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Journal of Clinical Microbiology, September 2000, p. 3323-3328, Vol. 38, No. 9
0095-1137/00/$04.00+0
Distribution of Neisseria meningitidis
Serogroup B Serosubtypes and Serotypes Circulating in the United
States
Maria Lucia C.
Tondella,1,2,*
Tanja
Popovic,1
Nancy E.
Rosenstein,1
D. B.
Lake,2
George M.
Carlone,2
Leonard W.
Mayer,1
Bradley A.
Perkins,1 and
The Active
Bacterial Core Surveillance Team
Meningitis and Special Pathogens
Branch1 and Respiratory Diseases
Branch,2 Division of Bacterial and Mycotic
Diseases, National Center for Infectious Diseases, Centers for
Disease Control and Prevention, Atlanta, Georgia 30333
Received 10 April 2000/Returned for modification 14 June
2000/Accepted 30 June 2000
 |
ABSTRACT |
Because the Neisseria meningitidis serogroup B (NMSB)
capsule is poorly immunogenic in humans, immunization strategies have focused on noncapsular antigens. Both PorA and to a lesser extent PorB
are noncapsular protein antigens capable of inducing protective bactericidal antibodies, and vaccines based on the outer membrane protein (OMP) components of serogroup B meningococci have been shown to
be effective in clinical trials. Multiple PorA antigens seem to be
needed to prevent endemic meningococcal disease around the world, and a
hexavalent PorA-based meningococcal vaccine has recently been developed
in The Netherlands. To evaluate the distribution of NMSB PorA and PorB
antigens in the United States, serosubtyping and serotyping were done
on 444 NMSB strains isolated in the active surveillance areas of the
United States (total population, 32 million) during the period 1992 to
1998. A total of 244 strains were isolated from sporadic cases of
meningococcal disease, and 200 strains were isolated from an epidemic
in Oregon. A panel of 16 mouse monoclonal antibodies reactive with PorA
and 15 monoclonal antibodies reactive with PorB were used. Among the
NMSB isolates obtained from sporadic cases, the most prevalent
serosubtypes were P1.7,16 (14.3%), P1.19,15 (9.8%), P1.7,1 (8.6%),
P1.5,2 (7.8%), P1.22a, 14 (7.8%), and P1.14 (5.3%) and the most
prevalent serotypes were 4,7 (27.5%), 15 (16%), 14 (8.6%), 10 (6.1%), 1 (4.9%), and 2a (3.7%). A multivalent PorA-based OMP
vaccine aimed at the six most prevalent serosubtypes could have
targeted about half of the sporadic cases of NMSB disease that occurred
between 1992 and 1998 in the surveillance areas. Twenty serosubtypes
would have had to be included in a multivalent vaccine to achieve 80% coverage of strains causing sporadic disease. The relatively large number of isolates that did not react with murine monoclonal antibodies indicates that DNA sequence-based variable region typing of NMSB will
be necessary to provide precise information on the distribution and
diversity of PorA antigens and correlation with nonserosubtypeable isolates. The high degree of variability observed in the PorA and PorB
proteins of NMSB in the United States suggests that vaccine strategies
not based on OMPs should be further investigated.
| |
INTRODUCTION |
Neisseria meningitidis is
a common cause of meningitis and sepsis in children and adults.
Effective vaccines for most of the major disease-causing serogroups (C,
Y, W135, and A) have been developed using their antigenically unique
capsular polysaccharides, leaving Neisseria
meningitidis serogroup B (NMSB) as the only major
disease-associated serogroup for which there is no licensed vaccine in
the United States. NMSB causes about one-third of all invasive disease
in the United States, has epidemic potential, and compared to other
serogroups causes a disproportionately large number of cases among infants.
Unlike other major meningococcal serogroups, serogroup B capsular
polysaccharide is poorly immunogenic in humans, and consequently most
research has focused on the use of noncapsular antigens as vaccine
candidates. The PorA and to a lesser extent PorB outer membrane
proteins (OMPs) have been shown to be major immunogens. They have also
been used to serologically classify N. meningitidis into
serosubtypes and serotypes, respectively. PorA (class 1 OMP) is
expressed by most meningococcal isolates and is encoded by the
porA gene. PorB is expressed by all meningococcal isolates, and class 2 and 3 OMPs are encoded by alleles of the single-copy porB gene (2, 31). PorA and PorB function as
porins with eight surface-exposed loop regions, designated loops I to
VIII (34). The murine serotype-specific monoclonal
antibodies (MAbs) recognize the epitopes located in the variable
regions of loops I, V, VI, and VII of PorB, designated VR1 through VR4.
