Vaccination of Experimental Monkeys Against
            <i>Plasmodium falciparum</i>
            : A Possible Safe Adjuvant

Siddiqui, Wasim A.; Taylor, Diane Wallace; Kan, Siu-Chow; Kramer, Kenton J.; Richmond-Crum, Suzanne M.; Kotani, Shozo; Shiba, Tetsuo; Kusumoto, Shoichi

doi:10.1126/science.99814

Cited by 108 publications

(42 citation statements)

References 16 publications

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“…Administered in an aqueous medium certain lipophilic derivatives of MDP have been shown capable of enhancing the cell-mediated immune response (44,47) whereas MDP and most of its analogues enhance humoral antibody production. Such an adjuvant activity has been demonstrated with classical laboratory antigens, but also with conventional vaccines against viral, bacterial, or parasitic pathogens (4,45) or with several synthetic antigens which copy epitopes of these pathogens (31,36,3,5). Anti-hormone vaccines have also been produced using as antigens the terminal fragment of .a-HCG or a hypothalamic peptide, LH-RH (for luteinizing hormone-releasing hormone) (6).…”

Section: A) Adjuvant Activitymentioning

confidence: 99%

Muramyl Peptides as Possible Endogenous Immunopharmacological Mediators

Chedid

1983

Microbiology and Immunology

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Synthetic N-acetylmuramyl-L-alanyl-D-isoglutamine, also called MDP for muramyl dipeptide, is a copy of a fragment of bacterial peptidoglycan. Soon after the recognition ofMDP as being the minimal subunit responsible for the activity of Freund's complete adjuvant, a great number of derivatives were synthesized. Because of their very low molecular weight it was hoped that they could retain selectively certain of the numerous effects produced by complex bacterial agents. Evidence was gathered showing MDP's direct effect on lymphocytes and on macrophages. The ensuing studies reviewed that MDP and several of its derivatives have marked immunopharmacological and neuropharmacological activities. Thus, besides being adjuvants, they are capable of producing hyperthermia by acting directly on thermoregulation centers or by inducing in vivo and in vitro endogenous pyrogens (EP). More recently, Krueger et al have shown that slow-wave sleep (SWS) factor was a muramyl peptide of a molecular weight close to 1,000 daltons. They have also shown that MDP and several of its synthetic analogs had a somnogenic activity. I t has previously been hypothesized that several of the immunological activities of the muramyl peptides could be due to biological mimicry with endogenous products. Recent observations argue in favor of the presence of an MDP bacterial structure in mammalian mediators which increase slow-wave sleep and/or produce fever. The implications of these findings will be discussed.

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Section: A) Adjuvant Activitymentioning

confidence: 99%

Muramyl Peptides as Possible Endogenous Immunopharmacological Mediators

Chedid

1983

Microbiology and Immunology

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“…Successful experimental vaccinations with erythrocytic stages of malaria parasites have indicated that merozoites and schizonts are the best sources of antigens that elicit a protective immune response (1)(2)(3). Identification of these stage-specific functional antigens would provide a rational basis for developing a malaria vaccine suitable for humans.…”

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confidence: 99%

Stage-specific proteins and glycoproteins of plasmodium falciparum: identification of antigens unique to schizonts and merozoites.

Kilejian¹

1980

Proc. Natl. Acad. Sci. U.S.A.

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Establishment of highly synchronized cultures of Plasmodium falciparum enabled identification of stagespecific proteins, glycoproteins, and antigens. Comparison of metabolically labeled constituents of rings, trophozoites, mature schizonts, and merozoites indicated the absence of major proteins or glycoproteins unique to rings or trophozoites. A burst of new synthetic activity occurred during schizogony when several schizont-and merozoite-specific proteins and glycoproteins became apparent. In addition to the knob protein, which was previously shown to be associated with protrusions on the host erythrocyte membrane, a major glycoprotein of parasite origin was identified on the surface membrane of schizonts. Analysis of antigens solubilized from different developmental stages indicated that immune sera, which inhibit growth of parasites in vitro, react mainly with merozoite-and schizont-associated antigens.Successful experimental vaccinations with erythrocytic stages of malaria parasites have indicated that merozoites and schizonts are the best sources of antigens that elicit a protective immune response (1-3). Identification of these stage-specific functional antigens would provide a rational basis for developing a malaria vaccine suitable for humans. Although an in vitro method for the cultivation of Plasmodium falciparum, the most virulent species of human malaria, has been available for over 3 years (4), there is no published information on stage-specific constituents or antigens. The major obstacle has been the asynchronous development of parasites in culture which has created difficulties in collection of sufficient numbers of nondegraded free merozoites. After emergence from erythrocytes, merozoites lose infectivity within about half an hour.In this study, a combination of two published methods was used to establish highly synchronized cultures. These cultures enabled the identification of stage-specific proteins and glycoproteins. In addition, by using sera from infected humans and experimentally immunized rabbits, antigenic constituents of merozoites and schizonts were determined.MATERIALS AND METHODS Synchronized Cultures. P. falciparum (FCR-3/Gambia) was cultured in 100-mm petri dishes in a candle jar (4). To obtain highly synchronized cultures, the infection of erythrocytes by merozoites was limited to 3-4 hr as follows. Starting with asynchronous cultures, multinucleate parasites were concentrated by flotation in gelatin (5) and subcultured with fresh erythrocytes. After 7-8 hr, cultures were collected and all multinucleate parasites that had failed to develop to mature schizonts and reinfect erythrocytes were eliminated with sorbitol treatment (6). On subsequent subcultures the identical The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "ad- For collection of merozoites and mature schizonts, cultures (to which labeled substrate had been added at 32 hr) were collected at 40 hr and multinucleate parasites were conce...

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“…Aotus monkeys, which are susceptible to infection with P. falciparum (8,9,17,27,34,35,39,41,(44)(45)(46)(47)58) without prior splenectomy (48), are a World Health Organizationrecommended model to test the efficacy of malaria blood stage vaccine candidates. An evaluation of the protective potential of a series of peptide sequences derived from proteins isolated from P. falciparum-infected erythrocytes in the Aotus infection model identified the partially protective peptides 35.1, 55.1, and 83.1 (34).…”

Section: Discussionmentioning

confidence: 99%

“…Polymeric SPf66 (SPf66 pol ) (CDELEAETQNVYAAPNANPYSLFQKEKMV LPNANPPANKKNAGC), monomeric SPf66 (SPf66 mon ) without the terminal cysteines of the SPf66 pol peptide, and the polymeric SPf66 building blocks 35.1 pol (CYGGPANKKNAGC), 55.1 pol (CGDELEAETQNVYAAGC), and 83.1 pol (CGYSLFQKEKMVLGC) were a kind gift of M. E. Patarroyo. 35.1 mon (YGG PANKKNAG) and RAP-1 [47][48][49][50][51][52][53][54][55][56][57] (YWTPINKKEFL) were obtained from SigmaGenosys.…”

Section: Methodsmentioning

confidence: 99%