Revisiting Bacterial Interference in the Age of Methicillin-resistant Staphylococcus aureus: Insights Into Staphylococcus aureus Carriage, Pathogenicity and Potential Control.

Bacteria compete with each other for local supremacy in biologic and environmental niches. In humans, who host an array of commensal bacteria, the presence of one species or strain can sometimes prevent colonization by another, a phenomenon known as "bacterial interference." We describe how, in the 1960s, infants (and later adults) were actively inoculated with a relatively benign strain of Staphylococcus aureus, 502A, to prevent colonization with an epidemic S. aureus strain, 80/81. This introduced bacterial interference as a clinical approach to disease prevention, but little was known about the mechanisms of interference at that time. Since then, much has been learned about how bacteria interact with each other and the host to establish carriage, compete for niches and shift from harmless commensal to invasive pathogen. We provide an overview of these findings and summarize recent studies in which the genome and function of 502A were compared with those of the current epidemic strain, USA300, providing insight into differences in their invasiveness and immunogenicity. Although staphylococcal vaccines have been developed, none has yet been approved for clinical use. Further studies of staphylococcal strains and the molecular characteristics that lead to exclusion of specific bacteria from some niches may provide an alternative path to disease prevention.

Impact of vaccination on the epidemiology of varicella: 1995-2009.

BACKGROUND: When varicella vaccine was licensed in the United States in 1995, there were concerns that childhood vaccination might increase the number of adolescents susceptible to varicella and shift disease toward older age groups where it can be more severe. METHODS: We conducted a series of 5 cross-sectional studies in 1994 to 1995 (prevaccine), 2000, 2003, 2006, and 2009 in Kaiser Permanente of Northern California to assess changes in varicella epidemiology in children and adolescents, as well as changes in varicella hospitalization in people of all ages. For each study, information on varicella history and varicella occurrence during the past year was obtained by telephone survey from a sample of ∼8000 members 5 to 19 years old; varicella hospitalization rates were calculated for the entire membership. RESULTS: Between 1995 and 2009, the overall incidence of varicella in 5- to 19-year-olds decreased from 25.8 to 1.3 per 1000 person-years, a ∼90% to 95% decline in the various age categories (5-9, 10-14, and 15-19 years of age). The proportion of varicella-susceptible children and adolescents also decreased in all age groups, including in 15- to 19-year-olds (from 15.6% in 1995 to 7.6% in 2009). From 1994 to 2009, age-adjusted varicella hospitalization rates in the general member population decreased from 2.13 to 0.25 per 100,000, a ∼90% decline. CONCLUSIONS: In the 15 years after the introduction of varicella vaccine, a major reduction in varicella incidence and hospitalization was observed with no evidence of a shift in the burden of varicella to older age groups.

Long-term effectiveness of varicella vaccine: a 14-Year, prospective cohort study.

BACKGROUND: Varicella vaccine was licensed in the United States in 1995 for individuals ≥12 months of age. A second dose was recommended in the United States in June 2006. Varicella incidence and vaccine effectiveness were assessed in a 14-year prospective study conducted at Kaiser Permanente Northern California. METHODS: A total of 7585 children vaccinated with varicella vaccine in their second year of life in 1995 were followed up prospectively for breakthrough varicella and herpes zoster (HZ) through 2009. A total of 2826 of these children received a second dose in 2006-2009. Incidences of varicella and HZ were estimated and compared with prevaccine era rates. RESULTS: In this cohort of vaccinated children, the average incidence of varicella was 15.9 per 1000 person-years, nine- to tenfold lower than in the prevaccine era. Vaccine effectiveness at the end of the study period was 90%, with no indication of waning over time. Most cases of varicella were mild and occurred early after vaccination. No child developed varicella after a second dose. HZ cases were mild, and rates were lower in the cohort of vaccinated children than in unvaccinated children during the prevaccine era (relative risk: 0.61 [95% confidence interval: 0.43-0.89]). CONCLUSIONS: This study confirmed that varicella vaccine is effective at preventing chicken pox, with no waning noted over a 14-year period. One dose provided excellent protection against moderate to severe disease, and most cases occurred shortly after the cohort was vaccinated. The study data also suggest that varicella vaccination may reduce the risks of HZ in vaccinated children.

Overview of the development and current use of CRM(197) conjugate vaccines for pediatric use.

