Elsevier

Vaccine

Volume 23, Issues 17–18, 18 March 2005, Pages 2222-2227
Vaccine

Meningococcal surrogates of protection—serum bactericidal antibody activity

https://doi.org/10.1016/j.vaccine.2005.01.051Get rights and content

Abstract

Despite the availability of anti-microbial agents effective against Neisseria meningitidis, meningococcal disease continues to be a major global health problem, particularly in the very young. Serogroup A meningococci cause large epidemics in sub-Saharan Africa, whilst serogroups B and C organisms are responsible for sporadic cases and localised outbreaks of disease world-wide. For measuring functional activity, the serum bactericidal antibody (SBA) assay is the most important method. It is mediated by antibody and complement resulting in lysis of the bacterial cells. To date the SBA has proved to be the best surrogate of protection for all serogroups. For serogroup C, an SBA titre of either ≥4 or ≥8 has being utilised for putatively indicating protection when using either human or baby rabbit complement, respectively. For serogroup B, the proportions of vaccines with ≥4-fold rises in SBA pre- to post-vaccination or SBA titres ≥4 have been correlated with clinical efficacy in trials of outer membrane vesicle (OMV) vaccines in Cuba, Brazil and Norway. SBA activity as a correlate of protection for evaluating the immune response to meningococcal vaccines is described in this review.

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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