Vaccines for Prevention of Group B
Meningococcal Disease
Not Your Father’s Vaccines
Lee H. Harrison
For decades, there was no licensed vaccine for prevention of endemic capsular group B
meningococcal disease, despite the availability of vaccines for prevention of the other most common
meningococcal capsular groups. Recently, however, two new vaccines have been licensed for
prevention of group B disease. Although immunogenic and considered to have an acceptable safety
profile, there are many scientific unknowns about these vaccines, including effectiveness against
antigenically diverse endemic meningococcal strains; duration of protection; whether they provide
any herd protection; and whether there will be meningococcal antigenic changes that will diminish
effectiveness over time. In addition, these vaccines present societal dilemmas that could influence
how they are used in the U.S., including high vaccine cost in the face of a historically low incidence of
meningococcal disease. These issues are discussed in this review.
(Am J Prev Med 2015;49(6S4):S345–S354) & 2015 by American Journal of Preventive Medicine and Elsevier
Ltd. All rights reserved.
Introduction
D
uring the past year, two new vaccines to prevent
capsular group B meningococcal disease have
been licensed. These vaccines are different from
other licensed vaccines: the vaccine antigens were identified using reverse vaccinology, they have been unusually
painstaking to develop, it has been technically difficult to
estimate potential impact, and actual impact will be
unusually challenging to monitor post-licensure.
The licensure of these vaccines is an exciting and
much-anticipated development. However, many important scientific questions remain unanswered about the
potential public health impact that can only be answered
post-licensure. In addition, the relatively low incidence of
group B disease, in combination with the high cost of the
vaccines in the U.S., has raised concern that these
vaccines may not be widely used.
In this review, I will give a brief overview of meningococcal disease epidemiology and the two licensed group B
vaccines and then discuss some salient scientific and societal
issues that may influence their impact and how widely they
will be used. This is meant to be an overview of some of the
challenges in vaccine prevention of group B meningococcal
From the Infectious Diseases Epidemiology Research Unit, University of
Pittsburgh, Pittsburgh, PA USA
Address correspondence to: Tel.: þ1 412 624 1599. E-mail: [email protected].
0749-3797/$36.00
http://dx.doi.org/10.1016/j.amepre.2015.09.007
& 2015 by American Journal of Preventive Medicine and Elsevier Ltd.
All rights reserved.
disease; reviews of group B vaccines themselves have been
published elsewhere.1–3 Although the vaccines are technically not exclusively group B vaccines because the proteins
they employ are present in meningococci independent of
capsular group, for simplicity I refer to them as group B
vaccines throughout this review.
Background
Meningococcal Disease and Epidemiology
Neisseria meningitidis is a major cause of meningitis and
other invasive bacterial infections globally. There are 12
known meningococcal polysaccharide capsular groups
yet six, namely A, B, C, W, X, and Y cause almost all
infections. The case fatality rate is around 10–15% and
permanent sequelae are common.4–7 Transmission of
N. meningitidis occurs through contact with respiratory
secretions of colonized persons; pharyngeal carriage rates
vary widely by time and geography but typically are
highest in adolescents and young adults.8–11
Because of both the naturally dynamic nature of meningococcal disease epidemiology and the introduction of
conjugate vaccines, the epidemiology of meningococcal
disease has changed dramatically over the past few years.
In the U.S., there has been a huge decline in the incidence of
meningococcal disease since an incidence peak in the mid1990s. The prevalence of meningococcal carriage among
U.S. high school students has also declined.11,12 Most of the
decline in incidence was natural because it preceded the
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routine use of quadrivalent conjugate vaccine in 11–18 year
olds in 2005.13 In addition, the incidence of group B
infections has also declined, which would not have been
influenced by conjugate vaccine.6 The reasons for the
decline are unknown but are likely multifactorial, variable
by geographic location, and non-independent, and include
reductions in both active and passive tobacco smoking,
changing patterns of antibiotic use, use of influenza vaccines,
declines in meningococcal carriage, and lack of development
of novel antigenic variants among virulent strains to which
the population is not immune. The incidence of meningococcal disease is naturally cyclical and it is unknown whether
the incidence will increase in the future.
