Elsevier

Vaccine

Volume 27, Supplement 2, 24 June 2009, Pages B112-B116
Vaccine

Bactericidal antibody is the immunologic surrogate of protection against meningococcal disease

https://doi.org/10.1016/j.vaccine.2009.04.065Get rights and content

Abstract

It has been demonstrated that antibodies induced by meningococcal polysaccharide, polysaccharide-protein conjugates and outer membrane protein vaccines protect against meningococcal disease. This review will show that the induced antibody protects via complement mediated bactericidal killing and that induction of serum bactericidal antibody (SBA) is a good surrogate for efficacy. The critical role of SBA is shown by: (1) Highest incidence of meningococcal disease occurs in infants between 6 and 18 months of age, who have the lowest levels of SBA. (2) Studies published in 1969 in US Army recruits showed a direct correlation between susceptibility to meningococcal disease and absence of SBA. (3) Meningococcal polysaccharide, polysaccharide-protein conjugates, and outer membrane vesicle vaccines all induce SBA shown to be effective in direct proportion to the percent of vaccinees with SBA activity.

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;

References (38)

  • C.E. Frasch

    Production and control of Neisseria meningitidis vaccines

  • S. Flexner

    The results of the serum treatment in thirteen hundred cases of epidemic meningitis

    J Exp Med

    (1913)
  • C.E. Frasch et al.

    Protection against group b meningococcal disease. III. Immunogenicity of serotype 2 vaccines and specificity of protection in a guinea pig model

    J Exp Med

    (1978)
  • I. Goldschneider et al.

    Human immunity to the meningococcus. I. The role of humoral antibodies

    J Exp Med

    (1969)
  • I. Goldschneider et al.

    Human immunity to the meningococcus. II. Development of natural immunity

    J Exp Med

    (1969)
  • W.F. Vann et al.

    Bacillus pumilus polysaccharide cross-reactive with meningococcal group A polysaccharide

    Infect Immun

    (1976)
  • N. Guirguis et al.

    Escherichia coli K51 and K93 capsular polysaccharides are crossreactive with the group A capsular polysaccharide of Neisseria meningitidis. Immunochemical, biological, and epidemiological studies

    J Exp Med

    (1985)
  • G.R. Jones et al.

    Lack of immunity in university students before an outbreak of serogroup C meningococcal infection

    J Infect Dis

    (2000)
  • E.C. Gotschlich et al.

    Human immunity to the meningococcus. III. Preparation and immunochemical properties of the group A, group B, and group C meningococcal polysaccharides

    J Exp Med

    (1969)
  • Cited by (178)

    • Animal models in vaccinology: state of the art and future perspectives for an animal-free approach

      2022, Current Opinion in Microbiology
      Citation Excerpt :

      There have been, nevertheless, several failures in vaccines clinical trials, highlighting the limitations of preclinical animal models as predictor of immunogenicity and efficacy [63••,64,65]. For diseases in which serological correlates of protection have been already identified (e.g. bactericidal activity for meningococcus and opsonophagocytic activity for pneumococcus), vaccine evaluation is generally based on serological assays and therefore the choice of the animal model to use is less critical [66,67]. The question of which animal model may be more representative to study immune response after infection or vaccination is much more critical when correlates of protection are unknown or when the pathogen is human specific and therefore receptors mediating colonization and/or disease are missing in the animal model [68,69].

    View all citing articles on Scopus
    View full text