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

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

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

Mathematical modelling long-term effects of replacing Prevnar7 with Prevnar13 on invasive pneumococcal diseases in England and Wales

England and Wales recently replaced the 7-valent pneumococcal conjugate vaccine (PCV7) with its 13-valent equivalent (PCV13), partly based on projections from mathematical models of the long-term impact of such a switch compared to ceasing pneumococcal conjugate vaccination altogether. A compartmental deterministic model was used to estimate parameters governing transmission of infection and competition between different groups of pneumococcal serotypes prior to the introduction of PCV13. The best-fitting parameters were used in an individual based model to describe pneumococcal transmission dynamics and effects of various options for the vaccination programme change in England and Wales. A number of scenarios were conducted using (i) different assumptions about the number of invasive pneumococcal disease cases adjusted for the increasing trend in disease incidence prior to PCV7 introduction in England and Wales, and (ii) a range of values representing serotype replacement induced by vaccination of the additional six serotypes in PCV13. Most of the scenarios considered suggest that ceasing pneumococcal conjugate vaccine use would cause an increase in invasive pneumococcal disease incidence, while replacing PCV7 with PCV13 would cause an overall decrease. However, the size of this reduction largely depends on the level of competition induced by the additional serotypes in PCV13. The model estimates that over 20 years of PCV13 vaccination, around 5000–62000 IPD cases could be prevented compared to stopping pneumococcal conjugate vaccination altogether. Despite inevitable uncertainty around serotype replacement effects following introduction of PCV13, the model suggests a reduction in overall invasive pneumococcal disease incidence in all cases. Our results provide useful evidence on the benefits of PCV13 to countries replacing or considering replacing PCV7 with PCV13, as well as data that can be used to evaluate the cost-effectiveness of such a switch

Ex-situ biological hydrogen methanation in trickle bed reactors : Integration into biogas production facilities

Biological hydrogen methanation (BHM) is a biocatalytic process for biogas upgrading. Integrating ex-situ BHM processes into biogas facilities has the advantage of using inoculum, CO2, and nutrients directly from anaerobic digestion (AD) processes to enhance CH4 productivity. This study investigated the potential of biowaste digestate as an inoculum and digested biowaste reject water as the trickling liquid and nutrient source in thermophilic trickle bed reactors (TBRs). Use of reject water improved H2 conversion efficiency to up to 99 %, thus achieving a H2 loading rate of 10.8 LH2 L Rv-1 d-1 at a gas retention time (GRT) of 1.8 h and CH4 productivity of 2.6 L LRv-1 d-1 implying that reject water contains macronutrients beneficial to enriching hydrogenotrophic methanogens. However, at high H2 loading rates, a trace element supply was necessary to stabilize process performance. Hydrogenotrophic methanogens Methanothermobacter and Methanobacterium were selectively enriched, mainly due to the increased H2 loading rate.publishedVersionPeer reviewe

Similar impact and replacement disease after pneumococcal conjugate vaccine introduction in hospitalised children with invasive pneumococcal disease in Europe and North America.

High incidence of childhood invasive pneumococcal disease (IPD) in the US declined steeply after 7-valent pneumococcal conjugate vaccine (PCV7) introduction, outweighing reductions observed elsewhere. We re-analysed aggregate published data and compared pre- and post-PCV IPD-incidence in different countries to explore PCV impact on hospitalised and outpatient IPD separately. The proportion of hospitalised IPD cases was consistently high (>80%) in England&Wales, Finland, the Netherlands, and Quebec/Canada, but only 32% in the US before PCV introduction, increasing to 69% during the PCV era. In the US, a higher reduction in outpatient IPD incidence (94% in 2015 versus 1998-99) was observed compared to hospitalised IPD (79%); a 51% reduction in the non-PCV13-type IPD incidence among outpatient cases was estimated compared to a >2-fold increase for hospitalised cases. After stratification by hospitalization status, PCV programmes resulted in similar impact and serotype replacement in hospitalised IPD in US when compared to other countries

Educational and family-related determinants of organized sports participation patterns from adolescence to emerging adulthood: A four-year follow-up study

