Invasive Meningococcal Disease: The Rationale for Current Vaccine Policies

Author: Ahdi Amer, MD

Neisseria meningitidis has emerged as one of the leading causes of bacterial meningitis and sepsis in the United States following the significant decline in the incidence of both Haemophilus influenzae type B and Streptococcus pneumoniae after their respective conjugate vaccines were introduced.^1,2 Approximately 1.2 million cases of invasive disease are seen worldwide each year, and those cases result in 135,000 deaths.³

Most invasive disease is caused by about 5 serogroups: A, B, C, Y, and W-135. The importance of each serogroup depends on several factors, including geographic location and age. For example, serogroup A is responsible for both epidemic and endemic invasive meningococcal disease in sub-Saharan Africa and follows an east-to-west belt from Ethiopia to The Gambia below the Sahara desert (Figure 1).^4,5 Rates during epidemics are far higher than during endemic disease activity, with reported attack rates of up to 1 % of the population during major epidemics.⁴

The Changing Epidemiology of Meningococcal Disease

Serogroups B and C have become the most prevalent in many industrialized nations and are a major cause of endemic disease in Europe and North America. Multiple outbreaks at schools and universities have been attributed to serogroups B and C.

In the late 1990s, the prevalence of serogroup Y increased in North America. Serogroup Y has become responsible for approximately one-third of the disease burden (Figure 2) associated with meningococcal disease.⁶  More recently, rates of disease caused by serogroup C have been decreasing in Europe, North America, and Australia. In these regions, serogroup B is now more prevalent.^7,8

An examination of the epidemiology of infant meningococcal disease in the United States suggests that the disease burden is primarily caused by serogroup B. Active surveillance for disease caused by N meningitides and supported by the Centers for Disease Control and Prevention (CDC) was conducted from January 1, 2006 through December 31, 2012. Data generated from this surveillance revealed an estimated 113 cases that occurred annually in infants aged < 1 year, with an incidence rate of 2.74 per 100,000 infants. Serogroup B was responsible for most of these cases.⁹

During the past two decades, incidence rates of meningococcal disease in the United States have remained around 1 in 100,000, with the last peak in incidence occurring in the mid-1990s. By 2007, these rates decreased to 0.3 in 100,000,^6,10 a decline that was a result of decreases in the 3 most common serogroups (B, C, Y) in the United States. The exception to this trend was in the Pacific Northwest, which had higher rates of meningococcal disease in the 1990s due to hyperinvasive B strains.¹¹

Interestingly, the current reduction in incidence began well before the Tetravalent Meningococcal Conjugate Vaccine (MCV4) was introduced in 2005. MCV4 does not contain a serogroup B component, which means that the reduction in the incidence of serogroup B disease is unrelated to the introduction of the vaccine. There is no known explanation for the factors causing the significant decrease in the overall rate of meningococcal disease in the population, but population immunity to the strains currently circulating in the United States and fewer people displaying behavioral risk factors associated with invasive disease may have contributed to the decrease.

Risk of the disease varies between age groups, and this variation may be linked with behaviors that promote transmission. Transmission of meningococcal disease requires close and direct contact by droplet aerosol or secretions from the nasopharynx of colonized persons. The bacteria attach to and multiply on the mucosal cells of the nasopharynx. The organism penetrates the mucosal cells and enters the bloodstream in less than 1% of colonized persons.

Christensen and colleagues have shown that colonization prevalence increases through childhood from 4.5% in infants to a peak of 23.7% in adolescents aged 19 years. Rates in adulthood decrease, with a 7.8% prevalence rate in adults aged 50 years (Figure 3).¹² Typical adolescent behaviors such as sharing food and drinks, living in close quarters, and intimate kissing put individuals at increased risk for colonization and disease transmission.^13,14 Two studies from the United Kingdom indicate that the highest carriage rates are detected at the beginning of the first week of the first term in the first year of college, suggesting that college students are the group most at risk for contracting the disease.^15,16

The United States Morbidity and Mortality

An estimated 800-1,500 cases of meningococcal disease occur annually in the United States.¹⁷ The majority of these cases (> 95%) are sporadic, and < 5% are related to outbreaks.