As a result of this natural decline and the routine use
of quadrivalent conjugate vaccines in adolescents, the
current annual burden of meningococcal disease in the
U.S. is at historically low levels, approximately 0.14
cases per 100,000 population, in contrast to the most
recent peak of 1.3 cases per 100,000 population in 1997.
Meningococcal disease incidence is approximately tenfold higher in the U.K. than in the U.S.14
In the U.S., approximately a third of all cases are
caused by group B. However, the proportion varies by age
group, with two thirds of cases among infants under 1year-old and 39–45% of cases among 11–22 year olds
being caused by group B.15 During 2010–2012, there
were an estimated 48–56 annual group B cases among
11–24 year olds, down from 161 during 1997–19997; the
case fatality rate in this age group is approximately 10%,
somewhat lower than for groups C and Y. About a third
of cases among 18–23 year olds occur among persons
attending college, a high-risk group that historically was
targeted for meningococcal immunization in the U.S.16–18
University-associated outbreaks, traditionally caused by
group C strains, are now predominantly caused by group
B and are becoming relatively common.19,20 Since 2013,
there have been group B outbreaks at Princeton University, University of California-Santa Barbara, Providence
College, and University of Oregon.
Group B strains are also responsible for a substantial
proportion of meningococcal disease cases in many other
countries. In those in which monovalent group C
vaccines have been introduced, group B disease has
become a predominant cause of meningococcal disease.
For example, over 80% of cases in the U.K. and Australia
are caused by group B strains.21,22
decades; the advent of polysaccharide–protein conjugate vaccines has been more recent. Polysaccharide
vaccines are limited by lack of efficacy in infants and
lack of substantial herd protection. Therefore, polysaccharide vaccines were generally used for control of
outbreaks and epidemics and immunization of highrisk persons.23 Given the immunologic superiority of
conjugate vaccines, over the past 15 years they have
been replacing polysaccharide vaccines and have been
introduced into the routine immunization programs of
many countries.24,25
There are multiple licensed conjugate vaccines that
variably cover capsular groups A, C, W, and Y. Until
recently, however, a glaring problem with the meningococcal vaccine armamentarium has been the lack of
vaccines to prevent group B disease. This is because the
group B polysaccharide polysialic acid structure, α-2,8linked N-acetylneuraminic acid, is antigenically similar
to human neural tissue, which has raised concerns about
its use as a vaccine antigen. Therefore, group B vaccine
development has focused on antigenic meningococcal
outer membrane proteins and has lagged far behind the
conjugate vaccines.26
Over the past 15 years, meningococcal conjugate
vaccines have had an impressive impact in countries
that have introduced them. For example, monovalent
capsular group C conjugate vaccines have led to huge
reductions in group C disease in the United Kingdom
and other countries.27–29 MenAfriVac, a monovalent
group A conjugate vaccine that is being introduced at a
price of $0.40 per dose into the meningitidis belt of subSaharan Africa, has already had a dramatic impact on
the epidemiology of group A disease.30–32
A substantial proportion of the public health impact of
meningococcal conjugate vaccines has been mediated
through herd protection that results from vaccineinduced reductions in pharyngeal carriage.33 For example,
monovalent group C conjugate vaccines led to a 66% and
75% reduction in group C carriage in U.K. adolescents by
one to two years, respectively, after mass immunization.34,35 Similarly, MenAfriVac led to a dramatic reduction in group A carriage when high vaccine coverage rates
were achieved in African villages.36 Vaccine-induced
reductions in carriage have generally been accompanied
by large reductions in the incidence of meningococcal
disease among the unimmunized.37
Meningococcal Polysaccharide and Conjugate
Vaccines
Until very recently, all meningococcal vaccines in routine
use have been either capsular polysaccharide or capsular
polysaccharide-protein conjugate vaccines. Meningococcal polysaccharide vaccines have been available for
Group B Vaccines
Outer membrane vesicle vaccines, in which the outer
membrane protein PorA is the primary antigen, have been
used to control outbreaks of group B disease for many
years.38,39 However, immunity to these vaccines is specific
to the outbreak strain PorA type and they are therefore not
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useful for prevention of the antigenically very diverse strains
that cause endemic group B disease.40,41 Therefore, efforts
to develop group B vaccines have focused on relatively
conserved antigenic outer membrane proteins.
