Phase I Testing of a Malaria Vaccine Composed of Hepatitis B Virus Core Particles Expressing Plasmodium falciparum Circumsporozoite Epitopes

ABSTRACT We report the first phase I trial to assess the safety and immunogenicity of a malaria vaccine candidate, ICC-1132 (Malarivax), composed of a modified hepatitis B virus core protein (HBc) containing minimal epitopes of the Plasmodium falciparum circumsporozoite (CS) protein. When expressed in Escherichia coli, the recombinant ICC-1132 protein forms virus-like particles that were found to be highly immunogenic in preclinical studies of mice and monkeys. Twenty healthy adult volunteers received a 20- or a 50-μg dose of alum-adsorbed ICC-1132 administered intramuscularly at 0, 2, and 6 months. The majority of volunteers in the group receiving the 50-μg dose developed antibodies to CS repeats as well as to HBc. Malaria-specific T cells that secreted gamma interferon were also detected after a single immunization with ICC-1132-alum. These studies support ICC-1132 as a promising malaria vaccine candidate for further clinical testing using more-potent adjuvant formulations and confirm the potential of modified HBc virus-like particles as a delivery platform for vaccines against other human pathogens.

Download Full-text

A Malaria Vaccine Candidate Based on a Hepatitis B Virus Core Platform

Intervirology ◽

10.1159/000067928 ◽

2002 ◽

Vol 45 (4-6) ◽

pp. 350-361 ◽

Cited By ~ 17

Author(s):

Matti Sällberg ◽

Janice Hughes ◽

Joyce Jones ◽

Tom R. Phillips ◽

David R. Milich

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Malaria Vaccine ◽

Vaccine Candidate ◽

Virus Core ◽

B Virus ◽

Malaria Vaccine Candidate

Download Full-text

A Modified Hepatitis B Virus Core Particle Containing Multiple Epitopes of the Plasmodium falciparum Circumsporozoite Protein Provides a Highly Immunogenic Malaria Vaccine in Preclinical Analyses in Rodent and Primate Hosts

Infection and Immunity ◽

10.1128/iai.70.12.6860-6870.2002 ◽

2002 ◽

Vol 70 (12) ◽

pp. 6860-6870 ◽

Cited By ~ 61

Author(s):

A. Birkett ◽

K. Lyons ◽

A. Schmidt ◽

D. Boyd ◽

G. A. Oliveira ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

Immune Responses ◽

Malaria Vaccine ◽

B Cell Epitopes ◽

Virus Core ◽

B Virus ◽

Human Use

ABSTRACT Despite extensive public health efforts, there are presently 200 to 400 million malaria infections and 1 to 2 million deaths each year due to the Plasmodium parasite. A prime target for malaria vaccine development is the circumsporozoite (CS) protein, which is expressed on the extracellular sporozoite and the intracellular hepatic stages of the parasite. Previous studies in rodent malaria models have shown that CS repeat B-cell epitopes expressed in a recombinant hepatitis B virus core (HBc) protein can elicit protective immunity. To design a vaccine for human use, a series of recombinant HBc proteins containing epitopes of Plasmodium falciparum CS protein were assayed for immunogenicity in mice [A. Birkett, B. Thornton, D. Milich, G. A. Oliveira, A. Siddique, R. Nussenzweig, J. M. Calvo-Calle, and E. H. Nardin, abstract from the 50th Annual Meeting of the American Society of Tropical Medicine and Hygiene 2001, Am. J. Trop. Med. Hyg. 65(Suppl. 3):258, 2001; D. R. Milich, J. Hughes, J. Jones, M. Sallberg, and T. R. Phillips, Vaccine 20:771-788, 2001]. The present paper summarizes preclinical analyses of the optimal P. falciparum HBc vaccine candidate, termed ICC-1132, which contains T- and B-cell epitopes from the repeat region and a universal T-cell epitope from the C terminus of the CS protein. The vaccine was highly immunogenic in mice and in Macaca fascicularis (cynomolgus) monkeys. When formulated in adjuvants suitable for human use, the vaccine elicited antisporozoite antibody titers that were logs higher than those obtained in previous studies. Human malaria-specific CD4+-T-cell clones and T cells of ICC-1132-immunized mice specifically recognized malaria T-cell epitopes contained in the vaccine. In addition to inducing strong malaria-specific immune responses in naïve hosts, ICC-1132 elicited potent anamnestic antibody responses in mice primed with P. falciparum sporozoites, suggesting potential efficacy in enhancing the sporozoite-primed immune responses of individuals living in areas where malaria is endemic.

Download Full-text

Safety and Enhanced Immunogenicity of a Hepatitis B Core Particle Plasmodium falciparum Malaria Vaccine Formulated in Adjuvant Montanide ISA 720 in a Phase I Trial

Infection and Immunity ◽

10.1128/iai.73.6.3587-3597.2005 ◽

2005 ◽

Vol 73 (6) ◽

pp. 3587-3597 ◽

Cited By ~ 76

Author(s):

Giane A. Oliveira ◽

Kristiane Wetzel ◽

J. Mauricio Calvo-Calle ◽

Ruth Nussenzweig ◽

Annette Schmidt ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Hepatitis B ◽

Phase I ◽

Specific Antibody ◽

Phase I Trial ◽

Malaria Vaccine ◽

Mononuclear Cells ◽

Vaccine Candidate ◽

Interleukin 2 ◽

Malaria Vaccine Candidate

ABSTRACT Highly purified subunit vaccines require potent adjuvants in order to elicit optimal immune responses. In a previous phase I trial, an alum formulation of ICC-1132, a malaria vaccine candidate comprising hepatitis B core (HBc) virus-like particle containing Plasmodium falciparum circumsporozoite (CS) protein epitopes, was shown to elicit Plasmodium falciparum-specific antibody and cellular responses. The present study was designed as a single-blind, escalating-dose phase I trial to evaluate the safety and immunogenicity of single intramuscular doses of ICC-1132 formulated in the more potent water-in-oil adjuvant Montanide ISA 720 (ICC-1132/ISA 720). The vaccine was safe and well tolerated, with transient injection site pain as the most frequent complaint. All vaccinees that received either 20 μg or 50 μg of ICC-1132/ISA 720 developed antiimmunogen and anti-HBc antibodies. The majority of volunteers in these two groups developed sporozoite-specific antibodies, predominantly of opsonizing immunoglobulin G subtypes. Peak titers and persistence of parasite-specific antibody following a single injection of the ISA 720 formulated vaccine were comparable to those obtained following two to three immunizations with alum-adsorbed ICC-1132. Peripheral blood mononuclear cells of ICC-1132/ISA 720 vaccinees proliferated and released cytokines (interleukin 2 and gamma interferon) when stimulated with recombinant P. falciparum CS protein, and CS-specific CD4+ T-cell lines were established from volunteers with high levels of antibodies to the repeat region. The promising results obtained with a single dose of ICC-1132 formulated in Montanide ISA 720 encourage further clinical development of this malaria vaccine candidate.

Download Full-text