Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three subunit vaccines based on the major repeat, (QGPGAP)n, and flanking regions of the Plasmodium yoelii circumsporozoite protein were designed, produced, and tested. All were immunogenic, but none gave consistent protection against a 40-200 sporozoite challenge. To demonstrate that antibodies to P. yoelii CS protein could provide protection we established a passive transfer model. Passive transfer of NYS1, an IgG3 MAb against the P. yoelii CS protein, protected 100% of mice against challenge with 5000 P. yoelii sporozoites. Binding of NYS1 to sporozoites was inhibited by incubation with (QGPGAP)2, indicating that the epitope on sporozoites recognized by this MAb was included within this peptide. The levels of antibodies to (QGPGAP)2 by ELISA, and to sporozoites by IFAT and CS precipitation reaction were similar in sera from mice that received NYS1 in passive transfer and were protected against challenge with 5000 sporozoites, and from mice that had been immunized with subunit vaccines containing QGPGAP but were not protected against challenge with 40-200 sporozoites. To determine if antibody avidity, not the absolute concentration, could explain the striking differences in protection, we established a thiocyanate elution assay. The results suggest that NYS1, the protective MAb, has a lower avidity for (QGPGAP)2 and for sporozoites than do the vaccine-induced antibodies. The data clearly demonstrate that antibodies to the CS protein can protect against intense sporozoite infection. Improved understanding of the differences between protective MAbs and non-protective polyclonal antibodies will be important in the further development of malaria vaccines.
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PMID:Active and passive immunization against Plasmodium yoelii sporozoites. 170 34

We have evaluated the in vitro biological activities of antibodies directed against sporozoites and compared them with their capacity to protect against challenge with both human and rodent malaria. The anti-Plasmodium falciparum antibodies evaluated with the test included monoclonal antibodies (MAbs) NFS1 and NFS2 as well as polyclonal antibodies contained in human hyperimmune sera directed against sporozoites of P. falciparum. The inhibitory effect of these antibodies was dependent on their concentration. However, total inhibition was not observed except occasionally with highly concentrated MAbs (10-100 micrograms/ml). Strong but also incomplete inhibition was observed with sera from humans living in hyperendemic areas. In the P. yoelii rodent system, we tested sera from mice immunized with subunit vaccines. None of these mice were protected in vivo against challenge with 40-200 sporozoites. In vitro only a sub-total inhibition was achieved (maximum 91% at 1:10 serum dilution). In contrast, we tested sera from mice that received NYS1, an IgG3 MAb, in passive transfer and were protected against challenge with 5000 sporozoites. At 1:10 dilution, 100% inhibition was achieved in vitro while IFA titres from these mice were similar to those of vaccinated mice. These data show a close correlation between in vivo and in vitro findings and thus suggest that the inhibition of liver-stage development assay (ILSDA) appears appropriate to evaluate the potential of antibodies.
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PMID:Evaluation of an in vitro assay aimed at measuring protective antibodies against sporozoites. 209 92

Passive transfer of monoclonal antibodies (MAbs) against malaria circumsporozoite (CS) proteins protects animals against malaria. Active immunization with synthetic or recombinant peptides induces a level of polyclonal antibodies to sporozoites comparable to those found after passive immunization but does not provide comparable protection. In the Plasmodium yoelii system, synthetic or recombinant peptide-induced antibodies have never been shown to protect. The current studies were designed to determine whether immunogen structure (native protein versus synthetic peptide) or immunoglobulin G (IgG) subclass of antibodies was responsible for the absolute differences between protective, passively transferred MAbs and nonprotective, actively induced polyclonal antibodies. In this study we produced two MAbs, QGP-S1 (IgG1) and QGP-S2 (IgG2b), by immunization with a synthetic peptide based on the P. yoelii CS major repeat, (QGPGAP)4, conjugated to keyhole limpet hemocyanin. These MAbs were compared tp NYS1 (IgG3), an anti-CS protein MAb previously produced by immunization with irradiated P. yoelii sporozoites, which recognizes (QGP GAP)2. QGP-S1 and QGP-S2 passively transferred protection. However, when compared with NYS1, there was a hierarchy of protection, NYS1 > QGP-S1 > QGP-S2. There was no correlation between antibody level at challenge as determined by immunofluorescent antibody test against sporozoites or enzyme-linked immunosorbent assay against (QGPGAP)2 or apparent antibody avidity for (QGPGAP)2 by sodium thiocyanate elution assay. The data demonstrate that a synthetic peptide can induce protective antibodies and that a specific antibody subclass is not required for protection. Work to determine whether antibody affinity or fine specificity can explain the hierarchy of protection among the MAbs is under way.
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PMID:Monoclonal antibodies of three different immunoglobulin G isotypes produced by immunization with a synthetic peptide or native protein protect mice against challenge with Plasmodium yoelii sporozoites. 850 Aug 85