There are two recently licensed group B vaccines; both
utilize meningococcal outer membrane proteins as their
antigens. Antigenic discovery was accomplished through
reverse vaccinology, a process that began over 15 years ago
with the mining of the meningococcal genome for possible
vaccine targets.42,43 Both vaccines exhibit substantial reactogenicity but are considered to have an acceptable safety
profile. Licensure was based on safety and immunogenicity;
no efficacy data are available for either vaccine because of
the difficulty in conducting a clinical trial for a lowincidence infection. Immunogenicity was determined using
serum bactericidal assays with human complement as an
immunologic marker of protection, which have been
validated for tailor-made outer membrane vesicle-based
vaccines that use PorA as the main antigen.38,44,45
One vaccine, (4CMenB, Bexsero, Novartis, whose
vaccine business, excluding influenza, was recently
acquired by GlaxoSmithKline) is licensed for infant and
adolescents in Europe, Canada, Australia, and elsewhere
and in the U.S. as a two-dose schedule for 10–25 year
olds. It is a cocktail of one variant each of factor H
binding protein (FHbp), NadA, Neisseria heparin binding antigen (NHBA), and the outer membrane vesicles
that contain the New Zealand outbreak strain PorA
serosubtype P1.4. The second vaccine (rLP2086, Trumenba, Pfizer), which is licensed in the U.S. as a 3-dose
schedule for ages 10–25 years, utilizes one variant of
lipidated FHbp from each of the two FHbp subfamilies.
FHbp is an important meningococcal virulence factor
that binds human factor H, which down-regulates the
alternative complement pathway. FHbp has been
described as a conserved antigen but exhibits substantial
antigenic diversity and has been classified into two subfamilies or 3 variant groups, each with many subvariants; antibody response is sub-family specific.46,47 FHbp
elicits antibodies that are bactericidal and that can
potentially block the binding of human factor H on
the meningococcal cell surface. NadA is a meningococcal adhesion molecule that has 5 known variants. NadA
is subject to phase variation and is absent from the
important sequence type 41/44 group B meningococcal
lineage.24 NHBA is expressed by most meningococcal
strains. The vaccine includes the most common variant
and this component induces antibody that results in
cross-reactivity with many variants.48 PorA serosubtype
P1.4 is the PorA variant that was successfully used in the
vaccine to control the New Zealand outbreak. P1.4 is a
relatively infrequent allele in settings of endemic group
B meningococcal disease and therefore its role as an
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antigen is relatively limited; however, the OMVs that
contain PorA serve both antigenic and adjuvant roles.
Group B vaccine effectiveness against group B disease
in a given population can be estimated based on immunogenicity against homologous and heterologous strains
and knowledge of the vaccine-antigen profile of strains
causing invasive disease, including presence and expression of vaccine antigen genes.46,49 Estimating potential
vaccine effectiveness for group B vaccines is technically
challenging because of the complexity of the vaccines, the
strengths and weakness of the various approaches that
are used, and the temporal and geographic dynamics of
the strains causing invasive disease.2 The proportion of
group B strains that potentially would be covered by the
vaccine in a given population has been estimated using
several methods that have been reviewed elsewhere.1,2
Use of group B vaccines. Based in part on the success
of group C conjugate vaccines in Canada, 94% of Québec
Province’s meningococcal cases among persons 1–24
during 2009–2011 were caused by group B strains.50
The annual incidence of group B meningococcal infection among persons 20 years old and younger in the
Saguenay-Lac-Saint-Jean region of Québec was 12.0 per
100,000, as compared to 1.7 in the rest of the province.51
In response, a 4CMenB campaign was initiated that
resulted in the immunization of over 45,000 infants,
young children and adolescents 2 months–20 years old,
using a schedule of four doses in infants 2–5 months old,
three doses for 6–11 months and two doses for persons
12 months and older.52 The campaign was conducted
from May through December 2014; an estimated 81% of
the target population received at least one dose.
