Effectiveness of pneumococcal Haemophilus influenzae protein D conjugate vaccine against pneumonia in children: A cluster-randomised trial.

BACKGROUND: Pneumococcal conjugate vaccines have potential to prevent significant proportion of childhood pneumonia. Finnish Invasive Pneumococcal disease vaccine trial was designed to assess the vaccine effectiveness (VE) of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against several outcomes. We now report results for pneumonia. METHODS: In this nationwide, cluster-randomised, double-blind trial, children younger than 19 months received PHiD-CV10 in 52 clusters or hepatitis vaccines as control in 26 clusters. Infants younger than 7 months at the first vaccination received either 3+1 or 2+1 vaccination schedule, children aged 7-11 months received 2+1, and those 12-18 months of age two-dose schedule. All hospitalizations and outpatient visits to hospital associated with ICD-10 codes compatible with pneumonia were identified through the National Care Register and 1-3 frontal chest X-ray images per event were collected. External readers who were unaware of the patients' vaccination status retrospectively interpreted the images. The evaluated outcomes were hospital-diagnosed, hospital-treated pneumonia as primary diagnosis, and radiologically confirmed pneumonia during the blinded, intention-to-treat follow-up period from the first vaccination to the end of 2011. Total VE was calculated as 1 minus rate ratio of all pneumonia episodes. RESULTS: 47 366 children were enrolled from February 2009, to October 2010. VE against all episodes of hospital-diagnosed pneumonia was 27% (95% confidence interval [CI]: 14%, 38%), 32% (95% CI: 3%, 52%), and 23% (95% CI: -5%, 44%) in subjects enrolled at age <7, 7-11, and 12-18 months, respectively. Corresponding rate reductions were 3.4, 4.7, and 2.5 per 1000 person-years. VE estimates against pneumonia with alveolar consolidation or pleural effusion (WHO criteria) in the three cohorts were 45% (95% CI: 26%, 60%), 56% (95% CI: 14%, 77%), and 48% (95% CI: 2%, 73%), respectively. CONCLUSION: PHiD-CV10 vaccination remarkably reduced disease burden due to pneumonia in infants and young children. CLINICAL TRIAL REGISTRATION: Main trial NCT00861380, nested carriage and otitis media trial NCT00839254 (ClinicalTrials.gov).

Effect of antimicrobial use on pneumococcal diagnostic tests in elderly patients with community-acquired pneumonia.

Antimicrobial treatment decreases bacterial culture yields. We assessed the impact of antimicrobial treatment on pneumococcal assays in a prospective study of community-acquired pneumonia (CAP) in the elderly. We enrolled 323 cases aged ≥65 years with radiologically confirmed CAP and collected detailed data on antimicrobial exposure and pneumococcal assays on various samples. Complete antimicrobial use data were available for 303 (94%) cases; 61% had no antimicrobial exposure, 19% had received antibiotics at the acute visit only, and 20% within 2 weeks before the acute visit (15% ongoing and 5 % completed treatment). Ongoing use before the visit reduced pneumococcal detection by culture (nasopharyngeal swab 2 vs. 16% in the unexposed; high-quality sputum 0 vs. 25%) and sputum lytA polymerase chain reaction (PCR) (0 vs. 25%). Urine antigen test and serology were not affected. Among those who had received antibiotics only at the acute visit before study sampling, serology (29 vs. 15%), urine antigen (19 vs. 8%), and blood culture (9 vs. 2%) were more often positive than among the unexposed. Antimicrobial exposure before the visit reduced both culture and PCR-based detection. Patients given antibiotics at the visit had higher proportions of positive blood culture, serology, and urine antigen tests, suggesting higher pneumococcal CAP prevalence.

Vaccine effectiveness of the pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against clinically suspected invasive pneumococcal disease: a cluster-randomised trial.

