The serotype distribution among healthy carriers before vaccination is essential for predicting the impact of pneumococcal conjugate vaccine on invasive disease.

Pneumococcal conjugate vaccines (PCVs) have substantially reduced morbidity and mortality of pneumococcal disease. The impact of the 7-valent PCV on all-serotype invasive pneumococcal disease (IPD) among children was reported to vary between high-income countries. We investigate the ability to predict this heterogeneity from pre-vaccination data. We propose a parsimonious model that predicts the impact of PCVs from the odds of vaccine serotype (VT) among carriers and IPD cases in the pre-PCV period, assuming that VT are eliminated in a mature PCV programme, that full serotype replacement occurs in carriage and that invasiveness of the NVT group is unchanged. We test model performance against the reported impact of PCV7 on childhood IPD in high-income countries from a recent meta-analysis. The odds of pre-PCV7 VT IPD, PCV schedule, PCV coverage and whether a catch up campaign was used for introduction was gathered from the same analysis. We conducted a literature review and meta-analysis to obtain the odds of pre-PCV7 VT carriage in the respective settings. The model predicted the reported impact on childhood IPD of mature PCV programmes; the ratio of predicted and observed incidence risk ratios was close to 1 in all settings. In the high income settings studied differences in schedule, coverage, and catch up campaigns were not associated with the observed heterogeneity in impact of PCV7 on childhood all-serotype IPD. The pre-PCV7 proportion of VT IPD alone also had limited predictive value. The pre-PCV7 proportion of VT carriage and IPD are the main determinants for the impact of PCV7 on childhood IPD and can be combined in a simple model to provide predictions of the vaccine preventable burden of IPD

Assessing the efficiency of catch-up campaigns for the introduction of pneumococcal conjugate vaccine: a modelling study based on data from PCV10 introduction in Kilifi, Kenya.

BACKGROUND: The World Health Organisation recommends the use of catch-up campaigns as part of the introduction of pneumococcal conjugate vaccines (PCVs) to accelerate herd protection and hence PCV impact. The value of a catch-up campaign is a trade-off between the costs of vaccinating additional age groups and the benefit of additional direct and indirect protection. There is a paucity of observational data, particularly from low- and middle-income countries, to quantify the optimal breadth of such catch-up campaigns. METHODS: In Kilifi, Kenya, PCV10 was introduced in 2011 using the three-dose Expanded Programme on Immunisation infant schedule and a catch-up campaign in children <5 years old. We fitted a transmission dynamic model to detailed local data, including nasopharyngeal carriage and invasive pneumococcal disease (IPD), to infer the marginal impact of the PCV catch-up campaign over hypothetical routine cohort vaccination in that setting and to estimate the likely impact of alternative campaigns and their dose efficiency. RESULTS: We estimated that, within 10 years of introduction, the catch-up campaign among children <5 years old prevents an additional 65 (48-84) IPD cases across age groups, compared to PCV cohort introduction alone. Vaccination without any catch-up campaign prevented 155 (121-193) IPD cases and used 1321 (1058-1698) PCV doses per IPD case prevented. In the years after implementation, the PCV programme gradually accrues herd protection, and hence its dose efficiency increases: 10 years after the start of cohort vaccination alone the programme used 910 (732-1184) doses per IPD case averted. We estimated that a two-dose catch-up among children <1 year old uses an additional 910 (732-1184) doses per additional IPD case averted. Furthermore, by extending a single-dose catch-up campaign to children aged 1 to <2 years and subsequently to those aged 2 to <5 years, the campaign uses an additional 412 (296-606) and 543 (403-763) doses per additional IPD case averted. These results were not sensitive to vaccine coverage, serotype competition, the duration of vaccine protection or the relative protection of infants. CONCLUSIONS: We find that catch-up campaigns are a highly dose-efficient way to accelerate population protection against pneumococcal disease

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

Mathematical models to evaluate the impact of increasing serotype coverage in pneumococcal conjugate vaccines

