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author:("puranen, Kari")
Biometrics  2013;69(1):235-244.
Evaluating vaccine efficacy for protection against colonisation with bacterial pathogens is an area of growing interest. Colonisation 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 colonisation requires repeated active sampling of the same individuals over time, an expensive and invasive undertaking. Motivated by feasibility constraints in efficacy trials with colonisation 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 colonisation by Streptococcus pneumoniae (pneumococcus). This study presents a framework for defining and estimating strain-specific and overall vaccine efficacy for susceptibility to acquisition of colonisation (VEacq) when there is a large number of strains with mutual interactions and recurrent dynamics of colonisation. We develop estimators based on one observation of the current status per study subject, evaluate their robustness, and re-analyse 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.
PMCID: PMC3622115  PMID: 23379663
Case-control studies; Multiple colonisation; Pneumococcus; Polyvalent vaccine; Recurrent infection; Risk-set sampling; Strain interaction; Vaccine efficacy
2.  Optimal Serotype Compositions for Pneumococcal Conjugate Vaccination under Serotype Replacement 
PLoS Computational Biology  2014;10(2):e1003477.
Pneumococcal conjugate vaccination has proved highly effective in eliminating vaccine-type pneumococcal carriage and disease. However, the potential adverse effects of serotype replacement remain a major concern when implementing routine childhood pneumococcal conjugate vaccination programmes. Applying a concise predictive model, we present a ready-to-use quantitative tool to investigate the implications of serotype replacement on the net effectiveness of vaccination against invasive pneumococcal disease (IPD) and to guide in the selection of optimal vaccine serotype compositions. We utilise pre-vaccination data on pneumococcal carriage and IPD and assume partial or complete elimination of vaccine-type carriage, its replacement by non-vaccine-type carriage, and stable case-to-carrier ratios (probability of IPD per carriage episode). The model predicts that the post-vaccination IPD incidences in Finland for currently available vaccine serotype compositions can eventually decrease among the target age group of children <5 years of age by 75%. However, due to replacement through herd effects, the decrease among the older population is predicted to be much less (20–40%). We introduce a sequential algorithm for the search of optimal serotype compositions and assess the robustness of inferences to uncertainties in data and assumptions about carriage and IPD. The optimal serotype composition depends on the age group of interest and some serotypes may be highly beneficial vaccine types in one age category (e.g. 6B in children), while being disadvantageous in another. The net effectiveness will be improved only if the added serotype has a higher case-to-carrier ratio than the average case-to-carrier ratio of the current non-vaccine types and the degree of improvement in effectiveness depends on the carriage incidence of the serotype. The serotype compositions of currently available pneumococcal vaccines are not optimal and the effectiveness of vaccination in the population at large could be improved by including new serotypes in the vaccine (e.g. 22 and 9N).
Author Summary
The bacterial pathogen Streptococcus pneumoniae (pneumococcus) is a major contributor to child mortality worldwide. Hence, effective pneumococcal vaccination programmes are globally among the most cost-effective public health interventions. Three different conjugate vaccine compositions, targeting 7, 10 or 13 pneumococcal serotypes, have been used in infant vaccination programmes. The use of these vaccines has both decreased the disease burden and changed the patterns of pneumococcal carriage in locations where they have been in use. However, due to serotype replacement, where the lost vaccine serotype carriage is replaced by carriage of the non-vaccine serotypes, the net effect of vaccination on the disease burden has generally been milder than expected. Here, we apply a concise model for serotype replacement and present a ready-to-use tool for the prediction of patterns in post-vaccination pneumococcal incidence of carriage and invasive disease. We introduce a sequential algorithm for the identification of the most optimal additional serotypes to current vaccine formulations and demonstrate how differences in the invasiveness across serotypes imply that the disease incidence may either decrease or increase after vaccination. The methods we outline have direct relevance in decision making while reviewing the performance of the current pneumococcal vaccination programmes.
PMCID: PMC3923658  PMID: 24550722
3.  Impact of Vaccination on 14 High-Risk HPV Type Infections: A Mathematical Modelling Approach 
PLoS ONE  2013;8(8):e72088.
