Early detection and response to meningococcal disease epidemics in sub-Saharan Africa: appraisal of the WHO strategy.

OBJECTIVE: To assess the sensitivity, specificity and predictive value positive of the WHO threshold strategy for detecting meningococcal disease epidemics in sub-Saharan Africa and to estimate the impact of the strategy on an epidemic at district level. METHODS: Data on meningitis cases at the district level were collected weekly from health ministries, WHO country and regional offices, and nongovernmental organizations in countries where there were epidemics of meningococcal disease in 1997. An epidemic was defined as a cumulative district attack rate of at least 100 cases per 100,000 population from January to May, the period of epidemic risk. The sensitivity, specificity and predictive value positive of the WHO threshold rate were calculated, and curves of sensitivity against (1 - specificity) were compared with alternatively defined threshold rates and epidemic sizes. The impact of the WHO strategy on a district epidemic was estimated by comparing the numbers of epidemic cases with cases estimated to have been prevented by vaccination. FINDINGS: An analysis was made of 48 198 cases reported in 174 districts in Benin, Burkina Faso, the Gambia, Ghana, Mali, Niger, and Togo. These cases were 80.3% of those reported from Africa to WHO during the 1997 epidemic period. District populations ranged from 10,298 to 573,908. The threshold rate was crossed during two consecutive weeks in 69 districts (39.7%) and there were epidemics in 66 districts (37.9%). Overall, the sensitivity of the threshold rate for predicting epidemics was 97%, the specificity was 95%, and the predictive value positive was 93%. Taken together, these values were equivalent or better than the sensitivity, specificity and predictive value positive of alternatively defined threshold rates and epidemics, and remained high regardless of district size. The estimated number of potential epidemic cases decreased by nearly 60% in the age group targeted for vaccination in one district where the guidelines were followed in a timely manner. CONCLUSION: The use of the WHO strategy was sensitive and specific for the early detection of meningococcal disease epidemics in countries of sub-Saharan Africa during 1997 and had a substantial impact on a district epidemic. Nevertheless, the burden of meningococcal disease in these countries remains formidable and additional control measures are needed.

Introduction of Hib conjugate vaccines in the non-industrialized world: experience in four 'newly adopting' countries.

Hib conjugate vaccines are widely used in the industrialized world, but are just now beginning to be introduced into other countries. To identify factors facilitating rapid global introduction, we evaluated the decision-making process, mode of introduction, effectiveness, and impact on the immunization program of Hib conjugate vaccine introduction in four non- industrialized countries through site visits and use of a standardized questionnaire. The key promoters of Hib introduction were the pediatric community and ministries of health. Local surveillance and severity data were critical in the decision to adopt Hib vaccine. Assistance with surveillance, introduction guidelines, educational material, tenders, and funding is needed to accelerate wider adoption.

Efficacy of Haemophilus influenzae type b conjugate vaccines and persistence of disease in disadvantaged populations. The Haemophilus Influenzae Study Group.

OBJECTIVES: The purpose of this study was to evaluate the effectiveness of Haemophilus influenzae type b (Hib) conjugate vaccines among children aged 2 to 18 months and to determine risk factors for invasive Hib disease during a period of declining incidence (1991-1994). METHODS: A prospective population-based case-control study was conducted in a multistate US population of 15.5 million. A laboratory-based active surveillance system was used for case detection. RESULTS: In a multivariate analysis, having a single-parent mother (odds ratio [OR] = 4.3, 95% confidence interval [CI] = 1.2, 14.8) and household crowding (OR = 3.5, 95% CI = 1.03, 11.7) were risk factors for Hib disease independent of vaccination status. After adjustment for these risk factors, the protective efficacy of 2 or more Hib vaccine doses was 86% (95% CI = 16%, 98%). Among undervaccinated subjects, living with a smoker (P = .02) and several indicators of lower socioeconomic status were risk factors for Hib disease. CONCLUSIONS: Hib disease still occurs at low levels in the United States, predominantly in socioeconomically disadvantaged populations. Low immunization coverage may facilitate continuing transmission of Hib. Special efforts to achieve complete and timely immunization in disadvantaged populations are needed.

Epidemiology of Haemophilus influenzae type b disease and impact of Haemophilus influenzae type b conjugate vaccines in the United States and Canada.