BACKGROUND: Vaccine effectiveness of pneumococcal conjugate vaccines against culture-confirmed invasive pneumococcal disease has been well documented. In the Finnish Invasive Pneumococcal disease (FinIP) trial, we reported vaccine effectiveness and absolute rate reduction against laboratory-confirmed invasive pneumococcal disease (confirmation by culture or antigen or DNA detection irrespective of serotype). Here, we assessed vaccine effectiveness of PHiD-CV10 against clinically suspected invasive pneumococcal disease in children by use of diagnoses coded in hospital discharge registers. METHODS: For this phase 3/4 cluster-randomised, double-blind trial, undertaken between Feb 18, 2009, and Dec 31, 2011, in municipal health-care centres and the Tampere University Vaccine Research Centre (Finland), we randomly assigned (2:2:1:1) 78 clusters into PHiD-CV10 three plus one, PHiD-CV10 two plus one, control three plus one, control two plus one groups (26:26:13:13 clusters) to give PHiD-CV10 in either three plus one or two plus one schedule (if enrolled before 7 months of age; infant schedules), two plus one (if enrolled between 7 and 11 months; catch-up schedules), and two doses at least 6 months apart (if enrolled between 12 and 18 months; catch-up schedules). Children were eligible if they had not received and were not anticipated to receive any of the study vaccines and had no general contraindications to vaccinations. We collected all inpatient and outpatient discharge notifications from the national hospital discharge register with International Classification of Diseases (ICD) 10 diagnoses compatible with invasive pneumococcal disease or unspecified sepsis, and verified data with patient files. We excluded invasive pneumococcal disease cases confirmed by positive culture or DNA/RNA detection from normally sterile body fluid. The primary objective was to estimate vaccine effectiveness against all register-based non-laboratory-confirmed invasive pneumococcal disease or unspecified sepsis and patient-file verified non-laboratory-confirmed invasive pneumococcal disease in infants younger than 7 months at enrolment. Masked follow-up lasted from the date of the first vaccination to Dec 31, 2011. Vaccine effectiveness was calculated against all episodes. This trial is registered with ClinicalTrials.gov, numbers NCT00861380 and NCT00839254. FINDINGS: We enrolled 47,366 children. On the basis of ICD-10 diagnoses, we recorded 264 episodes of register-based non-laboratory-confirmed invasive pneumococcal disease or unspecified sepsis, of which 102 were patient-file verified non-laboratory-confirmed invasive pneumococcal disease. The vaccine effectiveness was 50% (95% CI 32-63) in the 30,527 infants with three plus one and two plus one schedules combined and the absolute incidence rate reduction was 207 episodes per 100,000 person-years (95% CI 127-286). The vaccine effectiveness against the patient-file verified non-laboratory-confirmed invasive pneumococcal disease was 71% (95% CI 52-83) in infant three plus one and two plus one schedules combined. The absolute rate reduction was 142 episodes per 100,000 person-years (95% CI 91-191) in infant cohorts. INTERPRETATION: This vaccine-probe analysis is the first report showing the effect of pneumococcal conjugate vaccines on clinically suspected invasive pneumococcal disease. The absolute rate reduction was markedly higher compared with laboratory-confirmed invasive pneumococcal disease, which implies low sensitivity of the laboratory-based case definitions and subsequently higher public health effect of pneumococcal conjugate vaccines against invasive pneumococcal disease than previously estimated. FUNDING: GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare (THL), Finland.

Modelling the impact of varicella vaccination on varicella and zoster.

It has been suggested that the incidence of herpes zoster may increase due to lack of natural boosting under large-scale vaccination with the varicella vaccine. To study the possibility and magnitude of such negative consequences of mass vaccination, we built a mathematical model of varicella and zoster epidemiology in the Finnish population. The model was based on serological data on varicella infection, case-notification data on zoster, and new knowledge about close contacts relevant to transmission of infection. According to the analysis, a childhood programme against varicella will increase the incidence of zoster by one to more than two thirds in the next 50 years. This will be due to increase in case numbers in the 35 years age groups. However, high vaccine coverage and a two-dose programme will be very effective in stopping varicella transmission in the population.

