Rosenstein N, Levine O, Taylor JP, Evans D, Plikaytis BD, Wenger JD, Perkins BA. Efficacy of Meningococcal Vaccine and Barriers to Vaccination. JAMA. 1998;279(6):435-439. doi:10.1001/jama.279.6.435
From the Childhood and Respiratory Diseases Branch (Drs Rosenstein, Levine, Wenger, and Perkins) and Biostatistics and Information Management Branch (Mr Plikaytis), Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Ga; and Infectious Disease Epidemiology and Surveillance Division, Texas Department of Health, Austin (Mr Taylor) and Tyler (Ms Evans).
Context.— Use of the quadrivalent meningococcal vaccine for control of outbreaks
has increased in recent years, but the efficacy of meningococcal vaccine during
mass vaccination campaigns in US civilian populations has not been assessed.
Objectives.— To evaluate the efficacy of the quadrivalent meningococcal vaccine against
serogroup C meningococcal disease in a community outbreak setting and to evaluate
potentially modifiable barriers to vaccination in an area with persistent
meningococcal disease following immunization.
Design.— Matched case-control study of vaccine efficacy using cases of serogroup
C meningococcal disease in persons eligible for vaccination during mass vaccination
campaigns. Control patients were matched by neighborhood and age. The control
group was used to identify possible barriers to vaccination.
Setting.— Gregg County, Texas, population 106076, from 1993 to 1995.
Participants.— A total of 17 case patients with serogroup C meningococcal disease eligible
for vaccine and 84 control patients.
Main Outcome Measures.— Vaccine efficacy and risk factors associated with nonvaccination.
Results.— Vaccine efficacy among 2- to 29-year-olds was 85% (95% confidence interval,
27%-97%) and did not change in bivariate analyses with other risk factors
that were significant in univariate analysis. Among control patients, older
age was strongly associated with nonvaccination; vaccination rates for 2-
to 4-year-olds, 5- to 18-year-olds, and 19- to 29-year-olds were 67%, 48%,
and 20%, respectively (χ2for linear trend, P=.01).
Conclusions.— The meningococcal polysaccharide vaccine was effective against serogroup
C meningococcal disease in this community outbreak. Although specific barriers
to vaccination were not identified, older age was a risk factor for nonvaccination
in the target population of 2- to 29-year-olds. In future outbreaks, emphasis
should be placed on achieving high vaccination coverage, with special efforts
to vaccinate young adults.
NEISSERIA MENINGITIDIS is a leading cause of
bacterial meningitis in the United States, causing an estimated 2600 cases
of invasive disease annually, with a mortality rate between 10% and 15%.1 In the United States, N meningitidis serogroup C accounts for 30% to 40% of invasive disease and is the
most common cause of outbreaks.2 Outbreaks of
serogroup C meningococcal disease (SCMD) have been rare in the United States
since World War II; however, since 1991, the number of serogroup C outbreaks
has increased.2 The quadrivalent meningococcal
polysaccharide vaccine, which contains the purified polysaccharide capsules
of serogroups A, C, W-135, and Y, has been recommended for the control of
Local and state public health authorities have conducted multiple vaccination
campaigns in response to SCMD outbreaks in US schools and communities, resulting
in a dramatic increase in vaccine usage. While only 7600 doses of vaccine
were used in the United States between January 1989 and June 1991 for control
of 4 outbreaks, 180000 vaccine doses were administered between January 1992
and June 1993 in response to 8 outbreaks.2 Because
the pattern of disease occurrence during outbreaks is difficult to predict
and the number of cases is usually small,2 the
efficacy of meningococcal vaccine during mass vaccination campaigns in US
civilian populations has not been assessed.
In February 1994, an increase in the number of cases of SCMD was recognized
in Gregg County, Texas (population 106076). In a county this size, only 1
case of SCMD per year would be expected annually; however, over the 3-month
period from December 1993 through February 1994, 4 cases of SCMD occurred
in children younger than 10 years. The Texas Department of Health (TDH) conducted
a county-wide vaccination campaign among residents aged 2 to 10 years, which
was then expanded to residents aged 2 to 29 years as additional cases occurred
over a 12-month period. Ultimately, approximately 36000 people were vaccinated
in 30 clinics. The steps taken by TDH were in accordance with the current
Advisory Committee on Immunization Practices (ACIP) recommendations for evaluation
and management of suspected community-based SCMD outbreaks.3
Despite the enormous public health effort undertaken by TDH, cases continued
to occur. By September 1995, 39 cases of meningococcal disease had been identified,
2 of which were reported to have occurred in persons who had been vaccinated.