The development of high-risk human papillomavirus (hrHPV) infection to cervical cancer is a complicated process. We considered solely hrHPV infections, thus avoiding the confounding effects of disease progression, screening, and treatments. To analyse hrHPV epidemiology and to estimate the overall impact of vaccination against infections with hrHPVs, we developed a dynamic compartmental transmission model for single and multiple infections with 14 hrHPV types. The infection-related parameters were estimated using population-based sexual behaviour and hrHPV prevalence data from Finland. The analysis disclosed the important role of persistent infections in hrHPV epidemiology, provided further evidence for a significant natural immunity, and demonstrated the dependence of transmission probability estimates on the model structure. The model predicted that vaccinating girls at 80% coverage will result in a 55% reduction in the overall hrHPV prevalence and a higher 65% reduction in the prevalence of persistent hrHPV infections in females. In males, the reduction will be 42% in the hrHPV prevalence solely by the herd effect from the 80% coverage in girls. If such high coverage among girls is not reached, it is still possible to reduce the female hrHPV prevalence indirectly by the herd effect if also boys are included in the vaccination program. On the other hand, any herd effects in older unvaccinated cohorts were minor. Limiting the epidemiological model to infection yielded improved understanding of the hrHPV epidemiology and of mechanisms with which vaccination impacts on hrHPV infections.
PMCID: PMC3756967  PMID: 24009669
4.  Comparative analysis of Streptococcus pneumoniae transmission in Portuguese and Finnish day-care centres 
BMC Infectious Diseases  2013;13:180.
Day-care centre (DCC) attendees play a central role in maintaining the circulation of Streptococcus pneumoniae (pneumococcus) in the population. The prevalence of pneumococcal carriage is highest in DCC attendees but varies across countries and is found to be consistently lower in Finland than in Portugal. We compared key parameters underlying pneumococcal transmission in DCCs to understand which of these contributed to the observed differences in carriage prevalence.
Longitudinal data about serotype-specific carriage in DCC attendees in Portugal (47 children in three rooms; mean age 2 years; range 1–3 years) and Finland (91 children in seven rooms; mean age 4 years; range 1–7 years) were analysed with a continuous-time event history model in a Bayesian framework. The monthly rates of within-room transmission, community acquisition and clearing carriage were estimated.
The posterior mean of within-room transmission rate was 1.05 per month (Portugal) vs. 0.63 per month (Finland). The smaller rate of clearance in Portugal (0.57 vs. 0.73 per month) is in accordance with the children being younger. The overall community rate of acquisition was larger in the Portuguese setting (0.25 vs. 0.11 per month), in agreement with that the groups belonged to a larger DCC. The model adequately predicted the observed levels of carriage prevalence and longitudinal patterns in carriage acquisition and clearance.
The difference in prevalence of carriage (61% in Portuguese vs. 26% among Finnish DCC attendees) was assigned to the longer duration of carriage in younger attendees and a significantly higher rate of within-room transmission and community acquisition in the Portuguese setting.
PMCID: PMC3652738  PMID: 23597389
Streptococcus pneumoniae; Pneumococcus; Day care; Child; Transmission; Carriage; Prevalence; Longitudinal studies; Portugal; Finland; Statistical models; Bayesian inference; Data augmentation
5.  Pneumococcal Transmission and Disease In Silico: A Microsimulation Model of the Indirect Effects of Vaccination 
PLoS ONE  2013;8(2):e56079.
The degree and time frame of indirect effects of vaccination (serotype replacement and herd immunity) are key determinants in assessing the net effectiveness of vaccination with pneumococcal conjugate vaccines (PCV) in control of pneumococcal disease. Using modelling, we aimed to quantify these effects and their dependence on coverage of vaccination and the vaccine's efficacy against susceptibility to pneumococcal carriage.
Methods and Findings
We constructed an individual-based simulation model that explores the effects of large-scale PCV programmes and applied it in a developed country setting (Finland). A population structure with transmission of carriage taking place within relevant mixing groups (families, day care groups, schools and neighbourhoods) was considered in order to properly assess the dependency of herd immunity on coverage of vaccination and vaccine efficacy against carriage. Issues regarding potential serotype replacement were addressed by employing a novel competition structure between multiple pneumococcal serotypes. Model parameters were calibrated from pre-vaccination data about the age-specific carriage prevalence and serotype distribution. The model predicts that elimination of vaccine-type carriage and disease among those vaccinated and, due to a substantial herd effect, also among the general population takes place within 5–10 years since the onset of a PCV programme with high (90%) coverage of vaccination and moderate (50%) vaccine efficacy against acquisition of carriage. A near-complete replacement of vaccine-type carriage by non-vaccine-type carriage occurs within the same time frame.
