MAJOR ARTICLE
Effectiveness of Serogroup C Meningococcal Polysaccharide Vaccine: Results from a Case-Control Study in Quebec Philippe De Wals,1,2 Genevie`ve Deceuninck,3 Gaston De Serres,1,2 Jean-Franc¸ois Boivin,4,5 Bernard Duval,2 Robert Remis,6 and Richard Masse´2,4 1 Department of Social and Preventive Medicine, Laval University, 2Quebec National Public Health Institute, and 3Public Health Research Unit, Quebec University Hospital Centre, Quebec City, 4Department of Epidemiology and Biostatistics, McGill University, and 5Centre for Clinical Epidemiology, Jewish General Hospital, Montreal, and 6Department of Public Health Sciences, University of Toronto, Toronto, Canada
In the province of Quebec, Canada, an increase in the incidence of meningococcal disease, caused by a virulent clone of Neisseria meningitidis C-2a-ET15, started during the winter of 1989–1990 [1]. The epidemic continued during the following years, and immunization programs with polysaccharide vaccines were initiated in January 1992, first targeting the regions and age groups with the highest incidence of disease and ending with a mass-immunization campaign during the winter of 2002–2003 [2]. A total of 84% of the 1.9 million residents aged 6 months to 20 years were vaccinated
Received 1 June 2004; accepted 3 December 2004; electronically published 11 March 2005. Reprints or correspondence: Dr. Philippe De Wals, De´partement de Me´decine sociale et pre´ventive, Universite´ Laval, Pavillon de l’Est, 2180 chemin Sainte-Foy, Ste. 1108, Que´bec, Canada G1K 7P4 (
[email protected]). Clinical Infectious Diseases 2005; 40:1116–22 2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4008-0007$15.00
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with a tetravalent vaccine (including serotypes A, C, Y, and W135) from Connaught (24% of total doses) or a bivalent vaccine (including serotypes A and C) from Smith-Kline-Beecham (4%) or from Me´rieux (72%). Rates of coverage were 190% among children 6–14 years of age but were lower for younger and older groups. Since this was the first mass use of a serogroup C meningococcal polysaccharide vaccine in North America, a comprehensive research program was instituted [3]. First, a cohort analysis was done to evaluate the effectiveness of the vaccine over a 2-year period [2] and then over a 5-year period [4]. In these analyses, the only controlled variable was age at vaccination. Since immunization status may be associated with other risk factors, such as place of residence, socioeconomic status, tobacco use, and participation in certain social activities, the ability to control for the possible confounding effects of these variables was important, to produce unbiased estimates
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Background. After a mass-immunization campaign in the province of Quebec, Canada, from 1992 to 1993, a case-control study was conducted to evaluate the effectiveness of the polysaccharide vaccine, while controlling for the potential confounding effects of selected risk factors for serogroup C meningococcal disease. Methods. The case patient group comprised 74 individuals with confirmed serogroup C meningococcal disease reported after the beginning of the campaign until 31 March 1998. Four control subjects, matched for age and place of residence, were randomly selected from the Quebec health insurance registry. Information on case patients was obtained from regional public health departments. Case patients and control subjects (or a family member) were interviewed by telephone. The analyses were conducted by using conditional logistic regression models. Results. Although the 95% confidence intervals (CIs) were large as a result of the small sample sizes, a high level of protection was found among children aged ⭓6 years, during the first 2 years after vaccination (vaccine effectiveness, 95%; 95% CI, 68%–99%; P ! .002 ), and protection remained high during the following 3 years (77%; 95% CI, ⫺364% to 99%; P p .34). For children aged 2–5 years, the estimated effectiveness was positive during the first 2 years (62%; 95% CI, ⫺403% to 97%; P p .47 ) but was negative during the following period (⫺74%; 95% CI, ⫺1956% to 85%; P p .66). Among children aged !2 years, there was no evidence of protection. Household crowding and disadvantaged socioeconomic conditions were associated with increased risk of disease. Conclusions. The polysaccharide vaccine remains a cost-effective option for the short-term protection of school-aged children and adults; however, conjugate vaccines are needed for younger children.
