De Wals P, Deceuninck G, Boulianne N, De Serres G. Effectiveness of a Mass Immunization Campaign Using Serogroup C Meningococcal
Conjugate Vaccine. JAMA. 2004;292(20):2491–2494. doi:10.1001/jama.292.20.2491
Context Meningococcal polysaccharide vaccines are of limited effectiveness.
New protein-polysaccharide conjugate vaccines have yet to be evaluated in
Objective To assess the effectiveness of a serogroup C conjugate meningococcal
vaccine in an outbreak setting.
Design, Setting, and Participants Population-based observational study of cases of invasive serogroup
C meningococcal disease from 1996 through 2002 in Quebec identified from the
provincial registry of notifiable diseases and from the provincial reference
laboratory. In 2001, a mass immunization campaign with a conjugate vaccine
was conducted to control an emerging epidemic. The number of vaccinated individuals
was extracted from meningococcal immunization registries.
Main Outcome Measures Incidence of invasive meningococcal disease before and 1 year after
the campaign in vaccinated and unvaccinated individuals.
Results Vaccination coverage of those 2 months to 20 years was 82.1%. After
the campaign, the number of cases of serogroup C disease decreased from 58
in 2001 to 27 in 2002, and the incidence from 7.8 per million to 3.6 per million.
Vaccine effectiveness was found to be 96.8% (95% confidence interval, 75.0%-99.9%).
There was no observed increase in the incidence of the other serogroups.
Conclusion The new conjugate vaccine was effective in controlling an emerging epidemic
of serogroup C meningococcal disease, as well as providing short-term protection
across a wide age range.
Serogroup C polysaccharide meningococcal vaccines are not effective
in young children, and protection is of short duration in older children and
adults.1 In contrast, protein-polysaccharide
conjugate vaccines elicit a T-cell dependent immunologic response that is
present in young infants and characterized by the production of high levels
of high-avidity bactericidal antibodies and the induction of immunologic memory.2 The use of bactericidal assays and possibly other
functional tests has been proposed as a standard to license new meningococcal
conjugate vaccines, as phase 3 randomized trials aiming at assessing vaccine
efficacy would be impracticable.3,4(pp371-393) However, carefully conducted observational studies are of
paramount importance to evaluate the effectiveness of these new vaccines.
An increase in the incidence of meningococcal disease was identified
in the province of Quebec in 1990, caused by a virulent C:2a ET15 clone.5,6 To control the epidemic, a mass immunization
campaign was conducted in the winter of 1992-1993, using polysaccharide vaccines
and targeting the population between the ages of 6 months and 20 years.7 Disease incidence decreased markedly in the following
years. In February of 2001, several outbreaks caused by a parent clone occurred,
mainly in the Quebec City area.8 Localized
immunization programs using plain polysaccharide vaccines were conducted that
targeted secondary school students. However, the epidemic extended to younger
age groups and other regions, generating a high level of anxiety in the population
and extensive media coverage. A serogroup C oligosaccharide-CRM197 protein
conjugate vaccine (Menjugate, Chiron, Emeryville, Calif) was licensed following
a fast-track process and a mass immunization campaign was launched in the
Quebec City area from May through June 2001. The campaign was extended to
other regions during the autumn of 2001, targeting all residents in the province
between the ages of 2 months and 20 years. The vaccine was mainly administered
through the local public health units in special clinics and education facilities.
This intervention provided a unique opportunity to assess the effectiveness
of the conjugate vaccine.
The population targeted for vaccination encompassed all residents in
the province of Quebec born between July 17, 1980, and November 30, 2001.
The size of the target population and its age distribution on January 31,
2002, was estimated from projections based on the 1996 census. A meningococcal
immunization registry was established in the Quebec City region in the spring
of 2001 and a provincial registry was established in the fall of 2001. This
enabled the processing of immunization records received from vaccine providers,
both nurses and physicians, in public health units and private clinics. Data
concerning the number of vaccinated individuals and doses administered were
extracted from the 2 registries.