The changed patterns in pneumococcal carriage after PCV vaccination predicted by the model are unequivocal. The overall effect on disease incidence depends crucially on the magnitude of age- and serotype-specific case-to-carrier ratios of the remaining serotypes relative to those of the vaccine types. Thus the availability of reliable data on the incidence of both pneumococcal carriage and disease is essential in assessing the net effectiveness of PCV vaccination in a given epidemiological setting.
PMCID: PMC3566073  PMID: 23457504
6.  Between-Strain Competition in Acquisition and Clearance of Pneumococcal Carriage—Epidemiologic Evidence From a Longitudinal Study of Day-Care Children 
American Journal of Epidemiology  2009;171(2):169-176.
The state of pneumococcal carriage—that is, pneumococcal colonization in the nasopharynx of healthy persons—represents a reservoir for the spread of pneumococci among individuals. In light of the introduction of new pneumococcal conjugate vaccines, further knowledge on the dynamics of pneumococcal carriage is important. Different serotypes (strains) of pneumococcus are known to compete with each other in colonizing human hosts. Understanding the strength and mode of between-serotype competition is important because of its implications for vaccine-induced changes in the ecology of pneumococcal carriage. Competition may work through reduced acquisition of new serotypes, due to concurrent carriage in the individual, or through enhanced clearance of serotypes in carriers who harbor more than 1 serotype simultaneously. The authors employed longitudinal data (1999–2001) on pneumococcal carriage in Danish day-care children to analyze between-serotype competition. The data included observations of carriage in children who had not been vaccinated against pneumococcus, and the level of pneumococcal antibiotic resistance and antibiotic usage in the community was very low. Clearance of any single serotype was not affected by simultaneous carriage of other serotypes. In contrast, acquisition of other serotypes in already-colonized hosts was weak (relative rate of acquisition = 0.09, 95% credible interval: 0.05, 0.15).
PMCID: PMC2800239  PMID: 19969530
child; day care; disease reservoirs; longitudinal studies; models, statistical; Streptococcus pneumoniae
7.  Outbreaks of Streptococcus pneumoniae carriage in day care cohorts in Finland – implications for elimination of transmission 
Day care centre (DCC) attendees play a central role in maintaining the circulation of Streptococcus pneumoniae (pneumococcus) in the population. Exposure within families and within DCCs are the main risk factors for colonisation with pneumococcal serotypes in DCC attendees.
Transmission of serotype specific carriage was analysed with a continuous time event history model, based on longitudinal data from day care attendees and their family members. Rates of acquisition, conditional on exposure, were estimated in a Bayesian framework utilising latent processes of carriage. To ensure a correct level of exposure, non-participating day care attendees and their family members were included in the analysis. Posterior predictive simulations were used to quantify transmission patterns within day care cohorts, to estimate the basic reproduction number for pneumococcal carriage in a population of day care cohorts, and to assess the critical vaccine efficacy against carriage to eliminate pneumococcal transmission.
The model, validated by posterior predictive sampling, was successful in capturing the strong temporal clustering of pneumococcal serotypes in the day care cohorts. In average 2.7 new outbreaks of pneumococcal carriage initiate in a day care cohort each month. While 39% of outbreaks were of size one, the mean outbreak size was 7.6 individuals and the mean length of an outbreak was 2.8 months. The role of families in creating and maintaining transmission was minimal, as only 10% of acquisitions in day care attendees were from family members. Considering a population of day care cohorts, a child-to-child basic reproduction number was estimated as 1.4 and the critical vaccine efficacy against acquisition of carriage as 0.3.
Pneumococcal transmission occurs in serotype specific outbreaks of carriage, driven by within-day-care transmission and between-serotype competition. An amplifying effect of the day care cohorts enhances the spread of pneumococcal serotypes within the population. The effect of vaccination, in addition to reducing susceptibility to pneumococcal carriage in the vaccinated, induces a herd effect, thus creating a counter-effect to the amplifying effect of the cohort. Consequently, the critical vaccine efficacy against carriage, required for elimination of transmission, is relatively low. Use of pneumococcal conjugate vaccines is expected to induce a notable herd protection against pneumococcal disease.
PMCID: PMC2717096  PMID: 19558701
8.  Clustering of serotypes in a longitudinal study of Streptococcus pneumoniae carriage in three day care centres 
Streptococcus pneumoniae (pneumococcus) causes a wide range of clinical manifestations that together constitute a major burden of disease worldwide. The main route of pneumococcal transmission is through asymptomatic colonisation of the nasopharynx. Studies of transmission are currently of general interest because of the impact of the new conjugate-polysaccharide vaccines on nasopharyngeal colonisation (carriage). Here we report the first longitudinal study of pneumococcal carriage that records serotype specific exposure to pneumococci simultaneously within the two most important mixing groups, families and day care facilities.
