A randomized phase I study of the safety and immunogenicity of three ascending dose levels of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults

Background: Staphylococcus aureus is a common cause of healthcare-acquired morbidity and mortalityand increased healthcare resource utilization. A prophylactic vaccine is being developed that may reducethis disease burden.Methods: Volunteers in good general health aged 50–85 (n = 312) and 18–24 (n = 96) years were random-ized to receive a single intramuscular dose of one of three dose levels of a non-adjuvanted, 3-antigen S.aureus vaccine (SA3Ag) or placebo. SA3Ag antigens included capsular polysaccharides 5 and 8 (CP5 andCP8), each conjugated to cross-reactive material 197 (CRM197), and recombinant clumping factor A (ClfA).Safety, tolerability, and immunogenicity were evaluated.Results: At day 29 post-vaccination, robust immune responses were observed in both age cohorts at allthree SA3Ag dose levels. In the primary analysis population, the 50- to 85-year age stratum, geometricmean-fold-rises in competitive Luminex® immunoassay antibody titers from baseline ranged from 29.2to 83.7 (CP5), 14.1 to 31.0 (CP8), and 37.1 to 42.9 (ClfA), all (P < 0.001) exceeding the pre-defined two-fold rise criteria. Similar rises in opsonophagocytic activity assay titers demonstrated functionality ofthe immune response. Most injection-site reactions were mild in severity and there were no substantial differences (SA3Ag vs. placebo) with regard to systemic or adverse events.Conclusions: In this study of healthy adults aged 50–85 and 18–24 years, SA3Ag elicited a rapid and robustimmune response and was well tolerated, with no notable safety concerns.Michael Nissen, Helen Marshall, Peter Richmond, Sepehr Shakib, Qin Jiang, David Cooper, Denise Rill, James Baber, Joseph Eiden, William Gruber, Kathrin U. Jansen, Emilio A. Emini, Annaliesa S. Anderson, Edward T. Zito, Douglas Girgent

Prediction of Peptide Reactivity with Human IVIg through a Knowledge-Based Approach

The prediction of antibody-protein (antigen) interactions is very difficult due to the huge variability that characterizes the structure of the antibodies. The region of the antigen bound to the antibodies is called epitope. Experimental data indicate that many antibodies react with a panel of distinct epitopes (positive reaction). The Challenge 1 of DREAM5 aims at understanding whether there exists rules for predicting the reactivity of a peptide/epitope, i.e., its capability to bind to human antibodies. DREAM 5 provided a training set of peptides with experimentally identified high and low reactivities to human antibodies. On the basis of this training set, the participants to the challenge were asked to develop a predictive model of reactivity. A test set was then provided to evaluate the performance of the model implemented so far

Direct Interaction between Two Viral Proteins, the Nonstructural Protein 2CATPase and the Capsid Protein VP3, Is Required for Enterovirus Morphogenesis

In spite of decades-long studies, the mechanism of morphogenesis of plus-stranded RNA viruses belonging to the genus Enterovirus of Picornaviridae, including poliovirus (PV), is not understood. Numerous attempts to identify an RNA encapsidation signal have failed. Genetic studies, however, have implicated a role of the non-structural protein 2CATPase in the formation of poliovirus particles. Here we report a novel mechanism in which protein-protein interaction is sufficient to explain the specificity in PV encapsidation. Making use of a novel “reporter virus”, we show that a quasi-infectious chimera consisting of the capsid precursor of C-cluster coxsackie virus 20 (C-CAV20) and the nonstructural proteins of the closely related PV translated and replicated its genome with wild type kinetics, whereas encapsidation was blocked. On blind passages, encapsidation of the chimera was rescued by a single mutation either in capsid protein VP3 of CAV20 or in 2CATPase of PV. Whereas each of the single-mutation variants expressed severe proliferation phenotypes, engineering both mutations into the chimera yielded a virus encapsidating with wild type kinetics. Biochemical analyses provided strong evidence for a direct interaction between 2CATPase and VP3 of PV and CAV20. Chimeras of other C-CAVs (CAV20/CAV21 or CAV18/CAV20) were blocked in encapsidation (no virus after blind passages) but could be rescued if the capsid and 2CATPase coding regions originated from the same virus. Our novel mechanism explains the specificity of encapsidation without apparent involvement of an RNA signal by considering that (i) genome replication is known to be stringently linked to translation, (ii) morphogenesis is known to be stringently linked to genome replication, (iii) newly synthesized 2CATPase is an essential component of the replication complex, and (iv) 2CATPase has specific affinity to capsid protein(s). These conditions lead to morphogenesis at the site where newly synthesized genomes emerge from the replication complex