We searched PubMed Medline electronic database with the keywords ‘Neisseria meningitidis and vaccination’, ‘meningococcal vaccine’, and ‘meningococcal epidemiology’, for articles published between 1991 and October, 2001. We selected articles in English describing candidate vaccines if (in our opinion) the candidates were already in clinical trials, or had a high likelihood of entering clinical trials in the next 2 years.
ReviewDevelopment of vaccines against meningococcal disease
Introduction
Bacterial meningitis is a serious threat to global health, accounting for an estimated 171 000 deaths worldwide per year.1 Even with antimicrobial therapy and the availability of advanced intensive care, case fatality rates are 5–10% in industrialised countries,2, 3, 4, 5, 6, 7, 8, 9 and are even higher in the developing world.10, 11, 12 Between 10% and 20% of survivors develop permanent sequelae, such as epilepsy, mental retardation, or sensorineural deafness.13, 14, 15, 16
Three species—Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis—account for most cases of bacterial meningitis occurring after the neonatal period. Polysaccharide vaccines for prevention of these diseases have been available for many years. However, they are not effective in young children, who are at increased risk of disease. Therefore, with the exception of pneumococcal vaccine in elderly people, use of these vaccines has been restricted.
Polysaccharide–protein conjugate vaccines are much more effective than unconjugated polysaccharide vaccines in young children. For example, vaccination with H influenzae type b (Hib) conjugate vaccines has nearly eliminated such disease both in affluent and in nonindustrialised countries.5, 6, 17, 18, 19 A polysaccharide-protein conjugate vaccine for S pneumoniae has been licensed in the USA and Europe. In clinical trials, this vaccine was effective for the prevention of pneumococcal bacteraemia and meningitis.20 It contains seven strains of S pneumoniae that are responsible for most cases in infants and children, and its widespread use is expected to eliminate invasive disease caused by these strains.
Effective conjugate vaccines for the prevention of meningococcal disease caused by group C strains have been licensed in the UK and in other European countries.21 However, to eliminate all bacterial meningitis as well as septicaemia caused by N meningitidis, new vaccines against the remaining pathogenic meningococcal groups are needed.
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Endemic disease
In industrialised countries, annual attack rates of meningococcal disease average 1–3 per 100 000 of the population.22, 23 The highest incidence is in children under the age of 5 years, with a secondary peak in teenagers and young adults. Case-fatality rates in under-5s are about 5%, whereas rates of up to 25% are seen in teenagers and adults.24 Some groups in the general population, such as university students living in dormitories,25, 26 or those using catered dining facilities,27 are at
Genetic adaptability of the meningococcus
Horizontal genetic exchange happens continually in meningococcal populations.72 It not only provides the mechanism by which hypervirulent isolates continue to emerge, through the acquisition of genes that enhance invasiveness, but also allows meningococci to exchange the genes that encode variable antigens. This exchange has important implications for the design of vaccines, because the organism can switch antigen genes within the meningococcal gene pool and thereby evade the immune response.
Polysaccharide vaccine
The polysaccharide capsules of N meningitidis are important determinants of virulence. Mutants without capsular expression are serum sensitive—ie, killed by complement, and non-pathogenic. Serum antibody to capsule polysaccharide protects against disease by activating complement-mediated bacteriolysis or opsonisation, or both. Polysaccharide vaccines against groups A and C, or A, C, Y, and W135, are licensed and available worldwide. There is no polysaccharide vaccine against group B.
The first
Vaccines against group B meningococcal disease
Despite nearly 25 years of work, conventional approaches have failed to produce any vaccines that can elicit broad protection against diverse group B meningococcal strains. Efforts to develop a group B polysaccharide–protein conjugate vaccine have been hindered by the dangers of induction of autoantibodies that cross-react with glycosylated host antigens. Therefore, investigators also looked at non-capsular approaches such as outer membrane proteins. So far, antigenic variability and poor
In-vivo gene expression
It has long been known that some candidate meningococcal vaccine antigens are only expressed in vivo. Therefore, approaches that rely on antigens from bacteria grown in vitro will fail to find potentially important new candidates. Recent developments in genetic technology provide approaches that can be used to identify genes that are only expressed in vivo and are likely to be involved in meningococcal virulence.163, 164 For example, in-vivo expression technology is designed to identify genes
Search strategy
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