In response to the group B outbreaks associated with
Princeton (9 cases from March 2013 to March 2014,
including one fatal case) and University of CaliforniaSanta Barbara (4 cases during November 2013), approximately 5,000 and 20,000 persons were vaccinated with
4CMenB, respectively.53 Vaccine was provided under an
investigation new drug designation by the Food and Drug
Administration because at the time 4CMenB was not
licensed in the U.S.7 At the February 2015 ACIP meeting,
it was stated that no concerning patterns of adverse events
have been observed based on this Canadian and U.S.
experience with 4CMenB, but no data were provided.
In a recent outbreak at Providence College involving 2
cases since February 1, 2015, rLP2086 was administered
to students.54 In a University of Oregon outbreak
involving 6 cases since January 2015, including one fatal
case, approximately 10,000 doses of group B vaccine had
been administered as of April 8, 2015, 80% of which was
rLP2086 and the remainder 4CMenB (Paul Cieslak,
personal communication).
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The Joint Committee on Vaccination and Immunization, which advises U.K. health departments on immunization issues, recommends an infant 4CMenB schedule,
with doses to be given at 2, 4, and 12 months of age.55
Vaccine implementation is expected to begin soon.
At its February 2015 meeting, ACIP recommended
routine use of rLP2086 or 4CMenB for high-risk
individuals 10 years of age and older: persons with
medical conditions such as complement deficiencies and
apslenia, microbiologists with routine or potential exposure to N. meningitis, and during outbreaks.56 Together,
these persons are estimated to total around 340,000 in
the U.S. At the June 2015 meeting, ACIP made a
category B recommendation for use of these vaccines
in persons 16–23 years old, meaning that the decision
whether to vaccinate or not is based on “individual
clinical decision making”. This is opposed to a category
A recommendation, which would have meant that all
persons in that age group are recommended for immunization. Based on the discussion at the meeting, the
reticence for a category A recommendation was based
on the low disease burden and many of the unresolved
issues that are outlined below. The recommendation will
not be official until it is approved by the CDC director
and published in the Morbidity and Mortality Weekly
Report.
Routine immunization of infants is not currently being
considered by ACIP because there will be no licensed
group B vaccine in this age group in the U.S. for at least
several years. ACIP does not recommend routine use of
meningococcal conjugate vaccines for all U.S. infants.57,58
The recommendation was based in part on a low burden
of disease and that the conjugate vaccines do not prevent
group B disease. The manufacturer of 4CMenB will not
seek licensure for U.S. infants as a standalone vaccine
because it has developed an investigational pentavalent
vaccine that covers groups A, B, C, W and Y.59,60
rLP2086 induced fever in a substantial proportion of
infants and is not being pursued for licensure in infants.61
Unresolved Scientific and Societal Issues
Scientific Issues
Although there are many unresolved issues regarding new
group B vaccines, the following predictions can be made:
(1) they will be effective in preventing group B disease, (2)
cross protection for vaccine antigen component variants
will occur, with the breadth likely being variable by age
(e.g., less in infants than adolescents) and meningococcal
strain (e.g., cross protection will correlate with the degree
of antigenic relatedness to the vaccine components and
degree of protein expression).48,62,63 (3) effectiveness will
decline over time, (4) herd protection, if any, will be less
than for the monovalent group A and C conjugate
vaccines, and (5) achieving high vaccine coverage in
adolescents with these multi-dose vaccines will be challenging in some countries.
Potential vaccine effectiveness against group B
strains. Determination of immunogenicity of 4CMenB
involves measuring the proportion of subjects who
respond to each of the vaccine components, which is
technically difficult. That said, immunogenicity among
infants (three-dose schedule) and adolescents (two doses)
has been high.64 Persistent albeit waning antibody levels
have been demonstrated in adolescents at 18–24 months
and children immunized before the age of 5 years;
antibody persistence differed by vaccine antigen.62,65 In
a European study, it was estimated that 4CMenB could
potentially provide protection against 78% of group B
strains.66 For the U.S., group B strain coverage was
estimated at 91%.67
Among healthy adults 18–40 years old immunized
with three doses of rLP2086, 94% achieved seroprotection, defined as an hSBA titer of Z1:4, against the a strain
with the FHbp variant contained in the vaccine. For
strains with heterologous FHbp variants, seroprotection
was achieved in 70–95%.68 The vaccine was also immunogenic in children 8–14 years old.69 Sera from adults
immunized with rLP2086 induced killing in 84.5% of
isolates causing invasive disease.1 No published antibody
persistence data are available for rLP2086.