Glycoconjugate vaccines have been proven safe and effective against various diseases in children. Although these vaccines have a history of effectiveness, there are still many unanswered questions to be addressed, including conjugate interference when multiple vaccines are administered at one time, expansion of serotype coverage, effectiveness in special populations, and issues relating to conjugate vaccine use in the developing world. This paper focuses on the use of CRM(197) as a carrier protein, contrasting it to other carrier proteins used in single-antigen pediatric vaccines as well as identifying areas for future study.

Staphylococcal infections: a historical perspective.

Staphylococcus aureus is an unusually successful and adaptive human pathogen that can cause epidemics of invasive disease despite its frequent carriage as a commensal. Over the past 100 years and more, S aureus has caused cycles of outbreaks in hospitals and the community and has developed resistance to every antibiotic used against it, yet the exact mechanisms leading to epidemics of virulent disease are not fully understood. Approaches such as bacterial interference have been effective in interrupting outbreaks, but to better prevent staphylococcal disease, we will need to be vigilant about environmental factors that facilitate its spread. Even more importantly, we need to understand more about the mechanisms that lead to its virulence and transmission. With such information, it may be possible to develop a vaccine that will prevent endemic and epidemic staphylococcal disease.

Varicella immunogenicity with 1- and 2-dose regimens of measles-mumps-rubella-varicella vaccine.

A quadrivalent vaccine combining measles, mumps, rubella, and varicella antigens (MMRV) was developed to increase the coverage of varicella vaccine and reduce the number of injections children receive. Although the varicella antigen is as immunogenic in the latest formulation of MMRV vaccine as when it is administered alone, up to 14% of vaccine recipients do not achieve protective levels of anti-varicella antibodies after a single dose, which can result in breakthrough varicella. A second dose of varicella vaccine raises response rates to 99% and was recently recommended by the Advisory Committee on Immunization Practices. Giving the second dose 3 months after the first (at approximately 15 months of age) would provide more protection against varicella but would necessitate a change in the childhood vaccination schedule, which currently calls for a second dose of MMRV vaccine between the ages of 4 and 6 years.

Impact of maternal influenza vaccination during pregnancy on the incidence of acute respiratory illness visits among infants.

OBJECTIVE: To determine whether influenza vaccination of pregnant women prevents visits for respiratory illness in their infants born during the influenza season. DESIGN: Retrospective matched cohort study. SETTING: Four managed care organizations in the United States. Patients A total of 41 129 infants (3160 and 37 969 born to vaccinated and unvaccinated mothers, respectively) born between 1995 and 2001. Main Exposure Maternal influenza vaccination. Infants were considered exposed if their gestational age at birth was at least 30 weeks, if the time from maternal vaccination to birth was at least 28 days, and if they were exposed to at least 14 days of the influenza season. MAIN OUTCOME MEASURES: Incidence of acute respiratory illnesses (outpatient, emergency department, and inpatient settings combined) and incident rate ratios (IRRs) for infants exposed and unexposed to maternal vaccination during the following 4 periods: peak influenza, respiratory syncytial virus predominant, periseasonal, and summer weeks. The time to the first acute respiratory illness during peak influenza weeks was also assessed. RESULTS: During the peak influenza weeks, infant visit rates were 15.4 and 17.1 per 100 person-months for exposed and unexposed infants, respectively (IRR, 0.90; 95% confidence interval, 0.80-1.02). Adjusted IRRs for the 4 periods found a protective effect of infant female sex, whereas Medicaid status and maternal high-risk status increased infant visit rates. Maternal influenza vaccination did not reduce visit rates during any of the 4 time periods (IRR for peak influenza season, 0.96; 95% confidence interval, 0.86-1.07) and did not delay the onset of first respiratory illness. CONCLUSION: We were unable to demonstrate that maternal influenza vaccination reduces respiratory illness visit rates among their infants.

Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old.

