Background: Control of meningococcal infection has a high priority in many industrialized nations, because of the high mortality rates associated with invasive infection, the public health effects of disease outbreaks, and the position of Neisseria meningitidis as a leading infectious cause of death in childhood. Throughout the past 200 years, epidemics of meningococcal infection have been noted in Europe, Africa, Asia, the United States, and New Zealand. The proportions of cases caused by the 5 predominant capsular types (A, B, C, Y, and W135) associated with the disease vary among different regions and within specific geographic areas with time. Comprehensive disease control can be achieved only with the use of vaccines that target all of these disease-causing serogroups.
Methods: Routine immunization with a new generation of conjugate vaccines against serogroup C meningococci in the United Kingdom since 1999 has had a major effect on serogroup C disease in the region. The success of the vaccine involves 2 mechanisms, ie, (1) direct protective effects for vaccinated individuals through induction of bactericidal antibodies and (2) reductions in nasopharyngeal carriage of the organism and consequent generation of herd immunity through reductions in transmission to unimmunized individuals.
Conclusions: Ongoing development of tetravalent A, C, Y, and W135 conjugate vaccines raises the hope that disease caused by these serogroups can be controlled in the near future. However, development of effective strategies to control serogroup B meningococcal disease is still needed for comprehensive control of meningococcal disease.
From the University of Oxford, John Radcliffe Hospital, Oxford, England.
Dr. Pollard has conducted trials of meningococcal vaccines on behalf of the University of Oxford, sponsored by manufacturers of meningococcal vaccines, including Chiron Vaccines, and his Department has received financial support for his attendance at scientific meetings from the same manufacturers.
Address for reprints: Andrew J. Pollard, PhD, FRCPCH, University of Oxford, Level 4, John Radcliffe Hospital, Oxford, England OX3 9DU. Fax +44 (0) 1865 220479; E-mail firstname.lastname@example.org.
Meningococcal disease is a serious public health concern that continues to be associated with high morbidity and mortality rates.1–3 Approximately 500,000 cases of invasive meningococcal disease occur annually worldwide, of which ≥50,000 result in death.4–6 Although the incidence of meningococcal disease is relatively low, compared with many other infections of childhood, the disease is characterized by a case fatality rate of approximately 10%.7,8 Survivors of the disease may sustain permanent sequelae, such as deafness, seizures, amputation, and mental retardation.7,9,10 Meningococcal disease is most common among infants and young children, among whom protective antibodies have not yet developed, and it is one of the leading causes of infectious death in early childhood in developed countries.2,3,5,6,8 Increased rates of the disease are also observed among adolescents 15–17 years of age in some populations; at this age, young people often change residence to enter college, university, or the military.3,6 The serious and often fatal consequences associated with meningococcal disease in the pediatric population have resulted in close surveillance of the disease in many countries throughout the world and an increased focus on vaccination as a means of prevention. In the United Kingdom, introduction of the serogroup C meningococcal vaccine for all children in 1999 led to a reduction in serogroup C meningococcal disease of >80%, providing hope that vaccine intervention might someday prevent all meningococcal disease.
