Serological correlates of protection for evaluating the response to meningococcal capsular polysaccharide vaccines
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.