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Title: Serological correlates of protection for evaluating the response to meningococcal capsular polysaccharide vaccines
Author: Findlow, Helen.
ISNI:       0000 0001 3465 0704
Awarding Body: Manchester Metropolitan University
Current Institution: Manchester Metropolitan University
Date of Award: 2003
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With the development of monovalent serogroup A and tetravalent serogroup A, C, W135 and Y conjugate vaccines, attention is now focused on the use of serological assays for correlates of vaccine-induced protection, particularly for serogroup A. The main aim of this project was to further understand the immune response to meningococcal capsular polysaccharides with an emphasis on serogroup A. Due to concerns over the most appropriate complement source to use in the serum bactericidal antibody (SBA) assay, a comparison between human and rabbit complement was performed, using three different target strains. The degree of serogroup A capsular polysaccharide expression and the immunotype of the three strains were determined. Serum bactericidal activity which was high in the presence of rabbit complement, was abolished when human complement was used. Factor H was not the cause of this inhibition. An enzyme-linked immunosorbent assay (ELISA) was developed to measure the level of vaccine-induced antibodies to meningococcal serogroup A polysaccharide (MenA). Several methods of attaching the antigen to microtitre plates were investigated and the use of methylated human serum albumin (MHSA) was found to be the most appropriate method. This method was used to investigate the antibody isotype response following vaccination. The predominant subclass following conjugate or polysaccharide vaccination was IgG with a greater proportion of IgM in those that received polysaccharide vaccine. Due to poor correlations between SBA titres and total IgG concentrations, methods for measuring or selecting for high avidity antibodies using ammonium thiocyanate were also investigated with the determination of avidity indices being the most appropriate. The avidity indices in an infant cohort following three doses of meningococcal serogroup A and C conjugate (MACC) vaccine were shown to increase progressively over time indicating avidity maturation. Determination of avidity indices in a toddler cohort which had received either MACC or meningococcal serogroup A and C polysaccharide (MACP) vaccine, showed that MenA polysaccharide may not behave as a classical T-cell independent antigen. Avidity indices in adults were shown to be less useful with no significant difference in the avidity indices of those that were vaccinated with either MACC or MACP. As multiple doses of meningococcal serogroup A polysaccharide vaccine have been recommended for protecting African children from disease the effect of this on serogroup A antibody levels was investigated. It was found that a second dose of MACP vaccine 6 months after primary vaccination elicited a reduced immunological response in young U. K. adults. Three international reference sera were quantified for meningococcal serogroup A, C, W135 and Y specific IgG subclass concentrations. Using the calibrated reference serum, the serogroup A-specific IgGi and IgG2 distribution following MenA vaccination in adults and infants was determined. The serogroup A-specific IgG response in infants was shown to be restricted to IgG1, whereas in adults both IgG1 and IgG2 were present. The serogroup A, C, W135 and Y specific IgGi and IgG2 responses following tetravalent A, C, W135 and Y conjugate vaccination in adults was shown to be heterogeneous with either IgG1 or IgG2 dominating the response. Assays were developed and optimised for the determination of the immune response to MenA polysaccharide and will be valuable for the future evaluation of meningococcal serogroup A vaccines. The information gained on the immune response to MenA polysaccharide adds to our knowledge and will assist in the understanding of the immune response to MenA polysaccharide.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: null Meningitis, Cerebrospinal Vaccination Bacterial vaccines Polysaccharides