Hanna Rinta-Kokko

Estimation of vaccine efficacy against acquisition of pneumococcal carriage.

Evaluation of the effect of new conjugate vaccines on nasopharyngeal carriage of Streptococcus pneumoniae (pneumococcus) has been based on simple comparisons of the prevalence of carriage in vaccinees and controls. However, the definition and measurement of vaccine efficacy should be based on knowledge of the actual mechanism of the vaccines effect. According to current knowledge, conjugate vaccines affect acquisition. We propose a simple-to-use method to measure vaccine efficacy against serotype-specific acquisition that needs only cross-sectional measurements of carriage. We demonstrate the use of the method by application to a data set where it is also possible to estimate efficacy against acquisition from longitudinal measurements.

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).

Colonisation endpoints in Streptococcus pneumoniae vaccine trials

Evaluating vaccine efficacy for protection against colonisation (VEcol) with bacterial pathogens is an area of growing interest. In this article, we consider estimation of VEcol for colonisation with Streptococcus pneumoniae (the pneumococcus). Colonisation is a common, recurrent and multi-type endpoint that requires both careful definition of the vaccine efficacy parameter and the corresponding method of estimation. We review recent developments in the area and provide practical guidelines for choosing the estimand and the estimation method in trials with a colonisation endpoint. We concentrate on methods that are based on a cross-sectional study design, in which only one nasopharyngeal sample is obtained per study subject.

Estimating Strain-Specific and Overall Efficacy of Polyvalent Vaccines Against Recurrent Pathogens From a Cross-Sectional Study

Evaluating vaccine efficacy for protection against colonization with bacterial pathogens is an area of growing interest. Colonization of the nasopharynx is an asymptomatic carrier state responsible for person-to-person transmission. It differs from most clinical outcomes in that it is common, recurrent, and observed only in its prevalent state. To estimate rates of acquisition and clearance of colonization requires repeated active sampling of the same individuals over time, an expensive and invasive undertaking. Motivated by feasibility constraints in efficacy trials with colonization endpoints, investigators have been estimating vaccine efficacy from cross-sectional studies without principled methods. We present two examples of vaccine studies estimating vaccine efficacy from cross-sectional data on nasopharyngeal colonization by Streptococcus pneumoniae (pneumococcus). This study presents a framework for defining and estimating strain-specific and overall vaccine efficacy for susceptibility to acquisition of colonization (VE(acq)) when there is a large number of strains with mutual interactions and recurrent dynamics of colonization. We develop estimators based on one observation of the current status per study subject, evaluate their robustness, and re-analyze the two vaccine trials. Methodologically, the proposed estimators are closely related to case-control studies with prevalent cases, with appropriate consideration of the at-risk time in choosing the controls.

Pneumococcal Conjugate Vaccine and Clinically Suspected Invasive Pneumococcal Disease

OBJECTIVE: Ten-valent pneumococcal conjugate vaccine (PCV10) was earlier shown to reduce clinically suspected, non–laboratory-confirmed invasive pneumococcal disease (IPD) in a cluster-randomized trial (the Finnish Invasive Pneumococcal disease trial). PCV10 was introduced into the Finnish national vaccination program in September 2010 using a 3-dose schedule. We evaluated the impact of PCV10 on clinically suspected IPD among vaccine-eligible children in a population-based nationwide study. METHODS: The target cohort eligible for vaccination program (children born June 2010–September 2013) was compared with 2 season- and age-matched (ages 3–42 months) reference cohorts before PCV10 introduction. The trial period (January 2009–August 2010) was excluded. Hospitals’ inpatient and outpatient discharge notifications with International Classification of Diseases, 10th Revision, diagnoses compatible with IPD (A40.3/B95.3/G00.1/M00.1) and unspecified sepsis (A40.9/A41.9/A49.9/G00/G00.9/I30.1/M00/M00.9/B95.5) were collected from the national Care Register. Laboratory-confirmed IPD cases were excluded. Rates of register-based non–laboratory-confirmed IPD (or unspecified sepsis) before and after PCV10 implementation were calculated. RESULTS: The rate of register-based non–laboratory-confirmed IPD episodes was 32 in 100 000 person-years in the vaccine-eligible target cohort and 94 in the combined reference cohorts. Relative rate reduction was 66% (95% confidence interval: 59–73) and absolute rate reduction 62 in 100 000 person-years. For the more sensitive case definition of register-based non–laboratory-confirmed IPD or unspecified sepsis, the relative rate reduction was 34% (95% confidence interval 29–39), but the absolute reduction was as high as 122 in 100 000 person-years. CONCLUSIONS: This is the first report demonstrating nationwide PCV impact on clinically suspected IPD during routine vaccination program. The large absolute rate reductions observed have major implications for cost-effectiveness of PCVs.

