Pneumococcal conjugate vaccines for preventing otitis media

BACKGROUND: Acute otitis media (AOM) is a very common early infancy and childhood disease. The marginal benefits of antibiotics on AOM, the increasing problem of bacterial resistance to antibiotics, and the huge estimated direct and indirect annual costs associated with otitis media (OM) have prompted a search for effective vaccines to prevent AOM. OBJECTIVES: To assess the effect of pneumococcal conjugate vaccines (PCVs) in preventing AOM in children up to 12 years of age. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, issue 2), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register; MEDLINE (January 1995 to November 2007); and EMBASE (January 1995 to November 2007). SELECTION CRITERIA: Randomised controlled trials of PCVs to prevent AOM in children aged 12 years or younger, with a follow up of at least six months after vaccination. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial quality and two review authors extracted data. MAIN RESULTS: We included seven trials on 7- to 11-valent PCV (with different carrier proteins). There was large heterogeneity regarding study population, type of conjugate vaccine, and outcome measures between trials, therefore, results were not pooled. The only currently licensed 7-valent PCV Prevenar with CRM197 as carrier protein (CRM197-PCV7) administered during infancy was in two studies associated with a 6% (95% confidence interval (CI) -4% to 16%) and 7% (95% CI 4% to 9%) relative reduction in risk of AOM episodes. Another 7-valent PCV with the outer membrane protein complex of Neisseria meningitidis (N. meningitidis) serogroup B as carrier protein, administered in infancy, did not reduce overall AOM episodes, while an 11-valent PCV with Haemophilus influenzae (H. influenzae) protein D as carrier protein was associated with a relative reduction in risk of AOM episodes of 34% (95% CI 21% to 44%). 9-valent PCV (with CRM197 carrier protein) administered in healthy toddlers was associated with a 17% (95% CI -2% to 33%) relative reduction in risk of OM episodes. CRM197-PCV7 followed by 23-valent pneumococcal polysaccharide vaccination administered after infancy in older children with a history of AOM showed no beneficial effect on further AOM episodes. AUTHORS' CONCLUSIONS: Based on current evidence of the effectiveness of PCVs for the prevention of AOM, the currently licensed 7-valent PCV administered during infancy has marginal beneficial effects. Discrete reductions of 6% to 7% may mean substantial reductions from a public health perspective. Administering PCV7 in older children with a history of AOM appears to have no benefit in preventing further episodes

Adverse reactions to simultaneous influenza and pneumococcal conjugate vaccinations in children:randomized double-blind controlled trial

In a randomized double-blind controlled trial, the safety was assessed of simultaneous administration of influenza and pneumococcal conjugate vaccines in children with previous physician-diagnosed respiratory tract infections. In total, 579 children aged 18-72 months were assigned to receive simultaneous intramuscular influenza and pneumococcal heptavalent conjugate vaccinations (IV + PV), influenza and placebo vaccinations (IV + plac) or control hepatitis B and placebo vaccinations (HepB + plac) in separate extremities. Local and systemic adverse events were recorded in parental diaries for 7 days after vaccination. No immediate adverse reactions were recorded. In most children local adverse reactions disappeared 2 days after vaccination. Local and systemic reactions were more prevalent (30% and 10% more) in the IV + PV group compared with the IV + plac and HepB + plac group. These results are important for designing future vaccination schedules