Subclass distribution of natural salivary IgA antibodies against pneumococcal capsular polysaccharide of type 14 and pneumococcal surface adhesin A (PsaA) in children.

A number of studies have shown that the ratio of IgA1 and IgA2 subclasses in secretions can depend upon the nature of the antigen inducing their production. In order to evaluate the effect of the nature of the antigen on the subclass distribution of the naturally occurring salivary IgA antibodies against Streptococcus pneumoniae, we used enzyme immunoassay to measure the levels of natural IgA, IgA1 and IgA2 antibodies to pneumococcal capsular polysaccharide type 14 (PS14) and pneumococcal surface adhesin A (PsaA) in saliva of children during their first 2 years of life. The sum of anti-PS14 and anti-PsaA IgA1 and IgA2 correlated significantly with the antigen-specific total IgA, which showed that IgA1 and IgA2 add up to IgA. IgA1 was the predominant subclass for both antigens. The median of anti-PS14 and anti-PsaA IgA1 was higher than that of IgA2, and the antigen-specific IgA1 was found in a larger proportion of samples than IgA2. The ratio of IgA1 to IgA2 (IgA1/IgA2 ratio) was lower for anti-PS14 than for anti-PsaA, suggesting that the PS antigen induced more IgA2 than the protein antigen. The possible impact of the IgA subclass distribution on protection of mucosal surfaces by natural or vaccine-induced antibodies needs to be determined.

Type-specific enzyme immunoassay for detection of pneumococcal capsular polysaccharide antigens in nasopharyngeal specimens.

We developed a new competitive EIA method for the demonstration of pneumococcal capsular polysaccharides from respiratory samples. The pediatric types 4, 6B, 9V, 14, 18C, 19F and 23F were selected for this study, because these capsular polysaccharides were included in the first heptavalent pneumococcal conjugate vaccines, which were used in the Finnish Otitis Media Vaccine Trial. Sensitivity of the EIA tests for purified polysaccharide antigens varied between 5 and 100 ng/ml, depending on the type. The assays performed well in 100 nasopharyngeal samples (NPS) samples processed through an enrichment culture, with an almost 100% sensitivity compared with routine culture. The method appeared type-specific, except that EIA for 6B capsule also detected 6A. The method is applicable for type-specific identification of pneumococcus in carriage studies.

The effect of a pneumococcal conjugate vaccine on the risk of otitis media with effusion at 7 and 24 months of age.

OBJECTIVE: To explore the effect of a pneumococcal conjugate vaccine on the risk of otitis media with effusion and to search for subgroups in which the vaccine had a higher or lower effect. METHODS: Analyses were performed on data from the Finnish Otitis Media Vaccine Trial, a randomised controlled double-blind trial to evaluate the efficacy of pneumococcal conjugate vaccination against acute otitis media. Data on the vaccination effect against otitis media with effusion were obtained by means of symptom interview and pneumatic otoscopy during pre-scheduled follow-up visits at the age of 7 and 24 months. Two endpoint definitions were considered: otitis media/tube (otitis media or tympanostomy tube in situ (OM/T)) as the primary endpoint and otitis media with effusion as the secondary endpoint. No evidence was found of an age-dependent association with vaccination effect. Therefore, the final marginal logistic regression analyses were performed on the combined data from the two follow-up visits. RESULTS: The risk of otitis media tended to be lower in the pneumococcal vaccine group. The odds ratio for otitis media/tube was 0.94 (95% confidence interval 0.77-1.14) and the odds ratio for otitis media with effusion was 0.90 (95% confidence interval 0.69-1.19). Presence of older siblings increased the risk of otitis media/tube and otitis media with effusion at 7 months of age. In addition, it appeared that children without older siblings and attending day-care at 24 months of age tended to benefit more from the pneumococcal conjugate vaccine. In this subgroup, the odds ratio for otitis media/tube was 0.81 (95% confidence interval 0.55-1.20) and for otitis media with effusion the odds ratio was 0.43 (95% confidence interval 0.22-0.86). CONCLUSION: The effect of pneumococcal conjugate vaccination on the risk of otitis media with effusion was concordant with the efficacy seen against acute otitis media, although not distinguishable from no effect in the overall analysis. In children without older siblings, vaccination appeared to reduce the point prevalence of otitis media with effusion; this effect was not apparent in children with older siblings.