Effectiveness of the Ten-valent Pneumococcal Conjugate Vaccine Against Tympanostomy Tube Placements in a Cluster-randomized Trial.

Background: We evaluated the impact of the new pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10, GSK Vaccines) on tympanostomy tube placements (TTPs). Methods: Finnish Invasive Pneumococcal disease vaccine trial was a nationwide phase III/IV cluster-randomized, double-blind trial. Children younger than 19 months received PHiD-CV10 in two thirds of clusters (N = 52) or hepatitis B or A vaccine as control in 26 clusters according to 3 + 1 or 2 + 1 schedules (infants younger than 7 months) or catch-up schedules. A secondary objective of the trial was to assess vaccine effectiveness (VE) against TTPs in children who received at least one vaccine dose before or after 7 months of age. Blinded follow-up lasted from the date of first vaccination (from February 2009 through October 2010) to December 31, 2011. Outcome data were collected through the National Care register and Social Insurance Institution reimbursement register. Results: More than 47,000 children were enrolled. In 30,527 infants younger than 7 months of age at enrolment, 4369 TTPs were reported in 3594 subjects. The incidence was 7.9 per 100 person-years in the infant control cohort. The VE estimate was 13% [95% confidence interval (CI): −2% to 26%] for combined PHiD-CV10 3 + 1 and 2 + 1 infant schedules. The VE estimates for the 3 + 1 and 2 + 1 infant schedules when estimated separately were similar. For the catch-up schedules, the VE was 11% (95% CI: −7% to 26%) for children enrolled at 7–11 months of age and −1% (95% CI: −21% to 16%) for children enrolled at 12–18 months of age. Conclusions: Our study results suggest that PHiD-CV10 immunization according to a 3 + 1 or 2 + 1 schedule initiated before 12 months of age may reduce the frequency of TTPs, although the primary analysis did not reach statistical significance.

Design questions for Streptococcus pneumoniae vaccine trials with a colonisation endpoint.

Evaluation of vaccine efficacy for protection against colonisation (VEcol) with Streptococcus pneumoniae and other bacterial pathogens is often based on a cross-sectional study design, in which only one nasopharyngeal sample is obtained per study subject. Here we investigate the feasibility of this study design by investigating a number of practical design problems. Specific questions are related to the timing of colonisation measurement with respect to the time of vaccination, the adjustment for the within-host replacement of vaccine-type colonisation by the non-vaccine type pneumococci, and the impact of multiple serotype colonisation on VEcol estimation. We also discuss the issue of choosing the control vaccine, including comparison of two active pneumococcal vaccines, as well as the sample size and the statistical power of colonisation endpoint trials. In addition, the statistical design with the specific aim to include information about VEcol in the licensure process of new pneumococcal vaccine products is discussed.

Impact of ten-valent pneumococcal conjugate vaccine on pneumonia in Finnish children in a nation-wide population-based study

Background The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Program (NVP) in September 2010 using a 2+1 schedule (3, 5, 12 months). We estimated the direct and indirect effects of PCV10 on pneumonia among children to evaluate the public health impact of the vaccine. Methods We conducted a nation-wide population-based, observational study comparing rates of pneumonia in children before and after the NVP introduction. For the total (direct and indirect) effect, the cohort of vaccine-eligible children (born June 1, 2010 or later) was followed until the end of 2013 (age range 3–42 months). For the indirect effect, a cohort of older children (age range 7–71 months) not eligible for the PCV vaccination was followed from 2011 to 2013. Both cohorts were compared with two season- and age-matched reference cohorts before NVP introduction. Hospitals’ in- and outpatient discharge notifications with ICD-10 diagnoses compatible with pneumonia (J10.0, J11.0, J12-J18, J85.1 or J86) as set by the hospital pediatricians were collected from the national Care Register. The main outcome was hospital-treated primary pneumonia (HTPP), defined as primary diagnosis of pneumonia after in-patient hospitalization. We compared rates of pneumonia in the NVP target and reference cohorts by using Poisson regression models. Results The rate of HTPP episodes was 5.3/1000 person-years in the combined reference cohorts and 4.1/1000 person-years in the target cohort vaccine-eligible children. Compared with the reference cohort, the relative rate reduction in target cohort was 23% (95%CI 18–28) and the absolute reduction 1.3/1000 person-years. In the indirect effect evaluation, we observed continued increase in HTPP incidence until 2011 with a subsequent reduction of 18% (95%CI 10–25) during years 2012 to 2013. Number of empyema diagnoses remained low. Conclusions A substantial decrease in pneumonia rates was observed both among vaccine-eligible children and among older, unvaccinated children after PCV10 introduction.