Haemophilus influenzae type b (Hib) was the major cause of invasive bacterial disease in the United States and Canada before the introduction of Hib conjugate vaccines. Between 10000 and 20000 cases of Hib meningitis and other serious diseases occurred each year, leading to death in at least 3% of all patients and long term neurologic problems in up to 25% of survivors of meningitis. Introduction of Hib conjugate vaccines in Canada and the United States, first in children 18 months and older and later as a routine infant immunization, dramatically decreased the incidence of disease. By 1995 Hib disease levels had declined by more than 95% below preimmunization levels. The remarkably rapid reduction in disease incidence was partly because of the ability of the vaccine to reduce nasopharyngeal carriage of the organism, leading, when given widely, to reduced rates of exposure and infection even in those not immunized. Complete elimination of Hib disease in North America, however, will require achievement of relatively high coverage rates, especially in hard to reach populations where much of the remaining disease is occurring.

Immunogenicity of two efficacious outer membrane protein-based serogroup B meningococcal vaccines among young adults in Iceland.

Serum bactericidal activity (SBA) and ELISA antibody levels elicited by two efficacious serogroup B meningococcal vaccines were measured in a controlled trial involving 408 15- to 20-year-olds. Subjects were given two doses at a 6-week interval of a serogroup B or control vaccine. Response was defined as > or = 4-fold rise in antibody level. After two doses of the Finlay Institute (Havana) vaccine at 12 months, the proportions of SBA and ELISA responders were not different from those of the control group (15% and 17% [vaccine] vs. 13% and 9% [control], P > .05). After two doses of the National Institute of Public Health (Oslo) vaccine, there were more SBA and ELISA responders than in the control group (47% and 34% [vaccine] vs. 10% and 1% [control]) or the Finlay Institute vaccine group (P < .05 for both). SBA and ELISA may be insensitive correlates for protective efficacy for some outer membrane protein-based serogroup B meningococcal vaccines.

Efficacy of meningococcal vaccine and barriers to vaccination.

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 (chi2 for 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.

Informal workshop on potential regulatory and 2 licensing issues for pneumococcal conjugate vaccines. 13 June 1998, Helsingor, Denmark.

(1) It is likely that a seven-valent pneumococcal conjugate vaccine will be licensed in the next few years based on efficacy studies. Licensure of nine- or 11-valent vaccines will be sought soon thereafter. Further studies of nine- or 11-valent vaccines which can evaluate efficacy of the added serotypes will be unlikely. (2) Licensure of other vaccines (including those with additional serotypes), will depend on evaluation of surrogates for efficacy. (3) The most accepted surrogate of efficacy at this point is some combination of functional assay (e.g. opsonophagocytosis), and/or serology of anticapsular antibody by ELISA or RIA that correlates closely with the functional test. (4) An additional important correlate of immunity for polysaccharide conjugate vaccines may be measurement of the booster response. (5) Although effect on nasopharyngeal carriage may be developed into a useful correlate of efficacy in the future, much additional work must be done before carriage data can be interpreted usefully for this purpose. (6) Testing for consistency of production of pneumococcal conjugate vaccines will follow lines similar to that for Hib conjugate vaccines. Thus, instead of one set of universally applicable lot release criteria, vaccine-specific criteria must be developed collaboratively between industry and national control authorities.

Molecular epidemiology of sporadic (endemic) serogroup C meningococcal disease.

Understanding the basis of sporadic (endemic) meningococcal disease may be critical to prevention of meningococcal epidemic outbreaks and to understanding fluctuations in incidence. Active, prospective, population-based surveillance and molecular epidemiologic techniques were used to study sporadic serogroup C meningococcal disease in a population of 2.34 million persons (Atlanta area). During 1988-1994, in which no outbreaks or case clusters were reported, 71 patients developed sporadic serogroup C meningococcal disease (annual incidence, 0.51/100,000). Eighty-three percent of patients were >2 years old. By multilocus enzyme electrophoresis, pulsed-field gel electrophoresis, and serotyping, 84% (52/62) of the isolates available for study were identical or closely related members of the electrophoretic type 37 (ET 37) complex responsible for multiple serogroup C outbreaks in the United States in the 1990s. Sporadic disease caused by 9 clonal strains occurred over periods up to 4 years and accounted for 45% (28/62) of cases. Sporadic serogroup C meningococcal disease was most often due to a limited number of related strains that appear to slowly circulate in the population.

Tobacco smoke as a risk factor for meningococcal disease.