The serosubtype-specific MAbs recognize the epitopes located in loops I
(VR1) and IV (VR2) of PorA (2, 10, 14, 16, 27, 28, 32).
OMP vaccines based on unique epidemic serogroup B strains have been
shown to be efficacious among older children and adults (3, 4, 8,
30). Subsequent immunogenicity studies of vaccines have suggested
that protection may be strain specific and that bactericidal activity
is principally directed toward epitopes on the PorA antigens (18,
19, 22, 25, 33, 38). Following the recognition that more than a
single PorA protein would be needed to prevent and control endemic
meningococcal disease, researchers in The Netherlands developed a
hexavalent PorA-based meningococcal vaccine (21, 35). This
vaccine contains six different PorA OMPs (serosubtypes P1.7,16; P1.5,2;
P1.19,15; P1.7h,4; P1.5c,10; and P1.12,13).
Available data suggest that, if clinically effective, this combination
of PorA would provide substantial coverage against NMSB strains
currently in The Netherlands and some other European countries (5,
21, 36). Since invasive N. meningitidis strains are
not routinely serosubtyped or serotyped in the United States, we used a
set of NMSB strains collected through the Active Bacterial Core
surveillance project, a part of the activities of the Centers for
Disease Control and Prevention (CDC) Emerging Infections Program, to
determine the distribution of serosubtypes and serotypes in the United
States. This study will aid in deciding if an OMP vaccine is feasible,
defining how many and which PorA OMPs would need to be included in a
multivalent OMP vaccine for control of endemic NMSB disease in the
United States.
| |
MATERIALS AND METHODS |
Active surveillance.
All isolates analyzed in this study
were collected through active, laboratory-based surveillance for
invasive disease caused by N. meningitidis that is part of
an ongoing multistate Active Bacterial Core surveillance project now
coordinated by the CDC's Emerging Infections Program (26).
Between 1992 and 1998, staff of the CDC collaborated with investigators
in state and local health departments and universities in 4 to 10 geographically dispersed areas of the United States; participating
areas included sites in California, Connecticut, Georgia, Maryland,
Minnesota, Missouri, New York, Oklahoma, Oregon, and Tennessee. Because
the active surveillance was not conducted continuously in all
surveillance areas, the aggregate population under surveillance varied
from 12.8 million in 1995 to 32 million in 1998.
A case of meningococcal disease was defined as the isolation of
N. meningitidis from a normally sterile site, such as blood or cerebrospinal fluid, of a resident of the surveillance area. Between
1 January 1992 and 31 December 1998, 1,696 cases of meningococcal disease were detected in the surveillance areas, for an average annual
incidence of 1.1 cases per 100,000 members of the population.
N. meningitidis strains.
From a total of 470 serogroup B meningococcal disease cases identified in the United States
in the period from 1992 to 1998, 444 NMSB strains were available for
analysis. All strains were isolated from blood or cerebrospinal fluid.
Two hundred forty-four isolates were collected from patients with
sporadic meningococcal disease: 70 in California, 37 in Georgia, 34 in
Maryland, 31 in Minnesota, 26 in Tennessee, 24 in Connecticut, 11 in
Oklahoma, 9 in Missouri, and 2 in New York. The additional 200 isolates were collected during the meningococcal disease epidemic in the state
of Oregon, ongoing since 1994 (6, 9).
The reference strains B16B6, 126E, 2996, 2396, M981, M982, M136, M990,
M992, M1027, M1080, BB393, 870227, 882066, S3032, S3436,
S3446, H355,
H44/76, 6557, 51/90, and 503/93 were kindly provided
by C. E. Frasch, Center for Biologics Evaluation and Research,
Bethesda, Md.;
W. D. Zollinger, Walter Reed Army Medical Center,
Washington,
D.C.; J. T. Poolman, SmithKline Beecham Biologicals,
Rixensart,
Belgium; C. T. Sacchi, Institute Adolfo Lutz, Sao Paulo,
Brazil;
and P. Kriz, National Institute of Public Health, Prague,
Czech
Republic.