For both vaccines, actual vaccine effectiveness and
duration of protection are unknown.
Herd protection. As indicated above, herd protection
has been a huge contributor to the success of monovalent
meningococcal conjugate vaccines. A major question has
been whether group B vaccines induce herd protection.
In a recent study of two doses of 4CMenB in U.K.
university students, the vaccine was associated with a
26% reduction in carriage of capsular groups B, C, W,
and Y 2–12 months after vaccination.70 There was a
similar reduction in carriage of capsular group B strains
but the finding was not statistically significant. There was
no statistically significant impact on acquisition of strains
of any vaccine group; the mechanism by which conjugate
vaccines are believed to reduce carriage is through
prevention of carriage acquisition.71
In short, the results of this study were inconclusive;
many questions about potential herd protection provided
by these vaccines remain unanswered. While reduction
in carriage was not demonstrated specifically for group B
strains, the study suggested that the vaccines may
influence meningococcal carriage. However, the point
estimate for the reduction was substantially lower than
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for group C vaccines, namely 66% at one year following
immunization. Importantly, the durability of any impact
on carriage is unknown. I am skeptical that herd
protection from these vaccines, if any, will be close to
that provided by monovalent capsular group A and C
vaccines.
Changes in strains causing invasive disease. Bacterial
genomes are highly dynamic and can undergo changes
that lead to reduced vaccine effectiveness. Changes in
meningococcal strain antigenic profile occur in the
absence of vaccination41,72,73; group B vaccine-induced
population immunity could theoretically select for strains
not covered by vaccines, including those with no or
reduced vaccine antigen expression. While this has not
been observed for meningococcal vaccines, it has for
vaccines against other bacterial pathogens. For example,
the emergence of serotype 19A pneumococcus following
introduction of seven-valent pneumococcal conjugate
vaccine was caused in part by strains that had undergone
capsular switching from vaccine serotype strains.74 In
addition, there has been a large increase in the proportion
of clinical Bordetella pertussis isolates that do not express
the pertussis vaccine antigen pertactin and there is
evidence of possible vaccine-induced selection of
pertactin-deficient strains.75,76
Although it is unknown whether this phenomenon
will occur with the new group B vaccines, there are
worrisome signs that were evident pre-licensure. Invasive meningococcal strains that lack porA or fHbp have
been described.72,77 and, as mentioned above, nadA is
absent from a substantial proportion of meningococcal
strains. The ability to cause invasive disease despite
absence of FHbp is preserved because of alternative
mechanisms by which N. meningitidis can bind to
human factor H.78,79 Disruption of the nhbA gene by
insertion sequence IS1301 in a Brazilian invasive group
C isolate, which also lacked the nadA gene, has been
identified.80 Invasive meningococcal strains lacking
fetA, another outer membrane protein that has been
proposed as a possible meningococcal vaccine antigen,
have also been described.81
Selection for vaccine antigen-negative strains represents perhaps one of the biggest theoretical threats to the
long-term effectiveness of licensed group B vaccines.
Even if vaccine antigen-negative strains do not become a
problem, vaccine effectiveness could be reduced by the
changes in the allelic distribution of protein antigens
among strains causing invasive disease.82
Difficulties in achieving high vaccine coverage. High
coverage rates for recommended vaccines are generally
achieved among infants, regardless of the number of
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required doses. In contrast, achieving high coverage rates
in U.S. adolescents has been challenging. For example,
quadrivalent meningococcal conjugate vaccine coverage
in adolescents, which originally involved only a single
dose when first recommended in 2005, increased gradually from 11% in 2006 to only 78% in 2013.83,84 Human
papilloma virus vaccine, which is given in the U.S. as a 3
dose schedule, had only 57.3% coverage for one or more
doses among females in 2013 and substantially lower
coverage for all three doses.84 Thus, there will be
substantial challenges in achieving high vaccine coverage
in adolescents, particularly with the current category B
recommendation.