of vaccine effectiveness [5]. To do this, a matched case-control study was planned as soon as the mass-immunization campaign started and included a detailed interview regarding risk factors for the disease. The objective of the study was to evaluate the effectiveness of the serogroup C meningococcal polysaccharide vaccine in preventing invasive serogroup C meningococcal disease, while taking into account age at vaccination and time since vaccination, identifying selected risk factors for the disease, and controlling for the possible confounding effects of these factors on estimates of vaccine effectiveness. METHODS
RESULTS Seventy-four case patients with invasive serogroup C meningococcal disease that had been confirmed by blood and/or CSF culture and that met the selection criteria were identified and Serogroup C Meningococcal Vaccine • CID 2005:40 (15 April) • 1117
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The study protocol was approved by the Research Ethics Board of the Sherbrooke University Hospital Centre (Sherbrooke, Quebec), and the Quebec Information Access Committee (Quebec City, Quebec) authorized the collection of personal information from provincial files. The study population comprised all persons targeted by the mass-immunization campaign, namely, those born between 4 December 1971 and 30 September 1992 who resided in the province of Quebec. The case patients were individuals in the study population who were identified as having serogroup C meningococcal disease between the vaccination start date in each region (1 January 1992 being the earliest and 1 January 1993 being the latest) and 31 March 1998. Cases were identified from the provincial registry of notifiable diseases. Cases of invasive meningococcal disease diagnosed by a physician or a laboratory must be reported to the regional public health department, when consistent with standardized case definitions [6]. Hospital laboratories also are asked to transmit samples and/or cultures to the Quebec Public Health Laboratory (Montreal, Quebec) for confirmation of the bacteriological diagnosis and additional strain characterization. The list of cases identified by the reference laboratory was cross-checked against the notifiable-diseases file. Excluded from the study were cases that occurred outside the province of Quebec, since the selection of control subjects would have been impossible, and cases that occurred in patients who did not reside in the province. The names and addresses of the case patients were provided by the regional public health departments. Control subjects were randomly selected from the provincial health insurance file, which includes all Canadians and immigrants residing in Quebec. For each case patient, date of birth and the postal code of the individual’s residence were sent to the provincial health insurance board, which provided a list of 10 potential control subjects matched by date of birth (1 month) and place of residence (i.e., the first 3 characters of the postal code were the same). The lists of control subjects contained parents’ names and postal addresses, and directories were checked for telephone numbers. Case patients with illness that occurred before 26 January
1994 and their matched control subjects were contacted retrospectively during 1994. Case patients with illness that occurred after this date were contacted prospectively, usually in the month after the illness occurred. The case patients and control subjects were interviewed by telephone, and a standardized questionnaire was used. For deceased persons, individuals aged !18 years, and individuals unable to answer the questions, a family member was interviewed. The interview questions covered the individual’s history of meningococcal vaccination and included information on place, date, and circumstances, as well as reasons for not being vaccinated, when relevant to case patients. Respondents were asked to consult their vaccination booklet, if available, and to provide detailed information on the date of vaccination and the type of vaccine received. Other questions concerned medical history, tobacco use, travel, and participation in social events 2–7 days before the onset of disease in the case patients (i.e., the incubation period). Finally, information was collected on household composition, dwelling size, type of heating, presence of tobacco smoke, family income, and education level of the mother or primary caregiver of the person in the study. For some of the control subjects, some doubt remained regarding whether exact vaccination dates were before or after onset of disease in the case patients. To account for this uncertainty, sensitivity analyses were performed under 2 possible scenarios—namely, that all these control subjects had been vaccinated or that all these control subjects had not been vaccinated at the time of onset of disease in the case patient. The statistical analyses were done with SAS software (SAS Institute) [7]. ORs and their 95% CIs were calculated by using conditional logistic regression. Vaccine effectiveness was defined as 1 ⫺ relative risk, as approximated by means of the OR [8]. In the first step, risk factors for the disease were tested one by one in a model that included vaccine status and age at vaccination, defined as continuous variables (the effect of time since vaccination was no longer significant when these 2 variables were included in the model). Factors significantly associated with disease risk at the 5% level were then entered into a multivariate model. In the second step, the effects of age at vaccination and time since vaccination were explored in a series of models, to identify the model that provided the best fit, as defined by the likelihood ratio. A model using 3 categories for age at vaccination (!2 years, 2–5 years, and ⭓6 years) and 2 categories for time since vaccination (!2 years and ⭓2 years) was selected. All potential confounding variables were then entered into a multivariate model with no interaction between variables.