Cases of invasive meningococcal disease were identified from the provincial
registry of notifiable diseases. Any case suspected or diagnosed by a physician
or a laboratory had to be reported to the regional public health department.
An investigation was conducted by the public health department to collect
additional information, including the clinical presentation and outcome, the
vaccination status of the patient, and the results of diagnostic tests. Cases
were classified as clinical or confirmed according to standardized criteria.9 Hospital laboratories were asked to transmit samples
and/or cultures to the Quebec Public Health Laboratory for confirmation of
the bacteriological diagnosis and strain characterization. Polymerase chain
reaction and additional strain characterization tests were performed by the
Health Canada National Reference Laboratory in Winnipeg.10 The
list of cases identified by the Quebec Public Health Laboratory in 1996-2002
was cross-checked against the notifiable diseases file.
Incidence rates for serogroup C disease were calculated as number of
cases divided by mid year projections of the population of Quebec based on
the 1996 census obtained from the Institut de La Statistique du Quebec. Incidence
rates in the total population and target population 2 months to 20 years were
compared between the period 1996-2000 (before the mass vaccination campaign),
2001 (during the outbreak), and 2002 (after the campaign). The incidence rates
of serogroup B and serogroup Y meningococcal disease were also compared to
identify any ecological effect. To assess vaccine effectiveness, the incidence
of confirmed serogroup C meningococcal disease during the year 2002 was compared
between vaccinated and unvaccinated individuals in the target population.
Vaccine effectiveness was defined as 1 minus the relative risk of disease
(or the odds ratio).11 Confidence intervals
and P values were computed using StatXact software.12P<.05 was considered
statistically significant. The study was approved by the Quebec Ministry of
Health and Social Services.
The population of Quebec was 7 399 931, while the target population
(2 months to 20 years) included 1 919 070 individuals. During the mass campaign,
51 781 doses of plain polysaccharide vaccine were administered, mainly
to adolescents in the Quebec City area. A total of 1 606 635 doses
of serogroup C congugate vaccine were administered; 1 524 003 individuals
received at least 1 dose. The vast majority of vaccines (94.7%) were given
before December 31, 2001, and the vaccines administered in 2002 were mostly
second and third doses given to young infants. Vaccination coverage was 82.1%;
81.5% were fully immunized. Vaccine coverage was higher in children aged 6
through 16 years than in younger or older age groups (Figure 1).
The number of cases of serogroup C meningococcal disease reported in
Quebec from 1996 to 2000 ranged from 3 to 12. In 2001, the number of cases
suddenly increased to 58 (Table 1).
In 2002, the year following the mass campaign, the number of cases of serogroup
C decreased to 27 but was still higher than in the endemic period 1996-2000.
The incidence rates were 1.04 per million in 1996-2000, 7.84 in 2001 (P<.001), and 3.63 in 2002 (P<.001
comparing 2001 rates; Table 2). For
the age group targeted for vaccination, the incidence increased from 2.90
per million in 1996-2000 to 21.47 in 2001, then decreased to 3.26 in 2002.
In contrast, for those 21 years and older, the incidence was similar between
2001 (3.26) and 2002 (3.77; Table 2).
For serogroup B, the incidence rate in 2002 (4.0 per million) was close
to that observed in the period between 1996-2000 (3.8 per million, P = .26). For serogroup Y, the incidence rate in 2002 (0.7 per million)
was not significantly different than in the period 1996-2000 (1.2 per million, P = .07).
In the Quebec City area (Figure 2),
the number of cases of serogroup C in the population younger than 21 years
decreased markedly after the mass campaign. However, sporadic cases continued
to occur in individuals exceeding this age bracket. A similar pattern was
observed throughout the entire province (Figure
2). A second wave of the epidemic was expected to occur in the winter
2001-2002 but was not observed.
In 2002, 7 serogroup C cases were reported among unvaccinated individuals
from the target population, and 2 cases of vaccine failure were documented.