Dot blot analysis.
Strains were tested with a set of 16 murine MAbs produced against the variable regions of PorA and 15 murine
MAbs produced against the variable regions of PorB. The MAbs and their
respective sources are shown in Table 1.
These MAbs have been evaluated in 11 laboratories, and results
confirmed a high level of specificity (23). The dot blotting
analysis was performed as previously described (37).
Briefly, the whole-cell suspensions were dotted onto
0.45-µm-pore-size nitrocellulose membrane strips (Schleicher & Schuell, Inc., Keene, N.H.). After drying for 10 min at room temperature, the strips were transferred to Accutran eight-well incubation trays (Schleicher & Schuell) and blocked for 30 min with 1 ml of 3% bovine serum albumin (Sigma Chemical Co., St. Louis, Mo.) in
phosphate-buffered saline (PBS; Gibco BRL, Grand Island, N.Y.). MAbs
were pipetted directly into the blocking buffer at dilutions ranging
from 1 in 8,000 to 1 in 64,000. After overnight incubation at room
temperature on a rotator, the strips were washed three times with PBS
and incubated for 2 h with goat anti-mouse immunoglobulin G
conjugated to peroxidase (dilution, 1 in 4,000) (Sigma). Strips were
washed three times with PBS and developed with the substrate 3-amino-9
ethyl-carbazole (Sigma) and hydrogen peroxidase.
Statistical analysis.
The 
2 test was used for
analysis of potential association of particular serosubtypes and
serotypes with a variety of demographic and other denominators
(temporal and geographic distribution, patients' age groups, etc).
| |
RESULTS |
The distribution of NMSB serosubtypes and serotypes causing
meningococcal disease in the United States in the period from 1992 to
1998 are shown in Tables 2 and
3, respectively. Among all strains
isolated from sporadic cases of NMSB disease (n = 244),
37 (15.2%) were nonserosubtypeable (Table 2) and 63 (25.8%) were
nonserotypeable (Table 3). Among the serosubtypeable strains, the six
most prevalent serosubtypes were P1.7,16 (14.3%), P1.19,15 (9.8%),
P1.7,1 (8.6%), P1.5,2 (7.8%), P1.22a,14 (7.8%), and P1.14 (5.3%).
Among the serotypeable strains, the six most prevalent serotypes were
4,7 (27.5%), 15 (16.0%), 14 (8.6%), 10 (6.1%), 1 (4.9%), and 2a
(3.7%). Serosubtype P1.7,16 accounted for 78.5% and serotype 15 accounted for 69.0% of the total number of strains isolated in Oregon
from 1992 to 1998 (Tables 2 and 3), reflecting the epidemic caused by
the phenotype B:15:P1.7,16 (6, 9).
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TABLE 2.
Serosubtypes (PorA) of NMSB strains isolated during
laboratory-based active surveillance of sporadic cases of meningococcal
disease in geographically diverse regionsa
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TABLE 3.
Serotypes (PorB) of NMSB strains isolated during
laboratory-based active surveillance of sporadic cases of meningococcal
disease in geographically diverse regionsa
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|
The results show that a vaccine aimed at the six most prevalent
serosubtypes could have targeted 53.6% of the sporadic cases of NMSB
disease that occurred in the United States between 1992 and 1998 (Table
2). No statistically significant differences were found in the
distribution of individual serosubtypes and/or serotypes by patients'
age groups, and no particular temporal clustering was observed. The
numbers of strains with particular serosubtypes were too small to allow
for analysis of their geographic distribution (data not shown).
Contrary to observations for endemic disease, the same hexavalent
vaccine could have targeted 88% of the epidemic cases of serogroup B
meningococcal disease that occurred in Oregon during the same time
period (Table 2). To achieve comparable (80%) coverage of sporadic
disease, a total of 20 serosubtypes would have to be included in a
multivalent PorA-based vaccine (Fig. 1).