Meningococcal disease was first described by Vieusseux11 in 1805, after an outbreak occurred in Geneva, Switzerland, but it was not until 1887 that Anton Weichselbaum12 observed the bacterium in cerebrospinal fluid and named the organism Diplococcus intracellularis. Numerous epidemics of the disease have been observed in the past 200 years, in all populated continents, including major outbreaks that coincided with the 2 world wars.5,13 Current endemic rates of meningococcal disease range from <1 to 5 cases per 100,000 population in most industrialized countries.5 Because of the epidemic nature of the disease, however, there are wide variations in its incidence over time and among geographic regions.5
In the past several decades, rates of meningococcal disease in the United States have remained relatively stable, with an annual incidence of 0.9–1.5 cases per 100,000 population.2,7 In the middle 1990s, the overall annual incidence of meningococcal disease in Europe was estimated to be ∼1.3–1.7 cases per 100,000 population, with substantial variability among the individual countries.14 The incidence of the disease ranged from ∼0.3 cases per 100,000 in Italy to 0.6 cases per 100,000 in France and 3.6 cases per 100,000 in England and Wales.8,14
Neisseria meningitidis is enveloped in a polysaccharide capsule and is classified into 12 serogroups on the basis of the chemical composition of the polysaccharide.8 Serogroups A, B, C, W135, and Y account for most cases of meningococcal disease throughout the world.2 There are significant variations in the distribution of these serogroups, both geographically and with time. Higher rates of meningococcal disease in England and Wales were associated with a period of hyperendemic serogroup C disease that began in 1985 and continued through the 1990s, with a peak incidence in the late 1990s (Fig. 1).3,13
Serogroups B and C are now responsible for most cases of meningococcal disease in developed countries,2,15–18 although patterns of serogroup distribution vary among geographic locations at any given time, as shown in Figure 2. 2,15–19 For example, the proportion of cases attributable to serogroup Y meningococcal disease in the United States increased from ∼9% during the period of 1990–1992 to ∼34% between 1995 and 1998, but this serogroup continues to occur relatively infrequently in most other developed countries around the world.2,15–19
Although outbreaks of serogroup A meningococcal disease were common in developed countries during the early 1900s, cases associated with this serogroup have been rare in these countries since World War II.2 In contrast, the majority of cases of meningococcal disease in Africa and Asia continue to be attributed to serogroup A,3 and more recently serogroup W135,20 particularly in a region of sub-Saharan Africa called the “meningitis belt.”5,8,21 During epidemics, the local incidence of the disease in some sub-Saharan African regions may approach 1000 cases per 100,000 population.2,22 Epidemiologic data suggest that the natural ecology of meningococcal disease results in varying rates of disease throughout the world, differences in serogroup distribution among geographic regions, and changes in serogroup distribution with time.
VACCINES FOR PREVENTION OF SEROTYPE C MENINGOCOCCAL DISEASE
Meningococcal disease affects a relatively small proportion of the general population (<1–5 cases per 100,000 population in most industrialized countries).13,23 Despite the relative rarity of meningococcal disease, the high mortality rate associated with this disease elevates the status of the disease as a serious public health concern. In addition, the unpredictable epidemiologic patterns associated with the disease complicate the implementation of strategies for its prevention.
Plain polysaccharide vaccines have been available since the 1960s for serogroup A and C meningococcal disease.8,22 The serogroup A/C vaccines have demonstrated efficacy in clinical trials and have been effective in controlling community outbreaks and epidemics.8,22 However, the effectiveness of serogroup C plain polysaccharide vaccines appears to be reduced or absent among infants and young children,8,22,24 presumably because plain polysaccharides are poorly immunogenic among children <2 years of age. In addition, these vaccines do not appear to induce immunologic memory, and repeated administration of plain polysaccharide vaccine leads to a degree of immunologic hyporesponsiveness,8 probably because of the T cell-independent nature of immune responses to polysaccharide antigens. It may be that plain polysaccharide vaccines drive a population of polysaccharide-specific memory B cells to become terminally differentiated as antibody-secreting plasma cells, with consequent depletion of the memory pool.8 Additional doses of polysaccharide vaccines induce stimulation of a depleted memory pool, resulting in a reduced antibody response.8 Tetravalent meningococcal serogroup A/C/Y/W135 plain polysaccharide vaccines are also poorly immunogenic among young children.8 Therefore, plain polysaccharide vaccines do not appear to be optimal candidates for preventing outbreaks of meningococcal disease in early childhood.
