USA As Represented by Secretary of the Navy

Yupin Charoenvit

Stephen L Hoffman

Trevor R Jones

Denise L Doolan

Richard C Hedstrom

Srisin Khusmith

Richard Hedstrom

Richard L Beaudoin

William O Rogers, Iv

The invention relates to a passive protective agent against . The passive protective agent is an antibody that, when a concentration of the antibody is injected intravenously, protects a subject to the limits of that concentration of antibody from developing malaria when the subject is subsequently challenged with live, infectious sporozoites. The invention includes methods of treatment and pharmaceutical formulations of the agent.

Murine monoclonal antibody protective against Plasmodium vivax malaria

An IgG1 monoclonal antibody, Navy Yoelii Liver Stage 3 (NYLS3) does not recognize sporozoites, but recognizes P. yoelii liver stage parasites within 6 hours of invasion of mouse hepatocytes, and throughout the hepatic and asexual erythrocytic stages of the life cycle. When added to primary cultures of mouse hepatocytes 24 hours after inoculation with P. yoelii sporozoites, when all sporozoites have invaded hepatocytes, NYLS3 eliminates up to 98% of liver stage parasites. Intravenous injection of NYLS3 into mice delays the onset and reduces the density of blood stage parasitemia after sporozoite or blood stage challenge. The protein recognized by this mAb is identified and designated P. yoelii hepatic and erythrocytic stage protein, 17-kDa or PyHEP17. The gene encoding PyHEP17 and a DNA vaccine comprising exons of the DNA that encodes PyHEP17 are disclosed. A DNA vaccine consisting of exon 1 and part of exon 2 of the gene encoding PyHEP17 protects 86% of A/J mice, 33%-43% of B10.BR mice, 17%-29% of BALB/c mice and 14%-20% of B10.Q mice from development of blood-stage parasitemia. A combination of DNA vaccines consisting of a PyHEP17 DNA vaccine and a PyCSP DNA vaccine confers complete protection against development of blood-stage parasitemia in BALB/c mice and 71% protection in A/J and B10.BR mice. This DNA vaccine-induced protection may be additive. Combinations of other malaria antigens are covered. The application discloses the P. falciparum homolog of PyHEP17 and includes the means of identification of the PyHEP17 homologs of the other Plasmodium species which infect humans, specifically P. vivax, P. ovale and P. malariae.

Protective 17 KDA malaria hepatic and erythrocytic stage immunogen and

An agent and pharmaceutical formulations of the agent containing a synthetic peptide of the human malaria Plasmodium vivax, containing at least one repeat of a synthetic peptide having the amino acid sequence Ala-Gly-Asp-Arg (AGDR) which is a protective epitope found on the circumsporozoite (CS) protein of the sporozoites of the human malaria Plasmodium vivax. When a monoclonal antibody specific for this four amino acid sequence binds to the CS protein of the P. vivax sporozoite in vivo, infection is prevented.

Immunogenic four amino acid epitope against Plasmodium vivax

A protein antigen (SSP2) on the surface of Plasmodium sporozoites is disclosed as a candidate immunogen for vaccination against malaria. This use of this protein, which is distinct from the extensively characterized circumsporozoite (CS) protein, will also facilitate research into host immunological responses to malaria. This antigen is detected by a monoclonal antibody (NYS4) which is specific for a 140 kilodalton (kD) protein on the sporozoite cell surface. Immunoreactive genomic clones are described which express this surface antigen gene and the primary nucleic acid sequence and the deduced amino acid sequence derived from this DNA sequence are disclosed. Unique repetitive sequences of amino acids are described which further demonstrate the distinction between SSP2 and the CS protein. A synthetic peptide containing repeating epitopes of SSP2 derived protein antigen and which are substantially shorter in length than the intact antigen are disclosed. The peptide when administered to a host elicits antibodies which bind to the SSP2 protein on the sporozoite surface. A recombinant plasmid bearing SSP2 DNA sequences expresses SSP2 epitopes in mammalian cells and the introduction of these transfected cells into mice elicits antibody and cytotoxic T-cell lymphocytic responses which confer partial protection to the recipient animals against challenge infection. In combination, the SSP2 protein and the CS protein elicit immunological responses in the mammalian host which confer 100% protection against challenge infection.

Protective malaria sporozoite surface protein immunogen and gene

A synthetic peptide of the human malaria Plasmodium vivax, containing at st one repeat of a synthetic peptide having the amino acid sequence Ala-Gly-Asp-Arg (AGDR) which is a protective epitope found on the circumsporozoite (CS) protein of the sporozoites of the human maleria Plasmodium vivax. When a monoclonal antibody specific for this four amino acid sequence binds to the CS protein of the P. vivax sporozoite in vivo, infection is prevented. Also described are pharmaceutical formulations of these peptides.

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Silver Spring, MD, United States of America

Yupin Charoenvit