Effect measures, their estimation and interpretation : Applications to pneumococcal conjugate vaccination

The direct and indirect effects of pneumococcal vaccination on an individual and the population are of great interest. This study focuses on the definition, estimation and interpretation of different effect measures of vaccines and vaccination against pneumococcal colonisation and disease. Vaccine efficacy, effectiveness and impact are considered as epidemiological parameters of interest which are estimated using observations gathered according to some study design. In this thesis, vaccine efficacy against colonisation is defined through pneumococcal acquisition, which describes the natural process of incident occurrences of colonisation better than prevalence. Moreover, a general definition of vaccine efficacy against a multi-type pathogen is presented, with an epidemiologically meaningful interpretation as a weighted average of strain-specific efficacies. A feasible estimation method is then proposed, based on cross-sectional measurement on the current status of colonisation. When the differences in times at-risk between vaccinated and unvaccinated individuals are taken into account, the estimation of vaccine efficacy against colonisation is shown to be less biased by within-host competition between different serotypes (strains). The estimation method is exemplified with empirical data of pneumococcal colonisation in Israeli children. At the population level, vaccine effectiveness is the measure of vaccine-induced protection during an ongoing vaccination programme when both vaccinated and unvaccinated individuals experience the indirect effects of the vaccination programme. Vaccine impact is the population prevented fraction of the incidence of infection when exposure is the vaccination programme rather than each individual’s own vaccination. Both vaccine effectiveness and impact are parameters that depend on the population dynamics of pneumococcal colonisation and disease after vaccine introduction. In this thesis, the time trends of vaccine effectiveness and impact are described with a pseudo-dynamic model that incorporates the incidences of pneumococcal carriage and disease. The model shows that the effectiveness and impact against vaccine-serotype invasive pneumococcal disease (IPD) are expected to be high and largely of the same magnitude through the post-introduction period. By contrast, the vaccine effectiveness and impact against non-vaccine-serotype IPD follow very divergent paths while the vaccine-type colonisation and disease become eliminated. The practical estimation of vaccine effectiveness is exemplified with register data of Finnish children eligible for pneumococcal conjugate (PCV10) vaccination. Three parallel study designs, the cohort, nested case-control and indirect cohort designs, are shown to provide estimates that are broadly concordant with each other. The parameters of vaccine efficacy as proposed in this thesis can be interpreted as measures of the biological effect of the vaccine on new vaccine-type acquisitions and should therefore allow more robust comparisons across different epidemiological settings with differing levels of exposure by non-vaccine strains. Moreover, the thesis helps to interpret the time-varying parameters of vaccine impact and effectiveness during large-scale vaccinations, and their manifestation in Finnish children.Pneumokokkirokotusten yksilöön ja koko väestöön kohdistuvat suorat ja epäsuorat vaikutukset on tärkeää tuntea. Tämä tutkimus keskittyy pneumokokkirokotteiden tehomittojen määritelmiin, estimointiin ja tulkintaan. Rokotteen teho ennen rokotusohjelman aloittamista sekä teho ja vaikuttavuus ohjelman aikana ovat kiinnostavia parametreja, jotka estimoidaan keräämällä havaintoja jonkin koeasetelman mukaisesti. Työssä tarkastellaan pneumokokkirokotteen tehoa nenänielukantajuutta vastaan kantajuuden ilmaantuvuuden kautta. Ilmaantuvuus kuvaa kantajuuden biologista luonnetta paremmin kuin sen esiintyvyys, mutta vaatii tyypillisesti pitkittäismittauksia. Työssä osoitetaan, että rokotusteho kantajuuden ilmaantuvuutta vastaan voidaan estimoida poikkileikkausaineistosta odds-suhteena. Lisäksi näytetään, että kun rokotusteho määritellään patogeenille, jolla on monta alatyyppiä kuten pneumokokille, on huomioitava eri alatyyppien keskinäinen kilpailu nenänielussa. Tällöin rokotustehon estimaatti vastaa tarkemmin todellista rokotustehoa. Tätä havainnollistetaan israelilaisten päiväkotilasten kantajuusmittausten avulla. Laajamittaisen rokotusohjelman aikana rokotusteho mittaa rokotteen yksilölle tarjoamaa suoraa suojaa tilanteessa, jossa sekä rokotetut että rokottamattomat lapset kokevat myös epäsuoria vaikutuksia (laumasuojaa ja ei-rokotetyyppien korvautumista). Rokotusohjelman vaikuttavuus mittaa kantajuuden tai taudin ilmaantuvuuden muutosta verrattuna tilanteeseen ennen rokotusohjelmaa. Sekä rokotusteho että vaikuttavuus ovat parametreja, jotka riippuvat pneumokkikantajuuden ja -taudin väestödynamiikasta. Rokotustehon ja vaikuttavuuden aikatrendejä kuvataan pseudodynaamisella mallilla, joka ottaa huomioon kantajuuden ja taudin ilmaantuvuuden muutokset ajassa. Mallin mukaan sekä rokotusteho että vaikuttavuus rokotetyypin vakavaa pneumokokkitautia vastaan pysyvät korkeina ja liki samansuuruisina koko rokotusohjelman ajan. Sitä vastoin rokotusteho ja vaikuttavuus ei-rokotetyypin vakavaa pneumokokkitautia vastaan ovat hyvin erisuuruiset silloin, kun rokotetyypin kantajuus on vähentynyt ja poistumassa väestöstä. Rokotustehon estimointia havainnollistetaan käyttäen suomalaista terveysrekisteriaineistoa vakavan pneumokokkitaudin tapauksista lapsilla, jotka ovat oikeutettuja pneumokokkirokotusohjelmaan. Kolmen tutkimusasetelman eli kohortti-, pesäytetyn tapaus-verrokki- ja epäsuoran kohorttiasetelman näytetään tarjoavan likimain samansuuruisia estimaatteja. Esitetyt rokotustehon parametrit nenänielukantajuutta vastaan tarjoavat mahdollisuuden verrata rokotetutkimuksia erilaisissa asetelmissa, vaikka ei-rokotetyypin kantajuuden ilmaantuvuus voi vaihdella paljonkin. Lisäksi tutkimus tarjoaa keinoja tulkita ajassa muuttuvia rokotustehon ja vaikuttavuuden mittoja laajojen rokotusohjelmien aikana, erityisesti suomalaisten lasten näkökulmasta

