Arto A. Palmu

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.

Protective Efficacy of a Second Pneumococcal Conjugate Vaccine against Pneumococcal Acute Otitis Media in Infants and Children: Randomized, Controlled Trial of a 7-Valent Pneumococcal Polysaccharide-Meningococcal Outer Membrane Protein Complex Conjugate Vaccine in 1666 Children

To assess the efficacy of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine (PncOMPC) against acute otitis media (AOM), 1666 infants were randomly assigned to receive either PncOMPC or control vaccine (hepatitis B vaccine) at 2, 4, 6, and 12 months of age. Of the 835 children assigned to receive PncOMPC, 187 received a 23-valent pneumococcal polysaccharide vaccine (PncPS) at 12 months of age instead. Whenever AOM was diagnosed, middle ear fluid was aspirated for bacterial culture. In the PncOMPC and control groups, there were 110 and 250 AOM episodes, respectively, in children between 6.5 and 24 months of age that could be attributed to vaccine serotypes, which indicates a vaccine efficacy of 56% (95% confidence interval, 44%-66%). The serotype-specific efficacy ranged from 37% for 19F to 82% for 9V. The 2 boosters seemed to provide equal protection against AOM, but PncPS induced markedly higher antibody concentrations. The efficacy of PncOMPC was comparable to that of the recently licensed pneumococcal conjugate vaccine.

Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial

BACKGROUND The Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was designed to assess the effectiveness of a pneumococcal vaccine containing ten serotype-specific polysaccharides conjugated to Haemophilus influenzae protein D, tetanus toxoid, and diphtheria toxoid as the carrier proteins (PHiD-CV10) against invasive pneumococcal disease. METHODS In this cluster-randomised, double-blind trial, children aged younger than 19 months received PHiD-CV10 in 52 clusters or hepatitis vaccines as control in 26 clusters. Infants aged younger than 7 months at the first vaccination received either a 3+1 or a 2+1 vaccination schedule, children aged 7-11 months received a 2+1 schedule, and those 12-18 months of age received a two-dose schedule. The primary and secondary objectives were to assess vaccine effectiveness against culture-confirmed invasive pneumococcal disease due to any of the ten vaccine serotypes for the 3+1 and 2+1 schedules, respectively, in children who received at least one PHiD-CV10 dose before 7 months of age. Masked follow-up of pneumococcal disease lasted from the first vaccination (from February, 2009, to October, 2010) to January 31, 2012. Invasive disease data were retrieved from data accumulated in the national infectious diseases register. This trial and the nested acute otitis media trial are registered with ClinicalTrials.gov, numbers NCT00861380 and NCT00839254, respectively. FINDINGS 47,369 children were enrolled from February, 2009, to October, 2010. 30,528 participants were assessed for the primary objective. 13 culture-confirmed vaccine-type cases of invasive pneumococcal disease were detected: none in the PHiD-CV10 3+1 group, one in the PHiD-CV10 2+1 group, and 12 in the control groups. The estimates for vaccine effectiveness were 100% (95% CI 83-100) for PHiD-CV10 3+1 and 92% (58-100) for PHiD-CV10 2+1 groups. Two cases of any culture-confirmed invasive disease irrespective of serotype were detected in combined PHiD-CV10 infant cohorts compared with 14 in the corresponding control cohorts (vaccine effectiveness 93%, 75-99). In catch-up cohorts, seven cases of invasive disease were reported, all in the control group: two cases in the children enrolled at 7-11 months of age; and five cases in children enrolled at 12-18 months of age (vaccine effectiveness 100%, 79-100). Non-fatal serious adverse events suspected to be vaccine-related were reported via routine post-immunisation safety surveillance in 18 children. INTERPRETATION This nationwide trial showed high PHiD-CV10 effectiveness against invasive pneumococcal disease when given in different schedules. For the first time, effectiveness of a 2+1 schedule in infants was confirmed in a clinical trial. FUNDING GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare, Finland.

The seven-valent pneumococcal conjugate vaccine reduces tympanostomy tube placement in children.

