Seroprotection against serogroup C meningococcal disease
Authors: Lucieni O Conterno, Paul T Heath
Journal: BMJ (2008)

Neisseria meningitidis is a leading cause of bacterial meningitis worldwide. Most cases in developed countries are caused by endemic disease. The incidence is around 1-2 per 100 000,1 2 3 with rates among infants as high as 20 per 100 000.2 Children younger than 2 years have the highest incidence of meningococcal disease, with a second peak between 15 and 24 years. Most cases are caused by serogroups A, B, C, W-135, and Y. Serogroups C and B predominate in temperate countries.1 2 3

In the accompanying study, Snape and colleagues evaluate the persistence of serum bactericidal antibody against meningococcal serogroup C in a large cohort of adolescents originally immunised with serogroup C meningococcal conjugate vaccines at 6-15 years of age.4 These vaccines, now used in many countries, were licensed on the basis of immunogenicity rather than clinical efficacy.5 Despite the high public profile of meningococcal disease, it is relatively rare, which makes traditional efficacy studies prohibitive and impractical. The approach to licensing this vaccine was therefore novel and was based on its ability to induce serum bactericidal antibody at titres known to correlate with clinical protection. Since the licence was granted, effectiveness studies have confirmed the validity of this approach and have allowed further fine tuning of these serological correlates of protection.5 6 7 8

A systematic review conducted in 2006 confirmed that serogroup C meningococcal conjugate vaccines are highly immunogenic in all age groups.9 However, a decline in serological protection over time was noted in children who were vaccinated in infancy, a phenomenon also seen with the Haemophilus influenzae type b conjugate vaccines. The relevance of this finding was not clear, as the presence of immunological memory implied that a rapid immune response should occur when antigen was encountered. This might result in clinical protection, even in the absence of detectable circulating antibody. But meningococcal disease has a short incubation period, so the speed of response is crucial. Subsequent observations on vaccine failures and analysis of vaccine effectiveness (for both the meningococcal and influenza vaccines) now support the need for persistence of bactericidal antibody.10 In the United Kingdom, the public health response to this has been the recent addition of a booster dose of these vaccines in the second year of life.

Snape and colleagues found that five years after immunisation, 84.1% (95% confidence interval 81.6 to 86.3) of 987 participants had bactericidal antibody titres ≥1:8. However, geometric mean titres were significantly lower in 11-13 year olds (147; 115 to 188) than in 14-16 year olds (300; 237 to 380) and 17-20 year olds (361; 253 to 513) (P<0.0001 for both comparisons). Protective titres were achieved in around 10% fewer of the 11-13 year olds than in the older groups. The authors conclude that antibody titres five years after immunisation are higher if children are vaccinated in the second decade of life rather than the first.4

These data emphasise the importance of age at vaccination for conjugate vaccines with regard to protection and persistence, and they have implications for the number of vaccine doses needed at different ages. The increased immune response seen in the second decade of life is difficult to explain. The authors suggest that the older participants may have had more natural exposure to serogroup C meningococci just before or after they were immunised and so were better primed (or boosted) by carriage, with better primary responses and better persistence. In the era before vaccination, carriage was highest in the adolescent age group (albeit only at around 0.5%).11 Study participants over the age of 15 were therefore vaccinated around the time of maximum carriage and exposure. Seroepidemiological studies of group C (pre-vaccine) and group B meningococci also show sharp increases in antibody titres in adolescent age groups, which lends support to this argument.

The authors’ second hypothesis is that immune responses mature in the second decade of life, so that primary and persistent vaccine responses are enhanced. They found no literature to support this with respect to conjugate vaccines, but it may be possible to test this hypothesis in the next phase of the UK meningococcal vaccine programme.

The meningococcal vaccination programme has been a great success—high levels of direct and indirect vaccine protection have been recorded; carriage and invasive disease have declined significantly12; for the first time ever, no one under 19 years old has died of this disease in the past year; and the feared replacement by serogroup B disease has not occurred. This experience may help other countries to define the best strategy to prevent serogroup C disease, taking into account their own epidemiological reality.

However, concerns about ongoing control of disease as children in certain age groups get older and perhaps lose their antibodies—as shown by Snape and colleagues4—remind us that continued high quality surveillance must continue, even long after disease seems to have been controlled.