CONTEXT: Beginning with the winter season of 2004-2005, influenza vaccination has been recommended for all children 6 to 23 months old in the United States. However, its safety in young children has not been adequately studied in large populations. OBJECTIVE: To screen for medically attended events in the clinic, emergency department, or hospital after administration of trivalent inactivated influenza vaccine in children 6 to 23 months old. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort using self-control analysis, with chart review of significant medically attended events at 8 managed care organizations in the United States that comprise the Vaccine Safety Datalink. Participants were all children in the Vaccine Safety Datalink cohort 6 to 23 months old who received trivalent inactivated influenza vaccine between January 1, 1991, and May 31, 2003 (45,356 children with 69,359 vaccinations). MAIN OUTCOME MEASURE: Any medically attended event significantly associated with trivalent inactivated influenza vaccine in risk windows 0 to 3 days, 1 to 14 days (primary analysis), 1 to 42 days, or 15 to 42 days after vaccination, compared with 2 control periods, one before vaccination and the second after the risk window. All individual ICD-9 codes as well as predefined aggregate codes were examined. RESULTS: Before chart review, only 1 diagnosis, gastritis/duodenitis, was more likely to occur in the 14 days after trivalent inactivated influenza vaccine (matched odds ratio [OR], 5.50; 95% confidence interval [CI], 1.22-24.81 for control period 1, and matched OR, 4.33; 95% CI, 1.23-15.21 for control period 2). Thirteen medically attended events were less likely to occur after trivalent inactivated influenza vaccine, including acute upper respiratory tract infection, asthma, bronchiolitis, and otitis media. After chart review, gastritis/duodenitis was not significantly associated with trivalent inactivated influenza vaccine (matched OR, 4.00; 95% CI, 0.85-18.84 for control period 1; matched OR, 3.34; 95% CI, 0.92-12.11 for control period 2). CONCLUSIONS: In the largest population-based study to date of the safety of trivalent inactivated influenza vaccine in young children, there were very few medically attended events, none of which were serious, significantly associated with the vaccine. This study provides additional evidence supporting the safety of universally immunizing all children 6 to 23 months old with influenza vaccine.

Use of a conjugate polysaccharide vaccine in the prevention of invasive staphylococcal disease: is an additional vaccine needed or possible?

Staphylococcus aureus is a ubiquitous bacterial species that causes serious disease in certain settings. S. aureus disease is difficult to treat, and antibiotic-resistant strains have become common. A vaccine to protect against infection would therefore be beneficial. However, the virulence of S. aureus is determined by a number of different factors, which makes design of a widely effective vaccine difficult. Here, various bacterial virulence factors and attempts to develop vaccines based on these factors are briefly reviewed. In particular, the success of a Phase 3 clinical study of a vaccine directed at capsular polysaccharides types 5 and 8 is discussed.

Changing epidemiology of outpatient bacteremia in 3- to 36-month-old children after the introduction of the heptavalent-conjugated pneumococcal vaccine.

BACKGROUND: The introduction of routine vaccination with heptavalent conjugated pneumococcal vaccine has changed the overall incidence of bacteremia in children 3 months-3 years old. OBJECTIVE: To describe the changing incidence and etiology of bacteremia in previously healthy toddlers presenting to outpatient clinical settings. METHODS: Retrospective case series of all blood cultures obtained between September 1998 and August 2003 in Kaiser Permanente Northern California outpatient clinics and emergency departments from previously healthy children 3 months-3 years old. RESULTS: Implementation of routine vaccination with the conjugated pneumococcal vaccine resulted in an 84% reduction of Streptococcus pneumoniae bacteremia (1.3-0.2%) and a 67% reduction in overall bacteremia (1.6-0.7%) in the study population. The rate of blood culture isolation of contaminating organisms remained unchanged at 1.8%; therefore, by the end of the study, >70% of organisms identified in blood cultures were contaminants. During the 5 study years, total blood cultures drawn decreased by 35% in outpatient pediatric clinics but remained unchanged in emergency departments. By 2003, one-third of all pathogenic organisms isolated from blood cultures were Escherichia coli, one-third were non-vaccine serotype S. pneumoniae, the majority of the remaining one-third were Staphylococcus aureus, Salmonella spp., Neisseria meningitidis and Streptococcus pyogenes. In our population of children routinely immunized with the conjugated pneumococcal vaccine, a white blood cell count >15,000 by itself is a poor predictor of bacteremia in the febrile toddler (sensitivity, 74.0%; specificity, 54.5%; positive predictive value, 1.5%; negative predictive value, 99.5%). CONCLUSION: In the United States, routine vaccinations with Haemophilus influenzae type b and S. pneumoniae vaccines have made bacteremia in the previously healthy toddler a rare event. As the incidence of pneumococcal bacteremia has decreased, E. coli, Salmonella spp. and Staphylococcus aureus have increased in relative importance. The use of the white blood cell count alone to guide the empiric use of antibiotics is not indicated. New guidelines are needed to approach the previously healthy febrile toddler in the outpatient setting.

Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine.

BACKGROUND: Rotavirus is a leading cause of childhood gastroenteritis and death worldwide. METHODS: We studied healthy infants approximately 6 to 12 weeks old who were randomly assigned to receive three oral doses of live pentavalent human-bovine (WC3 strain) reassortant rotavirus vaccine containing human serotypes G1, G2, G3, G4, and P[8] or placebo at 4-to-10-week intervals in a blinded fashion. Active surveillance was used to identify subjects with serious adverse and other events. RESULTS: The 34,035 infants in the vaccine group and 34,003 in the placebo group were monitored for serious adverse events. Intussusception occurred in 12 vaccine recipients and 15 placebo recipients within one year after the first dose including six vaccine recipients and five placebo recipients within 42 days after any dose (relative risk, 1.6; 95 percent confidence interval, 0.4 to 6.4). The vaccine reduced hospitalizations and emergency department visits related to G1-G4 rotavirus gastroenteritis occurring 14 or more days after the third dose by 94.5 percent (95 percent confidence interval, 91.2 to 96.6 percent). In a nested substudy, efficacy against any G1-G4 rotavirus gastroenteritis through the first full rotavirus season after vaccination was 74.0 percent (95 percent confidence interval, 66.8 to 79.9 percent); efficacy against severe gastroenteritis was 98.0 percent (95 percent confidence interval, 88.3 to 100 percent). The vaccine reduced clinic visits for G1-G4 rotavirus gastroenteritis by 86.0 percent (95 percent confidence interval, 73.9 to 92.5 percent). CONCLUSIONS: This vaccine was efficacious in preventing rotavirus gastroenteritis, decreasing severe disease and health care contacts. The risk of intussusception was similar in vaccine and placebo recipients. (ClinicalTrials.gov number, NCT00090233.)

Prevention of Staphylococcus aureus infections: advances in vaccine development.

Staphylococcus aureus is a ubiquitous bacterial species that causes serious disease in a minority of carriers, particularly in hospital settings. S. aureus disease is difficult to treat, and antibiotic-resistant strains have become common. Prevention of S. aureus disease would therefore be the best way to limit the morbidity and mortality caused by this organism, but its virulence is determined by a number of different factors, making design of a widely effective vaccine difficult. Here, various S. aureus virulence factors and attempts to develop vaccines or other protective drugs based on these factors are reviewed. In particular, the results of a Phase III clinical study of a vaccine directed at capsular polysaccharides types 5 and 8 are discussed.

Compliance with national immunization guidelines for children younger than 2 years, 1996-1999.

OBJECTIVES: To evaluate compliance with national immunization guidelines among a large cohort of children cared for at health maintenance organizations (HMOs) and to examine effects on immunization status. METHODS: A cohort study of 176134 children born between January 1, 1994, and December 31, 1997, and monitored from birth to the second birthday was performed. Subjects belonged to the Vaccine Safety Datalink Project, a study of children enrolled in 1 of 4 HMOs. Children were continuously enrolled in a HMO for the first 2 years of life. Prevailing recommendations regarding optimal ages of immunization and intervals between doses were applied to define appropriate immunization timing and immunization status. Noncompliance was defined as having a missing or late immunization or an immunization error. Immunization errors included invalid immunizations (too early to be acceptable), extra immunizations (superfluous immunizations or make-up immunizations for invalid immunizations), and missed opportunities resulting in late or missing immunizations. RESULTS: Although 75.4% of children in these HMOs were up to date for all immunizations at 2 years, only 35.6% of children were fully compliant with recommended immunization practices. Less than 8% of children received all immunizations in accordance with strict interpretation of recommended guidelines. Fifty-one percent of children had at least 1 immunization error by age 2 years; 29.7% had a missed opportunity with subsequent late or missing immunization, 20.4% had an invalid immunization, and 11.6% had an extra immunization. Common reasons for noncompliance included missed opportunities for the fourth Haemophilus influenzae type b vaccine (14.6%), invalid fourth diphtheria-tetanus-pertussis/acellular pertussis immunizations (11.0%), and superfluous polio immunizations (9.8%). CONCLUSIONS: Approximately 35.6% of children were compliant with prevailing childhood immunization recommendations from 1996 to 1999. Efforts to improve compliance with guidelines are recommended, to optimize childhood infectious disease prevention.