Background: The novel pneumococcal conjugate vaccine, PncCRM, has been shown to prevent acute otitis media caused by vaccine serotypes and to reduce otitis surgery. Our aim was to assess long term efficacy of the vaccine on tympanostomy tube placements. Methods: Children with complete follow-up in the Finnish Otitis Media Vaccine Trial up to 24 months of age and still living in the study area (1490 of 1662 randomized at 2 months of age) were invited to a single visit at 4–5 years of age. The children had been vaccinated at 2, 4, 6 and 12 months of age with PncCRM or hepatitis B vaccine (control). Tympanostomy tube placements reported by parents at the visit were verified from hospital and private medical center records. Additionally, tympanostomy tube placements of all children were verified from the hospital discharge registry. Vaccine efficacy (VE) was estimated by comparing all events of tympanostomy tube placement between vaccine groups. Results: During the vaccine trial (2–24 months of age), VE (95% confidence interval) in preventing tympanostomy tube placement was only 4% (– 19–23%). Altogether 756 children were enrolled for the follow-up study. After 24 months of age, the rate of surgery was 3.5 per 100 person-years in the PncCRM and 5.7 per 100 person-years in the control children, giving VE of 39% (4–61%). In the hospital-based data of all children (N = 1490), VE of 44% was obtained (19–62%). Conclusions: Receipt of PncCRM vaccine at infancy was associated with a reduction in tympanostomy tube placement from 2 to 4–5 years of age.

Association of Clinical Signs and Symptoms with Bacterial Findings in Acute Otitis Media

In acute otitis media (AOM), a means of prediction of the bacterial pathogen based on symptoms and signs would be valuable in selecting appropriate antimicrobial treatment. Children in the control arm (n=831) in the Finnish Otitis Media Vaccine Trial were prospectively observed in a study clinic setting from the age of 2 to 24 months. In patients with AOM, myringotomy with aspiration was performed, and middle ear fluid samples were cultured for bacterial pathogens. Symptoms and signs of respiratory infections were thoroughly recorded. Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae were the most common bacterial pathogens. Pneumococcal AOM was associated with more-severe AOM characterized by fever and earache. AOM due to H. influenzae was associated with eye symptoms and findings. Accurate prediction of a bacterial cause of infection based on symptoms and signs of AOM was not possible, but a specific cause was predicted in some situations, with a high probability of applicability to clinical practice.

Diagnostic value of tympanometry in infants in clinical practice

One hundred and twenty-one visits of 58 infants (2-11 months of age) were evaluated in the Finnish Otitis Media Vaccine Trial. Infants were examined with tympanometry (Grason-Stadler GSI 38 Autotymp) and pneumatic otoscopy by one study doctor. Diagnosis of otitis media was verified by myringotomy in 74% of cases. Tympanometry was technically successful in 94% of ears. The success rate was statistically significantly higher (P < 0.05) among infants less than 7 months of age than those above 7 months. The sensitivity of tympanometry (type B) to detect ears with middle ear fluid was 0.70 and the specificity 0.98 with a positive predictive value of 0.93 and negative predictive value of 0.94. The sensitivity was somewhat lower in the younger age group (0.61); specificity and positive and negative predictive values were good in both age groups. The high success rate and high negative and positive predictive values of tympanometry make it a useful aid for assuring the correct diagnosis of otitis media in infants in routine clinical practice.

Aging reduces the functionality of anti-pneumococcal antibodies and the killing of Streptococcus pneumoniae by neutrophil phagocytosis.

We evaluated the effect of aging on the functional activity of naturally acquired anti-pneumococcal antibodies, the function of neutrophils in phagocytic killing of opsonized pneumococci, and the complement activity. Opsonic activities of antibodies to all tested pneumococcal serotypes were significantly lower and phagocytic killing of pneumococci by neutrophils was significantly impaired among the elderly, whereas the complement activity was slightly higher in the elderly than in the young adults. The reduced functional activity of serotype-specific antibodies and the compromised function of neutrophils in the opsonophagocytosis of pneumococci are likely to contribute to the increased susceptibility of the elderly to pneumococcal diseases.

