A routine infant schedule versus an older infant/toddler schedule for Neisseria meningitidis vaccination: what do experience and reason tell us?

Response to: Pelton SI, Gilmet GP. Expanding prevention of invasive meningococcal disease. Expert Rev. Vaccines 8(6), 717–727 (2009) [1].

Prior to universal infant immunization programs that focused on infants in the first 6 months of life, the three bacterial pathogens responsible for most cases of bacterial meningitis in the USA were Haemophilus influenzae type b (Hib), Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis (meningococcus) [2–5]. Beginning in the early and mid-1990s, routine infant immunization with Hib conjugate vaccines and the heptavalent pneumococcal conjugate vaccine began to dramatically reduce the incidence of invasive disease caused by these encapsulated bacterial pathogens. With the successes of universal Hib and pneumococcal immunization programs, and the consequent reduction in morbidity and mortality due to these two organisms, the remaining morbidity and mortality due to the one remaining encapsulated organism in infants were highlighted.

Current vaccines approved for protection against invasive meningococcal disease are not licensed for use in infants younger than 2 years of age. However, with clinical trials of an investigational quadrivalent conjugate vaccine showing immunogenicity in infants as young as 2 months of age [6,7], the prevention of infant meningococcal disease through vaccination appears to be on the horizon. This important development has led to a policy debate concerning the optimal pediatric meningococcal disease immunization schedule. Experience would dictate that the optimal approach to invasive meningococcal disease in infants would follow the successful approaches used to control Hib and pneumococcus. This approach is used in the UK and elsewhere for the prevention of meningococcus type C [8]. Alternative and novel approaches have, however, been proposed. In the June issue of this journal, Pelton and Gilmet propose a vaccination strategy targeting later infancy and the early second year of life as the preferred approach [9]. Their reasoning is based on analyses of data and modeling showing greater cost–effectiveness with projected comparable disease prevention effectiveness and fewer vaccine doses administered [9].

The highest age-specific incidence of invasive meningococcal disease occurs in infants, an age group for which there is currently no vaccine available in the USA [10–12]. Between 1991 and 2002, the US CDC estimated that the incidence of meningococcal disease in US infants younger than 1 year of age was 9.2 per 100,000, declining to approximately three per 100,000 by 1 year of age [12]. Importantly, meningococcal disease incidence in US infants peaks at 1–6 months of age [13]. A second, smaller peak in meningococcal disease incidence occurs in adolescents aged 11–19 years (1.2/100,000 individuals in 1991–2002) [12]. Thus, infants experience meningococcal disease at an incidence rate more than sevenfold higher than that seen among adolescents. Reflecting this high incidence, the age-specific mortality rate from invasive meningococcal disease (in the period 1990–2002) is also highest among infants (0.95/100,000 individuals), followed by adolescents (~0.2/100,000 individuals), compared with the overall population (0.1/100,000 individuals) [14]. Serogroup distribution varies somewhat by age group. But for each of the five primary meningococcal serogroups that cause invasive disease (serogroup A, B, C, Y and W-135), the highest age-specific disease incidence rate occurs early within the first year of life [101].

Current polysaccharide and glycoconjugate N. meningitidis vaccines licensed in the USA contain antigens for serogroups A, C, W-135 and Y [11]. In 2007 in the USA, these serogroups (plus nongroupable serogroups) accounted for approximately 75% of meningococcal disease cases, with serogroup B, for which no vaccine currently is available, accounting for approximately the remaining 25% [101]. The relative predominance of serogroup B incidence in infants relative to other serogroups has led to the widely held misperception that serogroup B meningococcal disease is the ‘infant disease’, and the related misconception that infant immunization with a nonserogroup B vaccine would have minimal impact on disease burden for this age group. In fact, meningococcal serogroups C and Y are among the leading causes of infectious disease morbidity and mortality among US infants, collectively accounting for approximately half of such cases [101].

The quadrivalent meningococcal conjugate vaccine (MCV4) currently available in the USA is approved for use in children 2 years of age and older. However, the Advisory Committee on Immunization Practices (ACIP) guidelines recommend routine (age-based) vaccination only for those 11–18 years of age. (Vaccination is recommended for all individuals 2–55 years of age with increased underlying risk factors such as functional asplenia or terminal complement deficiencies). ACIP based their decision not to extend recommendations for routine vaccination in part on an assessment of the relative risk for invasive disease among age groups, determining that children 2–10 years of age have a lower risk compared with children aged younger than 2 years and adolescents aged 11–19 years [11]. The current meningococcal immunization strategy, therefore, is based on providing direct protection to age groups with a high incidence of meningococcal disease for whom an effective vaccine is currently licensed. As noted, infants under 6 months of age experience an incidence rate of invasive meningococcal disease far higher than that seen among 11–18-year-olds. The future availability of vaccines for infants as young as 2 months of age would allow for a vaccination strategy based on:

