Adolescents need a booster of serogroup C meningococcal vaccine to protect them and maintain population control of the disease
- Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK
- Correspondence to Professor Andrew J Pollard, Department of Paediatrics, University of Oxford, Level 2, Children's Hospital, Oxford OX3 9DU, UK;
- Received 20 December 2012
- Revised 7 February 2013
- Accepted 8 February 2013
The serogroup C meningococcal immunisation programme was reviewed during 2012 by the Department of Health's Joint Committee on Vaccination and Immunisation (JCVI), and an adolescent booster has been recommended as a result of concerns over duration of immunity in the childhood population.1
During the 1990s, a clone of Neisseria meningitidis (sequence type 11; ST11) with a serogroup C polysaccharide capsule (repeating units of the sugar, α-2-9 N acetyl neuraminic acid) swept through the UK causing outbreaks of meningococcal disease in schools and universities, generating considerable media attention and anxiety for parents and those doctors, including paediatricians, in the front line of early diagnosis. The highest rates of disease were in the first 2 years of life, presumably as a result of immunological naivety, and among adolescents and young adults (see figure 1) as a result of various well known risk factors and behaviours (smoking, bar attendance, interpersonal proximity).2 ,3 The response to this serious public health problem, with some 955 microbiologically confirmed cases in the year from mid-1998, was the development, clinical testing and licensure of three serogroup C meningococcal (MenC) conjugate vaccines.4 These vaccines contain the MenC polysaccharide, chemically conjugated to a carrier protein (either tetanus toxoid or a mutant diphtheria toxoid, CRM197). The Department of Health launched an ambitious campaign of vaccination against MenC in the autumn of 19994 with the majority of infants, children and young people from 2 months to 19 years of age receiving MenC vaccine (see table 1) in a mass vaccination campaign over the next 12 months.5 Cases of disease caused by serogroup C meningococci plummeted over the next year, and continued to fall during the ensuing decade.6 Based on the prevaccination 1998 levels of disease, the vaccine may now have prevented more than 10 000 cases (see figure 2).
A striking effect of the vaccine programme was that disease also disappeared rapidly among those who were not vaccinated, including adults and unvaccinated children.7 Meningococci colonise the human nasopharynx, with very high rates of carriage of the organism observed among teenagers and young adults, contrasting with very low rates of colonisation in young children.8 Since young children do not appear to be important vehicles of carriage of this organism, we now believe that vaccination among teenagers in 1999 blocked adolescent acquisition of serogroup C strains, and thus, interrupted transmission of meningococci, protecting other age groups as a result.9
Since the first observations more than 80 years ago that meningococci may be killed by some human and animal sera,10 ,11 and observations in the 1960s among military recruits that those without serum killing activity were susceptible to disease,12 immunity against N meningitidis has been measured using an in vitro assay, the serum bactericidal assay, which measures complement-mediated antibody-dependent killing.13 The MenC conjugate vaccine induces high levels of this bactericidal antibody among vaccinees of all ages, and vaccine effectiveness correlates closely with the ability of the vaccine to induce these functional antibodies with a titre ≥1:8 in the population.13
In addition to inducing bactericidal antibody, the MenC glycoconjugate vaccines induce immunological memory (measured as augmented responses to subsequent doses of MenC vaccine and/or the presence of MenC-specific memory B cells in the peripheral blood), which should allow rapid (about 4 days) and high-magnitude responses to occur when a vaccinated individual is exposed to serogroup C N meningitidis.14 This contrasts with the much slower immune response among unimmunised infants when they first are exposed to MenC vaccines (about 10 days for a response which is low magnitude).15 However, in view of the rapid invasiveness of meningococci after acquisition in the nasopharynx (perhaps within hours or days), it seems unlikely that the 4-day delay for the memory response is fast enough to prevent all cases of meningococcal disease. Therefore, maintenance of serum bactericidal antibody is likely to be necessary to preserve vaccine effectiveness; we cannot rely on immune memory once antibody levels decline.