Establishment of streptococci in the upper respiratory tract: longitudinal changes in the mouth and nasopharynx up to 2 years of age.

As part of a series of longitudinal studies on the development of the indigenous microflora of the upper respiratory tract, the establishment of streptococci in the oral cavity and nasopharynx and IgA1 protease production by the early streptococcal flora was examined in 50 healthy Caucasian infants at the ages of 2, 6, 12, 18 and 24 months. In the oral cavity, streptococci were found in all infants on every sampling occasion, Streptococcus mitis biovar 1 being the main finding in each age group. S. salivarius and S. mitis biovar 2 reached their highest prevalence during the first year of life, whereas the prevalence of S. oralis and S. sanguis showed no significant increase before 12 months of age. Salivary streptococci mainly consisted of the above-mentioned species during the follow-up period. In contrast to the oral cavity, no stable colonisation pattern was observed for viridans streptococci in the nasopharynx. S. mitis biovar 1 and S. pneumoniae, a traditional respiratory pathogen, were the principal streptococcal species among nasopharyngeal isolates. IgA1 protease production by early streptococci was common in infancy. Among the oral streptococcal microflora, S. mitis biovar 1 (especially during the first year of life) and S. oralis and S. sanguis constituted the main species responsible for this enzyme activity. In the nasopharynx, IgA1 protease was produced by S. mitis biovar 1, S. oralis and S. pneumoniae. In conclusion, streptococcal colonisation differs in these two close habitats in the upper respiratory tract.

Negative pressure tympanograms in children less than 2 years of age--different bacterial findings in otitis media by tympanometric results.

OBJECTIVE: The interpretation of negative pressure tympanograms as indicators of the presence of middle ear fluid has been ambiguous. Our purpose was to assess the occurrence and implications of negative pressure tympanograms and to study their association with bacterial pathogens in otitis media. METHODS: Altogether 329 infants were enrolled at a well-baby clinic for the Finnish Otitis Media Cohort Study, a longitudinal prospective cohort study. The children were closely followed in a special study clinic from 2 to 24 months of age for respiratory diseases, especially acute otitis media. Children were examined at the study clinic with tympanometry and pneumatic otoscopy whenever visiting the study clinic for respiratory disease. Myringotomy with aspiration was performed if middle ear fluid was suspected in otoscopy. Occurrence of middle ear fluid in ears with negative pressure tympanograms (less than -100 daPa) was assessed. Nested case control design matched by visit type (acute or follow-up visit) and month of visit was used for analysis of association of bacterial pathogens and tympanometric results. RESULTS: Middle ear fluid was encountered in 15% of ears with negative tympanometric peak pressure, a lower proportion than described previously. In otitis media with a negative tympanometric peak pressure, 71% of bacterial cultures remained negative for the main pathogens, compared to 36% in matched controls (P<0.001). Especially Streptococcus pneumoniae but also Haemophilus influenzae were rarely found in samples from negative pressure ears. Moraxella catarrhalis was equally often found. CONCLUSIONS: Negative pressure tympanogram is a poor indicator for the presence of middle ear fluid. Furthermore, if otitis media is diagnosed with negative tympanometric peak pressure negative middle ear bacterial culture for the main pathogens is highly probable. Expectant follow-up might be more appropriate than routine antibiotic treatment.

Natural development of antibodies to pneumococcal capsular polysaccharides depends on the serotype: association with pneumococcal carriage and acute otitis media in young children.