immunization form provided by the regional health authority) was obtained for 34 (79%) of the 43 case patients and 153 (75%) of the 204 control subjects who were considered to have been vaccinated. Whether 4 of the vaccinated control subjects had in fact been immunized before onset of disease in the case patients could not be determined with certainty. In view of their medical history and the vaccination campaign in their area of residence, 2 of these control subjects were likely to have been vaccinated at that time, but vaccination was not likely for the other 2 control subjects. The matched analysis indicated an overall vaccine effectiveness of 75.9% (95% CI, 42.9%–89.9%). When the 4 control subjects with uncertain vaccination status were considered as not having been vaccinated, vaccine effectiveness decreased to 70.9% (95% CI, 34.0%–87.2%). When the possibility that they were vaccinated was considered, effectiveness increased to 79.6% (95% CI, 50.8%–91.6%). As presented in table 2, both age at vaccination and time since vaccination were variables that substantially modified vaccine effectiveness. After adjustment for potential confounders, estimates of effectiveness were reduced for younger age groups but remained unchanged for individuals aged ⭓6 years. Although the CIs were large, owing to the small number of case
Table 1. Sociodemographic characteristics of case patients and control subjects, and association of these variables with risk of serogroup C meningococcal disease.
Characteristic Male sex Household ⭓5 People ⭓4 People !21 years of age
Case patients, % (n p 74)
Control subjects, % (n p 285)
OR
P
52.7
56.1
0.9
.58
a
36.6
32.3
1.2
.53
16.7
8.1
3.2
.01
20.8 9.7 46.5
0.1 1.8 38.6
0.3 4.5 1.4
!.01
⭓3 People sharing a bedroom ⭐5 Rooms Person-to-room ratio ⭓0.8 Electric heating Central or bedroom humidifier
31.0 71.2 16.4
17.2 67.7 27.3
2.0 1.4 0.6
.04 .34 .17
Smoking status Occasional or regular cigarette
13.5
10.5
2.1
.14
40.5 18.8
38.0 13.6
1.1 1.8
.76 .16
38.8
24.1
2.2
.01
Went to day care Went to school
10.8 45.9
10.5 55.4
1.2 0.4
.77 .06
Went to work Went to a bar or party
9.5 44.4
8.8 33.3
0.8 1.9
.79 .23
!2 People ⭓21 years of age
Passive Mother with a primary school education Annual family income ! Can$25,000
.02 .25
Exposureb
a
Conditional logistic regression model including vaccine status and age at vaccination, unadjusted for the other risk factors. b Defined on the basis of the incubation period, that is, 2–7 days before onset of disease in the case patient; applies only to those interviewed in the prospective part of the study.
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subsequently participated in the study (mean age, 10.9 years). Of the 740 individuals selected as potential control subjects, 429 were selected to be contacted, but only 285 of the planned 296 control subjects were recruited. Reasons for nonparticipation were as follows: 99 people could not be reached, 14 refused, 24 did not live in the same area as the case patient during the exposure period, the vaccination status of 4 people was impossible to determine, 2 were twins of case patients, and 1 had died by the time of the study. The first 34 case patients and their 136 control subjects were recruited retrospectively, during 1994, and the other 40 case patients and their 149 control subjects were recruited prospectively, between 1994 and 1998. The interviews took place between 4 weeks and 46 months after onset of disease in the case patients. The sociodemographic characteristics of the case patients and control subjects are presented in table 1. Compared with the control subjects, there were a higher proportion of females, individuals residing in smaller dwellings, and more-crowded households among the case patients, as well as more individuals from socioeconomically disadvantaged families. Of the case patients, 58.1% had been vaccinated, compared with 71.6% of the control subjects. Written proof of vaccination (vaccination booklet reviewed during telephone interview or
!2 Years 2–5 Years ⭓6 Years
31.3 (⫺401.8 to 90.6) 83.7 (⫺35.6 to 98.0) 94.6 (72.0 to 99.0)
Effectiveness, % (95% CI) .71 .09 .001
P
P .95 .47 .002
Effectiveness, % (95% CI) ⫺7.9 (⫺1057.2 to 89.9) 61.8 (⫺403.6 to 97.1) 95.0 (68.3 to 99.2)
Adjusted
a
3 7 12
No. of case-control sets
.18 .92 .33
⫺284.3 (⫺2651.1 to 46.3) 9.0 (⫺622.3 to 88.5) 69.9 (⫺251.5 to 97.4)
⫺390.5 (⫺4599.2 to 48.8) ⫺73.8 (⫺1956.2 to 85.3) 77.3 (⫺364.0 to 98.9)
Effectiveness, % (95% CI) P
Effectiveness, % (95% CI)
a
Adjusted
Unadjusted
⭓24 Months since vaccination
.17 .66 .34
P
Conditional logistic regression model adjusted for no. of people !21 years of age and no. of people ⭓21 years of age in the household; ⭓3 people sharing a bedroom; no. of rooms; electric heating; central or bedroom humidifier; annual family income; mother’s level of education; active and passive smoking; attendance at day care, school, or work; and attendance at a bar or party.
a
NOTE. Four control subjects whose vaccine status was uncertain at the time of onset of disease in the case patients were excluded from the analysis. Vaccine effectiveness was defined as described in Methods.