To increase the effectiveness of polysaccharide capsule-based vaccines, N meningitidis polysaccharides are conjugated to carrier proteins through technology developed for Haemophilus influenzae type b glycoconjugate vaccines. Unlike plain polysaccharide vaccines, conjugate polysaccharide vaccines appear to facilitate T cell help (through the protein carrier) for the polysaccharide-specific antibody response and to induce immunologic memory. As a result, sustained and boostable antibody responses can be generated, even among infants.25 Because conjugate vaccines offer the prospect of protection for young children and induction of long-term immunity, it was theorized that mass immunization with these agents might be an improved strategy for prevention of meningococcal disease during epidemics.19 Therefore, a meningococcal serogroup C conjugate vaccine was developed to control the increasing incidence and high mortality rate associated with an epidemic of serogroup C meningococcal disease in the United Kingdom in the 1990s.6,8
MASS IMMUNIZATION WITH MENINGOCOCCAL SEROGROUP C CONJUGATE VACCINE IN THE UNITED KINGDOM
In 1999, the United Kingdom became the first country to implement a mass-immunization program against serogroup C meningococcal disease with a conjugate vaccine.19 The vaccine was introduced in a stepwise manner to children and adolescents in different age groups, beginning with adolescents 15–17 years of age, an age group for which serogroup C was the leading cause of meningococcal disease and the highest mortality rate associated with the disease was noted (Fig. 3). 19 The vaccine was also introduced initially to infants 2–4 months of age and toddlers 13–15 months of age, age groups for which the highest prevalence of serogroup C meningococcal disease was reported and no effective vaccine alternative was available.19 The vaccine was then provided during a 1-year period, with a staggered schedule, to infants 5–12 months of age, toddlers 13–24 months of age, children 11–14 years of age, children 2–4 years of age, children 9–10 years of age, and, lastly, children 5–8 years of age.19 Children >5 years of age were vaccinated at school, whereas those <5 years of age were vaccinated by their general practitioners.26 Coverage rates for most age groups exceeded 85% of the population.26
A comprehensive postlicensure surveillance program was initiated by the U.K. Health Protection Agency (formerly the Public Health Laboratory Service) to monitor the impact of immunization with the meningococcal serogroup C conjugate vaccine on the incidence of the disease.19,26 After mass immunization, there was a substantial reduction in the incidence of serogroup C meningococcal disease in England and Wales (Fig. 4). 26 An overall reduction of 81% in the incidence of serogroup C meningococcal disease was observed from the period of 1998–1999 to that of 2000–2001.26 Vaccine efficacy estimates as of September 2001 were 80–92% for infants 2–5 months of age, 90% for children 1–2 years of age, 100% for children 3–4 years of age, 95% for children 5–14 years of age, and 92% for adolescents 15–17 years of age.19
Unvaccinated individuals also appeared to receive some protection from meningococcal disease through herd immunity.19 An analysis of the attack rates for serogroup C meningococcal disease in unvaccinated cohorts before and after the introduction of the meningococcal C serogroup conjugate vaccine found a reduction in meningococcal disease among those individuals that ranged from 34% for 9-14-year-old subjects to 61% for 15-17-year-old subjects.19 Therefore, it appears that the conjugate vaccine protects not only vaccinated individuals but also the larger community, presumably as a result of reduced nasopharyngeal carriage of the organism among transmitters.