To study the natural development of antibodies to pneumococcal capsular polysaccharides of types 1, 6B, 11A, 14, 19F, and 23F and its association with pneumococcal carriage and acute otitis media (AOM), 329 children were followed-up prospectively during their first 2 years of life. Nasopharyngeal carriage was determined by cultures of nasopharyngeal swab samples, and etiology of AOM was determined by cultures of middle ear fluid. Antibodies were measured in serum samples collected at 6, 12, 18, and 24 months by EIA. Antibodies increased modestly but significantly with age. Contact with serotypes 11A and 14 was associated with increased antibody concentration as early as age 6 months. Children with contact with serotypes 6B, 19F, and 23F had antibody levels similar to those in children without contact. Antibodies increased modestly, even in children without known contact with Streptococcus pneumoniae and in children with contact with heterologous serotypes. Antibody concentrations were equal after carriage or AOM.

Do antibodies to pneumococcal surface adhesin a prevent pneumococcal involvement in acute otitis media?

Antibodies to the pneumococcal (Pnc) surface protein PsaA are immunogenic and protective in experimental animal models, but their role in protection from Pnc disease in humans is not known. In the present study, the ability of antibodies to PsaA to prevent the progression of Pnc carriage to Pnc acute otitis media (Pnc AOM) was evaluated. Antibodies to PsaA were measured in acute-phase serum samples of children with AOM and with Streptococcus pneumoniae cultured from the nasopharynx. The risk of Pnc AOM was evaluated by a logistic regression model with anti-PsaA concentration as the predictive variable. Higher concentrations of antibodies to PsaA were associated with lower risk of the Pnc nasopharyngeal carriage progression to Pnc AOM. This was true in children 9-24 months old (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.31-0.78) but not in children <9 months old (OR, 0.81; 95% CI, 0.48-1.35).

Normative values for tympanometry in 7- and 24-month-old children.

The objective was to determine normative values for tympanometric variables for 7- and 24-month-old children and to assess the effect of various factors on these variables. Tympanometry was performed at scheduled health visits at 7 and 24 months of age on children recruited to a prospective vaccine efficacy trial (n=2497 children at enrolment). Tympanograms obtained successfully from healthy ears with no recent otitis media were analysed. Normative values for static acoustic admittance (SAA), tympanometric peak pressure (TPP) and tympanometric width (TW) were calculated. The mean SAA was 0.25 cm3 at the 7-month visit compared to 0.34 cm3 at the 24-month visit. The TW decreased and TPP remained unchanged with age. Higher SAA values were found in boys. A history of recurrent acute otitis media and history of tympanostomy tubes were found to increase SAA and decrease TW at 24 months. In conclusion, age-specific normative values for interpretation of SAA and TW are necessary.

Bacteriology of acute otitis media in a cohort of Finnish children followed for the first two years of life.

BACKGROUND: Timely information on the bacteriology of primary, noncomplicated acute otitis media (AOM) may today be needed more than ever, because of the increasing antimicrobial resistance of its major bacterial causes and because of the potential of new pneumococcal and other bacterial vaccines for prevention of AOM. METHODS: The study followed 329 children from 2 to 24 months of age at scheduled healthy visits and sick visits at the study clinic. Whenever AOM was diagnosed during the follow-up, myringotomy was performed and middle ear fluid was aspirated for bacterial culture. RESULTS: At least one middle ear fluid sample was available from 772 AOM events; Streptococcus pneumoniae (Pnc) was isolated in 201 (26%), Moraxella catarrhalis (Mc) in 177 (23%) and Haemophilus influenzae (Hi) in 174 events (23%). The incidence of Pnc AOM peaked at 12 months of age, whereas the incidence of Mc AOM showed the first peak at 6 months and Hi AOM at 20 months. Pnc AOM showed less prominent seasonality in occurrence than Mc and Hi AOM. Hi was a rare cause of the first 2 AOM episodes (13%) but became increasingly common from the third episode on (32% on average). CONCLUSIONS: Pnc, Mc and Hi were almost equally common findings in AOM. Pnc seems to be the most pathogenic of these three, the role of Mc is increasing and Hi is clearly associated with recurrent AOM.

Nasopharyngeal carriage of Streptococcus pneumoniae in Finnish children younger than 2 years old.