Effects of influenza plus pneumococcal conjugate vaccination versus influenza vaccination alone in preventing respiratory tract infections in children:a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To evaluate the effects of influenza vaccination with or without heptavalent pneumococcal conjugate vaccination on respiratory tract infections (RTIs) in children. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled trial comprising 579 children age 18 to 72 months with a previous history of physician-diagnosed RTI, recruited between 2003 and 2005. The children were assigned to 2 doses of parenteral inactivated trivalent subunit influenza plus heptavalent pneumococcal conjugate vaccination (TIV+PCV7), influenza plus placebo vaccination (TIV+plac), or control hepatitis B virus vaccination plus placebo (HBV+plac). Main outcome measures were febrile RTI and related polymerase chain reaction (PCR)-confirmed influenza, primary care visits, antibiotic prescriptions, and acute otitis media (AOM) episodes. RESULTS: During influenza seasons, febrile RTI were reduced by 24% (95% confidence interval [CI] = 1% to 42%) in the TIV+PCV7 group and by 13% (95% CI = -12% to 32%) in the TIV+plac group compared with the control group. The occurrence of PCR-confirmed influenza was reduced by 52% (95% CI = 7% to 75%) in the TIV+PCV7 group and by 51% (95% CI = 3% to 75%) in the TIV+plac group. Episodes of AOM were reduced by 57% (95% CI = 6% to 80%) in the TIV+PCV7 group and by 71% (95% CI = 30% to 88%) in the TIV+plac group. Outside of the influenza seasons, no significant effects of vaccinations were demonstrated on the studied outcomes. CONCLUSIONS: During influenza seasons, influenza vaccination with or without pneumococcal conjugate vaccination substantially reduced cases of confirmed influenza and AOM episodes

Decline in influenza-associated mortality among Dutch elderly following the introduction of a nationwide vaccination program

With a retrospective nationwide cohort study in the Netherlands over 1992-2003, using mortality and viral surveillance data, the aim was to assess by means of rate difference methods the influenza-associated mortality in the elderly before and after the introduction of a nationwide influenza vaccination program in 1996 (vaccination coverage raised from below 50 to 80%). The average annual influenza-associated mortality declined in the years before and after the introduction from 131 to 105 per 100,000 persons (relative risk 0.80). The decline was largest in the age group 65-69 years (relative risk 0.54) and less in those aged 75 years and older. Validation by Serfling-type regression analysis revealed similar results. In conclusion, routine influenza vaccination among Dutch elderly was associated with a significant decrease in influenza-associated mortality, notably in those aged 65-69 years

Rate-difference method proved satisfactory in estimating the influenza burden in primary care visits

OBJECTIVE: To compare different methods to estimate the disease burden of influenza, using influenza and respiratory syncytial virus-(RSV) associated primary care data as an example. STUDY DESIGN AND SETTING: In a retrospective study in the Netherlands over 1997-2003, primary care attended respiratory episodes and national viral surveillance data were used to compare the rate-difference method to other, more complex methods. RESULTS: The influenza-associated excess estimated by the different methods varied. The estimates provided by the rate-difference model lay well within this range. According to the rate-difference method, influenza-associated primary care consultations were present for all ages, including low-risk adults. The highest influenza-associated burden was demonstrated for children below the age of 5 years. The RSV-associated primary care burden was highest in the youngest age category and well above that associated with influenza. Significant RSV-associated excess was also recorded among adults, particularly in high-risk adults and the elderly. CONCLUSION: The straightforward rate-difference model seemed satisfactory to estimate the influenza-associated burden. Significant influenza-associated excess was demonstrated among persons not yet recommended for influenza vaccination in The Netherlands. The RSV-associated burden was highest for the youngest children, but also significant for adults

Invasive Pneumococcal Disease among Adults:Associations among Serotypes, Disease Characteristics, and Outcome

Background. The Streptococcus pneumoniae polysaccharide capsule may be related to invasive pneumococcal disease (IPD) course. Methods. We performed a retrospective cohort study with nationally representative surveillance data from 1075 hospitalized patients with IPD from the Netherlands from 1 June 2004 through 31 May 2006 in the prevaccination era. Serotypes were grouped according to invasive disease potential, rate of the most serious clinical syndromes of meningitis and bacteremia without focus, and case-fatality rates. Multivariable logistic regression analysis was performed to obtain odds ratios adjusted for baseline confounders for the association of serotypes and these outcomes, using the serotypes with the lowest rates as reference. Results. IPD caused by serogroups with low invasive disease potential concerned meningitis or bacteremia without focus in 22% of cases, and 74% of patients had an underlying comorbidity. For highly invasive serogroups these figures were 10% (P <.01) and 56% (P <.01). Individual serotypes varied in the relative rate by which they caused meningitis or bacteremia without focus. Compared with the reference group composed of serotypes 1, 5, 7F, 15B, 20, and 33F, the group of serotypes 3, 19F, 23A, 16F, 6B, 9N, and 18C was associated with increased case-fatality rates (group adjusted odds ratio, 2.6; 95% confidence interval, 1.5-4.7). Conclusions. The serotype appeared to be independently associated with IPD severity in adults, which indicates that careful monitoring of IPD after implementation of conjugate vaccines is necessary