BACKGROUND: Since 1992 the US Pacific Northwest has experienced a substantial increase in the incidence of serogroup B meningococcal disease. The current meningococcal polysaccharide vaccine is poorly immunogenic in young children and does not protect against N. meningitidis serogroup B. Defining alternative approaches to the prevention and control of meningococcal disease is of considerable public health importance. METHODS: We performed a case-control study comparing 129 patients in Oregon and southwest Washington with 274 age- and area-matched controls. We used conditional logistic regression analysis to determine which exposures remained associated with disease after adjusting for other risk factors and confounders and calculated the proportion of disease attributable to modifiable exposures. RESULTS: After adjustment for all other significant exposures identified, having a mother who smokes was the strongest independent risk factor for invasive meningococcal disease in children < 18 years of age [odds ratio (OR), 3.8; 95% confidence interval (CI) 1.6 to 8.9)], with 37% (CI 15 to 65) of all cases in this age group potentially attributable to maternal smoking. Adult patients were more likely than controls to have a chronic underlying illness (OR 10.8, CI 2.7 to 43.3), passive tobacco smoke exposure (OR 2.5, CI 0.9 to 6.9) and to smoke tobacco (OR 2.4, CI 0.9 to 6.6). Dose-response effects were seen for passive smoke exposure and risk of disease in all age groups. CONCLUSION: Tobacco smoke exposure independently increases the risk of developing meningococcal disease.

School-based clusters of meningococcal disease in the United States. Descriptive epidemiology and a case-control analysis.

OBJECTIVE: To evaluate the epidemiologic features and risk factors for multiple cases of meningococcal disease in schools. DESIGN: Population-based prospective evaluation and case-control study of clusters of meningococcal disease that occurred in schools from January 1989 to June 1994. SETTING: Surveillance conducted through state health departments in the United States. MAIN OUTCOME MEASURES: Descriptive epidemiology of school-based clusters of meningococcal disease and determinants of their occurrence. RESULTS: We identified 22 clusters of meningococcal disease in 15 states. The estimated incidence of secondary meningococcal disease among schoolchildren aged 5 to 18 years was 2.5 per 100000 population, a relative risk of 2.3 (95% confidence interval [CI], 1.6-3.3). The median number of students per cluster was 2 (range, 2-4). Of 30 subsequent cases, 10 (33%) occurred 2 or fewer days after the index case, and 22 (73%) occurred 14 or fewer days after the index case. Among the 8 schools with 2 or more cases, 50% of the additional cases occurred 2 or more days after the second case. Secondary schools (grades 7 through 12) accounted for 15 (75%) of 20 cluster schools compared with 9 (45%) of 20 matched control schools (P<.05). In 16 (73%) of 22 clusters, interaction between case patients was noted. The index patient in cluster schools was more likely than the controls to have participated in a school-based group activity 14 or fewer days before illness (matched odds ratio, 7.0; 95% CI, 0.9-57). CONCLUSIONS: Three quarters of the school clusters occurred in secondary schools, with over 70% of subsequent cases occurring within 2 weeks of the index case. Rapid initiation of a chemoprophylaxis program after 2 cases of meningococcal disease in a school would have potentially prevented 50% of subsequent cases in the clusters described.

Capsule switching of Neisseria meningitidis.

The different sialic acid (serogroups B, C, Y, and W-135) and nonsialic acid (serogroup A) capsular polysaccharides expressed by Neisseria meningitidis are major virulence factors and are used as epidemiologic markers and vaccine targets. However, the identification of meningococcal isolates with similar genetic markers but expressing different capsular polysaccharides suggests that meningococcal clones can switch the type of capsule they express. We identified, except for capsule, isogenic serogroups B [(alpha2-->8)-linked polysialic acid] and C [(alpha2-->9)-linked polysialic acid] meningococcal isolates from an outbreak of meningococcal disease in the U. S. Pacific Northwest. We used these isolates and prototype serogroup A, B, C, Y, and W-135 strains to define the capsular biosynthetic and transport operons of the major meningococcal serogroups and to show that switching from the B to C capsule in the outbreak strain was the result of allelic exchange of the polysialyltransferase. Capsule switching was probably the result of transformation and horizontal DNA exchange in vivo of a serogroup C capsule biosynthetic operon. These findings indicate that closely related virulent meningococcal clones may not be recognized by traditional serogroup-based surveillance and can escape vaccine-induced or natural protective immunity by capsule switching. Capsule switching may be an important virulence mechanism of meningococci and other encapsulated bacterial pathogens. As vaccine development progresses and broader immunization with capsular polysaccharide conjugate vaccines becomes a reality, the ability to switch capsular types may have important implications for the impact of these vaccines.

Prevention practices for perinatal group B streptococcal disease: a multi-state surveillance analysis. Neonatal Group B Streptococcal Disease Study Group.