This study aimed to identify organized sports participation patterns and their prevalence from adolescence to emerging adulthood, and the educational and family-related determinants of the patterns. Adolescents in the Finnish Health Promoting Sports Club (FHPSC) study answered a health behaviour questionnaire and reported on sports club participation at ages 15 and 19 (N = 609). In emerging adulthood, dropouts (total 41.05%; females 43.72%; males 36.56%), maintainers (30.87; 26.44; 38.33), nonparticipants (27.59; 29.32; 24.67), and joiners (0.49; 0.52; 0.44) (p = .024) were identified. A mixed multinomial logistic regression analysis showed, that male gender, as compared to female gender, increased the odds of being a maintainer rather than a nonparticipant or dropout. Among females, high achievement at school and aspiration towards upper secondary school at age 15 increased the odds of being a maintainer at age 19 rather than a nonparticipant. High achievement at school and experiencing a (strong) decrease in parental support for physical activity/sport increased the odds of being a dropout rather than a nonparticipant. Having no experience of a strong decrease in parental support increased the odds of being a maintainer rather than a dropout. Among males, aspiration towards upper secondary school increased the odds of being a maintainer or dropout rather than a nonparticipant. The most common reason for dropping out was study, which was also the most prevalent life status at age 19. The findings highlight a need for more flexible possibilities to combine organized sports participation and school studies, and the importance of parental support for physical activity/sport

Estimating rates of carriage acquisition and clearance and competitive ability for pneumococcal serotypes in Kenya with a Markov transition model.

BACKGROUND: There are more than 90 serotypes of Streptococcus pneumoniae, with varying biologic and epidemiologic properties. Animal studies suggest that carriage induces an acquired immune response that reduces duration of colonization in a nonserotype-specific fashion. METHODS: We studied pneumococcal nasopharyngeal carriage longitudinally in Kenyan children 3-59 months of age, following up positive swabs at days 2, 4, 8, 16, and 32 and then monthly thereafter until 2 swabs were negative for the original serotype. As previously reported, 1868/2840 (66%) of children swabbed at baseline were positive. We estimated acquisition, clearance, and competition parameters for 27 serotypes using a Markov transition model. RESULTS: Point estimates of type-specific acquisition rates ranged from 0.00025/d (type 1) to 0.0031/d (type 19F). Point estimates of time to clearance (inverse of type-specific immune clearance rate) ranged from 28 days (type 20) to 124 days (type 6A). For the serotype most resistant to competition (type 19F), acquisition of other serotypes was 52% less likely (95% confidence interval = 37%-63%) than in an uncolonized host. Fitness components (carriage duration, acquisition rate, lack of susceptibility to competition) were positively correlated with each other and with baseline prevalence, and were associated with biologic properties previously shown to associate with serotype. Duration of carriage declined with age for most serotypes. CONCLUSIONS: Common S. pneumoniae serotypes appear superior in many dimensions of fitness. Differences in rate of immune clearance are attenuated as children age and become capable of more rapid clearance of the longest-lived serotypes. These findings provide information for comparison after introduction of pneumococcal conjugate vaccine

Pneumococcal carriage in sub-Saharan Africa--a systematic review.

BACKGROUND: Pneumococcal epidemiology varies geographically and few data are available from the African continent. We assess pneumococcal carriage from studies conducted in sub-Saharan Africa (sSA) before and after the pneumococcal conjugate vaccine (PCV) era. METHODS: A search for pneumococcal carriage studies published before 2012 was conducted to describe carriage in sSA. The review also describes pneumococcal serotypes and assesses the impact of vaccination on carriage in this region. RESULTS: Fifty-seven studies were included in this review with the majority (40.3%) from South Africa. There was considerable variability in the prevalence of carriage between studies (I-squared statistic = 99%). Carriage was higher in children and decreased with increasing age, 63.2% (95% CI: 55.6-70.8) in children less than 5 years, 42.6% (95% CI: 29.9-55.4) in children 5-15 years and 28.0% (95% CI: 19.0-37.0) in adults older than 15 years. There was no difference in the prevalence of carriage between males and females in 9/11 studies. Serotypes 19F, 6B, 6A, 14 and 23F were the five most common isolates. A meta-analysis of four randomized trials of PCV vaccination in children aged 9-24 months showed that carriage of vaccine type (VT) serotypes decreased with PCV vaccination; however, overall carriage remained the same because of a concomitant increase in non-vaccine type (NVT) serotypes. CONCLUSION: Pneumococcal carriage is generally high in the African continent, particularly in young children. The five most common serotypes in sSA are among the top seven serotypes that cause invasive pneumococcal disease in children globally. These serotypes are covered by the two PCVs recommended for routine childhood immunization by the WHO. The distribution of serotypes found in the nasopharynx is altered by PCV vaccination