Invasive pneumococcal disease in the Netherlands:Syndromes, outcome and potential vaccine benefits

With a retrospective study of invasive pneumococcal disease (IPD) surveillance data representative for approximately 25% of the Dutch population (1275 hospitalized cases) over the period June 2004-June 2006 prior to the implementation of the 7-valent pneumococcal conjugate vaccine (PCV7), the aim was to provide baseline data on IPD for the interpretation of changes after implementation of conjugate vaccines. The IPD incidence peaked in 3-5-mnth-olds (63 cases per 100,000 persons yearly) and increased in adulthood, particularly after the age of 60yrs, from 26 cases in 60-64-yr-olds to 97 cases per 100,000 in persons >/=90yrs. Beyond the age of 4yrs, 19% of IPD patients were immunocompromised, and this considerable percentage may have implications for vaccine efficac

Cost effectiveness of pneumococcal vaccination among Dutch infants: economic analysis of the seven valent pneumococcal conjugated vaccine and forecast for the 10 valent and 13 valent vaccines

OBJECTIVES: To update cost effectiveness estimates for the four dose (3+1) schedule of the seven valent pneumococcal conjugated vaccine (PCV-7) in the Netherlands and to explore the impact on cost effectiveness of reduced dose schedules and implementation of 10 valent and 13 valent pneumococcal vaccines (PCV-10 and PCV-13). DESIGN: Economic evaluation comparing PCV-7, PCV-10, and PCV-13 with no vaccination using a decision tree analytic model built from data in previous studies. SETTING: The Netherlands. Population A cohort of 180 000 newborns followed until 5 years of age. MAIN OUTCOME MEASURES: Costs; gains in life years and quality adjusted life years (QALYs); and incremental cost effectiveness ratios. RESULTS: Under base case assumptions-that is, assuming a five year protective period of the vaccine and no assumed net indirect effects (herd protection minus serotype replacement) among children aged over 5 years-vaccination with PVC-7 in a four dose (3+1) schedule was estimated to prevent 71 and 5778 cases of invasive and non-invasive pneumococcal disease, respectively, in children aged up to 5 years. This corresponds with a total net gain of 173 life years or 277 QALYs. The incremental cost effectiveness ratio of PCV-7 was estimated at euro113 891 ( pound98 300; $145 000) per QALY, well over the ratio of euro50 000 per QALY required for PCV-7 to be regarded as potentially cost effective. A three dose (2+1) schedule of PCV-7 reduced the incremental cost effectiveness ratio to euro82 975 per QALY. For various assumptions and including 10% of the maximum net indirect effects among individuals aged 5 years and over, PCV-10 and PCV-13 had incremental cost effectiveness ratios ranging from euro31 250 to euro52 947 per QALY. CONCLUSIONS: The current Dutch infant vaccination programme of four doses of PCV-7 is not cost effective because of increases in invasive disease caused by non-vaccine serotypes, which reduces the overall direct effects of vaccination and offsets potential positive herd protection benefits in unvaccinated individuals. The 10 valent and 13 valent pneumococcal vaccines could have better net health benefits than PCV-7 through less replacement disease and increased herd protection. Both these effects could substantially reduce the incremental cost effectiveness ratio to possibly acceptable levels, if total programme costs can be lowered by reduced schedules, reductions in vaccine prices, or bot