8 12 32
Age at vaccination
Unadjusted
!24 Months since vaccination
Number of case-control sets and vaccine effectiveness, by age at vaccination and time since vaccination.
No. of case-control sets
Table 2.
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DISCUSSION This is the first published study evaluating the effectiveness of serogroup C meningococcal polysaccharide vaccine according to age at vaccination and time since vaccination, while controlling for several confounding factors. Despite the relative imprecision of the estimates of vaccine effectiveness in this casecontrol study, which was nested within a cohort of nearly 1.9 million people and had a follow-up period lasting 15 years, the results can nonetheless be interpreted if caution is used. During the first 2 years after vaccine administration, the vaccine appeared to be effective among children aged ⭓2 years; the initial level of protection was greater when the age at vaccination was
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higher. At 2–5 years after vaccination, some protection appeared to persist among children vaccinated at ⭓6 years of age, but no effectiveness persisted among children vaccinated at 2– 5 years of age. Evidence of vaccine protection among children aged !2 years was not found. The possibility of increased susceptibility to serogroup C meningococcal disease resulting from administration of a polysaccharide vaccine at a young age cannot be excluded. This confirms results observed in the cohort analysis [4], although estimates of vaccine effectiveness among children aged !6 years were slightly reduced when confounding variables were taken into account. The sensitivity of the mandatory notification of meningococcal disease in Quebec was estimated to be 94% [9]. In the current study, additional information was provided by the reference laboratory, to ensure the completeness of case finding. Although control subjects were randomly selected from the provincial heath insurance file, several could not be contacted, and characteristics for these control subjects were unknown. However, the participation rate was excellent among those invited to be interviewed. To determine vaccination status, data from a detailed interview were used, and, for case patients, additional information was obtained from the regional public health departments. For all the case patients and a large majority of control subjects, vaccine status was determined with a high degree of certainty, and sensitivity analyses were done for the few control subjects for whom the date of vaccination was uncertain. The efficacy of serogroup C polysaccharide vaccines was evaluated in a series of clinical trials with US army recruits followed during an 8-week basic training period; protection was found to be 90% overall [10–12]. In a randomized trial done during an epidemic in Brazil, with a follow-up period of ∼18 months, the reduction of incidence was 12% among children aged 6– 23 months and 55% among children aged 24–36 months [13]. In a case-control study performed after an outbreak in the United States, a short-term protection rate of 85% was observed among those vaccinated who were 2–29 years of age [14]. After a mass-immunization program during an epidemic in Catalonia, Spain, the age-adjusted effectiveness rate was 94% for the entire population of those between 18 months and 19 years of age, who were followed for a 2-year period [15]. In addition, 2 other studies done in different regions of Spain indicated that the protection conferred by the polysaccharide vaccine was better in adolescents than in young children [16, 17]. Overall, these results are consistent with those obtained in Quebec. In a study in Quebec [18], the proportion of children aged !2 years who had a 4-fold increase in bactericidal antibody titers after 1 dose of serogroup C polysaccharide vaccine was only 10.2%. In older children, the level of bactericidal antibodies 1 month after administration of 1 dose of serogroup C
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patients, a high level of protection was observed among children aged ⭓6 years, during the first 2 years after vaccination (vaccine effectiveness, 95.0%; 95% CI, 68.3%–99.2%). A high level of protection also was observed to persist during the following 3 years (77.3%; 95% CI, ⫺364.0% to 98.9%). Among children aged 2–5 years, some protection was likely to have been conferred during the first 2 years after vaccination (61.8%; 95% CI, ⫺403% to 97.1%). However, the estimate of effectiveness was negative during the following time period (⫺73.8%; 95% CI, ⫺1956.2% to 85.3%). Among children aged !2 years, no evidence of protection was found. The estimate of effectiveness was close to 0 in the first period (⫺7.9%; 95% CI, ⫺1057.2% to 89.9%) and was well below 0 in the second period (⫺390.5%; 95% CI, ⫺4599.2% to 48.8%). Four of the 43 vaccinated case patients and 2 of the 31 unvaccinated case patients were reported to have died. After adjustment for age, the case-fatality rate was not significantly different (age-adjusted OR, 0.9; P p .36). When the variables were tested individually in a logistic regression model that was controlled for vaccine status and age at vaccination, the following factors were not found to be significantly associated with the risk of disease: sex; total number of people in the household; number of rooms in the dwelling; type of heating; the presence of a central or room humidifier; attendance at day care, school, or work; being a regular or occasional smoker; living in a household with smokers; and mother’s level of education (table 1). In contrast, the presence of only 1 adult (⭓21 years of age) in the household, the presence of ⭓4 young people (!21 years of age), sharing a bedroom with ⭓2 individuals, and an annual family income of less than Can$25,000 were found to be statistically significant risk factors. In a model that was adjusted simultaneously for these 4 significant variables, the following 2 factors remained statistically associated with increased disease risk: the presence of ⭓4 young people (!21 years of age) in the household (OR, 3.7; 95% CI, 1.5–9.1) and the presence of only 1 adult in the household (OR, 3.5; 95% CI, 1.6–7.6).
