Elsevier

The Lancet

Volume 359, Issue 9316, 27 April 2002, Pages 1499-1508
The Lancet

Review
Development of vaccines against meningococcal disease

https://doi.org/10.1016/S0140-6736(02)08416-7Get rights and content

Summary

Neisseria meningitidis is a major cause of bacterial meningitis and sepsis. Polysaccharide–protein conjugate vaccines for prevention of group C disease have been licensed in Europe. Such vaccines for prevention of disease caused by groups A (which is associated with the greatest disease burden worldwide), Y, and W135 are being developed. However, conventional approaches to develop a vaccine for group B strains, which are responsible for most cases in Europe and the USA, have been largely unsuccessful. Capsular polysaccharide-based vaccines can elicit autoantibodies to host polyslalic acid, whereas the ability of most non-capsular antigens to elicit broad-based immunity is limited by their antigenic diversity. Many new membrane proteins have been discovered during analyses of genomic sequencing data. These antigens are highly conserved and, in mice, elicit serum bactericidal antibodies, which are the serological hallmark of protective immunity in man. Therefore, there are many promising new vaccine candidates, and improved prospects for development of a broadly protective vaccine for group B disease, and for control of all 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.

Section snippets

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

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.

References (165)

  • K Cartwright et al.

    Meningococcal disease in Europe: epidemiology, mortality, and prevention with conjugate vaccines. Report of a European advisory board meeting Vienna, Austria, 6-8 October, 2000

    Vaccine

    (2001)
  • HC Whittle et al.

    Recognition of diphtheria

    Lancet

    (1975)
  • GreenwoodBM

    Manson Lecture Meningococcal meningitis in Africa

    Trans R Soc Trop Med Hyg

    (1999)
  • MK Taha et al.

    Serogroup W135 meningococcal disease in Hajj pilgrims

    Lancet

    (2000)
  • S De Maeyer et al.

    Epidemiology of meningococcal meningitis in Belgium

    J Infect

    (1981)
  • TY Liu et al.

    Studies on the meningococcal polysaccharides. I. Composition and chemical properties of the group A polysaccharide

    J Biol Chem

    (1971)
  • BM Greenwood et al.

    Control of meningococcal infection in the African meningitis belt by selective vaccination

    Lancet

    (1980)
  • N Binkin et al.

    Epidemic of meningococcal meningitis in Bamako, Mali: epidemiological features and analysis of vaccine efficacy

    Lancet

    (1982)
  • MKA Hassan-King et al.

    Meningococcal carriage, meningococcal disease and vaccination

    J Infect

    (1988)
  • AL Reingold et al.

    Age-specific differences in duration of clinical protection after vaccination with meningococcal polysaccharide A vaccine

    Lancet

    (1985)
  • JB Robbins et al.

    “Love's labours lost”: failure to implement mass vaccination against group A meningococcal meningitis in sub-Saharan Africa

    Lancet

    (1997)
  • World Health Report Geneva: World Health Organization;...
  • BM Andersen

    Mortality in meningococcal infections

    Scand J Infect Dis

    (1978)
  • A Halstensen et al.

    Solberg CO. Case fatality of meningococcal disease in western Norway

    Scand J Infect Dis

    (1987)
  • TV Murphy et al.

    Declining incidence of Haemophilus influenzae type b disease since introduction of vaccination

    JAMA

    (1993)
  • WG Adams et al.

    Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era

    JAMA

    (1993)
  • VJ Quagliarello et al.

    New perspectives on bacterial meningitis

    Clin Infect Dis

    (1993)
  • H Laurichesse et al.

    Pneumococcal bacteraemia and meningitis in England and Wales, 1993 to 1995

    Commun Dis Public Health

    (1998)
  • VenetzI et al.

    Paediatric, invasive pneumococcal disease in Switzerland, 1985 1994. Swiss Pneumococcal Study Group

    Int J Epidemiol

    (1998)
  • Prospective multicentre hospital surveillanceof Streptococcus pneumomae disease in India

    Lancet

    (1999)
  • G Campagne et al.

    Epidemiology of bacterial meningitis in Niamey, Niger, 1981-96

    Bull World Health Organ

    (1999)
  • EA Kirsch et al.

    Pathophysiology, treatment and outcome of meningococcemia: a review and recent experience

    Pediatr Infect Dis J

    (1996)
  • J Wenger et al.

    Epidemiological impact of conjugate vaccines on invasive disease caused by Haemophilus influenzae type b

  • M Landaverde et al.

    Introduction of a conjugate vaccine against Hib in Chile and Uruguay

    Rev Panam Salud Publica

    (1999)
  • HR Shinefield et al.

    Efficacy of pneumococcal conjugate vaccines in large scale field trials

    Pediatr Infect Dis J

    (2000)
  • B Hubert et al.

    Recent changes in meningococcal disease in Europe

    Eurosurveillance

    (1997)
  • LH Harrison et al.

    Invasive meningococcal disease in adolescents and young adults

    JAMA

    (2001)
  • MG Bruce et al.

    Risk factors for meningococcal disease in college students

    JAMA

    (2001)
  • LH Harrison et al.

    Risk of meningococcal infection in college students

    JAMA

    (1999)
  • KR Neal et al.

    Invasive meningococcal disease among university undergraduates: association with universities providing relatively large amounts of catered hall accommodation

    Epidemiol Infect

    (1999)
  • GA Filice et al.

    Group A meningococcal disease in skid rows: epidemiology and implications for control

    Am J Public Health

    (1984)
  • RE Stanwell-Smith et al.

    Smoking, the environment and meningococcal disease: a case control study

    Epidemiol Infect

    (1994)
  • K Krasinski et al.

    Possible association of mycoplasma and viral respiratory infections with bacterial meningitis

    Am J Epidemiol

    (1987)
  • J Merino et al.

    Prevalence of deficits of complement components in patients with recurrent meningococcal infections

    J Infect Dis

    (1983)
  • KAV Cartwright

    Meningococcal carriage and disease

  • SE Branham

    Serological relationships among meningococci

    Bact Rev

    (1953)
  • M Connolly et al.

    Is group C meningococcal disease increasing in Europe? A report of surveillance of meningococcal infection in Europe 1993-6. European Meningitis Surveillance Group

    Epidemiol Infect

    (1999)
  • NE Rosenstein et al.

    The changing epidemiology of meningococcal disease in the United States, 1992-1996

    J Infect Dis

    (1999)
  • M Guibourdenche et al.

    Epidemics of serogroup A Neisseria meningitidis of subgroup III in Africa, 1989-94

    Epidemiol Infect

    (1996)
  • CV Broome et al.

    Epidemic group C meningococcal meningitis in Upper Volta, 1979

    Bull World Health Organ

    (1983)
  • Cited by (223)

    • Quality by design approach in the development of an ultra-high-performance liquid chromatography method for Bexsero meningococcal group B vaccine

      2018, Talanta
      Citation Excerpt :

      Bacterial meningitis is an infection of the membranes and cerebrospinal fluid surrounding the brain and spinal cord and it is a major cause of death and disability worldwide. Three organisms are responsible for most cases of bacterial meningitis: Neisseria meningitidis, Haemophilus influenzae type b and Streptococcus pneumoniae [4–7]. N. meningitidis is a pathogen bacterium that is transmitted through contact with respiratory droplets.

    View all citing articles on Scopus
    View full text