Effect of pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) on outpatient antimicrobial purchases: a double-blind, cluster randomised phase 3–4 trial

BACKGROUND Antimicrobial drugs are frequently prescribed to children for respiratory tract infections such as otitis, tonsillitis, sinusitis, and pneumonia. We assessed the effect of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; GlaxoSmithKline) on antimicrobial purchases. METHODS In this nationwide phase 3-4 cluster-randomised, double-blind trial, children younger than 19 months were randomly assigned to receive PHiD-CV10 in 52 of 78 clusters or hepatitis B or A vaccine as control in 26 clusters according to three plus one or two plus one schedules (infants younger than 7 months) or catch-up schedules (children aged 7-18 months). The main objective for the antimicrobial treatment outcome was to assess vaccine effectiveness against outpatient prescriptions of antimicrobial drugs recommended by national treatment guidelines for acute otitis media in Finland in children who received at least one dose of study vaccine before 7 months of age. Masked follow-up lasted from the date of first vaccination (from Feb 18, 2009, through Oct 5, 2010) to Dec 31, 2011. We obtained data on all purchased antimicrobial prescriptions through the benefits register of the Social Insurance Institution of Finland. This and the nested acute otitis media trial are registered at ClinicalTrials.gov, numbers NCT00861380 and NCT00839254. FINDINGS More than 47,000 children were enrolled. In 30,527 infants younger than 7 months at enrollment, 98,436 outpatient antimicrobial purchases were reported with incidence of 1.69 per person-year in the control clusters. Analysis of the main objective included 91% of all antimicrobial purchases: 31,982 in the control and 57,964 in the PHiD-CV10 clusters. Vaccine effectiveness was 8% (95% CI 1-14) and the incidence rate difference 0.12 per person-year corresponding to the number needed to vaccinate of five (95% CI 3-67) to prevent one purchase during the 2 year follow-up for combined PHiD-CV10 three plus one and two plus one infant schedules. The vaccine effectiveness was identical for the two infant schedules. In the catch-up schedules, the vaccine effectiveness was 3% (95% CI -4 to 10). INTERPRETATION Despite low relative rate reductions the absolute rate reductions were substantial because of the high incidence of the outcome. This reduction would lead to over 12,000 fewer antimicrobial purchases per year in children younger than 24 months in Finland (birth cohort of 60,000 children).

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.

Nasopharyngeal carriage of Streptococcus pneumoniae and pneumococcal urine antigen test in healthy elderly subjects

Abstract Background: Children frequently carry Streptococcus pneumoniae (pneumococcus) in their nasopharynx, even when healthy. Lower carriage rates have been reported in adults and only sparse data are available for the elderly. We sampled healthy elderly subjects for nasopharyngeal carriage to assess the prevalence of pneumococcal carriage using various assays. Methods: A deep nasopharyngeal swab sample was taken from 590 healthy elderly subjects aged ≥ 65 y. The samples were stored in STGG (skim milk–tryptone–glucose–glycerol) medium and cultured directly and after incubation in enrichment broth using routine identification methods. Real-time polymerase chain reaction (PCR) assays specific for pneumolysin and pneumococcal surface antigen A genes was performed on the same samples. Urine was also collected and assayed using the commercial Binax Streptococcus pneumoniae NOW urine antigen test. Results: The prevalence of pneumococcal carriage in healthy elderly persons was 1.5% for encapsulated pneumococci and 5.3% for all presumptive pneumococci. The use of the enrichment broth did not increase the yield of positives. PCR assays gave higher numbers of positives, but pneumolysin PCR in particular gave probable false-positive results. Only 1 urine antigen test was positive, and this was in a person not carrying pneumococcus. Conclusions: Nasopharyngeal carriage of pneumococci in the elderly was rare. Identification of presumptive pneumococci in culture requires further confirmation, e.g. by serotyping. The urine antigen test was not affected by concurrent carriage. Low carriage prevalence suggests that encapsulated pneumococci detected in a respiratory tract sample during sickness may be the true cause of disease, since contamination from asymptomatic nasopharyngeal carriage seems unlikely.