Acknowledgments Monique Douville-Fradet, Nicole Boulianne, and Louise Ringuette from the Quebec National Public Health Institute (Quebec City) provided valuable assistance during the study. Financial support. Quebec Ministry of Heath and Social Services. Potential conflicts of interest. P.D.W. has received research grants, reimbursement for travel expenses, and honoraria for conferences from vaccine manufacturers, including Aventis Pasteur, GlaxoSmithKline, Shire, Chiron, Baxter, Merck Frosst, and Wyeth-Ayerst. G.D.S. has received research grants, reimbursement for travel expenses, and honoraria for conferences from vaccine manufacturers, including Aventis Pasteur, GlaxoSmithKline, Shire, Chiron, Baxter, and Merck Frosst. J.-F.B. has received research grants from GlaxoSmithKline, Merck Frosst, Aventis Pasteur, Shire, and Dynavax. All other authors: no conflicts.
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polysaccharide vaccine was observed to increase as age at vaccination increased [19]. A decrease in the serological concentration of antibodies over time also was influenced by age. In infants vaccinated at 7 months of age, antibodies virtually disappeared by 2 years of age [20]. In children vaccinated at 6–8 years of age, antibodies persisted longer: at 4 years after vaccination, 40% of the children still had antibody concentrations 12.0 mg/mL [21]. These results may explain the persistence of protection observed in our study when the vaccine was administered to school-aged children and adolescents. Polysaccharide vaccines induce a T cell–independent immune response characterized by the absence of immunologic memory [22]. Another characteristic of the serogroup C polysaccharide vaccine is the inhibition of the serological response after a booster dose. This phenomenon has been observed in both children and adults [23–27]. Once the protective antibodies have disappeared, the inhibition of the serological response could result in greater susceptibility to invasive disease. In view of the negative estimates of protection in children aged !6 years after vaccine administration, this possibility cannot be discounted. In the present study, an increased risk of meningococcal disease was associated with household crowding and disadvantaged socioeconomic conditions. In the multivariate analysis, the presence of ⭓4 people !21 years of age and of only 1 adult (and 1 source of income) in the household were the most significant variables. However, it is difficult to disentangle the independent effects of socioeconomic and demographic variables that are highly correlated. For families with a large number of children and crowded living conditions, an increased risk of invasive meningococcal disease has already been noted elsewhere [28–31]. The association with socioeconomic status is not surprising, [32, 33], but knowing what biological mechanisms are involved is difficult. There may have been factors that were not measured or not measured accurately in our study. The fact that we could not demonstrate a significant association with other known factors, such as active and passive smoking [34–38] or participation in social events [39–41], may have been due to the lack of power in our study. The results of this study are consistent with a good level of protection provided, over a 5-year period, by 1 dose of serogroup C polysaccharide vaccine received by individuals aged ⭓6 years. In children aged 2–5 years, only short-term protection is probably provided. The new conjugate vaccines have demonstrated very good short-term effectiveness (i.e., ∼90%) starting at age 2 months [42, 43]. However, the level of protection may also wane, especially in individuals who received the conjugate vaccine when aged !1 year [44]. Both epidemiological and economic considerations will be important in deciding which vaccine to use in the future.
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