Long-term impact of 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease among children in Finland

BACKGROUND The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Programme (NVP) in September 2010. The impact of PCV10 vaccination against invasive pneumococcal disease (IPD) in vaccine-eligible children has been high. We evaluated the long-term impact of PCV10 vaccination against IPD in vaccine-eligible and older, unvaccinated children six years after PCV10 introduction with a special focus on cross-protection against PCV10-related serotypes (serotypes in the same serogroups as the PCV10 types). METHODS We used data on IPD from the national, population-based surveillance. A target cohort of vaccine-eligible children (born June 2010 or later) was followed from 3 months of age until the end of 2016. For the indirect effect, another cohort of older PCV10-ineligible children was followed from 2012 through 2016. IPD rates were compared with those of season- and age-matched reference cohorts before NVP introduction. RESULTS Among vaccine-eligible children, the incidence of all IPD decreased by 79% (95% CI 74-83%). There was a statistically significant reduction in the incidence of 6A IPD, but for 19A, the reduction was non-significant and the incidence of 19A increased towards the end of the study period in the older vaccine-eligible children. The increase in non-PCV10 related serotypes was non-significant. In the unvaccinated older children, the incidence of all IPD decreased by 33% (95% CI 8-52%) compared to the reference cohort, and there was no impact on serotype 6A or 19A IPD. CONCLUSION Overall, the impact of PCV10 vaccination on IPD was high in vaccine-eligible children, with a major reduction in vaccine-type disease, and without notable replacement by other serotype groups. Our data suggest that PCV10 results in long-lasting direct cross-protection against 6A IPD. For 19A, no net reduction was observed six years after NVP introduction in the vaccine-eligible cohort. The indirect impact on IPD in unvaccinated children sustained.

Impact of National Ten-Valent Pneumococcal Conjugate Vaccine Program on Reducing Antimicrobial Use and Tympanostomy Tube Placements in Finland

Background: Otitis media in young children is associated with major resource use including antimicrobial consumption and tympanostomy tube placements (TTPs). We evaluated the impact of 10-valent pneumococcal conjugate vaccine (PCV10) introduction into the Finnish National Vaccination Programme (NVP) against these outcomes in vaccine-eligible children. Methods: PCV10-NVP began September 2010 with a 2 + 1 schedule; uptake in 2012 was estimated at 92%. The relative and absolute reduction in the NVP-eligible target cohort was compared with a season and age-matched (3–54 months) cohort before NVP introduction. Outpatient antimicrobial purchase data were collected from the Social Insurance Institution register. Data on purchases of antimicrobials recommended for treatment of acute otitis media by the Finnish Current Care Guidelines (amoxicillin with/without enzyme inhibitor, cefuroxime, cefaclor, clarithromycin, azithromycin) were collected, but full data on penicillin and sulfadiazine/trimethoprim were not available. Data on all TTP procedures were obtained from national hospital discharge register and Social Insurance Institution benefits register. Generalized Cox regression was used in the analysis. Results: The incidence rates of antimicrobial purchases in the reference and target cohorts were 1.09 and 0.89 per person-year, respectively. The relative rate reduction was 17.5% (95% confidence interval: 17.0–18.1) and the absolute rate reduction 0.20 per person-year. The rates of TTP in the reference and target cohorts were 5.41/100 and 4.56/100 person-years, respectively. The relative rate reduction was 14.8% (95% confidence interval: 13.1–16.5) and the absolute rate reduction 0.86/100 person-years. Conclusions: Use of antimicrobials and TTPs reduced after PCV10 was introduced into a routine vaccination program. This suggests considerable savings in health care resource use.