To describe the natural course of nasopharyngeal carriage of Streptococcus pneumoniae and its relationship to acute otitis media (AOM), 329 Finnish children were followed from ages 2 to 24 months. In total, 3024 nasopharyngeal (NP) swabs (obtained at 10 scheduled healthy visits) and 2007 NP aspirates (obtained during respiratory infections) were cultured. Carriage during health increased gradually (9%-43%) with age. Within 4 age intervals, carriage was lower during health (13%-43%) than during respiratory infection without AOM (22%-45%). Higher proportions of positive samples were found during AOM (45%-56%), in particular during pneumococcal AOM (97%-100%). Antimicrobial treatment reduced carriage only temporarily. The most frequent NP serotypes were 6B, 6A, 11, 19F, and 23F. Both age and health status were important determinants of NP carriage of S. pneumoniae and these features should be considered carefully during analysis of carriage rates.

Epidemiology of documented viral respiratory infections and acute otitis media in a cohort of children followed from two to twenty-four months of age.

BACKGROUND: Viral upper respiratory infections (URIs) are considered major risk factors for acute otitis media (AOM) in young children. We studied the epidemiology and relative roles of different viruses in respiratory infections in a cohort of 329 Finnish children followed from 2 months to 2 years of age. METHODS: A nasopharyngeal aspirate (NPA) was collected whenever the child had signs and/or symptoms of URI and tested for the presence of common respiratory virus antigens or infectivity/nucleic acid (only rhinoviruses). Possible repeated detections of a given virus during a 30-day period were considered to represent a single designated virus-specific episode. AOM and URI episodes were defined in a similar way. RESULTS: At least one virus was detected in 837 (41.7%) of the 2005 NPA specimens examined. Rates of URI and virus-specific episodes showed expected seasonal variation with major peak occurrences coinciding with or preceding those of AOM. The proportions of rhinoviruses, respiratory syncytial (RS) virus, parainfluenza virus (PIV) type 3, influenza virus A and adenoviruses were 63.1, 14.7, 6.7, 6.7 and 6.2% of the total of 761 virus-specific episodes. Influenza virus B, PIV1 and PIV2 were each responsible for approximately 1% of the episodes. AOM was diagnosed in 870 URI cases (43.4%) and in 43.3% of cases associated with a virus-positive NPA. The latter figure was clearly higher (57.7%) for RS virus-positive specimens. CONCLUSIONS: The seasonal coincidence of URI and AOM demonstrated the obvious role of URI in the pathogenesis of AOM. The occurrence of rhinoviruses and RS virus in URI was strikingly more common than that of any other virus tested. Although rhinoviruses were definitely the most frequently found viruses in NPA specimens, the association of RS virus with concurrent AOM was relatively higher than that of any other virus.

Antibody response to the pneumococcal proteins pneumococcal surface adhesin A and pneumolysin in children with acute otitis media.

BACKGROUND: Pneumococcal surface adhesin A (PsaA) and pneumolysin (Ply) are common to virtually all Streptococcus pneumoniae isolates, and they are immunogenic and protective against pneumococcal challenge in experimental animals. We have recently shown production of antibodies to PsaA and Ply in young children, but data on the immune response to these antigens during culture-confirmed pneumococcal infection are lacking. OBJECTIVES: To evaluate whether young children respond to S. pneumoniae by producing antibodies to PsaA and Ply during acute otitis media (AOM). SUBJECTS AND METHODS: A cohort of 329 children was followed prospectively from the age of 2 months to the age of 2 years. Paired sera were obtained during episodes of AOM and used to measure antibodies to PsaA and Ply by enzyme-linked immunosorbent assay. S. pneumoniae cultured from the middle ear fluid was taken as evidence of pneumococcal AOM. The presence of S. pneumoniae in the nasopharyngeal aspirate collected in connection of AOM or any other respiratory infection or in the nasopharyngeal swab collected at scheduled visits was taken to indicate pneumococcal carriage and thus a history of previous contact with S. pneumoniae. RESULTS: Children with previous pneumococcal contacts had high anti-PsaA and anti-Ply concentrations in the acute phase sera regardless of the nature (AOM or carriage) of the current pneumococcal contact. Of the children with no previous pneumococcal contact, those with current pneumococcal AOM had lower antibody concentrations than those with current pneumococcal carriage only. Anti-PsaA and anti-Ply responses were found in children with current pneumococcal contact. The antibody response was strongly associated with low acute phase antibody concentration, but not significantly with age and the nature of the current pneumococcal contact. CONCLUSIONS: We showed that infants are capable of developing a specific antibody response to the pneumococcal proteins PsaA and Ply during AOM.

