid residues 78 and 82 of the hepatitis B core protein, forming the tip of the core antigen spikes.

The T* epitope, EYLNKIQNSLSTEWSPCSVT, is inserted starting at amino acid V149. The amino terminus is noted as H2N and the starting amino acid is labelled as M1. Adapted from Bottcher, et al.

Figure 2. Consort Flow Diagram.

A total of 51 volunteers received at least one injection and 29 volunteers completed the study to receive all three injections of ICC-1132 adjuvanted to Alhydrogel.

Figure 3. Comparison of Antibody Titer and Sporozoite Neutralizing Activity for Select Volunteers.

As measured by IFA against whole sporozoite (gradient bars), (T1B)4 ELISA (hatched bars) and transgenic sporozoite neutralization assay (TSNA) (percentages above bars). For the TSNA, 94.5% inhibition was obtained using a positive control monoclonal antibody specific for P. falciparum CS repeats and −5% for negative control MAB specific for P. berghei CS repeats. Volunteers with positive CSP assays, volunteers 1 and 10, are indicated with a plus sign (+) in the x-axis.