Neisseria meningitidis is an organism that is well-known to pediatricians as an important cause of sepsis, which can be fulminant, and of bacterial meningitis as well as invasive infections at other sites. These infections can lead to hearing loss, loss of limbs, and even death in a matter of hours.1 On the basis of the content of the polysaccharide capsule, N meningitidis can be divided into 12 serogroups, but serogroups A, B, C, D, Y, and W-135 are responsible for virtually all invasive infections. In the United States, the overall incidence of meningococcal disease has been on the decline over the past several decades, which, in part, may be related to the introduction of routine administration of the quadrivalent meningococcal conjugate vaccine directed against serogroups A, C, Y, and W-135 to adolescents.2 

Investigators from the Centers for Disease Control and Prevention using data from the National Notifiable Diseases Surveillance System recently reported that the overall average incidence of meningococcal disease was 0.26 cases per 100 000 population over the years 2006–2015.2 This translates into an average annual number of cases of 792 associated with 98 deaths (14.9%). On average per year, serogroup B isolates were responsible for the highest number of cases (n = 229), followed by serogroup Y (n = 183) and serogroup C (n = 146).

Over the past 3 years, 2 vaccines directed against serogroup B meningococcal isolates have been licensed in the United States (Trumenba [meningococcal B factor H binding protein]) and Bexsero (component meningococcal B vaccine [Bexsero] quadrivalent [4CMenB]). Both are licensed for use in people 10 to 25 years of age on the basis of bactericidal antibody responses to the vaccines that were considered protective when administered to healthy individuals. However, because the incidence of meningococcal infections has been relatively low in the United States, the Advisory Committee on Immunization Practices along with the Committee on Infectious Diseases of the American Academy of Pediatrics recommended that serogroup B vaccines only be given routinely to individuals with an increased risk for this infection or for risk of overwhelming infection.3,4 The groups included in this recommendation were individuals with persistent complement deficiency5 or individuals receiving eculizumab, which blocks complement (used in the treatment of atypical hemolytic uremic syndrome, transplant-associated thrombotic microangiopathy, and paroxysmal nocturnal hemoglobinuria),6,7 individuals with asplenia or splenic dysfunction such as occurs in hemoglobinopathies,5 specific populations of individuals identified during an outbreak of serogroup B meningococcal disease (such has occurred on college campuses),8 or microbiologists routinely working with meningococcus. Meningococcal vaccines are recommended to be administered at least 2 weeks before giving the first dose of eculizumab. However, researchers of the immunogenicity studies that led to licensure of these 2 vaccines did not include individuals with complement deficiency, either congenital or related to eculizumab, or individuals with asplenia or splenic dysfunction.

In this issue of Pediatrics, Martinón-Torres et al9 compared the immunogenicity of the 4CMenB-4 vaccine in children and adolescents 2 to 17 years old with complement deficiency (n = 40; approximately a third had complement component 3 and/or complement component 4 deficiency; 9 were receiving eculizumab) or asplenia or splenic dysfunction (n = 112; 7 had congenital asplenia, 8 had functional asplenia, and 92 underwent splenectomy) with responses in healthy control children (n = 87). This study was conducted at 18 sites in 5 countries. The 4 components in 4CMenB are factor H binding protein, neisserial adhesion binding antigen, neisserial adhesion A, and an outer membrane vesicle component with immunodominant porin protein (ProA). The vaccine 4CMenB was administered intramuscularly 2 months apart. Sera were obtained before receiving the vaccine and 1 month after the second dose. Immunogenicity was assessed by using the standard assay to determine serum bactericidal activity against 4 meningococcal test strains, each selected to specifically assess 1 of the 4 components of the vaccine. Bactericidal activity requires complement activity, and assays were conducted by using both added exogenous human complement or with just the endogenous complement already present in the sample.