Pneumococcal carriage and otitis media induce salivary antibodies to pneumococcal surface adhesin a, pneumolysin, and pneumococcal surface protein a in children.

Local antibodies probably contribute to defense against Streptococcus pneumoniae. This study examined whether pneumococcal carriage and acute otitis media (AOM) induce mucosal antibodies to potential vaccine candidates pneumococcal surface adhesin A (PsaA), pneumolysin (Ply), and pneumococcal surface protein A (PspA). IgA to all 3 proteins was detected by EIA in saliva of 329 children at ages 6, 12, 18, and 24 months and of 17 adults. A higher proportion of IgA-positive samples and higher antibody concentrations were seen in children with pneumococci-positive cultures of nasopharyngeal samples or middle ear fluid than in children with all cultures negative for pneumococci. The strong correlation between IgA and the presence of the secretory component suggests that the IgA was secretory. The findings indicate that pneumococcal carriage and AOM induce local production of anti-PsaA, anti-Ply, and anti-PspA antibodies early in life.

Efficacy of a pneumococcal conjugate vaccine against acute otitis media.

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 type b vaccine that was administered simultaneously. There were 2596 episodes of acute otitis media during the follow-up period between 6.5 and 24 months of age. The vaccine reduced the number of episodes of acute otitis media from any cause by 6 percent (95 percent confidence interval, -4 to 16 percent [the negative number indicates a possible increase in the number of episodes]), culture-confirmed pneumococcal episodes by 34 percent (95 percent confidence interval, 21 to 45 percent), and the number of episodes due to the serotypes contained in the vaccine by 57 percent (95 percent confidence interval, 44 to 67 percent). The number of episodes attributed to serotypes that are cross-reactive with those in the vaccine was reduced by 51 percent, whereas the number of episodes due to all other serotypes increased by 33 percent. CONCLUSIONS: The heptavalent pneumococcal polysaccharide-CRM197 conjugate vaccine is safe and efficacious in the prevention of acute otitis media caused by the serotypes included in the vaccine.

Treatment of acute otitis media with an antiadhesive oligosaccharide: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Antiadhesive compounds are promising candidates for prevention or treatment of infections. We have investigated the efficacy of such an agent, 3'-sialyllacto-N-neotetraose (NE-1530), given intranasally for prophylaxis of acute otitis media and for effect on nasopharyngeal carriage of bacteria. METHODS: We did a randomised, double-blind placebo-controlled study at one study site. 507 healthy children were randomly assigned either NE-1530 (n=254) or placebo (253) as intranasal sprays twice daily during 3 months. The children were examined by the study physicians once a month and during illness. Treatment efficacy was estimated from Cox proportional hazards model. A sample of nasopharyngeal secretion was taken at every visit for culture of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Adverse events were recorded in study diaries. FINDINGS: At least one event of acute otitis media was diagnosed in 108 (43%) of 254 children in the NE-1530 group and in 86 (34%) of 253 children in the placebo group. The efficacy of treatment was negative, -27% (95% CI -68 to 5; p=0.10). The nasopharyngeal carriage of S pneumoniae, H. influenzae, and M. catarrhalis was not affected by treatment, and the adverse event profiles were almost identical for NE-1530 and placebo. INTERPRETATION: NE-1530 did not have a beneficial effect on the occurrence of acute otitis media or on the nasopharyngeal carriage of bacteria in children.