Background Ear infections are a common cause of illness during the first two years of life. New conjugate vaccines may be able to prevent a substantial portion of cases of acute otitis media caused by Streptococcus pneumoniae. Methods We enrolled 1662 infants in a randomized, double-blind efficacy trial of a heptavalent pneumococcal polysaccharide conjugate vaccine in which the carrier protein is the nontoxic diphtheria-toxin analogue CRM197. The children received either the study vaccine or a hepatitis B vaccine as a control at 2, 4, 6, and 12 months of age. The clinical diagnosis of acute otitis media was based on predefined criteria, and the bacteriologic diagnosis was based on a culture of middle-ear fluid obtained by myringotomy. Results Of the children who were enrolled, 95.1 percent completed the trial. With the pneumococcal vaccine, there were more local reactions than with the hepatitis B vaccine but fewer than with the combined whole-cell diphtheria–tetanus–pertussis and Haemophilus influenzae t...

Efficacy of a Pneumococcal Conjugate Vaccine against Acute Otitis Media

This paper attempts to summarize current knowledge about immune responses to vaccines that correlate with protection. Although the immune system is redundant, almost all current vaccines work through antibodies in serum or on mucosa that block infection or bacteremia/viremia and thus provide a correlate of protection. The functional characteristics of antibodies, as well as quantity, are important. Antibody may be highly correlated with protection or synergistic with other functions. Immune memory is a critical correlate: effector memory for short-incubation diseases and central memory for long-incubation diseases. Cellular immunity acts to kill or suppress intracellular pathogens and may also synergize with antibody. For some vaccines, we have no true correlates, but only useful surrogates, for an unknown protective response.

Correlates of Protection Induced by Vaccination

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 mono...

Bacterial Meningitis in the United States in 1995

SUMMARY: The population biology of Streptococcus pneumoniae is poorly understood. Most of the important issues could be addressed by the molecular characterization of large, well sampled populations from carriage and from the different manifestations of pneumococcal disease. The authors have therefore developed a pneumococcal multilocus sequence typing scheme and database by sequencing - 450 bp fragments of seven housekeeping loci from 295 isolates. The combination of alleles at the seven loci provided an allelic profile, or sequence type (ST), and the relatedness between isolates was obtained by constructing a dendrogram from the matrix of paiwvise differences between STs. The typing scheme was validated using pneumococci of known genetic relatedness and could resolve 6 billion STs. Among 274 isolates from recent cases of invasive pneumococcal disease in eight countries,143 STs were resolved, but 12 STs contained at least five isolates (range 5-21 isolates). The repeated recovery of indistinguishable isolates from invasive disease in different countries implies that these STs define strains with an increased capacity to cause invasive disease. The relationship between STs and serotypes suggested that, in the longer term, capsular genes have been distributed horizontally within the pneumococcal population, but in the short term, expansion of clones occurs with only occasional changes of serotype. The multilocus sequence typing scheme provides a powerful new approach to the characterization of pneumococci, since it provides molecular typing datathat are electronically portable between laboratories, and which can be used to probe aspects of the population and evolutionary biology of these organisms. A Web sitefor themolecular characterization of pneumococci by MLST is available (http://mlst.zoo.ox.ac.uk).

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A multilocus sequence typing scheme for Streptococcus pneumoniae: identification of clones associated with serious invasive disease

Background Diseases caused by Streptococcus pneumoniae (S. pneumoniae) continue to cause substantial morbidity and mortality globally. Whilst pneumococcal polysaccharide vaccines (PPVs) have the potential to prevent disease and death, the degree of protection afforded against various clinical endpoints and within different populations is uncertain. Objectives To assess the efficacy and effectiveness of PPVs in preventing pneumococcal disease or death in adults. We did not assess adverse events. Search methods We searched CENTRAL 2012, Issue 6, MEDLINE (January 1966 to June Week 2, 2012) and EMBASE (1974 to June 2012). Selection criteria We considered randomised controlled trials (RCTs) in adults, provided the study outcome met the definition of the outcome considered in the review. We also considered non-RCTs in adults, where the study assessed PPV effectiveness against culture-confirmed invasive pneumococcal disease (IPD), provided the study controlled for important confounding factors. Data collection and analysis Two review authors assessed trial quality of RCTs and three review authors extracted the data. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. Two review authors assessed study quality and extracted data for non-RCTs. We calculated ORs and 95% CIs using a random-effects model following the conversion of each study outcome to a log OR and standard error (SE). Main results Twenty-five studies met our inclusion criteria (18 RCTs involving 64,852 participants and seven non-RCTs involving 62,294 participants). Meta-analysis of the RCTs found strong evidence of PPV efficacy against IPD with no statistical heterogeneity (OR 0.26, 95% CI 0.14 to 0.45; random-effects model, I(2) statistic = 0%). There was efficacy against all-cause pneumonia in low-income (OR 0.54, 95% CI 0.43 to 0.67, I(2) statistic = 19%) but not high-income countries in either the general population (OR 0.71, 95% CI 0.45 to 1.12, I(2) statistic = 93%) or in adults with chronic illness (OR 0.93, 95% CI 0.73 to 1.19, I(2) statistic = 10%). PPV was not associated with substantial reductions in all-cause mortality (OR 0.90, 95% CI 0.74 to 1.09; random-effects model, I(2) statistic = 69%). Vaccine efficacy against primary outcomes appeared poorer in adults with chronic illness. Non-RCTs provided evidence for protection against IPD in populations for whom the vaccine is currently utilised (OR 0.48, 95% CI 0.37 to 0.61; random-effects model, I(2) statistic = 31%). This review did not consider adverse events as it was outside the scope of the review. Authors' conclusions This meta-analysis provides evidence supporting the recommendation for PPV to prevent IPD in adults. The evidence from RCTs is less clear with respect to adults with chronic illness. This might be because of lack of effect or lack of power in the studies. The meta-analysis does not provide evidence to support the routine use of PPV to prevent all-cause pneumonia or mortality.

