The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l

Good News and Bad News — 4CMenB Vaccine for Group B

Neisseria meningitidis
Lee H. Harrison, M.D., and David S. Stephens, M.D.

Neisseria meningitidis remains a major cause of
meningitis, sepsis, and other serious infections
globally. Almost all meningococcal infections are
caused by one of six capsular groups (A, B, C, W,
X, and Y) that are distinguished by different
biochemical compositions of the polysaccharide
capsules. Over the past two decades, the use of
meningococcal capsular polysaccharide–protein
conjugate vaccines has led to major successes in
the prevention of invasive meningococcal disease.
For example, the introduction of monovalent
meningococcal capsular group A conjugate vac-
cine in the “African meningitis belt” (from Sene-
gal to Ethiopia) and meningococcal group C
conjugate vaccine in the United Kingdom led to
the virtual elimination of the burden of invasive
meningococcal disease caused by these capsular
groups.1,2
In addition to individual protection against
invasive meningococcal disease, a remarkable
feature of these conjugate vaccines is disease
prevention in unimmunized persons through
reductions in pharyngeal carriage and transmis-
sion in immunized persons (herd protection).
Adolescents typically have the highest carriage
rates, and immunization campaigns in this group
lead to protection of unimmunized persons in
the population. Herd protection adds substan-
tially to the cost-effectiveness and public health
benefit of meningococcal conjugate vaccines. In
the United States, quadrivalent meningococcal
conjugate vaccines that cover groups A, C, W, and
Y are recommended routinely for adolescents
and persons who are at high risk for invasive
meningococcal disease.
Meningococcal group B strains cause a large
proportion of cases of invasive meningococcal
disease in many countries. In the United States,
approximately one third of cases of invasive me-
ningococcal disease are caused by meningococcal
group B, and there have been numerous out-
breaks of meningococcal group B disease in in-
stitutions of higher learning. However, the devel-
opment of vaccines for meningococcal group B
lagged years behind meningococcal conjugate vac-
cines because group B polysaccharide resembles
human neural tissue and is poorly immunogenic.
Since late 2014, two meningococcal group B
vaccines using meningococcal outer-membrane
proteins as the primary antigens have been li-
censed in the United States.3 4CMenB is a four-
component combination of one variant of the
factor H–binding protein (FHbp); neisseria adhe-
sin A; neisserial heparin-binding antigen; and
outer-membrane vesicles containing the porin
proteinA (PorA). The other vaccine, MenB-FHbp,
includes two lipidated variants of FHbp. The pro-
portion of invasive meningococcal group B infec-
tions that are potentially preventable by 4CMenB
or MenB-FHbp in a given population depends in
part on the distribution of vaccine protein anti-
gen variants among strains causing sporadic
disease and outbreaks. However, although both
vaccines were developed for the prevention of
meningococcal group B infections, the vaccine
antigens are present in many meningococci and
therefore could provide protection against strains
other than group B. Licensure of both vaccines
was based on immunogenicity and safety, not on
clinical end points.

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 Editorial
Since 2015, the Advisory Committee on Im-
munization Practices has had a routine recom-
mendation for the use of meningococcal group
B vaccines for persons at high risk for invasive
meningococcal disease and a recommendation
based on shared clinical decision making for
persons 16 to 23 years of age who are not at
increased risk. The vaccines are not recommend-
ed routinely in persons in this age group be-
cause of the current historically low meningo-
coccal disease burden in the United States and
unanswered questions about the vaccines.4,5 For
example, what is the vaccine effectiveness
against invasive meningococcal capsular group
B disease? Do the vaccines reduce the prevalence
of pharyngeal carriage and therefore confer herd
protection?
In this issue of the Journal, two articles ad-
dress these fundamental questions for one of
these vaccines, 4CMenB. Ladhani et al.6 examine
the effect of the 2015 introduction of 4CMenB
into the immunization program for infants in
the United Kingdom (because of a high incidence
of group B disease there), with a schedule of
doses at 8 and 16 weeks of age and a booster at
12 months of age. This is an off-label schedule;
4CMenB was licensed in Europe with a four-
dose schedule in infants. The study by Ladhani
and colleagues, a follow-up to a previous study,
used well-established observational study designs
to estimate the effect of 4CMenB and vaccine
effectiveness during the first 3 years of the pro-
gram.7 There was a 75% reduction in cases of
meningococcal group B disease in vaccine-eligi-
ble age groups, and vaccine effectiveness was
estimated to be 59.1% against all meningococcal
group B disease. Although the confidence inter-
vals for the estimate of vaccine effectiveness
were wide and do not exclude 0% (−31.1 to 87.2),
taken together, the results suggest a substantial
effect of 4CMenB on capsular invasive meningo-
coccal group B disease in children in the United
Kingdom. This is good news and highlights the
real-world effectiveness of 4CMenB.
In another article in this issue, Marshall et al.8
examine the effect of 4CMenB on oropharyngeal
carriage of N. meningitidis in a randomized, con-
trolled trial involving more than 24,000 students
who were 15 to 18 years of age in 237 schools in
South Australia. The primary outcome was car-
riage of capsular groups A, B, C, W, X, or Y, as
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identified with the use of polymerase-chain-
reaction–based tests of oropharyngeal swabs
and cultures obtained from students 12 months
after they received two doses of 4CMenB, as
compared with those who received the vaccine at
the end of the trial. The rates of meningococcal
carriage among adolescents in the two groups
were historically low, which resulted in reduced
statistical power to detect differences in the
prevalence of carriage between the groups. Also,
the proportion of these carriage isolates that
would be predicted to be covered by 4CMenB
was not reported. Despite these limitations, no
appreciable effect of 4CMenB on the prevalence
of carriage or the acquisition of strains of any
capsular group, including meningococcal group B,
was detected. The lack of herd protection con-
ferred by 4CMenB against encapsulated menin-
gococci is the bad news. Although a previous
trial suggested a modest effect of 4CMenB on
meningococcal carriage 12 months after vacci-
nation,9 the trial by Marshall et al. showed no
discernible effect on the prevalence of carriage
of group B meningococci; these findings are
supported by other smaller studies that include
MenB-FHbp.10,11 Data from large studies of the
vaccine effectiveness of MenB-FHbp are lacking.
As compared with the results of the studies
of 4CMenB in this issue of the Journal, meningo-
coccal group C conjugate vaccines in the United
Kingdom have been reported to have an esti-
mated short-term vaccine effectiveness of 97% in
infants. In addition, the use of these vaccines
has resulted in a 75% reduction in the prevalence
of group C carriage among adolescents that has
led to reductions in the prevalence of group C
disease among unimmunized persons.2,12
What are the implications of the results of the
studies by Ladhani et al. and Marshall et al. for
policies on meningococcal immunization? First,
three doses of 4CMenB provide approximately
60% protection against invasive meningococcal
group B disease in infants; this provides assur-
ance of effectiveness through immunization pro-
grams. By extension and on the basis of other
studies cited by Ladhani et al., 4CMenB is prob-
ably effective in other age groups, such as ado-
lescents, and for control of outbreaks caused by
meningococcal strains that are covered by the
vaccine. Second, 4CMenB does not provide herd
protection against encapsulated meningococci,
377
 Editorial

so it will protect only persons who are adequate- adolescents and young adults: recommendations of the Advisory
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However, they also highlight the need for im- 7. Parikh SR, Andrews NJ, Beebeejaun K, et al. Effectiveness
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M, Martin SW. Use of serogroup B meningococcal vaccines in Copyright © 2020 Massachusetts Medical Society.

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The New England Journal of Medicine

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