Impact and effectiveness of a conjugate vaccine against invasive pneumococcal disease in Finland-a modelling approach

The evaluation of the public health impact of a vaccination program is essential in monitoring its policy relevance. Vaccine impact (VI) is usually assessed in a before-after design, in which data on disease burden without vaccination program is required from a historical reference period. It takes into account the indirect effects and therefore aims to describe the public health performance of the vaccination program in the population. Vaccine effectiveness (VE), measured in parallel settings, quantifies the benefit for an individual of being vaccinated but does not address the indirect effects of a vaccination program. The motivation of this paper is to gain insight into patterns of how VI and VE have manifested under large-scale use of a ten-valent pneumococcal conjugate vaccine in Finnish children. We construct a simple pseudo-dynamic model that mimics typical post-vaccination trends in the incidences of pneumococcal carriage and invasive disease in children when the proportion of vaccine-type carriage decreases. In the context of the model, we define the parameters of interest for VI and VE and explore how their expected values evolve over time. For comparison, we demonstrate the application of VI and VE estimation by using register data

Long-term population impact of infant 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in adults in Finland

Background: Limited data are available on long-term indirect effects of ten-valent pneumococcal conjugate vaccine (PCV10) programmes. We evaluated changes in invasive pneumococcal disease (IPD) incidence, mortality, and serotype distribution in adults up to 9 years after infant PCV10 introduction. Methods: Culture-confirmed IPD cases ≥18 years (n = 5610; 85% were pneumonia) were identified through national, population-based laboratory surveillance; data were linked with population registry to conduct nationwide follow-up study. In a time-series model, we compared serotype-specific IPD incidence and associated 30-day mortality rates before and after PCV10 by using negative binomial regression models. Results: During pre-PCV10 period (7/2004–6/2010), overall IPD incidence in adults ≥18 years increased yearly by 4.8%. After adjusting for trend and seasonality, the observed PCV10 serotype IPD incidence in 7/2018–6/2019 was 90% (12/100,000 person-years) lower than the expected rate without PCV10 program. Non-PCV10 serotype incidence was 40% (4.4/100,000 person-years) higher than expected; serotypes 3, 19A, 22F, and 6C accounted for most of the rate increase. However, incidence of non-PCV10 IPD levelled off by end of follow-up. The observed-expected incidence rate-ratio (IRR) was 0·7 (95 %CI 0·5–0.8) for all IPD and 0·7 (95 %CI 0·3–1·3) for IPD-associated 30-day mortality. Case-fatality proportion decreased from 11·9% to 10.0% (p < 0.01). In persons ≥65 years, the IRR was 0·7 (95 %CI 0·5–0.95). Conclusions: Significant indirect effects were seen for vaccine-serotype IPD and for overall IPD in all adult age groups. For non-vaccine IPD, the incidence stabilized 5 years after infant PVC10 program introduction, resulting in a steady state in which non-vaccine IPD accounted for nearly 90% of overall IPD. Substantial pneumococcal disease burden remains in older adults.publishedVersionPeer reviewe