Either meningococcal vaccine was not sufficiently efficacious or vaccine coverage
was not high enough to stop the outbreak, despite multiple vaccination campaigns.
To evaluate both of these potential explanations, we investigated both vaccine
efficacy and barriers to vaccination.
We identified all cases of meningococcal disease that occurred in Gregg
County from December 1993 through September 1995 by reviewing surveillance
records of TDH and contacting local hospitals and health care providers in
the area. For the purposes of surveillance, a case patient was defined as
any resident of Gregg County with a clinical diagnosis of meningococcal disease,
regardless of laboratory confirmation. Information collected as part of routine
surveillance included demographic characteristics, clinical illness, method
of diagnosis, and serogroup of N meningitidis isolated.
Blood and cerebrospinal isolates, if available, were collected from each identified
patient. The TDH provided information about the time and location of each
vaccination campaign and the number of vaccine doses given.
For each available isolate from a patient identified by surveillance,
laboratories at the Centers for Disease Control and Prevention, Atlanta, Ga,
confirmed the identification and serogroup and performed multilocus enzyme
electrophoresis with 24 enzymes.4- 6
Numbers were assigned to enzyme alleles on the basis of enzyme mobilities,
and each unique set of alleles was defined as an electrophoretic type. An
index of genetic relatedness was determined by weighing the degree of diversity
at each of the 24 enzyme loci, and similarities among the electrophoretic
types were assessed by dendrogram analysis.4
We performed a matched case-control study to estimate the efficacy of
the quadrivalent meningococcal polysaccharide vaccine against SCMD. For purposes
of case-control study enrollment, a case patient was defined as a resident
of Gregg County for at least 1 year, with SCMD confirmed by isolation of N meningitidis serogroup C from blood or cerebrospinal
fluid or detection of N meningitidis serogroup C
antigens by latex agglutination in cerebrospinal fluid.
Only case patients who were in an age group to which vaccination was
offered were eligible for enrollment. This included all children aged 2 to
10 years after March 3, 1994, when vaccination campaigns targeting 2- to 10-year-olds
were begun, as well as all persons aged 2 to 29 years after February 19, 1995,
when vaccine was offered to 2- to 29-year-olds. The study was conducted during
An eligible control patient was defined as a resident of Gregg County
for at least 1 year who lived in the same neighborhood as the case patient
and was appropriately age-matched to the patient. The control had to have
lived in that neighborhood at least 1 month before the onset of disease in
the patient and had to have been of the appropriate age to be eligible for
vaccination during at least 1 of the vaccination campaigns. Time of residence
in Gregg County was included as a requirement to provide an opportunity for
case patients and control patients to become integrated into the community,
learn of the outbreak, and be vaccinated. Control patients were matched to
case patients using the following age groupings: 2- to 5-year-olds, 6- to
11-year-olds, 12- to 17-year-olds, and 18- to 29-year-olds.
We systematically selected control patients by identifying the residence
of the case patient and then starting 3 houses to the right, asking if any
of those household members were in the age range of the case patient. If 5
control patients could not be identified on the same block as the case patient's
residence, investigators went from house to house in neighboring blocks. If
the end of the neighborhood was reached before 5 control patients were identified,
no further control patients were collected. If a potential control patient
was identified but not enrolled on the initial visit, the household was revisited.
After obtaining informed consent, we interviewed each case patient and
control patient (if younger than 18 years, a parent or guardian was interviewed)
using a standard questionnaire. When a reference period was needed, we asked
about the month preceding the onset of illness for case patients and about
the same calendar month of illness in the matched control patients. To adjust
for potential confounders of vaccine efficacy and to identify other potential
risk factors for meningococcal disease, data were collected about age, sex,
residence, family characteristics, medical history, active and passive smoke
exposure, and exposures to large groups of people.
For purposes of estimating vaccine efficacy, we defined a vaccinated
person as one who had received vaccine at least 2 weeks before the onset of
illness in the case patient and a nonvaccinated person as one who either had
not been vaccinated or who had received vaccine less than 2 weeks before the
onset of illness. Vaccination status for all persons who reported being vaccinated
was confirmed by (1) seeing the person's copy of the meningococcal vaccination
consent form; (2) finding the person's name in the TDH vaccine campaign electronic
database; (3) finding the TDH's copy of the consent form; or (4) contacting
the private physician if the person said that they had been vaccinated by
their physician. If none of these methods were successful, then the person
was considered to have an unconfirmed vaccination status.
