Bactericidal antibody is the immunologic surrogate of protection against meningococcal disease
Introduction
Neisseria meningitidis (the meningococcus) shows antigenic variability in a number of surface structures including the capsular polysaccharide (PS), outer membrane proteins, and lipooligosaccharides. It is likely that much of these antigenic differences were selected for by host immune mechanisms. N. meningitidis has 12 known serogroups based upon antigenic and chemical differences in the capsular polysaccharides, yet almost all meningococcal disease is caused by only five of these, A, B, C, W135 and Y [1].
Prior to and through the development of meningococcal PS vaccines various investigators clarified the role of humoral antibody in immunity to meningococcal disease. Observations pointing to the central role of antibody are the subject of this review and include:
- 1.
The ability of therapeutic meningococcal antisera raised in horses to greatly reduce the mortality of meningococcal disease.
- 2.
The rarity of second attacks of disease caused by the same serogroup under epidemic conditions
- 3.
A generally inverse relationship between the incidence of meningococcal disease caused by a serogroup and age-specific prevalence of serum bactericidal antibody (SBA) to that serogroup.
- 4.
The high susceptibility to invasive meningococcal disease in individuals having a defect in one of the higher complement components making up the membrane attack complex (C5, C6, C7 and C8).
- 5.
Meningococcal polysaccharide and outer membrane vaccines induce bactericidal antibodies and are efficacious.
An understanding of how people acquire natural immunity to the meningococcus helps strengthen the case for the central role of SBA in protection against the disease. The intent of this review is to provide multiple observations showing the central role of bactericidal antibody in protection against meningococcal disease, and to show that measurement of SBA in the presence of human complement is the best surrogate (biomarker) of protective immunity. Discussion of the assay per se is discussed by Granoff et al. (2009).
Meningococcal disease is rare in older children and adults, well under 1 case/100,000 population per year, even though at any given time 5 to 10 in 100 are actively carrying the organism in their nasopharynx [2], [3]. It is rare because most people acquire natural immunity. The fact that virulent meningococcal strains are rarely found in healthy carriers in the absence of exposure to a meningococcal patient, suggests that protective antibodies are acquired by exposure to non-capsular antigens on non-virulent meningococcal strains, and by exposure to other bacteria, often enteric bacteria, having carbohydrate antigens that cross-react with the meningococcal capsular PS.
Section snippets
Serum therapy
Without treatment, meningococcal disease has a mortality rate approaching 80%. The first successful treatment of meningococcal meningitis was serum therapy using immune sera produced in horses. Serum treatment began in 1904. Flexner described in 1913 the treatment of about 1,300 patients with therapeutic serum [4]. He made a cogent observation suggesting of antibody mediated killing. He described the appearance of meningococci in exudates from patients with meningitis:
“Exudates, as obtained
Surrogate endpoint versus correlate of protection
One needs to identify vaccine-induced immune responses that strongly predict protection against a disease, in place of formal vaccine efficacy trials where possible. Fleming and DeMets have defined a correlate as a variable correlated with the true clinical outcome, and a valid surrogate end point as a replacement for a true clinical outcome [35]. Recently, Qin et al. defined a correlate of protection in a vaccine trial as an immunological measurement that correlates with the rate or level of a
Conflicts of interest
CEF: Consultant (Novartis Vaccines and Diagnostics; GlaxoSmithKline-Biologicals). JD: Employee Novartis Vaccines and Diagnostics. RB: Assistance to attend scientific meetings from Wyeth, Novartis, Sanofi Pasteur, Baxter Bioscience; ad hoc consultant for Wyeth, GlaxoSmithKline, Novartis, Sanofi Pasteur, Baxter Bioscience; industry honoraria for consulting, lecturing and writing are paid directly into Central Manchester and Manchester Children's University Hospitals NHS Trust endowment fund;
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