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R Nussenzweig

Publications and source records attributed to R Nussenzweig.

18 recordsLinked to original sources
PubMed2002

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.

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.

Amino Acid Sequence↗
PubMed1998

Plasmodium falciparum polyoximes: highly immunogenic synthetic vaccines constructed by chemoselective ligation of repeat B-cell epitopes and a universal T-cell epitope of CS protein.

Effective immunoprophylaxis directed against the pre-erythrocytic stages of the malaria parasite requires a vaccine that can elicit humoral and cell mediated immunity in individuals of diverse genetic background. In order for a synthetic peptide malaria vaccine to meet these requirements, problems associated with genetic restriction, peptide chemistry, adjuvant formulation and physiochemical characterization of the final synthetic vaccine product must first be overcome. To address these issues, five polyoxime vaccine candidates have been constructed by ligating purified peptide epitopes of the P. falciparum CS protein to a branched template via oxime bonds. All five constructs, including two based on templates containing the synthetic adjuvant tripalmitoyl-S-glyceryl cysteine (Pam3Cys), were of sufficient purity for characterization by mass spectrometry. The immunogenicity of the malaria polyoximes in different murine strains was compared to that of multiple antigen peptide (MAP) constructs synthesized by standard step-wise synthesis. A tri-epitope polyoxime-Pam3Cys construct, based on the repeats and a universal T-cell epitope that contains both helper and CTL epitopes of the CS protein, was shown to be a precisely-defined synthetic malaria vaccine candidate that was highly immunogenic in murine strains of diverse H-2 haplotypes.

Adjuvants, Immunologic↗
PubMed1990

Incorporation of T and B epitopes of the circumsporozoite protein in a chemically defined synthetic vaccine against malaria.

We show here an effective and novel approach to engineer peptide-based vaccines using a chemically defined system, known as multiple peptide antigen systems (MAPs), to protect an inbred mouse strain from infection against rodent malaria. 10 mono- and di-epitope MAP models containing different arrangements and stoichiometry of functional B and/or T helper cell epitopes from the circumsporozoite protein of Plasmodium berghei were used to immunize A/J mice. While these mice did not respond to the mono-epitope MAP bearing only the B or T epitope, very high titers of antibody and protective immunity against sporozoite challenge were elicited by di-epitope MAPs, particularly those with the B and T epitopes in tandem and present in equimolar amounts. These results, obtained in a well-defined rodent malaria model, indicate that MAPs may overcome some of the difficulties in the development of synthetic vaccines, not only for malaria but also for other infectious diseases.

Amino Acid Sequence↗
PubMed1987

Ultrastructural localization of the 150/130 Kd antigens in sexual and asexual blood stages of Plasmodium falciparum-infected human erythrocytes.

The subcellular localization of the 150/130 Kd antigen in Plasmodium falciparum-infected erythrocytes was determined by electron microscopy using monoclonal antibody 9B11 and immuno-gold labeling. We now find that this antigen may be associated with the membrane of newly-infected human erythrocytes and the cytoplasm of ring stage parasites. During differentiation of the parasite to the trophozoite stage, the antigens are no longer detectable on the erythrocyte membrane, while gold particles become more numerous within the parasite and in the erythrocyte cytoplasm adjacent to the parasite. As the parasites develop into schizonts, more antigen appears within the parasites, and some of it appears in the erythrocyte cytoplasm. At the segmented schizont stage, many intraparasitic gold particles are associated with rhoptries and micronemes of developing merozoites. Likewise, gold particles are associated with elements of the rhoptry-microneme complex in free merozoites. No gold particles are detected on the surface of merozoites. These antigens are found most abundantly in erythrocytes infected with gametocytes, revealing a localization pattern similar to that of mature trophozoite-infected erythrocytes. These subcellular localization patterns are similar to those described for the ring-infected erythrocyte surface antigen.

Animals↗
PubMed1986

Experimental basis for the development of a synthetic vaccine against Plasmodium falciparum malaria sporozoites.

Malaria continues to cause extensive morbidity and mortality in man. The exact number of individuals affected is not known. Estimates vary from 200 to 400 million, and more than one million die each year. Protective immunity against malaria can be obtained by vaccination with irradiated sporozoites. The protective antigens are polypeptides (circumsporozoite [CS] proteins) which cover the surface membrane of the parasite. CS proteins contain species-specific immunodominant epitopes, formed by tandem repeated sequences of amino acids. The dominant epitope of Plasmodium falciparum is represented in the synthetic peptide asparagine-alanine-asparagine-proline repeated in tandem three times; that is, (NANP)3. Monoclonal antibodies and most or all polyclonal human antibodies to P. falciparum sporozoites react with (NANP)3. Polyclonal antibodies raised against the synthetic peptide (NANP)3 react with the surface of the parasite and neutralize its infectivity. Since (NANP)3 repeats are present worldwide in CS proteins from P. falciparum, this epitope is a logical target for vaccine development.

Animals↗
PubMed1984

Ultrastructure of in vitro cultured exoerythrocytic stage of Plasmodium berghei in a hepatoma cell line.

Because of difficulties in cultivation of the exoerythrocytic (EE) stages of mammalian malaria parasites, investigation of the development of the EE stages has been hindered as compared to that of the other stages. Recently, human hepatoma cells (HepG2-A16) have been shown to be useful for the complete developmental cycle of the EE stage of Plasmodium berghei. In order to define the morphological events during this process, we evaluated the EE stages developing from sporozoites in these human hepatoma cells using electron microscopy and compared their structure to those grown in vivo. This study demonstrates that sporozoites of P. berghei can transform into EE stages within the hepatoma cells in a manner morphologically identical to that seen in vivo, and suggests that this cell line is a useful model for the study of the EE stages of mammalian malaria parasites.

Carcinoma, Hepatocellular↗
PubMed1982

Inhibition of idiotype--anti-idiotype interaction for detection of a parasite antigen: a new immunoassay.

Described in this report is an immunoradiometric assay of general applicability that is based on a new principle: the inhibition of the interaction between monoclonal antibodies by an antigen. The advantages of this assay are that it measures concentrations of single epitopes, purified antigen is not required, and the reagents can be obtained in unlimited amounts and are homogeneous. Its features are particularly attractive when the antigen has not been purified and is a minor component of a complex mixture of molecule.

Animals↗
PubMedDate not supplied

Gamma interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites.

This study was designed to test the hypothesis that T-cell effector mechanisms are required for protective immunity to malaria sporozoites. Administration of neutralizing monoclonal antibodies against gamma interferon (gamma IFN) to immune hosts, reversed sterile immunity to sporozoite challenge, by allowing the growth of exoerythrocytic forms (EEF) and thus the development of parasitaemia. Immune animals also developed infections when depleted in vivo of their suppressor/cytotoxic T cells expressing the CD8 antigen (CD8+) but not when depleted of helper T cells expressing CD4 antigen (CD4+), before sporozoite challenge. Passive transfer of immune immunoglobin alone, or adoptive transfer of immune T cells alone, conferred partial protection to naive recipients. Transfer of both immune components resulted in significantly greater protection. This transferred immunity was reversed by the in vivo neutralization of gamma IFN. Thus, sterile immunity to sporozoite challenge requires the neutralization of sporozoites by antibodies and the inhibition of EEF development by gamma IFN with the participation of CD8+ cells.

Animals↗