Even when antibiotic therapy is initiated, the case-fatality rate of invasive meningococcal disease ranges between 9% and 12%.⁶ The case-fatality ratio reaches up to 40% in cases of meningococcemia. Of those who survive the disease, about one-fifth develop permanent sequelae that may include loss of hearing, neurologic damage, or loss of a limb.¹⁸

Meningococcal vaccines and the rationale for current USA vaccine policy

In 2005, the first meningococcal quadrivalent (MCV4) (Men A, C, Y, W) conjugate vaccine was licensed for use in the United States.¹⁹ The Advisory Committee on Immunization Practices (ACIP) made the recommendation with the goal of protecting adolescents through the peak of disease seen in people aged 16 to 21 years. The assumption at the time of recommendation was that the efficacy of the vaccine would endure for at least 10 years. However, by 2010 the Centers for Disease Control and Prevention recorded 12 cases of serogroup C or Y meningococcal disease among individuals who had received MCV4. Their mean age was 18.2 years and mean time since vaccination was 3.25 years.²⁰

In 2010, the Advisory Committee on Immunization Practices (ACIP) updated existing recommendations for the use of quadrivalent (serogroups A, C, Y, and W-135) meningococcal conjugate vaccines with 2 new recommendations: 1) to continue the routine vaccination of adolescents, preferably at age 11 or 12 years, followed by a booster dose at age 16 years, and 2) persons aged 2 through 54 years can receive a 2-dose primary series administered with a minimum interval of 2 months if risk factors such as persistent complement component deficiency, functional or anatomic asplenia, or human immunodeficiency virus (HIV) infection in an adolescent are present.²⁰

These recommendations followed a thorough review process by the Meningococcal Vaccines Work Group of ACIP for data available on immunogenicity in high-risk groups, persistence of bactericidal antibody following immunization, vaccine effectiveness, current disease epidemiology, and cost-effectiveness of different strategies for vaccination of adolescents.

The Work Group concluded that serologic data were consistent with waning immunity and that the presence of sufficient circulating antibodies is the most important of the 3 characteristics of conjugate vaccines that are believed to be essential for establishing long-term protection against a bacterial pathogen (memory response, herd immunity, and circulating antibody).²¹ The ACIP conclusion was based on data from the United Kingdom for serogroup C meningococcal conjugate vaccine (MenC). These data showed that the memory response after exposure was not rapid enough to protect against meningococcal disease and that a memory response after a booster dose was not measurable until 5 to 7 days later.²² 

Serogroup B Meningococcal Vaccines (MenB)

For years, vaccination of US adolescents against the bacteria that cause meningitis has been advised. However, the widely administered vaccine that was used since 2005 protected against only 2 (C and Y) of 3 main strains. It did not protect against the B strain that is responsible for about 30% of the disease burden in the United States.

Two serogroup B meningococcal vaccines (MenB) vaccines were licensed in 2014-2015 by the US Food and Drug Administration (FDA) for use in the United States and were approved for persons aged 10 to 25 years. These vaccines were MenB-FHbp (Trumenba, Wyeth Pharmaceuticals, Inc.) and MenB-4C (Bexsero, GlaxoSmithKline).²³

Current available data suggest that MenB vaccines will provide an important tool for controlling serogroup B meningococcal disease and that they may provide protection against the majority of currently circulating strains. However, these vaccines are not expected to provide protection against disease caused by all serogroup B strains circulating in the United States.²³

Based on the initial available data, there is no evidence that suggests serious adverse events for either of the MenB vaccines, but more safety data through postlicensure surveillance are needed. Also, considering the low prevalence of serogroup B meningococcal disease and the relative new availability of both vaccines, there are no available data on vaccine effectiveness against clinical disease endpoints or on the duration of protection against clinical disease.

ACIP recommended vaccination of all adolescents rather than college students only because a significant number of serogroup B meningococcal disease cases occurs in persons aged 18 to 23 years who are not attending college. Therefore, limiting vaccination options to college students would prevent the fewest cases and deaths among all the options reviewed by ACIP work group.²³  

Currently, ACIP recommends that MenB vaccine series may be administered to adolescents and young adults aged 16 to 23 years. The preferred age for MenB vaccination is 16 to 18 years (recommendation Category B). MenB vaccine should either be administered as a 3-dose series of MenB-FHbp or a 2-dose series of MenB-4C. Both MenB vaccines are not interchangeable and the same vaccine product must be used for all doses. However, MenB-FHbp or MenB-4C can be administered concomitantly with other vaccines indicated for this age, but at a different anatomic site.²³

CONCLUSION

With the introduction of the MenB vaccines, one should consider few interesting points. The new B vaccines contain proteins that are expressed by strains of the other non-B serogroups. This means that we may experience the potential impact of MenB vaccines on non-B disease and on nasopharyngeal carriage, as well as on the population of N meningitidis.

Another interesting point is the potential impact of B vaccines on herd immunity, which is not yet established, but could suggest a possible impact on B disease in infants and young children. Additionally, in the near future there is the possibility of developing a combined single pentavalent conjugate vaccine MCV5 (A, B, C, Y, W). Such a vaccine would potentially have an impact on the cost-effectiveness and overall strategy and recommendations for preventing meningococcal disease in the United States.

Adhi Amer, MD, is an associate professor in the Carman and Ann Adams Department of Pediatrics at Wayne State University School of Medicine in Detroit, Michigan.

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