OBJECTIVE: To evaluate hospital-based practices for perinatal group B streptococcal disease prevention and to identify institutional factors related to the disease. METHODS: We surveyed microbiology laboratories and obstetric programs during 1994 at hospitals in five states with active surveillance for invasive group B streptococcal disease. Institutions provided information on methods for detecting carriers and on obstetric policies for group B streptococcal disease prevention. We used linear regression to identify prevention practices and hospital characteristics that correlated with the number of cases of early-onset disease. RESULTS: Of 295 hospitals, 247 (84%) laboratories and 154 (52%) obstetric programs completed the survey. Most (83%) laboratories performed group B streptococcal cultures on rectal and vaginal specimens, but only 12 (6%) used selective broth media. Among the obstetric programs, 54 (35%) had policies on some aspect of group B streptococcal disease prevention. Of the hospitals with policies, 21 (48%) recommended intrapartum antimicrobial prophylaxis for women with risk factors outlined by the 1992 ACOG statement. Adjusting for the number of births, there were more cases of early-onset group B streptococcal disease in institutions providing care for more African American women and for more women with no prenatal care. Institutions that had group B streptococcal screening policies had fewer early-onset cases. CONCLUSIONS: Many institutions with prevention policies followed practices that differed from those recommended in published prevention statements. Having any screening policy, however, was associated with reduced early-onset disease, independent of the risk profile of the patient population. Adopting prevention policies is most urgent for practices serving individuals at increased risk, such as African American women and women without prenatal care.

Bacterial meningitis in the United States in 1995. Active Surveillance Team.

BACKGROUND: Before the introduction of the conjugate vaccines, Haemophilus influenzae type b was the major cause of bacterial meningitis in the United States, and meningitis was primarily a disease of infants and young children. We describe the epidemiologic features of bacterial meningitis five years after the H. influenzae type b conjugate vaccines were licensed for routine immunization of infants. METHODS: Data were collected from active, population-based surveillance for culture-confirmed meningitis and other invasive bacterial disease during 1995 in laboratories serving all the acute care hospitals in 22 counties of four states (total population, more than 10 million). The rates were compared with those for 1986 obtained by similar surveillance. RESULTS: On the basis of 248 cases of bacterial meningitis in the surveillance areas, the rates of meningitis (per 100,000) for the major pathogens in 1995 were Streptococcus pneumoniae, 1.1; Neisseria meningitidis, 0.6; group B streptococcus, 0.3; Listeria monocytogenes, 0.2; and H. influenzae, 0.2. Group B streptococcus was the predominant pathogen among newborns, N. meningitidis among children 2 to 18 years old, and S. pneumoniae among adults. Pneumococcal meningitis had the highest case fatality rate (21 percent) and in 36 percent of cases was caused by organisms that were not susceptible to penicillin. From these data, we estimate that 5755 cases of bacterial meningitis were caused by these five pathogens in the United States in 1995, as compared with 12,920 cases in 1986, a reduction of 55 percent. The median age of persons with bacterial meningitis increased greatly, from 15 months in 1986 to 25 years in 1995, largely as a result of a 94 percent reduction in the number of cases of H. influenzae meningitis. CONCLUSIONS: Because of the vaccine-related decline in meningitis due to H. influenzae type b, bacterial meningitis in the United States is now a disease predominantly of adults rather than of infants and young children.

Evaluation of the use of mass chemoprophylaxis during a school outbreak of enzyme type 5 serogroup B meningococcal disease.

BACKGROUND: A vaccine for prevention of serogroup B meningococcal disease is not available in the United States, and indications for the use of mass chemoprophylaxis for control of meningococcal outbreaks are not well-defined. In response to an outbreak of six cases of enzyme type 5 serogroup B meningococcal disease among students at a middle school, we implemented a program of mass rifampin prophylaxis and evaluated the effectiveness of this preventive measure. METHODS: Oropharyngeal cultures were obtained from 351 of the 900 students before prophylaxis; 196 participants were recultured 3 weeks later. Meningococcal isolates were subtyped and tested for rifampin susceptibility, and risk factors for disease or carriage among students were evaluated. RESULTS: No cases occurred after prophylaxis. Before prophylaxis 10% (34 of 351) of students were meningococcal carriers and 3.4% (12 of 351) carried the epidemic strain. After prophylaxis 2.5% (5 of 196) were carriers and 1.0% (2 of 196) carried the epidemic strain. Rifampin was 85% effective in eradicating carriage, and the rate of acquisition of carriage during the 3-week period was low (0.5%). Carriage persisted after prophylaxis in 4 students; 3 of these postprophylaxis isolates were rifampin-resistant. Rifampin resistance thus developed in 12% (3 of 26) of preprophylaxis isolates. Disease/epidemic strain carriage was associated with enrollment in the school band and certain other classes. CONCLUSIONS: These findings suggests that mass chemoprophylaxis may be effective and should be considered for control of school serogroup B meningococcal outbreaks. This approach is less likely to be effective for control of outbreaks affecting larger, less well-defined populations and is associated with the rapid development of antibiotic resistance.