Societal Issues
In addition to the scientific uncertainties that are outlined
above, there are the societal issues that are relevant for
group B vaccines. One of the key issues about meningococcal vaccines in developed countries in general, including those for group B disease, is that they are in some
settings not cost-effective because of high vaccine price
and low disease incidence. In some countries, such as the
U.K., cost-effectiveness is a criterion for introduction into
the national immunization program. In the U.S., costeffectiveness is “considered” by ACIP but ACIP members
are not provided with specific guidance on how to
incorporate cost-effectiveness data into decision making.
Vaccine prices have risen dramatically in the
U.S., which has placed a strain on both society and
physicians.85,86 The per-dose price to the CDC Vaccines
for Children Program is $122.95 for 4CMenB and $95.75
for rLP2086 (www.cdc.gov/vaccines/programs/vfc/awar
dees/vaccine-management/price-list/). As with other
vaccines, cost-effectiveness analyses are presented to
ACIP when considering use of group B vaccines.57 The
cost of 4CMenB has been a major issue in the U.K., where
the government only recently agreed upon a price with
the manufacturer. The price per dose has not been
officially disclosed but was reported in the U.K. press
to be £20 (approximately $31), which is around the upper
limit of the cost effective price range under favorable
assumptions.87,88 However, this price could not be
verified.
The high cost of vaccines for rare but devastating
infections raises the question as to what burden of
disease “qualifies” for a recommendation to immunize a
population. At the October 2014 ACIP meeting, an
informational session was held to discuss possible uses
of group B vaccines. What follows below is a sample of
sentiments and opinions that were expressed during a
public comment period at that meeting following a
presentation about possible uses of group B vaccines in
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the U.S., including individuals at high risk for meningococcal infection and immunization of all adolescents
versus just those enrolled in college. The comments
below addressed the issues of vaccine prevention for a
rare but unusually severe disease, cost, immunization
of college students versus all adolescents, impact on
the vaccine industry, and precedents with other
vaccines.
Vaccine prevention of a rare but severe infectious
disease. Ms. Frankie Milley, National Executive Director of Meningitis Angels stated that “Nobody in this
country should die from a vaccine preventable disease.”
Dr. Carol Baker, former ACIP Chairwoman, asked what
other vaccine preventable disease in the U.S. has a 10%
case fatality rate.
Immunization of a select group rather than all adolescents. Dr. Stanley Plotkin, a former ACIP liaison
member, expressed the opinion that a recommendation
for college students, rather than all adolescents, would be
discriminatory because only 29% of disease in this age
group occurs among college students.
Vaccine cost/cost effectiveness. Dr. Baker also commented on the difficulty in knowing how much the U.S.
should spend on vaccine prevention of rare diseases, and
that this will be an issue with which CDC and ACIP will
continue to struggle. She also reminisced about when
vaccines were inexpensive.
Precedent and consistency. Dr. Paul Offit, also a
previous ACIP member, discussed when ACIP recommended replacement of oral polio vaccine (OPV) with
inactivated vaccine (IPV) in the 1990s because essentially all poliomyelitis cases in the U.S. at the time were
caused by OPV. This change was estimated to cost $3
million ($4.7 million adjusted for inflation) per case
prevented.89 During 1980–1994, there was an average of
8 reported vaccine-associated paralytic polio cases
per year.
Although not discussed at the meeting, in 2012 ACIP
recommended immunizing women with acellular pertussis vaccine during every pregnancy in large part to
prevent around 15 annual infant pertussis deaths. Thus,
ACIP has a history of making routine vaccine recommendations for prevention of relatively few cases.
Impact on vaccine industry of lack of routine ACIP
recommendation for licensed vaccines. Dr. Plotkin
also observed that two vaccine manufacturers had
invested large sums of money to develop group B
vaccines and that “if these vaccines are not recommended
then this puts a pall on vaccine development. This has
great implications for vaccine development.” Dr. Plotkin
described this issue as an undiscussed “400 pound
gorilla”.
The opinions expressed during the public comment,
including those from former ACIP members, appeared to
favor routine use of group B vaccines in adolescents.
However, ACIP has taken a cautious middle ground with
its category B recommendation in 16–23 year olds, as
opposed to no recommendation or a category A
recommendation.