• • Direct protection of the age group at the highest risk of invasive disease (infants 1–6 months of age) [13]

• • Practical and feasible immunization of children during the first year of life when they are making frequent preventive healthcare visits

The most direct method of protecting an at-risk group from disease is through targeting that group for vaccination. Disease protection can also be extended to at-risk unvaccinated subpopulations indirectly through the development of herd effects at the population level. For encapsulated bacterial pathogens, immunizing infants against pneumococcus has been shown to reduce (through herd effects) pneumococcal disease in unvaccinated older adults [15]. Thus the proof-of-concept for achieving broad indirect protection across the population via universal infant immunization exists. However, pneumococcal epidemiology and meningococcal epidemiology differ. The alternative approach (protecting infants through the vaccination of adolescents and adults) has been taken with influenza and pertussis vaccination policies, partly because the immunogenicity of the vaccines is less optimal in infants. For influenza, currently the only mode of providing protection to infants is the indirect protection of infants through ‘cocooning’ effects from parents and healthcare providers. In the case of invasive meningococcal disease, protecting infants indirectly through the vaccination of older population subgroups is a new concept. Achievable rates of vaccination among adolescents, together with social interaction norms, cast serious doubt as to whether any herd effects secondary to immunization of older children would afford protection to young infants [16–18]. More importantly, the success of an older infant/toddler meningococcal disease vaccination program for extending indirect protection to younger infants is contingent upon initiating it in conjunction with an effective catch-up vaccination program for older children/adolescents to maximize the development of herd immunity through the reduction of carriage [9,19]. Such a catch-up component was part of the meningococcal serogroup C (MenC) vaccination program instituted in the UK in 1999, during which vaccination was offered to all children younger than 18 years of age with an 85% coverage rate [20]. Based on ACIP discussions and recent experience with pneumococcal conjugate, however, the USA appears unlikely to implement a similar mass catch-up campaign. Even if one assumes initiation of a catch-up vaccination program, modeling indicates that a new steady-state level of disease would not be achieved until 10–15 years later with an older infant/toddler strategy [9,19], during which time infants would remain at risk for invasive meningococcal disease until appreciable herd effects could develop. In addition, it is worth noting that the MenC program in the UK not only employed a catch-up program but currently still includes a vaccination program beginning at 3 months of age, even though a steady-state disease level has been achieved there. Thus, the UK program cannot be used to justify using vaccination of older children and adolescents as a means of protecting young infants.

The Hib vaccination program, comprising two-to-three doses (depending on the vaccine administered) given between the ages of 2 and 4–6 months plus a dose given at 12–15 months of age [102], has resulted in a more than 99% reduction in incidence in children younger than 5 years of age, from 10,000–20,000 cases of invasive Hib disease annually in the USA prior to widespread immunization [3,21] to less than 100 [22]. The introduction of a heptavalent pneumococcal conjugate vaccine given in four doses at 2, 4, 6 and 12–15 months of age [102] has also resulted in a substantial decline in invasive pneumococcal disease among young children [23]. As a result of the reduction in incidence of invasive Hib and S. pneumoniae disease from these vaccines, meningococci have emerged as a primary cause of bacterial meningitis and septicemia. Why would we think differently about our approach for preventing meningococcal disease, given the notable success of these infant immunization programs and questions regarding the feasibility of a catch-up program for meningococcal vaccination in young children?

Although cost–effectiveness is an important consideration within the context of immunization policy recommendations, it alone should not drive the US immunization policy, especially for a disease that has high morbidity and mortality, even with appropriate therapy. By the same token, the fact that one approved meningococcal conjugate vaccine is not reliably immunogenic in children under 6 months of age should not drive immunization policy. Epidemiologic and immunologic data should drive immunization policy. Where possible, reliance on proven immunization strategies rather than modeling will give us the highest likelihood of defining a successful approach.

The universal vaccination of infants against the major diseases of childhood has resulted in dramatic reductions in most diseases causing morbidity and mortality in children. Hib and pneumococcus are but two of the more recent examples. Following the successes with Hib and pneumococcus, control of meningococcal disease through universal infant immunization is an important public-health target. Programs designed for success in this arena should build on our prior knowledge and success with infant immunization programs. Why should we experiment with an approach that has served us so well?

Financial & competing interests disclosure

Steven Black is a consultant and speaker for sanofi pasteur, Novartis and Merck. Henry Shinefield is a speaker for sanofi pasteur and Novartis, and is a consultant for Merck. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.