The malaria vaccine Combination B comprises recombinant Plasmodium falciparum ring-infected erythrocyte surface antigen and 2 merozoite surface proteins (MSP1 and MSP2) formulated in oil-based adjuvant. A phase 1-2b double-blind, randomized, placebo-controlled trial in 120 children (5-9 years old) in Papua New Guinea demonstrated a 62% (95% confidence limits: 13%, 84%) reduction in parasite density in children not pretreated with sulfadoxine-pyrimethamine. Vaccinees had a lower prevalence of parasites carrying the MSP2-3D7 allelic form (corresponding to that in the vaccine) and a higher incidence of morbid episodes associated with FC27-type parasites. These results demonstrate functional activity of Combination B against P. falciparum in individuals with previous malaria exposure. The specific effects on parasites with particular msp2 genotypes suggest that the MSP2 component, at least in part, accounted for the activity. The vaccine-induced selection pressure exerted on the parasites and its consequences for morbidity strongly argue for developing vaccines comprising conserved antigens and/or multiple components covering all important allelic types.

The interaction of heparan sulfate (HS) with basic fibroblast growth factor (bFGF) is influential in enabling the growth factor to bind to its cell surface tyrosine kinase receptor. In this study, we have investigated further the structural properties of HS required to mediate the activity of bFGF in a mitogenic assay. We have prepared a library of heparinase III-generated HS oligosaccharides fractionated by both their size (dp6-dp12) and sulfate content. The ability of these oligosaccharides to activate bFGF in a mitogenic assay was then correlated with their length and disaccharide composition. All octa-and hexasaccharide fractions tested were unable to activate bFGF. Dodeca-and decasaccharide fractions were found to contain both activating and nonactivating oligosaccharides, and showed a clear correlation between total sulfate content and the level of activatory activity. Disaccharide analysis of a range of dodeca-and decasaccharide fractions showed that both activating and non-activating oligosaccharides were composed mainly of N-sulfated and IdoA(2S)-containing disaccharides. The only significant difference between activating and non-activating oligosaccharides was the content of 6-O-sulfated disaccharides, in particular the disaccharide IdoA(2S)␣1,4GlcNSO 3 (6S). These results show that there is a requirement for 6-O-sulfation of N-sulfated glucosamine residues, in addition to the 2-Osulfation of IdoA, for the promotion of bFGF mitogenic activity by naturally occurring HS oligosaccharides. Analysis of the structure-activity relationships in the dodecasaccharide fractions in particular, suggests that a minimum bFGF activation sequence exists which is dependent on the positioning of at least one 6-O-sulfate group. Basic fibroblast growth factor (bFGF)1 is a member of a large family of polypeptides. It is found in a wide variety of mammalian tissues, and has been shown to influence a variety of cellular processes such as proliferation, migration, and differentiation (1-3). The FGFs act primarily through high affinity tyrosine kinase receptors (4), although, in addition, their activity is modulated by and largely dependent on lower affinity HS proteoglycan receptors (5-7). The mechanism by which HS promotes bFGF action is not clearly understood, with several hypotheses having been proposed. These include the proposition that HS binding confers a conformational change on bFGF, which in turn promotes binding to its high affinity receptor (5).Another model suggests that HS acts as a bridge by simultaneously binding both the growth factor and its tyrosine kinase receptor (8 -10). A further model, based on the ability of heparin to oligomerize bFGF, suggests that heparin/HS presents dimers of the growth factor to FGF receptors, to facilitate the receptor dimerization required for signal transduction (7,(11)(12)(13)(14). A mechanism akin to that involved in human growth hormone action has also been proposed (15, 16), in which a monomeric complex of HS and bFGF induces receptor dimerization through two distinct recep...

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