Moving Forward
I would prefer to eventually see routine use of group B
vaccines in adolescents and infants in the U.S. for several
reasons. First, use of these vaccines, in combination with
meningococcal conjugate vaccines, would allow for
prevention of as many meningococcal disease cases in
this group as possible. Second, the occurrence of multiple
university-associated group B outbreaks in the U.S. is
worrisome. The initiation of immunization campaigns in
response to outbreaks, particularly with the current
vaccines that require 2 (4CMenB) or 3 (rLP2086) doses
over 1 or 6 months, respectively, to achieve maximum
protection, is not particularly effective; it would be much
more desirable to prevent these outbreaks entirely. Third,
widespread use in large populations will allow for postlicensure studies to answer many of the key scientific and
public health questions that are outlined below. It is only
with these studies that it will become clear whether nextgeneration group B vaccines will be required. Fourth,
although not sufficient rationale in of itself for vaccine
use, I share the concern that failure to utilize licensed
meningococcal vaccines might have a negative impact on
industry’s willingness to develop new vaccines for this
and other low-incidence but devastating infections. On
the other hand, I am also quite concerned that, given the
high price of these vaccines in the U.S., it may be difficult
to justify their use to the fullest potential.
The uncertainties about the public health impact of
these vaccines can only be resolved through postlicensure studies in large populations in which the
vaccines are used. Much of what is known about the
impact of Haemophilus influenzae type b, pneumococcal,
and monovalent meningococcal conjugate vaccines
became known following widespread usage.90–93
Public health surveillance is needed to measure trends
in capsular group-specific meningococcal disease incidence, including in age groups that are not immunized to
make inferences about herd protection. Detailed molecular characterization of invasive meningococcal isolates
obtained through surveillance, including identification of
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vaccine antigen variants and quantification of antigen
expression, will be required to identify emergence of
strains that could diminish vaccine effectiveness. Largescale studies to measure the impact and durability of
group B vaccines on carriage are also needed. Although
measuring acquisition of carriage in immunized and
unimmunized cohorts over time is an ideal study design,
large cross-sectional studies conducted before and after
vaccine introduction were effective in demonstrating
impact of monovalent group C conjugate vaccines on
carriage.34,35 Observational studies to measure vaccine
effectiveness over time will address the issue of optimal
immunization schedules and need for booster doses.
However, it is doubtful that post-licensure vaccine
effectiveness can be measured in the U.S. with the current
category B recommendation and, given the current low
burden of disease, might be challenging even with a
category A recommendation. Long-term follow-up of
vaccinated individuals will be needed to measure the
persistence of serum bactericidal antibodies. All of these
data can be used to inform computational models to
estimate the impact of various approaches on disease
incidence and cost-effectiveness. Long-term safety will
also need to be monitored given the novel composition of
these vaccines. It is only after these types of studies are
performed that we will understand how far we have come
with these two new vaccines and what work lies ahead.
Conclusions and Future Directions
We are in an exciting era in which long-awaited group B
vaccines are finally licensed. The current low burden of
group B disease presents both scientific and policy
challenges for studying and implementing these vaccines.
Once widely used, it will take years to measure vaccine
impact. I doubt that the current vaccines will be the last
word in vaccine prevention of group B disease and I
believe that, depending on the outcome of post-licensure
studies, novel approaches will eventually be needed.
Group B meningococcal vaccines are different from
other licensed vaccines and there are many unresolved
scientific issues and barriers to implementation. However, global prevention of group B meningococcal disease
is a goal that is worth achieving.
This article is being published concurrently in the American
Journal of Preventive Medicine and Vaccine. The articles are
identical except for stylistic changes in keeping with each
journal’s style. Either of these versions may be used in citing
this article. Publication of this article was supported by Merck
and Novartis.
Dr. Harrison previously received research support from
Sanofi Pasteur and lecture fees from Sanofi Pasteur and
December 2015
S351
Novartis Vaccines. He previously served on scientific advisory
boards for GlaxoSmithKline, Merck, Novartis Vaccines, Pfizer,
and Sanofi Pasteur. All relationships with industry were
terminated before Dr. Harrison became a voting member of
the Advisory Committee on Immunization Practices on July
1, 2012.
The opinions expressed in this article are exclusively those of
Dr. Harrison and not those of the Advisory Committee on
Immunization Practices or the University of Pittsburgh.
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