Safety of the trivalent inactivated influenza vaccine among children: a population-based study.

BACKGROUND: To our knowledge, there are no published population-based studies on the safety of the inactivated trivalent influenza vaccine among children. OBJECTIVE: To screen a large population of children for evidence of increased medical visits in the 2 weeks after influenza vaccination compared with 2 control periods. Secondary analyses included shorter risk periods and restricted age categories. DESIGN: Self-control screening analysis. Children vaccinated from January 1, 1993, through December 31, 1999, were randomly divided into 2 equal groups. In group 1, risks of outpatient, emergency department, and inpatient visits during the 14 days after vaccination were compared with the risks of visits in 2 control periods. Significant plausible medically attended events identified in group 1 were then analyzed in group 2, using the same 2 control periods. Medically attended events significant in both groups were considered potentially associated with vaccination and were assessed by medical record review. SETTING: Five managed care organizations in the United States. PARTICIPANTS: Children younger than 18 years who received an influenza vaccination in one of the managed care settings (N = 251 600). MAIN OUTCOME MEASURE: Among vaccinated children seen for a medically attended event, the odds of the visit occurring in the 2 weeks after vaccination vs during 1 of the 2 control periods. RESULTS: Study participants incurred 1165, 230, and 489 different diagnoses during the 14 days after vaccination according to the outpatient, emergency department, and inpatient data, respectively. Four diagnoses were positively associated with the vaccine in both groups 1 and 2: impetigo, dermatitis, uncomplicated diabetes mellitus, and ureteral disorder not otherwise specified. After medical record review, impetigo (9 cases) in children 6 to 23 months old remained significantly associated with vaccination. CONCLUSION: This large screening safety study did not reveal any evidence of important medically attended events associated with pediatric influenza vaccination.

Effectiveness of influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants.

The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention recommends influenza vaccination for women who will be in the second or third trimester of pregnancy during the influenza season. We analyzed hospital admissions with principal diagnoses of influenza or pneumonia and influenza-like illness (ILI) outpatient visits to study the effectiveness of influenza vaccine during pregnancy in protecting women and infants from influenza-related morbidity. Estimates of influenza vaccine effectiveness across five flu seasons (Fall 1997 to Spring 2002) were calculated using Cox proportional hazards models for women and infant study populations in Kaiser Permanente Northern California. Outpatient utilization outcomes included physician visits with a diagnosis of upper respiratory infection, pharyngitis, otitis media, asthma, bronchial asthma, viral infection, pneumonia, fever, cough, or wheezing associated with respiratory illness. Inpatient outcomes included hospitalizations with principal diagnoses of influenza or pneumonia. Women who received influenza vaccine during pregnancy had the same risk for ILI visits compared with unvaccinated women, adjusting for women's age and week of delivery. When asthma visits were excluded from the outcome measure, we also found no difference in the risk of outpatient visits for vaccinated and unvaccinated women. Hospital admissions for influenza or pneumonia for women in the study population were quite rare and no women died of respiratory illness during pregnancy. Infants born to women who received influenza vaccination had the same risks for influenza or pneumonia admissions compared with infants born to unvaccinated women, adjusting for infant's gender, gestational age, week of birth, and birth facility. Maternal influenza vaccination was also not a significant determinant of risk of ILI (excluding otitis media) outpatient visits for infants, nor did it significantly affect the risk of otitis media visits. Influenza vaccination during pregnancy did not significantly affect the risk of cesarean section, adjusting for the woman's age. It also did not affect the risk of preterm delivery. Although the immunogenicity of influenza vaccination in pregnancy in mother and infant has been well documented, in this study, we were unable to demonstrate the effectiveness of influenza vaccination with data for hospital admissions and physician visits. One possible interpretation of these findings is that typical influenza surveillance measures based on utilization data are not reliable in distinguishing influenza from other respiratory illness. Hospitalizations for respiratory illness were uncommon in both vaccinees and nonvaccinees.

Vaccinations and risk of central nervous system demyelinating diseases in adults.