Subjects enrolled in the control group for the vaccine efficacy study
were used as a convenience sample of a population at high risk of disease
to investigate potentially modifiable barriers to vaccination. In addition
to information collected for the case-control vaccine efficacy study, control
patients were asked about the meningococcal disease outbreak and vaccination
campaigns, access to vaccination clinics, and perceptions about SCMD, issues
that could affect vaccine coverage in the target population (Table 1).
For measuring associations in univariate analyses to determine categorical
variables, χ2 or Fisher exact tests (when expected values in
any cell were <5) were used. Continuous variables were separated into dichotomous
categories on their median or a biologically relevant threshold level. Matched
odds ratios (ORs) with 95% confidence intervals (CIs) were also calculated
using the proportional hazards regression procedure in SAS, version 6.11 (SAS
Institute, Cary, NC). All test statistics were 2-tailed.
Matched ORs for the association of SCMD and vaccination with quadrivalent
meningococcal vaccine were calculated using the methods described above. Vaccine
efficacy was calculated by using the following equation: 1−(matched
OR for vaccination).7 Adjusted vaccine efficacy
estimates were calculated by creating separate bivariate models adding potential
confounders and effect modifiers of the association between SCMD and vaccination
and looking for meaningful changes in risk estimates. Potential confounders
and effect modifiers included variables that were associated with SCMD or
vaccination in univariate analyses and factors identified as confounders or
effect modifiers in previous studies.
To identify risk factors for failure to receive meningococcal vaccine,
the generalized estimating equation (GEE) was used to account for the intraclass
correlation inherent in the design of studies where the unit of sampling is
a cluster.8 The GEE module was used to calculate
ORs for the association of risk factors and nonvaccination. Adjusted ORs for
the association between nonvaccination and risk factors were calculated, adjusting
each potential risk factor for age. Age was included as a categorical variable
(among 2- to 4-year-olds, 5- to 18-year-olds, and 19- to 29-year-olds).
Among Gregg County residents, 39 cases of meningococcal disease were
identified between December 1993 and September 1995. In 31 cases, N meningitidis serogroup C was isolated from blood or cerebrospinal
fluid; in 1 case, serogroup C antigens were detected by latex agglutination.
Seven (22%) of the 32 case patients diagnosed as having SCMD died. Neisseria meningitidis serogroup B was isolated from 2 case patients,
isolates from 3 case patients were not serogrouped, and 2 case patients were
diagnosed by clinical syndrome alone.
Figure 1 shows the number of
confirmed SCMD cases (n=32) by month of onset. From December 1993 to February
1994, 4 cases of SCMD occurred in children younger than 10 years. Based on
1993 US census data, the attack rate was estimated at 21 cases per 100000
children younger than 10 years, more than 40 times the endemic SCMD rate of
0.5 cases per 100000 population per year.1 Because
the quadrivalent meningococcal polysaccharide vaccine, Menomune (Connaught
Laboratories, Swiftwater, Pa), has been shown to be less immunogenic in children
younger than 2 years,9 the TDH began a vaccination
campaign targeting children aged 2 to 10 years. Approximately 9600 children
were vaccinated in 10 vaccination clinics in March and April 1994.
For a few months, the number of new cases decreased, but in late 1994
additional cases of SCMD occurred among children, adolescents, and young adults.
As a result, in February 1995 a second vaccination campaign was initiated.
This time the target age group was expanded to include 11- to 29-year-olds,
among whom 15% of cases had occurred. By September 1995, despite vaccination
of a total of 366002- to 29-year-olds, 11 new cases had occurred in that age
group since March 1995.
In the 5 months preceding the first vaccination campaign (December 1993-April
1994), 5 (72%) of 7 cases occurred among 2- to 10-year-olds, and 1 (14%) of
7 occurred among 11- to 29-year-olds. In the 10 months between vaccination
campaigns (April 1994-February 1995), 5 (42%) of 12 cases occurred among 2-
to 10-year-olds, and 3 (25%) of 12 occurred among 11- to 29-year-olds. In
the 7 months after the onset of the second vaccination campaign, 4 (31%) of
13 cases occurred among 2- to 10-year-olds, and 7 (54%) of 13 occurred among
11- to 29-year-olds.