Of over 100 serotypes of Streptococcus pneumoniae, only 7 were included in the first pneumo- coccal conjugate vaccine (PCV). While PCV reduced the disease incidence, in part because of a herd immunity effect, a replacement effect was observed whereby disease was increasingly caused by serotypes not included in the vaccine. Dynamic transmission models can account for these effects to describe post-vaccination scenarios, whereas economic evaluations can enable decision-makers to compare vaccines of increasing valency for implementation. This thesis has four aims. First, to explore the limitations and assumptions of published pneu- mococcal models and the implications for future vaccine formulation and policy. Second, to conduct a trend analysis assembling all the available evidence for serotype replacement in Europe, North America and Australia to characterise invasive pneumococcal disease (IPD) caused by vaccine-type (VT) and non-vaccine-types (NVT) serotypes. The motivation behind this is to assess the patterns of relative abundance in IPD cases pre- and post-vaccination, to examine country-level differences in relation to the vaccines employed over time since introduction, and to assess the growth of the replacement serotypes in comparison with the serotypes targeted by the vaccine. The third aim is to use a Bayesian framework to estimate serotype-specific invasiveness, i.e. the rate of invasive disease given carriage. This is useful for dynamic transmission modelling, as transmission is through carriage but a majority of serotype-specific pneumococcal data lies in active disease surveillance. This is also helpful to address whether serotype replacement reflects serotypes that are more invasive or whether serotypes in a specific location are equally more invasive than in other locations. Finally, the last aim of this thesis is to estimate the epidemiological and economic impact of increas- ing serotype coverage in PCVs using a dynamic transmission model. Together, the results highlight that though there are key parameter uncertainties that merit further exploration, divergence in serotype replacement and inconsistencies in invasiveness on a country-level may make a universal PCV suboptimal.Open Acces

Directed vaccination against pneumococcal disease

Immunization strategies against commensal bacterial pathogens have long focused on eradicating asymptomatic carriage as well as disease, resulting in changes in the colonizing microflora with unknown future consequences. Additionally, current vaccines are not easily adaptable to sequence diversity and immune evasion. Here, we present a "smart" vaccine that leverages our current understanding of disease transition from bacterial carriage to infection with the pneumococcus serving as a model organism. Using conserved surface proteins highly expressed during virulent transition, the vaccine mounts an immune response specifically against disease-causing bacterial populations without affecting carriage. Aided by a delivery technology capable of multivalent surface display, which can be adapted easily to a changing clinical picture, results include complete protection against the development of pneumonia and sepsis during animal challenge experiments with multiple, highly variable, and clinically relevant pneumococcal isolates. The approach thus offers a unique and dynamic treatment option readily adaptable to other commensal pathogens

Frequency-dependent selection in vaccine-associated pneumococcal population dynamics

Many bacterial species are composed of multiple lineages distinguished by extensive variation in gene content. These often cocirculate in the same habitat, but the evolutionary and ecological processes that shape these complex populations are poorly understood. Addressing these questions is particularly important for Streptococcus pneumoniae, a nasopharyngeal commensal and respiratory pathogen, because the changes in population structure associated with the recent introduction of partial-coverage vaccines have substantially reduced pneumococcal disease. Here we show that pneumococcal lineages from multiple populations each have a distinct combination of intermediate-frequency genes. Functional analysis suggested that these loci may be subject to negative frequency-dependent selection (NFDS) through interactions with other bacteria, hosts or mobile elements. Correspondingly, these genes had similar frequencies in four populations with dissimilar lineage compositions. These frequencies were maintained following substantial alterations in lineage prevalences once vaccination programmes began. Fitting a multilocus NFDS model of post-vaccine population dynamics to three genomic datasets using Approximate Bayesian Computation generated reproducible estimates of the influence of NFDS on pneumococcal evolution, the strength of which varied between loci. Simulations replicated the stable frequency of lineages unperturbed by vaccination, patterns of serotype switching and clonal replacement. This framework highlights how bacterial ecology affects the impact of clinical interventions.Accessory loci are shown to have similar frequencies in diverse Streptococcus pneumoniae populations, suggesting negative frequency-dependent selection drives post-vaccination population restructuring

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

Characteristics of pneumococci causing disease in adults in Portugal in a time of private use of pneumococcal conjugate vaccines in children

