Characterization of Vaccines Targeting Surface Carbohydrates in Bacterial Disease and Associated Manufacturing and Product Testing Issues

Principal Investigator: Willie F. Vann, PhD
Office / Division / Lab: OVRR / DBPAP / LBP

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Overview

Public Health Issue: Bacteria and humans cells are coated with sugar chains often referred to as carbohydrates. Carbohydrate structures play essential roles in infection of humans by bacteria and in the protection of us against disease by vaccination. These carbohydrate coatings make excellent targets for prevention and control of disease. For example, tetanus and botulinum toxins enter human nerve cells through their interactions with carbohydrates on the surface of human cells. Furthermore, the carbohydrate coatings of bacteria that cause meningitidis are used to manufacture vaccines against these bacteria.

Regulatory Contribution: While the current vaccines based on derivatives of bacterial toxins and polysaccharides are quite effective, these pharmaceuticals are often not well characterized due to the current complex manufacturing procedures used. Tests of toxoid vaccines are often based on expensive time consuming animal assays. New approaches to the preparation of carbohydrate and toxoid vaccines are needed that facilitate their thorough characterization. More accurate tests that do not rely on animals for characterizing these products will reduce the time and costs associated with product characterization, while increasing predictability of assay results.

Research Approach: The research program on understanding the synthesis and interactions of bacterial carbohydrates and toxins provides needed scientific tools and knowledge to address these problems. The aims of this program are to (a) understand how bacteria make polysaccharide surface coats, (b) determine structural basis for the interaction of tetanus and botulinum toxins with carbohydrates on human cells (c) to use this information to develop improved methods for manufacturing vaccine targets and tests for monitoring vaccine potency.

Mission Relevance & Outcomes: These studies allow the evaluation and development of new approaches to the manufacture and characterization of vaccines that will improve both safety and effectiveness.

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Publications

Infect Immun 2008 Aug;76(8):3700-9
Phenotypic and genotypic analyses of Neisseria gonorrhoeae isolates that express frequently recovered PorB PIA variable region types suggest that certain P1a porin sequences confer a selective advantage for urogenital tract infection.
Garvin LE, Bash MC, Keys C, Warner DM, Ram S, Shafer WM, Jerse AE

Vaccine 2007 Nov 14;25(46):7972-80
Comparison of Neisseria meningitidis serogroup W135 polysaccharide-tetanus toxoid conjugate vaccines made by periodate activation of O-acetylated, non-O-acetylated and chemically de-O-acetylated polysaccharide.
Gudlavalleti SK, Lee CH, Norris SE, Paul-Satyaseela M, Vann WF, Frasch CE

Mol Microbiol 2007 Sep;65(5):1258-75
Biochemical characterization of a Neisseria meningitidis polysialyltransferase reveals novel functional motifs in bacterial sialyltransferases.
Freiberger F, Claus H, Günzel A, Oltmann-Norden I, Vionnet J, Mühlenhoff M, Vogel U, Vann WF, Gerardy-Schahn R, Stummeyer K

Glycobiology 2007 Jul;17(7):735-43
Successive glycosyltransfer of sialic acid by Escherichia coli K92 polysialyltransferase in elongation of oligosialic acceptors.
Vionnet J, Vann WF

Proc Natl Acad Sci U S A 2007 Jul 10;104(28):11557-61
Extracellular structure of polysialic acid explored by on cell solution NMR.
Azurmendi HF, Vionnet J, Wrightson L, Trinh LB, Shiloach J, Freedberg DI

Vaccine 2007 Nov 14;25(46):7972-80
Comparison of Neisseria meningitidis serogroup W135 polysaccharide-tetanus toxoid conjugate vaccines made by periodate activation of O-acetylated, non-O-acetylated and chemically de-O-acetylated polysaccharide.
Gudlavalleti SK, Lee CH, Norris SE, Paul-Satyaseela M, Vann WF, Frasch CE

BMC Evol Biol 2007 Jun 1;7:84
Distinguishing importation from diversification of quinolone-resistant Neisseria gonorrhoeae by molecular evolutionary analysis.
Pérez-Losada M, Crandall KA, Bash MC, Dan M, Zenilman J, Viscidi RP

Altern Lab Anim 2007 Jun;35(3):323-31
The potential of physicochemical and immunochemical assays to replace animal tests in the quality control of toxoid vaccines. The report and recommendations of ECVAM workshop 61.
Metz B, Brunel F, Chamberlin C, van der Gun J, Halder M, Jiskoot W, Kersten G, van Opstal O, Petersen JW, Ravetkar SD, Redhead K, Schwanig M, Wilhelmsen ES, Vann WF, Hendriksen C

J Clin Lab Anal 2007;21(4):237-43
Evaluation of PorB variable region typing of Neisseria gonorrhoeae using PCR-ELISA in samples collected from men who have sex with men.
Ling AE, Bash MC, Lynn F, Lister NA, Zhu P, Garland SM, Fairley CK, Tabrizi SN

Gene 2006 Dec 15;384:113-9
Escherichia coli BL21(DE3) chromosome contains a group II capsular gene cluster.
Andreishcheva EN, Vann WF

Biochemistry 2006 Nov 14;45(45):13511-13516
Functional Molecular Mass of Escherichia coli K92 Polysialyltransferase As Determined by Radiation Target Analysis.
Vionnet J, Kempner ES, Vann WF

J Bacteriol 2006 Sep;188(17):6195-206
Separate pathways for O acetylation of polymeric and monomeric sialic acids and identification of sialyl O-acetyl esterase in Escherichia coli K1.
Steenbergen SM, Lee YC, Vann WF, Vionnet J, Wright LF, Vimr ER

Biochem J 2006 Jul 1;397(1):195-201
Elimination of 2-keto-3-deoxy-D-glycero-D-galacto-nonulosonic acid 9-phosphate synthase activity from human N-acetylneuraminic acid 9-phosphate synthase by a single mutation.
Hao J, Vann WF, Hinderlich S, Sundaramoorthy M

J Bacteriol 2006 Mar;188(5):1786-97
Gene Products Required for De Novo Synthesis of Polysialic Acid in Escherichia coli K1.
Andreishcheva EN, Vann WF

Biochem J 2004 Oct 1;383(Pt 1):83-9
Characterization of N-acetylneuraminic acid synthase isoenzyme 1 from Campylobacter jejuni.
Sundaram AK, Pitts L, Muhammad K, Wu J, Betenbaugh M, Woodard RW, Vann WF

J Bacteriol 2004 Feb 1; 186(3): 706-712
The NeuC Protein of Escherichia coli K1 Is a UDP N-Acetylglucosamine 2-Epimerase.
Vann WF, Daines DA, Murkin AS, Tanner ME, Chaffin DO, Rubens CE, Vionnet J, Silver RP