A large study of nasopharyngeal carriage rates for meningococci, among adolescents 15–17 years of age, before and after the introduction of the conjugate vaccine explored the effect of vaccination on carriage rates.26 Samples were collected from a total of 14,064 students during vaccination in 1999 and then from 16,583 students of the same age in 2000.27 The number of meningococcal samples expressing serogroup C polysaccharide was reduced from 63 (0.45%) in 1999 to 25 (0.15%) in 2000.27 Overall, the proportion of meningococci expressing serogroup C polysaccharide decreased by 69% (P = 0.001), and nasopharyngeal carriage of serogroup C meningococci in this age group was reduced by an average of 66% (P = 0.004).27 There did not appear to be any increase in carriage rates for other serogroups of meningococci during the same period, which indicated that serogroup replacement did not occur as a result of mass immunization.27
The immunization program had a major impact on the incidence of serogroup C meningococcal disease in England and Wales.19 Before the initiation of the program in 1999, 38% of meningococcal cases were attributable to serogroup C; this number decreased to 16% in 2001.19 This reduction in the prevalence of serogroup C meningococcal disease led to concerns that immunologic pressure on populations of meningococci might result in capsule switching from serogroup C to serogroup B.19 However, surveillance data clearly showed that, as the incidence of serogroup C meningococcal disease decreased after mass immunization in the United Kingdom, the number of serogroup B cases did not increase (Fig. 5). 28 Although the percentage of meningococcal cases associated with serogroup B increased from 57% in 1999 to 73% in 2001, the actual numbers of cases remained relatively constant, at 951 and 902 cases, respectively.19 However, the possibility that capsule switching can occur in some circumstances after introduction of serogroup C vaccines is raised by the emergence in Spain of serogroup B meningococci of the ST11 lineage, which was previously associated predominantly with serogroup C meningococci.29
FUTURE OPPORTUNITIES FOR CONJUGATE MENINGOCOCCAL VACCINES
The United Kingdom experience provides strong support for the effectiveness of mass immunization with conjugate meningococcal serogroup C vaccines against outbreaks of serogroup C meningococcal disease. The initial reduction in serogroup C meningococcal disease seen after mass immunization in the United Kingdom likely reflected a combination of individual immunity and herd immunity through a reduction in the nasopharyngeal carriage rate. For infants, administration of 3 doses of serogroup C conjugate vaccine during the first few months of life provides adequate levels of the serologic correlate of protection from meningococcal disease at 1 month after administration of the first dose.25,30 However, approximately 25% to 47% of these infants are no longer adequately protected against the disease at 1 year of age, on the basis of these measures of seroprotection.25,30 Because conjugate vaccines induce immunologic memory, the majority of children are again protected (serologically) against the disease shortly after they receive a booster dose.25,30 It is not clear whether children simply require the immunologic memory that develops after vaccination or whether resting antibodies in blood also are required to provide protection. The requirement for resting antibodies may vary depending on the duration of carriage of the organism in the nasopharynx before invasion in a susceptible individual. If invasive disease occurs within a few days, then there is likely insufficient time to mount a memory response, because several days are required before antibody appears in the serum. Therefore, children in the United Kingdom are currently protected through a combination of herd immunity, immunologic memory, and resting antibody levels. It is possible that all of these factors may decline after infant immunization, and it may be appropriate in the future to consider administering booster doses of the conjugate vaccine in late childhood or early adolescence. Careful surveillance is in place in the United Kingdom and will need to be continued in the decades ahead.
Although serogroups A, Y, and W135 continue to be relatively rare in the United Kingdom, the prevalence of serogroup B meningococcal disease remains significant. In addition, cases of W135 meningococcal disease have been observed in the United Kingdom in relation to the Hajj pilgrimage to Mecca.6 It is likely that the serogroup distribution associated with meningococcal disease will continue to change with time. On the basis of the encouraging results seen with serogroup C meningococcal conjugate vaccines, conjugate vaccines are now being developed to address other meningococcal serogroups except serogroup B, for which alternative strategies are required.
In conclusion, there are wide variations in the rates and distribution of meningococcal disease throughout the world, and this complicating factor must be considered in the development of immunization programs. Meningococcal serogroup C conjugate vaccines have substantially reduced the incidence of serogroup C meningococcal disease in the United Kingdom, as well as in other countries where such vaccines have been introduced. On the basis of the favorable experience with mass immunization with meningococcal serogroup C conjugate vaccines in the United Kingdom, it is anticipated that newer conjugate vaccines being developed for meningococcal disease associated with serogroups A, Y, and W135 will provide similarly improved protection for individuals of all ages. The challenge ahead is the prevention of serogroup B meningococcal disease.
Since acceptance of this article, data have been published by the Health Protection Agency showing that effectiveness of the meningococcal conjugate vaccine in the United Kingdom wanes with time after immunization of infants supporting the view presented in this article that there is a need for booster doses of vaccine after infancy in order to maintain protection.31
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