Invasive pneumococcal disease (IPD) and non-invasive pneumococcal pneumonia (NIPP) are important causes of morbidity and mortality worldwide, particularly among young children, the elderly and the immunocompromised. Two types of vaccines are available to prevent pneumococcal disease, but these target a limited number of the 97 pneumococcal serotypes described so far. One type is a strictly polysaccharide-based vaccine, which includes 23 serotypes and is primarily indicated for adults (23-valent pneumococcal polysaccharide vaccine, PPV23, targeting serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F). The other type are pneumococcal conjugate vaccines (PCVs). Three PCVs have been licensed to date: a 7-valent formulation (PCV7), which covers serotypes 4, 6B, 9V, 14, 18C, 19F and 23F; a 10-formulation (PCV10), which includes all serotypes of PCV7, plus serotypes 1, 5 and 7F; and a 13-valent formulation (PCV13), which targets all serotypes of PCV10 and also serotypes 3, 6A and 19A. PCV7 became available in the USA in 2000 and in Europe in 2001. Several studies reported that the use of PCV7 in children was followed by decreases in the incidence of PCV7-type IPD in children. Since PCV7 reduced colonization due to the vaccine serotypes and because children are the main reservoirs of pneumococci in the community, PCV7 serotypes became less transmitted from children to the remaining population, with this resulting in decreases in the incidence of PCV7-type IPD also in non-vaccinated people, including adults (herd protection). However, at the same time, increases in the incidence of IPD due to particular non-PCV7 serotypes occurred in children and adults. In Portugal, PCV7 was used in children between 2001 and 2009, but was not included in the national immunization program. The uptake of PCV7 was initially low (43% in 2004), but increased steadily (75% in 2008). In mid-2009 and early-2010, PCV10 and PCV13, respectively, became available for children, with PCV13 replacing PCV7. PCV10 and PCV13 were given through the private market until June 2015, when PCV13 was included in the national immunization program for children. During the availability of PCV10 and PCV13 outside the national immunization program, PCV13 was the most frequently used PCV. Even though PPV23 and PCV13 are also available for adults, in Portugal, adult pneumococcal vaccination is estimated to be low. The studies presented in this thesis aimed to evaluate the characteristics of pneumococci causing adult IPD and adult NIPP in Portugal in a time of private PCVs use in children in the country. The isolates were collected by an epidemiological surveillance network, in work since 1999, which includes several laboratories throughout the country. All isolates analyzed were collected from adult patients (≥ 18 yrs). For the characterization of adult IPD isolates we determined the serotype and antimicrobial susceptibility of isolates responsible for adult IPD between 2009 and 2014 (n = 2428). The results were compared with previously published data from the same network (1999-2008, n = 2182). Adult IPD isolates were also characterized by Multi Locus Sequence Typing (MLST) and regarding the presence and type of two pilus islands (PI-1 and PI-2). For this characterization, 50% of adult IPD isolates recovered from 2008 to 2011 (n = 871), from each serotype, were randomly chosen. For the characterization of adult NIPP isolates, we determine the serotype and antimicrobial susceptibility of a collection of isolates responsible for adult NIPP between 1999 and 2015 (n = 2735). Previous studies from this epidemiological surveillance network, which analyzed the serotypes of adult IPD isolates recovered between 1999 and 2008, found that in Portugal there was a significant decrease in the proportion of PCV7 serotypes in adult IPD in the post-PCV7 period (from 30.3% in 1999-2003 to 16.4% in 2008, p < 0.001), accompanied by increases in the proportion of specific non-PCV7 serotypes (serotypes 1, 7F and 19A). When analyzing adult IPD data from 2009 to 2014, we found further changes in the serotype distribution of pneumococci causing adult IPD. Comparing adult IPD isolates recovered in 2009-2011 with those recovered in 2012- 2014, a new but small decrease in the representation of PCV7 serotypes in adult IPD was noted (from 19% to 14%, p = 0.003). In what concerns the overall proportion of PCV13 serotypes, it peaked in 2008 (70%) and then started a significant and gradual decline until 2014 (38%, p < 0.001), the last year analyzed. Since PCV10 and PCV13 became available in Portugal only in mid-2009 and early-2010, respectively, the initial decline in the overall proportion of PCV13 serotypes was independent of childhood vaccination. The PCV13 serotypes that decreased the most from 2008 to 2011 were serotypes 1 (from 10.7% in 2009 to 4.1% in 2011, p < 0.001) and 5 (from 2.0% in 2008 to 0% in 2011, p = 0.003). The early decreases of these two serotypes may be associated with long term fluctuations and outbreaks, described elsewhere. Other serotypes, instead, decreased when a herd effect with the use of PCV13 in children was expected. This was the case of serotype 7F (from 8.2% in 2012 to 2.7% in 2014, p < 0.001) and 19A (from 9.7% in 2012 to 5.6% in 2014, p = 0.027). In the post-PCV13 period, there were also significant increases in some of the serotypes not covered by PCV13 (i.e. serotypes 8, 15A, 20 and 22F). In what concerns antimicrobial resistance, and considering current Clinical Laboratory Standards Institute (CLSI) breakpoints, in 2012-2014, o.5% of the isolates were considered penicillin non-susceptible pneumococci (PNSP) and 17% erythromycin resistant pneumococci (ERP). Regarding the characterization of adult IPD isolates by MLST we found high genetic diversity, with 206 different sequence types (STs) detected. The STs represented 80 different clonal complexes (CCs), but the six more frequent CCs accounted for half of the isolates (CC156, CC191, CC180, CC306, CC62 and CC230). Most of the STs detected related to STs described in other countries. We found the changes in serotypes occurring in adult IPD following PCV7 use in children were mostly driven by the expansion of previously circulating clones or to decreases in most of the lineages expressing a given serotype. Concerning the presence and type of PI-1 and PI-2, only a small proportion of isolates was positive for any of the PIs (31.9%). Most of the isolates expressing PCV7 serotypes presented PI-1 (87.9%), while PI-2 positive isolates were mainly found among isolates expressing serotypes 1 and 7F, which are serotypes included in PCV10 and PCV13. In what concerns the characterization of adult NIPP isolates, we found significant declines in the proportion of vaccines serotypes following the use of PCVs in children, although these declines were less marked than those occurring in adult IPD. In adult NIPP, the proportion of PCV7 serotypes declined from 31% in 1999-2003 to 11% in 2011 (p < 0.001), while the overall proportion of PCV13 serotypes declined from 44% in 2010 to 30% in 2015 (p < 0.001). When considering the 2012-2015 period, and according to current CLSI breakpoints, 1% of adult NIPP isolates were PNSP and 21.7% were ERP. Comparison of NIPP serotypes with IPD serotypes identified associations of several serotypes with either disease presentation. The studies presented in this thesis showed that in Portugal in the time of PCVs use in children outside the national immunization program there were several changes in the characteristics of pneumococci causing disease in adults. While some of the changes suggested herd protection with the use of PCVs in children, others were independent. The inclusion of PCV13 in the national immunization program for children in June 2015 may be further reducing the importance of PCV13 serotypes in adult IPD and adult NIPP. However, increases of particular non-PCV13 serotypes in adult IPD are concerning and should be monitored. Continued IPD and NIPP epidemiological surveillance is important due to different serotype distribution and dynamics of pneumococci causing each disease presentation