Excluding the 37 nonserosubtypeable isolates, the results suggest that
8, 11, or 16 serosubtypes would have to be added to prevent 70, 80, and
90% of sporadic meningococcal disease caused by NMSB, respectively.
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FIG. 1.
Number of serosubtypes that would have to be added in a
multivalent OMP-based vaccine versus percentages of isolates of
sporadic NMSB disease targeted, including 37 (15%) nonserosubtypeable
isolates, collected in the United States from 1992 to 1998.
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| |
DISCUSSION |
NMSB is responsible for approximately one-third of the endemic
meningococcal disease in the United States and a higher proportion of
disease among young children (26). Because protection has been shown to be largely serosubtype specific (18, 22, 33), the identification of prevalent serosubtypes is important in evaluating the possibility of using multivalent OMP-based vaccines to control endemic NMSB disease. The results of this study provide information on
the prevalence and distribution of serosubtypes and serotypes of NMSB
in the United States from 1992 to 1998. In addition, the study
indicates that a multivalent OMP-based vaccine aimed at the six most
prevalent serosubtypes (P1.7,16; P1.19,15; P1.7,1; P1.5,2; P1.22a,14;
and P1.14) would target only half of the sporadic cases of NMSB disease
that occurred between 1992 and 1998 in the United States.
Information about the diversity of serosubtypes in other parts of the
world is presently available only to limited geographic areas. Among
the 1,647 NMSB strains from 23 European countries that were
serosubtyped in 1996, serosubtype P1.4 was identified in 30% of them
(Table 2) (7). In contrast, this serosubtype, associated
with an increase of endemic meningococcal cases in The Netherlands
since 1983 (1, 29) and the recent epidemic in New Zealand
(15), was seen in only 2% of isolates in our study.
Isolates of the serosubtype P1.7,16, the most common in the United
States in the observed period, ranked second in Europe (Table 2) and
has been responsible for an outbreak of meningococcal disease in Norway
since the mid-1970s (3, 25, 38). In the period of July 1977 to June 1998, 5,523 laboratory-confirmed cases of meningococcal disease
were reported in 20 European countries, with serogroup B being
predominant (61%) (20). Serosubtyping was available for
1,236 of the NMSB isolates, and as in 1996, serosubtypes P1.4 and
P1.7,16 predominated. Consequently, a vaccine developed in response to
an epidemic in Europe, New Zealand, or other parts of the world will
not necessarily be the optimal vaccine to prevent NMSB disease in the
United States. For instance, the hexavalent PorA vaccine
(21) contains three serosubtypes (P1.7h,4;
P1.5c,10; and P1.12,13) that are not among the most
prevalent in the United States. On the other hand, data from the NMSB
OMP-based vaccine trial in Chile (33) suggested that some
serum bactericidal activity against strains other than the vaccine
strain may have been elicited, although the specific surface components
responsible for the cross-protection have not been identified.
The data from this study show that a large number of serosubtypes (20 or more) might have to be included in a multivalent OMP-based vaccine
to target 80% of sporadic disease caused by NMSB. This estimate is
based solely on reactivity with mouse MAbs, as there are few data about
human responses to PorA immunogens. Consequently, there are reasons to
suggest that this estimate may be either too high or too low. First, we
can hypothesize that vaccination with a vaccine containing P1.5,2 would
protect not only against serogroup B strains of this PorA, but also
against the strains of other serogroups that express P1.5,2. This PorA type has been identified in one-third of serogroup C and Y isolates in
the United States, collected in the same time period as the NMSB
isolates (data not shown).
Second, a relatively large number of strains in our study did not react
with the currently available MAbs. There are several mechanisms that
explain the lack of reactivity with murine MAbs. Probably the most
important mechanism is the horizontal genetic exchange among N. meningitidis strains causing generation and spread of antigenic
variants of OMPs. By this mechanism, entire genes may have been
exchanged among strains, thus explaining why some strains with
divergent molecular fingerprints share identical porA genes
and, conversely, why some strains with similar chromosome structures
exhibit porA genes with different nucleotide sequences and
serological properties (11).