Estimating excess mortality and economic burden of <i>Clostridioides difficile</i> infections and recurrences during 2015–2019:The RECUR England study

Objective To generate real-world evidence on all-cause mortality and economic burden of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in England. Methods We conducted a cohort study using retrospective data from Clinical Practice Research Datalink linked to Hospital Episode Statistics. Patients diagnosed with CDI in hospital and community settings during 2015–2018 were included and followed for ≥1year. All-cause mortality was described at 6-, 12-, and 24-months. Healthcare resource usage (HCRU) and associated costs were assessed at 12-months of follow-up. A cohort of non-CDI patients, matched by demographic and clinical characteristics including Charlson Comorbidity Index score, was used to assess excess mortality and incremental costs of HCRU. Results All-cause mortality among CDI patients at 6-, 12-, and 24-months was 15.87%, 20.37%, and 27.03%, respectively. A higher proportion of rCDI patients died at any point during follow-up. Compared with matched non-CDI patients, excess mortality was highest at 6-months with 1.81 and 2.53 deaths per 100 patient-months among CDI and ≥1 rCDI patients. Hospitalisations were the main drivers of costs, with an incremental cost of £1,209.21 per CDI patient. HCRU and costs increased with rCDIs. Conclusions CDI poses a substantial mortality and economic burden, further amplified by rCDIs

Effect of childhood pneumococcal conjugate vaccination on invasive disease in older adults of 10 European countries: implications for adult vaccination.

BackgroundPneumococcal conjugate vaccines (PCVs) have the potential to prevent pneumococcal disease through direct and indirect protection. This multicentre European study estimated the indirect effects of 5-year childhood PCV10 and/or PCV13 programmes on invasive pneumococcal disease (IPD) in older adults across 13 sites in 10 European countries, to support decision-making on pneumococcal vaccination policies.MethodsFor each site we calculated IPD incidence rate ratios (IRR) in people aged ≥65 years by serotype for each PCV10/13 year (2011-2015) compared with 2009 (pre-PCV10/13). We calculated pooled IRR and 95% CI using random-effects meta-analysis and PCV10/13 effect as (1 - IRR)*100.ResultsAfter five PCV10/13 years, the incidence of IPD caused by all types, PCV7 and additional PCV13 serotypes declined 9% (95% CI -4% to 19%), 77% (95% CI 67% to 84%) and 38% (95% CI 19% to 53%), respectively, while the incidence of non-PCV13 serotypes increased 63% (95% CI 39% to 91%). The incidence of serotypes included in PCV13 and not in PCV10 decreased 37% (95% CI 22% to 50%) in six PCV13 sites and increased by 50% (95% CI -8% to 146%) in the four sites using PCV10 (alone or with PCV13). In 2015, PCV13 serotypes represented 20-29% and 32-53% of IPD cases in PCV13 and PCV10 sites, respectively.ConclusionOverall IPD incidence in older adults decreased moderately after five childhood PCV10/13 years in 13 European sites. Large declines in PCV10/13 serotype IPD, due to the indirect effect of childhood vaccination, were countered by increases in non-PCV13 IPD, but these declines varied according to the childhood vaccine used. Decision-making on pneumococcal vaccination for older adults must consider the indirect effects of childhood PCV programmes. Sustained monitoring of IPD epidemiology is imperative

Impact and effectiveness of a conjugate vaccine against invasive pneumococcal disease in Finland : a modelling approach

Published online: 17 Dec 202