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Vaccines for preventing pneumococcal infection in adults.

The oropharyngeal carriage of Haemophilus influenzae type b (Hib) was studied among 725 healthy 3-year-old children who had or had not been immunized with an Hib conjugate vaccine. Oropharyngeal swabs were collected during the childrens' well-child visit to their local child health center. Fourteen (3.5%) of the 398 unvaccinated children were oropharyngeal carriers of Hib, whereas none of the 327 children who had received Hib conjugate vaccine carried Hib (P less than .001). Carriage rates of non-type b H. influenzae (19%) or Streptococcus pneumoniae (18%) were the same irrespective of the Hib vaccination status of the children. Thus Hib conjugate vaccine, unlike Hib polysaccharide vaccine, seems to be able to prevent oropharyngeal colonization by Hib.

Reduction of Oropharyngeal Carriage of Haemophilus influenzae Type b (Rib) in Children Immunized with an Rib Conjugate Vaccine

During an epidemic caused by group A Neisseria meningitidis, 98,272 children (three months to five years of age) were vaccinated in three provinces of Finland. Meningococcal group A and Haemophilus influenzae type b polysaccharide vaccines were used in a double-blind fashion. Mlild side reactions were common, especially after group A meningococcal vaccine, which also caused high fever in 1.8% of the children. Antibody responses were measured by radioimmunoassay. The response to the group A meningococcal vaccine was consistently good in children older than 18 months of age and was fair in infants as young as six months of age. Good secondary responses were obtained at all ages (three to 17 months) when a booster dose was given. The response to H. influenzac type b vaccine was poor in children below one year of age and was good only in those above 18 months of age; booster doses did not appear to have any effect. Clinical efficacy of the group A N. meningitidis vaccine was good at all ages; protection seemed to extend to the entire age range and resulted in an age-specific decrease in the incidence of the disease. The H. influenzae type b vaccine afforded good protection in children older than 14 months of age at the time of vaccination but no protection in those below that age; this result correlates well with the age-related immunogenicity of the H. influenzae type b vaccine.

Polysaccharide Vaccines of Group A Neisseria meningitidis and Haemophilus influenzae Type b: A Field Trial in Finland

The persistence of antibodies to the capsular polysaccharide of group A Neisseria meningitidis was studied in 2,030 persons vaccinated at the age of 10 weeks to 19 years and followed for three years. Both the initial antibody response and the persistence of elevated serum titers of antibody were markedly age-dependent. In infants younger than 12 months, a statistically significant antibody response was obtained after a booster dose of vaccine and was maintained for one year. In infants aged 12-17 months, the response after booster vaccination was higher and was maintained for two years. Children older than 17 months did not receive a booster injection. The initial response in the age group 18-23 months was good, but the decline of antibody level was more rapid, so that an elevated antibody titer was not maintained for more than one year. With increasing age, the decrease of the vaccination-induced antibody levels was progressively slower throughout the age bracket studied.

Helena Käyhty

Papers

Reduction of Oropharyngeal Carriage of Haemophilus influenzae Type b (Rib) in Children Immunized with an Rib Conjugate Vaccine

Polysaccharide Vaccines of Group A Neisseria meningitidis and Haemophilus influenzae Type b: A Field Trial in Finland

Serum Antibodies to Capsular Polysaccharide Vaccine of Group A Neisseria meningitidis Followed for Three Years in Infants and Children

Dose dependency of antibody response in infants and children to pneumococcal polysaccharides conjugated to tetanus toxoid.

IgG subclass distribution of antibodies after vaccination of adults with pneumococcal conjugate vaccines