Molecular epidemiology of diphtheria in Russia, 1985-1994.

The largest diphtheria outbreak in the developed world since the 1960s began in the Russian federation in 1990. One hundred fifty-six Corynebacterium diphtheriae strains from throughout Russia, selected for temporal and geographic diversity, were assayed by ribotyping and multilocus enzyme electrophoresis (MEE). These tests showed significant genetic diversity within the C. diphtheriae species, and ribotyping and MEE data generally correlated well with epidemiologic data. A distinct clonal group of C. diphtheriae isolates (ET 8 complex) emerged in Russia in 1990 as the current outbreak began, and as the outbreak has progressed, these organisms have made up increasingly larger proportions of the strains that are isolated. Furthermore, the main characteristic of the epidemic strains is a specific combination of ET 8 and ribotypes G1 and G4. This study confirms the epidemiologic utility of the molecular subtyping methods that detected the epidemic clone and addresses the clone's origin and relation to C. diphtheriae from throughout Russia.

Meningococcal disease in Los Angeles County, California, and among men in the county jails.

BACKGROUND: From January through March 1993, there were 54 cases of meningococcal disease in Los Angeles County, California, of which 9 occurred among men incarcerated in the county's jail system, which was 40 percent above capacity at the time. Several of the 45 patients from the community had had contact with men recently released from a county jail. METHODS: We interviewed patients from the community (n=42) and neighborhood controls matched with the patients for age, race, and ethnic group (n=84) about potential exposures. We collected and cultured pharyngeal swabs for Neisseria meningitidis from men entering the central jail (n=162), men leaving the central jail (n=379), members of the jail staff (n=121), and patients at a community health center (n=214). Meningococcal isolates were identified by serotyping and multilocus enzyme electrophoresis. RESULTS: The presence of community-acquired meningococcal disease was strongly associated with exposure to a person who had been in or worked at one of the county jails (multivariate matched odds ratio, 18.5; 95 percent confidence interval, 3.8 to 90.8; P<0.001). Pharyngeal carriage of meningococcus was significantly more frequent among men released from jail (19 percent) or entering jail (17 percent) than among workers at the jails (3 percent) or community residents seen at the clinic (1 percent). Among men entering jail, those who had previously been incarcerated were more often carriers than those who had not (21 percent vs. 7 percent, P=0.03). Of the isolates from nine community residents with serogroup C meningococcal disease, eight were the same strain as that isolated from the eight inmates with serogroup C disease. CONCLUSIONS: In this outbreak of meningococcal disease in Los Angeles County, nearly half of community residents with the disease had contact with persons who had been in a county jail. The high rates of carriage among recidivists and released inmates suggests that the men became meningococcal carriers while in jail.

Invasive disease due to Haemophilus influenzae serotype f: clinical and epidemiologic characteristics in the H. influenzae serotype b vaccine era. The Haemophilus influenzae Study Group.

With the decline in the rate of infections caused by Haemophilus influenzae serotype b, H. influenzae serotype f (Hif) is becoming a relatively important cause of invasive disease due to H. influenzae. We identified 91 cases of invasive Hif infections in a multistate area over a 6-year period. The incidence of invasive Hif disease was 0.5 case per 1,000,000 population in 1989 and 1.9 cases per 1,000,000 population in 1994. The proportion of all invasive H. influenzae disease caused by Hif rose from 1% in 1989 to 17% in 1994. Seventy-two percent of cases occurred in adults, and 26% of cases occurred in children younger than 5 years of age. Respiratory tract infections accounted for 82% of adult cases, and most adults had significant underlying diseases. In children, pneumonia and meningitis each accounted for 40% of cases, respectively. Overall mortality was 30% among adults, and 21% among children. Molecular typing demonstrated limited overall diversity in Hif isolates. Continued surveillance is warranted to evaluate the trend toward the increasing incidence of Hif disease that was noted in this study.