Meningococcal surrogates of protection—serum bactericidal antibody activity
Introduction
Meningococcal disease is still a major global public health problem with approximately 1.2 million cases per year causing an estimated 135,000 deaths [1]. Neisseria meningitidis serogroup A is mainly responsible for the large epidemics observed in sub-Saharan Africa, in a region known as the “Meningitis Belt”. In 2002, a large outbreak of serogroup W135 occurred in Burkino Faso [2]. Endemic meningococcal disease due to mainly serogroups B and C is observed in Europe and the US, with the addition of serogroup Y contributing a significant proportion of meningococcal disease in the US. An epidemic of meningococcal serogroup B disease is ongoing in New Zealand [3], [4] and previous epidemics of serogroup B disease have occurred in Brazil [5], Norway [6], Chile [7] and Cuba [8].
The role of circulating antibody and complement in protection from meningococcal disease was demonstrated as early as the 1900s [9], [10]. Serum bactericidal antibody (SBA) activity has been shown to highly correlate with immunity to meningococcal disease [11]. An inverse correlation was observed between the age-related incidence of disease and the age-specific prevalence of complement-dependent serum bactericidal activity [11]. Induction of complement-dependent bactericidal antibodies after vaccination with meningococcal polysaccharide or protein conjugate vaccines is regarded as acceptable evidence of the potential efficacy of these vaccines [12], [13].
In 1976, the World Health Organisation (WHO) Expert Committee on Biological Standardization recommended a SBA assay to satisfy the requirements for production and release of meningococcal polysaccharide vaccine [12]. These SBA assay requirements have also been used to support vaccine licensure. In order for a vaccine to be acceptable for licensure, ≥90% of the immunised adult subjects must have at least a four-fold rise (increase of ≥2 dilutions) in SBA titre when tested against target strains by the specified SBA assay [12].
Section snippets
Mechanism of serum bactericidal antibody assay
Neisseria meningitidis target strains are lysed in the presence of meningococcal-specific antibody and complement (antibody-mediated, complement-dependent killing). To perform the SBA assay serial dilutions of human sera are incubated with appropriate target strains and complement. Meningococcal-specific antibody binds to the target cell surface via meningococcal-specific protein or carbohydrate moieties. The C1q subunit of C1 binds to the Fc portion of the surface-bound Ig. The binding of C1q
Individuals with defects in the complement pathway
The importance of complement mediated bactericidal activity is illustrated by the increased susceptibility of individuals with defects in the complement pathway to meningcoccal disease. Individuals with a deficiency in the classical or alternative pathway or a late complement component have a 5–10,000-fold greater risk of meningococcal disease than normal individuals and are more likely to have a recurrence of infection [14], [15], [16]. Men who have inherited an X-linked deficiency of
Serogroup C
The original surrogate of natural protection for meningococcal serogroup C (MenC) disease was established by Goldschneider et al. [11] as a SBA titre with human complement (hSBA) of ≥4. This was found to be mediated by serogroup C-specific anticapsular antibodies demonstrated by using adsorption studies with serogroup C polysaccharide [24]. The study involved bleeding army recruits at the commencement of their training and then the level of SBA was determined in those who went on to acquire
Natural immunity
Goldschneider et al. [11] was again the first to demonstrate an inverse relationship across different age groups between SBA activity against serogroup B meningococci and meningococcal disease. Cases occurring in 1965 and 1966 were mainly due to serogroups B (MenB) and C [34]. Age-dependent development of natural immunity as measured by SBA activity has been described by analysing sera from children and adults. Matsunami and Kolmer [9] concluded that the SBA activity from children aged 6 months
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