Finally, if a significant proportion of nonserosubtypeable strains are
variants of a prototype included in a vaccine, then some protection
might be expected after immunization because nonreactivity with the
murine MAb does not necessarily equate to lack of coverage of a
particular variant. As shown in Table 2, the number of serosubtypes needed for 80% coverage of sporadic disease would be smaller
(n = 11) if the nonserosubtypeable isolates were
included in the coverage or excluded from the analysis. Contrary to
that, the estimates of the coverage levels may be too high, if we
consider that different PorA variants that are still reactive with the murine MAb may not exhibit cross-reactivity with the human antibodies. The OMP's genetic variation in PorA not only restricts the usefulness of serosubtyping because many isolates become nonreactive to MAbs but,
more importantly, it may also have significant implications for vaccine
design (1, 12, 14, 17, 24, 28, 32). Therefore, sequencing of
the porA variable regions of the nonserosubtypeable strains
and additional knowledge about the extent of cross-protection for
variants of individual PorA types are needed to provide precise information on the diversity and distribution of PorA antigens and
correlation with nonserosubtypeable isolates.
Serogroup B meningococcus is the most common cause of meningococcal
disease in many countries, and epidemics continue to occur around the
world. Previously evaluated monovalent OMP-based vaccines have not been
shown to be efficacious in young children (4, 8). Several
strategies of vaccine development have been proposed for prevention of
serogroup B meningococcal disease such as production of strain-specific
OMP-based vaccines at the onset of an outbreak and use of multivalent
vaccines based on highly endemic and epidemic strain-specific PorA
antigens (39). Due to the substantial variations detected in
genes coding for PorA, even multivalent OMP-based vaccines may not be
effective in preventing the majority of endemic disease. Also,
technical and logistical parameters may limit how many different PorA
types may be included in such a vaccine and how rapidly a vaccine could
be manufactured and licensed to allow for its timely implementation.
Therefore, research is under way to address alternative strategies for
development of serogroup B vaccines (13; B. Manberg,
E. A. Hoiby, and E. Wedege, Abstr. 37th Intersci. Conf.
Antimicrob. Agents Chemother., abstr. 213, 1997). Continuous
surveillance of meningococcal disease as well as coordination and
commitment of public health personnel, government personnel, and the
vaccine industry will be required for successful development of
vaccines against all NMSB isolates.
| |
APPENDIX |
The members of The Active Bacterial Core Surveillance Team are as
follows: from the California Emerging Infections Program, Berkeley, G. Rothrock, N. Mukerjee, P. Daily, L. Gelling, and D. Vugia; from
Vanderbilt University Medical Center, Nashville, Tenn., B. Barnes and
C. Gilmore; from Veterans Affairs Medical Services and the Emory
University School of Medicine, Atlanta, Ga., M. Farley, W. Baughman, S. Whitfield, and M. Bardsley; from John Hopkins University, Baltimore,
Md., L. Billmann; from the Maryland Department of Health and Mental
Hygiene, Baltimore, D. Dwyer; from the Connecticut Emerging Infections
Program, Hartford, J. Hadler, P. Mshar, N. Barrett, C. Morin, and Q. Phan; from the Minnesota Emerging Infections Program, Minneapolis, M. Osterholm, R. Danila, J. Rainbow, C. Lexau, L. Triden, K. White, and J. Besser; from the Oregon Emerging Infections Program, Portland, K. Stefonek, J. Donegon, and S. Ladd-Wilson; and from the CDC, G. Ajello,
M. Berkowitz, B. Plikaytis, M. Reeves, K. Robinson, and S. Schmink.
| |
ACKNOWLEDGMENTS |
We thank Corie A. Noble for technical support. We also thank Carl
E. Frasch, Wendell D. Zollinger, Ian M. Feavers, Jan T. Poolman,
Claudio T. Sacchi, and Paula Kriz for providing the monoclonal antibodies and prototype strains.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Respiratory
Diseases Branch, Division of Bacterial and Mycotic Diseases (Mailstop
G03), NCID, Centers for Disease Control and Prevention, 1600 Clifton Rd., NE, Atlanta, GA 30333. Phone: (404) 639-3563. Fax: (404) 639-4215. E-mail: MLT5{at}CDC.GOV.
Members of The Active Bacterial Core Surveillance Team are
listed in the Appendix.
| |
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Abstract
Introduction