In mid September 1995, after the conclusion of the case-control study,
a third vaccination campaign was initiated; by December 1996, a total of 364000
(>100% of the estimated target population) 2- to 29-year-olds were vaccinated.
However, by December 1996, an additional 5 cases of SCMD occurred, suggesting
that disease pressure persisted. Of these 5 case patients, 3 were in the vaccination
target group, and 1, a 30-year-old, had been in the target group during the
second vaccination campaign. None had been vaccinated.
A total of 24 of 29 SCMD isolates identified between December 1993 and
September 1995 were electrophoretic type 24; the others were 2 subtypes identified
as closely related to electrophoretic type 24, which is identical to the strain
that caused outbreaks in Carroll County, Georgia, and eastern Canada. It is
also responsible for approximately one half of 1995 serogroup C cases detected
in active, population-based surveillance2,10
(Centers for Disease Control and Prevention, unpublished data, March 1997).
Of the 32 persons identified with SCMD between December 1993 and September
1995, 5 were excluded from our analysis because they became ill before the
first vaccination campaign and were, therefore, not eligible for vaccine.
Of the remaining 27, 10 were not eligible because they were older than 10
years (or 29 years) or younger than 2 years at the time of illness. The remaining
17 case patients (53%) who were eligible for vaccine at the onset of illness
were enrolled along with 84 matched control patients (a mean of 5 control
patients per case patient).
Case patients did not differ significantly from control patients by
age, sex, race, or income (Table 2).
Two control patients reported taking antimicrobial chemoprophylaxis. Two case
patients, aged 5 and 6 years, reported being vaccinated 15 and 14 months,
respectively, before their illness, when they were aged 3 years 11 months
and 5 years 4 months; in both instances, vaccination status was confirmed.
Vaccination status was confirmed for 28 of the 36 control patients who reported
In univariate matched analysis, maternal education of less than high
school was a risk factor for SCMD. Of several behaviors that would expose
an individual to large groups of people, none were associated with increased
risk of SCMD. Both church attendance and day care attendance were protective.
Church attendance was inversely related to socioeconomic status and smoking,
although not significantly (data not shown).
The estimated vaccine efficacy among 2- to 29-year-olds was 85% (95%
CI, 27%-97%). Among preschoolers aged 2 to 5 years, estimated vaccine efficacy
was 93% (95% CI, 16%-99%). Our point estimate of vaccine efficacy did not
change when adjusted for factors that were significant in univariate analysis,
including maternal education of less than high school, passive smoke exposure,
day care attendance, church attendance, or other variables that have been
previously shown to be risk factors for meningococcal disease, including income,
crowding, and underlying illness. Point estimates of vaccine efficacy were
not substantially altered when the subjects whose vaccination status was not
confirmed but who reported being vaccinated were excluded (vaccine efficacy,
82%; 95% CI, 0%-96%) or when the subjects who reported taking chemoprophylaxis
were excluded (vaccine efficacy, 86%; 95% CI, 34%-97%).
Age was strongly related to vaccine coverage. Among the 84 subjects,
older age was strongly associated with nonvaccination. Vaccination rates among
2- to 4-year-olds, 5- to 18-year-olds, and 18- to 29-year-olds were 67%, 48%,
and 20%, respectively (χ2 for linear trend, P=.01).
Table 3 shows several potential
barriers to vaccination, analyzed in bivariate analysis with age. Watching
television news once per week or less was significantly associated with nonvaccination
(OR, 5.3; 95% CI, 1.2-24.5), although 73% of nonvaccinated people did watch
television. For children aged 2 to 17 years, a risk factor for nonvaccination
was maternal education level of high school or higher (OR, 7.3; 95% CI, 1.0-56.2);
maternal education of less than high school has previously been shown to be
a risk factor for meningococcal disease.11,12
Access to vaccine, as indicated by the work schedule of the individual or
the primary caretaker and distance to the vaccination center, was not associated
with nonvaccination. Belief among case patients and primary caretakers that
mortality from meningococcal meningitis was less than 15% as well as their
beliefs about the protective efficacy and adverse effects of vaccine were
not significantly associated with nonvaccination.