It is reassuring that these investigators found that children with asplenia or splenic dysfunction had bactericidal antibody responses that were equivalent to those in the healthy control children when using either exogenous or endogenous complement. However, for the participants with congenital complement deficiencies or for participants who received eculizumab, bactericidal activity was basically equivalent in the majority of children only when exogenous complement was added. Lower bactericidal responses were noted when endogenous complement was employed. These findings are not unexpected and are consistent with reports of invasive serogroup B meningococcal disease occurring in patients receiving eculizumab despite being immunized with meningococcal conjugate vaccine directed against serogroups A, C, Y, and W-135 or a serogroup B vaccine.10,12 

Thus, the findings in the current study further support the recommendations to provide antibiotic prophylaxis while patients are receiving eculizumab despite having received meningococcal vaccines.12 The effectiveness of antibiotic prophylaxis for patients with congenital complement deficiencies, other than for complement component 6 deficiency, is not clear.13 Hopefully, authors of ongoing surveillance studies will shed light on the effectiveness of serogroup B vaccines for prevention of invasive meningococcal infections in the targeted high-risk populations for which it is recommended.

     
  • 4CMenB

    component Meningococcal B Vaccine (Bexsero) quadrivalent

Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.

FUNDING: No external funding.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2017-4250.

1
Kaplan
SL
,
Schutze
GE
,
Leake
JA
, et al
.
Multicenter surveillance of invasive meningococcal infections in children.
Pediatrics
.
2006
;
118
(
4
). Available at: www.pediatrics.org/cgi/content/full/118/4/e979
[PubMed]
2
MacNeil
JR
,
Blain
AE
,
Wang
X
,
Cohn
AC
.
Current epidemiology and trends in meningococcal disease-United States, 1996-2015 [published online ahead of print November 8, 2017].
Clin Infect Dis
. doi:
[PubMed]
3
Patton
ME
,
Stephens
D
,
Moore
K
,
MacNeil
JR
.
Updated recommendations for use of MenB-FHbp serogroup B meningococcal vaccine - advisory Committee on Immunization Practices, 2016.
MMWR Morb Mortal Wkly Rep
.
2017
;
66
(
19
):
509
513
[PubMed]
4
Committee on Infectious Diseases
.
Recommendations for serogroup B meningococcal vaccine for persons 10 years and older.
Pediatrics
.
2016
;
138
(
3
):
20161890
5
Ram
S
,
Lewis
LA
,
Rice
PA
.
Infections of people with complement deficiencies and patients who have undergone splenectomy.
Clin Microbiol Rev
.
2010
;
23
(
4
):
740
780
[PubMed]
6
Greenbaum
LA
,
Fila
M
,
Ardissino
G
, et al
.
Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome.
Kidney Int
.
2016
;
89
(
3
):
701
711
[PubMed]
7
Dhakal
P
,
Giri
S
,
Pathak
R
,
Bhatt
VR
.
Eculizumab in transplant-associated thrombotic microangiopathy.
Clin Appl Thromb Hemost
.
2017
;
23
(
2
):
175
180
[PubMed]
8
Oviedo-Orta
E
,
Ahmed
S
,
Rappuoli
R
,
Black
S
.
Prevention and control of meningococcal outbreaks: the emerging role of serogroup B meningococcal vaccines.
Vaccine
.
2015
;
33
(
31
):
3628
3635
[PubMed]
9
Martinón-Torres
F
,
Bernatowska
E
,
Shcherbina
A
, et al
.
Meningococcal B vaccine immunogenicity in children with defects in complement and splenic function.
Pediatrics
.
2018
;
141
(
6
):
e20174250
10
Lebel
E
,
Trahtemberg
U
,
Block
C
,
Zelig
O
,
Elinav
H
.
Post-eculizumab meningococcaemia in vaccinated patients.
Clin Microbiol Infect
.
2018
;
24
(
1
):
89
90
[PubMed]
11
Parikh
SR
,
Lucidarme
J
,
Bingham
C
, et al
.
Meningococcal B vaccine failure with a penicillin-resistant strain in a young adult on long-term eculizumab.
Pediatrics
.
2017
;
140
(
3
):
e20162452
[PubMed]
12
McNamara
LA
,
Topaz
N
,
Wang
X
,
Hariri
S
,
Fox
L
,
MacNeil
JR
.
High risk for invasive meningococcal disease among patients receiving eculizumab (soliris) despite receipt of meningococcal vaccine.
MMWR Morb Mortal Wkly Rep
.
2017
;
66
(
27
):
734
737
[PubMed]
13
Turley
AJ
,
Gathmann
B
,
Bangs
C
, et al
.
Spectrum and management of complement immunodeficiencies (excluding hereditary angioedema) across Europe.
J Clin Immunol
.
2015
;
35
(
2
):
199
205
[PubMed]

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The author has indicated he has no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The author has indicated he has no financial relationships relevant to this article to disclose.