BACKGROUND: Several case reports of the onset or exacerbation of multiple sclerosis or other demyelinating conditions shortly after vaccination have suggested that vaccines may increase the risk of demyelinating diseases. OBJECTIVE: To evaluate the association between vaccination and onset of multiple sclerosis or optic neuritis. DESIGN: Case-control study involving cases of multiple sclerosis or optic neuritis among adults 18 to 49 years of age. Data on vaccinations and other risk factors were obtained from computerized and paper medical records and from telephone interviews. SETTING: Three health maintenance organizations. PARTICIPANTS: Four hundred forty case subjects and 950 control subjects matched on health maintenance organization, sex, and date of birth. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Onset of first symptoms of demyelinating disease at any time after vaccination and during specified intervals after vaccination (<1 year, 1-5 years, and >5 years). RESULTS: Cases and controls had similar vaccination histories. The odds ratios (95% confidence intervals), adjusted for potential confounding variables, of the associations between ever having been vaccinated and risk of demyelinating disease (multiple sclerosis and optic neuritis combined) were 0.9 (0.6-1.5) for hepatitis B vaccine; 0.6 (0.4-0.8) for tetanus vaccination; 0.8 (0.6-1.2) for influenza vaccine; 0.8 (0.5-1.5) for measles, mumps, rubella vaccine; 0.9 (0.5-1.4) for measles vaccine; and 0.7 (0.4-1.0) for rubella vaccine. The results were similar when multiple sclerosis and optic neuritis were analyzed separately. There was no increased risk according to timing of vaccination. CONCLUSION: Vaccination against hepatitis B, influenza, tetanus, measles, or rubella is not associated with an increased risk of multiple sclerosis or optic neuritis.

Polio extraimmunization in children younger than 2 years after changes in immunization recommendations.

OBJECTIVE: To investigate trends over time in polio extraimmunization among children in 4 large health maintenance organizations and to study the association with recent changes in polio immunization policy. METHODS: Using 176 169 children who were born after 1994 and enrolled for their first 2 years of life, we assessed rates and trends of polio extraimmunization in the Vaccine Safety Datalink project. We used logistic regression to test the association of extraimmunization with different polio immunization schedules and with sociodemographic characteristics and used Poisson regression to test changes in rates over time. RESULTS: Overall, 10.5% were extraimmunized for poliovirus; children on the all inactivated polio virus or sequential schedule were one half as likely as those on the all oral polio virus schedule to be extraimmunized by 2 years of age. There was a significant decrease in extraimmunization over time, with <5% of children born at the end of 1997 being extraimmunized, compared with >15% at the beginning of 1994. CONCLUSIONS: Poliovirus extraimmunization rates have fallen dramatically in association with the change-over to the all inactivated polio virus schedule.

Impact of the pneumococcal conjugate vaccine on otitis media.

CONTEXT: The heptavalent pneumococcal conjugate vaccine (PCV) is recommended for infants to protect against invasive disease, but its impact on otitis might also have public health importance. OBJECTIVE: To examine the impact of PCV on the incidence of otitis media, frequent otitis media and tympanostomy tube procedures and to assess whether the effectiveness of the vaccine wanes after age 24 months and varies by race, sex or season. DESIGN, SETTING AND PATIENTS: From 1995 to 1998, 37 868 children at Kaiser Permanente in Northern California were randomized to receive PCV or a control vaccine in a double blind trial and were followed through April 1999. INTERVENTIONS: Children received a primary series at 2, 4 and 6 months of age and a booster at 12 to 15 months. MAIN OUTCOME MEASURES: Visits for otitis, frequent visits for otitis and tympanostomy tube procedures. Otitis was ascertained from diagnosis checklists routinely marked by physicians. RESULTS: Control children averaged 1.8 otitis visits per year. Children given PCV had fewer otitis visits than control children in every age group, sex, race and season examined. Intention-to-treat analysis permitted rejection of the null hypothesis that PCV is ineffective against otitis media (P < 0.0001). In children who completed the primary series per protocol, PCV reduced otitis visits by 7.8% [95% confidence interval (CI), 5.4 to 10.2%] and antibiotic prescriptions by 5.7% (CI 4.2 to 7.2%). Frequent otitis was reduced by amounts that increased with otitis frequency, from a 10% reduction in the risk of 3 visits to a 26% reduction in the risk of 10 visits within a 6-month period. Tube placements were reduced by 24% (CI 12 to 35%). CONCLUSION: In children followed up to 3.5 years, PCV provided a moderate amount of protection against ear infections while reducing frequent otitis media and tube procedures by greater amounts.