Meningococcal disease is a communicable and potentially fatal infectious
disease that occurs in healthy children and young adults. Outbreaks of meningococcal
disease generate tremendous community concern and pressure for public health
officials to intervene. The decision about when to vaccinate is complicated
by 2 factors: first, outbreaks usually consist of a small number of cases,
and second, mass vaccination, the recommended public health response, takes
a great deal of effort and resources. Frequently, no additional cases occur
after vaccination, even among the nonvaccinated, making it difficult to evaluate
the impact of vaccination campaigns. In Gregg County, despite extensive vaccination
campaigns, cases of SCMD continued to occur, raising skepticism about the
value of this public health response. Our investigation, the first study to
measure efficacy of meningococcal vaccine in a civilian population in the
United States, while controlling for other risk factors for disease, revealed
a high level of protective efficacy (85% among 2- to 29-year-olds). Multiple
controlled field trials of this vaccine in other populations have shown similar
estimates of vaccine efficacy (Table 4). 13- 17
Although our study did not directly address the cost-vs-benefit ratio of group
C immunization, it is important to note that the Gregg County outbreak continued
for several years, and many more cases probably would have occurred had there
been no vaccination campaigns. This study supports the utility of vaccine
in the management of SCMD outbreaks, as detailed in current recommendations
from the Advisory Committee on Immunization Practices designed to aid public
health officials in making the complex decision to undertake mass vaccination
One question that is frequently brought up during meningococcal vaccination
campaigns is the effect of vaccination on carriage. A recently introduced
polysaccharide-protein conjugate vaccine for Haemophilus
influenzae type b eliminated carriage of the organism, reducing exposure
of the at-risk population and "protecting" unimmunized persons (ie, herd immunity).18 In contrast, although 2 studies conducted among US
Army recruits demonstrated decreased meningococcal carriage after group C
vaccination,13,19 numerous other
studies have failed to show a lasting effect of meningococcal polysaccharide
vaccines on carriage.20- 22
Furthermore, during recent outbreaks, the rate of carriage of the responsible
strain was low.23- 25
The invasive potential of the electrophoretic type 24 strain may result from
enhanced ability to penetrate mucosal surfaces and invade the bloodstream
rather than more efficient person-to-person transmission or increased mucosal
colonization. The possible implication of this for vaccine use is not clear,
but even a vaccine that could alter carriage might not offer a great advantage
in control of outbreaks caused by this strain.
Serogroup C meningococcal conjugate vaccines that might provide herd
immunity and prolonged protection for infants and children are currently undergoing
initial human clinical trials. 26 These vaccines
may be incorporated into routine childhood immunization programs, changing
the characteristics of SCMD outbreaks and altering our approach to their control.
However, until that time, management of outbreaks should involve use of the
currently available polysaccharide vaccine with the goal of vaccinating every
person in the at-risk population.
To determine why cases continued to occur in Gregg County despite mass
vaccination campaigns with an efficacious vaccine, we looked for factors predictive
of nonvaccination. To investigate this, we used the control patients from
the vaccine efficacy study who had been matched to case patients by age and
neighborhood. Although not representative of the entire population, this group
was considered to be at high risk for meningococcal disease. In the target
population of 2- to 29-year-olds, older age was a risk factor for nonvaccination.
Late cases tended to occur among the older age groups, who had lower vaccination
coverage. During the Canadian mass immunization campaign in 1992, vaccination
coverage was also lower among young adults: among 20-year-olds, coverage was
36%; among children aged 5 to 14 years, coverage was greater than 90%.17 In our study, other than the differences in vaccination
rates by age, the nonvaccinated group was very similar to the vaccinated group.
Although the methods of addressing these issues are not well standardized,
we found that factors traditionally considered to be important programmatic
concerns (eg, perception of disease and concern about adverse effects) were
not significantly associated with vaccination. In contrast, a study in a university
campus population in which a meningococcal vaccination campaign took place
identified lower vaccination rates among older students. The study also found
that both the perception of poor access to vaccination centers and the belief
that the individual was at low or no risk of contracting meningitis were associated
with nonvaccination.27 Further studies should
focus on identifying the specific reasons why adolescents and young adults
are less likely to get vaccinated to have more effective vaccination campaigns.
Communicating information about high vaccine efficacy and the necessity for
high vaccination coverage to stop outbreaks may gain additional support from
health care workers, public health officials, and the public for vaccination
campaigns. Estimating not only overall community vaccination rates but also
age-specific rates may help to ensure that all targeted age groups are being
Our study demonstrated that the currently available meningococcal polysaccharide
vaccine provides a high level of protection in those immunized and is an effective
public health tool for use in SCMD outbreaks. However, achieving optimal coverage
in older age groups was problematic. When adolescents and young adults are
within the target group for vaccination, special emphasis aimed at ensuring
their participation is needed.