The first reported case was a 19-year-old man with meningococcemia and meningitis,
confirmed by blood culture. He had received a first dose of polysaccharide
vaccine in 1993 and a second dose in 2001. The second reported case was a
16-year-old girl with meningitis, confirmed by a polymerase chain reaction
test in a blood specimen. She had been treated for an astrocytoma 2 years
previously and had received the conjugate vaccine in 2001. Overall, the effectiveness
of the conjugate vaccine was 96.8% (95% confidence interval, 75.0%-99.9%).
In Quebec, a mass immunization campaign relying primarily on a serogroup
C conjugate vaccine was successful in controlling an emerging epidemic, and
a high level of protection was provided over a wide age range of individuals.
The 96.8% effectiveness rate measured in the present study is close to the
88% to 96% short-term effectiveness rates observed in the United Kingdom,
where 3 different conjugate vaccines have been used for a routine infant immunization
program with a catch-up program for older individuals.13,14 In
the year following the first mass immunization campaign in Quebec in 1993,
the age-adjusted effectiveness rate of the serogroup C polysaccharide vaccine
was 74.3% (95% confidence interval, 9.5%-91.6%).1
In industrialized countries, meningococcal diseases are infrequent,
even during outbreaks, and confidence intervals for estimates of vaccine effectiveness
from observational studies are likely to be wide, even when conducted in large
populations. This proved to be a major limitation of our study.
Although selection bias is always possible, in recent years, the increasing
use of polymerase chain reaction tests has improved the diagnosis of cases
of invasive meningococcal disease.4(pp23-39) This technique is now widely used in Quebec and is included in the
case-definition.9 The completeness of reporting
of meningococcal disease to public health authorities has been estimated to
be 94% in the Montreal, Quebec, area, using hospital records as a reference.15
Similarly, confounding bias is unlikely. Following the 1992-1993 mass
immunization campaign in Quebec, polysaccharide vaccine effectiveness was
measured in a case-control study, and vaccine effectiveness estimates did
not change markedly when potential confounders such as socioeconomic variables
were included in the analysis.16 Finally, only
short-term protection was assessed. More studies are needed to assess long-term
protection, especially for individuals vaccinated before the age of 1 year
in whom immunity may wane, as observed in the United Kingdom.17
Corresponding Author: Philippe De Wals,
MD, PhD, Département de Médecine sociale et préventive,
Université Laval, Pavillon de l'Est, 2180 chemin Sainte-Foy, Québec,
Canada G1K 7P4 (Philippe.De.Wals@ssss.gouv.qc.ca).
Author Contributions: Dr De Wals had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: De Wals, Deceuninck,
Acquisition of data: Deceuninck, Boulianne.
Analysis and interpretation of data: De Wals,
Deceuninck, Boulianne, De Serres.
Drafting of the manuscript: De Wals, Deceuninck.
Critical revision of the manuscript for important
intellectual content: De Wals, Deceuninck, Boulianne, De Serres.
Statistical analysis: De Wals, Deceuninck,
Obtained funding: De Wals, Boulianne.
Administrative, technical, or material support:
Study supervision: De Wals, Boulianne, De Serres.
Funding/Support: The study was supported by
the Quebec Ministry of Health and Social Services.
Role of the Sponsor: The Quebec Ministry of
Health and Social Services had no role in the design and conduct of the study;
in the collection, management, analysis, and interpretation of the data; or
in the preparation, review, and approval of the article.
Previous Presentation: The results of this
study have been presented in a poster session at the 12th Interscience Congress
on Infectious Diseases, held March 4 through 7, 2004, Cancun, Mexico.
Acknowledgment: Manon Lorange and Louise Ringuette
from the Quebec Public Health Laboratory, Diane Audet, and Manale Ouakki from
the Quebec Hospital Research Center, and Sylfreed Minzunza from the Quebec
Ministry of Health and Social Services provided valuable assistance for the