Effectiveness of the 10-valent pneumococcal conjugate vaccine among girls, boys, preterm and low-birth-weight infants - Results from a randomized, double-blind vaccine trial.

BACKGROUND: Several studies have shown differences in susceptibility to infections and immune response to vaccines by sex. Prematurely born infants are at higher risk for pneumococcal diseases, with lower effectiveness for some vaccines compared to term infants. We have reported the effectiveness of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) on several endpoints in the Finnish Invasive Pneumococcal disease (FinIP) vaccine trial. Now, we present the results of a post-hoc analysis evaluating PHiD-CV10 effectiveness in subgroups by sex, gestational age, and birth weight. METHODS: The FinIP trial was a phase III/IV cluster-randomized, double-blind trial. Infants enrolled < 7 months of age received PHiD-CV10 in two thirds of clusters (3 + 1 or 2 + 1 schedule) and hepatitis B vaccine as control in remaining third. Outcome data included invasive pneumococcal disease, pneumonia, tympanostomy tube placements, and antimicrobial purchases collected through national, routinely used health registers. Negative binomial model was used in the incidence and vaccine effectiveness estimation, and differences in incidences between subgroups were tested among control children. RESULTS: Of the 30,527 infants enrolled 51% were boys. The incidences of hospital-diagnosed pneumonia and otitis-related outcomes were higher among boys in control groups. There were no significant sex differences in the vaccine effectiveness estimates. Altogether, 1519 (5%) infants were born before 37th gestational week. The incidences of pneumonia outcomes were higher among premature infants when compared to term infants. The vaccine effectiveness estimates among preterm infants were not statistically significant except for antimicrobial purchases, but all point estimates were at the same level among preterm infants as among term infants. There was no significant difference between 2 + 1 and 3 + 1 schedules in any of the subgroups analysed. CONCLUSION: PHiD-CV10 had a similar effectiveness in both sexes, and seemed to be protective in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT00861380 and NCT00839254.

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).

A pneumococcal conjugate vaccination programme reduced clinically suspected invasive disease in unvaccinated children.

AIM: The 10-valent pneumococcal conjugate vaccine was introduced to the Finnish national vaccination programme for children born since June 2010. We evaluated the changes in the rates of clinically suspected invasive pneumococcal disease (IPD) in unvaccinated children to estimate the indirect herd protection impact of the programme. METHODS: The target cohort for this ecological before and after comparison were unvaccinated children born from January 2008 to May 2010 and ineligible for the vaccination programme, who were followed up from 2011 to 2014. The reference cohort was age and season-matched children born in January 2003 to 2005 and followed up from 2006 to 2009. National data on hospital discharge codes compatible with IPD or unspecified sepsis were collected. RESULTS: We compared the follow-up periods of 2007-2009 in the reference cohort and 2012-2014 in the target cohort. The incidence of non-laboratory-confirmed IPD in unvaccinated children fell by 68%, from 47 to 15/100 000 person-years. When unspecified sepsis was added, the decrease was 39%, from 171 to 104/100 000 person-years. Laboratory confirmed IPD fell by 44%, from 15 to 8/100 000 person-years. CONCLUSION: The pneumococcal vaccination programme provided herd protection against clinically suspected IPD. The absolute reduction was almost 10-times higher than for just laboratory-confirmed disease.

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.

Bacterial etiology of acute myringitis in children less than two years of age.

BACKGROUND: Acute myringitis is an inflammation of the tympanic membrane that occurs alone or in association with external otitis or otitis media. The two clinical entities, based on physical examination, are bullous myringitis and hemorrhagic myringitis. OBJECTIVES: To investigate the association of concomitant middle ear disease with acute myringitis and to analyze the bacteriologic findings of the middle ear fluid in children with acute myringitis. METHODS: A prospective longitudinal cohort study of 2028 children age 7 to 24 months at primary care level in the Finnish Otitis Media Vaccine Trial. Matched case-control design for analysis of bacterial pathogen distribution. RESULTS: There were 82 children in whom 92 ears were diagnosed with acute bullous myringitis and 37 children in whom 40 ears were diagnosed with hemorrhagic myringitis during the follow-up. Middle ear disease was associated with bullous myringitis in 97% of ears and with hemorrhagic myringitis in 82% of ears. Bacterial pathogen distribution was similar to that of acute otitis media, although a higher proportion of Streptococcus pneumoniae was detected in both bullous and hemorrhagic acute myringitis. CONCLUSIONS: Middle ear fluid was present in vast majority of ears with acute myringitis in young children. The same etiologic bacteria were found in acute myringitis as in acute otitis media, but S. pneumoniae was the major pathogen. Acute bullous myringitis should be treated as acute otitis media in children <2 years of age.