The impact of 10-valent pneumococcal vaccine introduction on invasive disease in Fiji.

BACKGROUND: In 2012, Fiji introduced the 10-valent pneumococcal conjugate vaccine (PCV10). We assessed the impact of PCV10 on invasive pneumococcal disease (IPD), probable bacterial or pneumococcal meningitis (PBPM), meningitis and sepsis 3-5 years post-introduction. METHODS: Laboratory-confirmed IPD and PBPM cases were extracted from national laboratory records. ICD-10-AM coded all-cause meningitis and sepsis cases were extracted from national hospitalisation records. Incidence rate ratios were used to compare outcomes pre/post-PCV10, stratified by age groups: 1-23m, 2-4y, 5-9y, 10-19y, 20-54y, ≥55y. To account for different detection and serotyping methods in the pre-and post-PCV10 period, a Bayesian inference model estimated serotype-specific changes in IPD, using pneumococcal carriage and surveillance data. FINDINGS: There were 423 IPD, 1,029 PBPM, 1,391 all-cause meningitis and 7,611 all-cause sepsis cases. Five years post-PCV10 introduction, IPD declined by 60% (95%CI: 37%, 76%) in children 1-23m months old, and in age groups 2-4y, 5-9y, 10-19y although confidence intervals spanned zero. PBPM declined by 36% (95%CI: 21%, 48%) among children 1-23 months old, and in all other age groups, although some confidence intervals spanned zero. Among children <5y of age, PCV10-type IPD declined by 83% (95%CI; 70%, 90%) and with no evidence of change in non-PCV10-type IPD (9%, 95%CI; -69, 43%). There was no change in all-cause meningitis or sepsis. Post-PCV10, the most common serotypes in vaccine age-eligible and non-age eligible people were serotypes 8 and 23B, and 3 and 7F, respectively. INTERPRETATIONS: Our study demonstrates the effectiveness of PCV10 against IPD in a country in the Asia-Pacific of which there is a paucity of data. FUNDING: This study was support by the Department of Foreign Affairs and Trade of the Australian Government and Fiji Health Sector Support Program (FHSSP). FHSSP is implemented by Abt JTA on behalf of the Australian Government