So, the remarkable success of the 1999 vaccine campaign appears to have been realised mainly through induction of high levels of serum bactericidal antibody which both protect the individual and also block acquisition of the bacteria in their nasopharynx and interrupt transmission, providing herd immunity, and a lesser contribution from immunological memory. Since the UK population is so critically dependent on anti-meningococcal antibody for protection against meningococcal disease, it is important to know how long the antibody will persist. Studies over the past decade have found that vaccine-induced MenC antibody wanes rapidly after infant vaccination,16 leading to an entirely rational decision in 2006 to add a booster dose of the vaccine in the UK at 12 months of age (combined with Haemophilus influenzae type b vaccine; see table 1). Unfortunately, it has now been shown that antibody wanes rapidly after this booster also17: boosted toddlers have similar levels of antibody 2 years after the booster when compared with those found in unboosted controls. Indeed, it is clear today that only a small proportion of children aged over 2 years have sustained levels of ‘protective’ bactericidal antibody if they have been immunised according to the UK infant immunisation schedules in place since the 1999 campaign.9 Furthermore, adolescents currently aged 13–18 years (immunised with a single dose of MenC vaccine at 1–6 years of age during the 1999 vaccine campaign) are similarly without protective antibodies (see figure 3). Taking these issues into account to give a snapshot of childhood MenC immunity in 2013, we can extrapolate from various studies to estimate that only 10% of individuals aged 2–18 years in the population have a level of MenC antibody above the protective threshold. For those under 2 years of age, there are protective levels of antibody after the primary doses and again after the 12-month booster, which wane rapidly in each case (see figure 3).9 ,18
While waning of antibody appears to be the rule after immunisation of young children, perhaps as a result of developmental differences in production of B cells or their maintenance in bone marrow niches, antibody persists for a prolonged period among those who received their first dose of vaccine over the age of 6 years back in 1999, who are now young adults (see figure 3).18 ,19 Since older children and young adults appear to be the main vehicles of transmission of meningococci, the high levels of antibody among individuals in this critical age group over the past decade may account for the persisting low levels of MenC disease in the UK, despite the loss of immunity in younger children. Indeed, today, protection against serogroup C meningococcal disease among most children, and adults above 32 years of age, may be almost entirely dependent on the high level of persisting immunity among those who are 18–32 years of age, which protects them directly, and the rest of the community indirectly.
If time stood still, this situation would be fine, but today's childhood population, whose immunity has all but vanished following immunisation as infants and young children, are now adolescents and will soon be entering adulthood (see figure 3). If we are to maintain their protection against MenC as they pass through this age of high risk of disease, and so also sustain protection for the rest of the community through herd immunity, there is now an urgent need to improve antibody levels among our adolescent population and to put in place a programme for future cohorts.
Fortunately, offering a booster dose of MenC vaccine during adolescence appears to induce very high levels of serum bactericidal antibody which are sustained.20 Providing earlier boosters, at preschool or in mid-childhood, is probably unnecessary since disease rates are low at this age and herd immunity from an adolescent booster should continue to provide protection. Provision of an adolescent booster is a potential solution to the problem, one that has recently been endorsed by JCVI.1
In order to accommodate the addition of an adolescent booster, JCVI also carefully re-evaluated the infant programme and recommended dropping one infant dose of MenC vaccine (see table 1).21 ,22 While this might seem to be a risky strategy, this schedule is immunogenic,23 and control of MenC disease has also been accomplished in other countries whose programmes started at 12 months of age,24 where a catch-up campaign among children and teenagers was used at the time of vaccine introduction. These observations indicate that infants can be protected through herd immunity if older children and young people are immunised. Indeed, such observations call into question the need for any infant doses, if high levels of immunity are present and sustained in the adolescent and young adult population. Perhaps further doses of vaccine in the infant programme could be dropped in the future, once population immunity has been re-established through the adolescent booster programme.
While maintaining a trimmed-back infant programme at 3 and 12 months of age, the addition of an adolescent booster of MenC vaccine, which is expected in 2013, will protect those who are vaccinated, and defend population immunity for the rest of us at the same time.
Contributors All authors contributed equally in the formulation of the manuscript and the review of the final draft.
Competing interests AJP and MDS conduct clinical trials on behalf of Oxford University sponsored by manufacturers of meningococcal vaccines but do not receive any personal payments from them. Honoraria and travel reimbursement for attendance at conferences and advisory board meetings by MDS are paid to a fund held at the University. The University receives unrestricted educational grants from these manufacturers for organisation of conferences and symposia. AJP is a member of the meningococcal subcommittee of the Joint Committee of Vaccination and Immunisation.
Provenance and peer review Commissioned; externally peer reviewed.