We followed attendees (N = 59) with their family members (N = 117) and the employees (N = 37) in three Finnish day care centres for 9 months with monthly sampling of nasopharyngeal carriage. Pneumococci were cultured, identified and serotyped by standard methods.
Children in day care constitute a core group of pneumococcal carriage: of the 36 acquisitions of carriage with documented exposure to homologous pneumococci, the attendee had been exposed in her/his day care centre in 35 cases and in the family in 9 cases. Day care children introduce pneumococci to the family: 66% of acquisitions of a new serotype in a family were associated with simultaneous or previous carriage of the same type in the child attending day care. Consequently, pneumococcal transmission was found to take place as micro-epidemics driven by the day care centres. Each of the three day care centres was dominated by a serotype of its own, accounting for 100% of the isolates of that serotype among all samples from the day care attendees.
The transmission of pneumococci is more intense within than across clusters defined by day care facilities. The ensuing micro-epidemic behaviour enhances pneumococcal transmission.
PMCID: PMC2639357  PMID: 19116005
9.  Social Contacts and Mixing Patterns Relevant to the Spread of Infectious Diseases 
PLoS Medicine  2008;5(3):e74.
Mathematical modelling of infectious diseases transmitted by the respiratory or close-contact route (e.g., pandemic influenza) is increasingly being used to determine the impact of possible interventions. Although mixing patterns are known to be crucial determinants for model outcome, researchers often rely on a priori contact assumptions with little or no empirical basis. We conducted a population-based prospective survey of mixing patterns in eight European countries using a common paper-diary methodology.
Methods and Findings
7,290 participants recorded characteristics of 97,904 contacts with different individuals during one day, including age, sex, location, duration, frequency, and occurrence of physical contact. We found that mixing patterns and contact characteristics were remarkably similar across different European countries. Contact patterns were highly assortative with age: schoolchildren and young adults in particular tended to mix with people of the same age. Contacts lasting at least one hour or occurring on a daily basis mostly involved physical contact, while short duration and infrequent contacts tended to be nonphysical. Contacts at home, school, or leisure were more likely to be physical than contacts at the workplace or while travelling. Preliminary modelling indicates that 5- to 19-year-olds are expected to suffer the highest incidence during the initial epidemic phase of an emerging infection transmitted through social contacts measured here when the population is completely susceptible.
To our knowledge, our study provides the first large-scale quantitative approach to contact patterns relevant for infections transmitted by the respiratory or close-contact route, and the results should lead to improved parameterisation of mathematical models used to design control strategies.
Surveying 7,290 participants in eight European countries, Joël Mossong and colleagues determine patterns of person-to-person contact relevant to controlling pathogens spread by respiratory or close-contact routes.
Editors' Summary
To understand and predict the impact of infectious disease, researchers often develop mathematical models. These computer simulations of hypothetical scenarios help policymakers and others to anticipate possible patterns and consequences of the emergence of diseases, and to develop interventions to curb disease spread. Whether to prepare for an outbreak of infectious disease or to control an existing outbreak, models can help researchers and policy makers decide how to intervene. For example, they may decide to develop or stockpile vaccines or antibiotics, fund vaccination or screening programs, or mount health promotion campaigns to help citizens minimize their exposure to the infectious agent (e.g., handwashing, travel restrictions, or school closures).
Respiratory infections, including the common cold, flu, and pneumonia, are some of the most prevalent infections in the world. Much work has gone into modeling how many people would be affected by respiratory diseases under various conditions and what can be done to limit the consequences.
Why Was This Study Done?
Mathematical models have tended to use contact rates (the number of other people that a person encounters per day) as one of their main elements in predicting the outcomes of epidemics. In the past, contact rates were not based on direct observations, but were assumed to follow a certain pattern and calibrated against other indirect data sources such as serological or case notification data. This study aimed to estimate contact rates directly by asking people who they have met during the course of one day. This allowed the researchers to study in more detail different patterns of contacts, such as those between different groups of people (such as age groups) and in different social settings. This is particularly important for respiratory diseases, which are spread through the air and by close contact with an infected individual or surface.
What Did the Researchers Do and Find?
The researchers wanted to examine the social contacts that people have in order to better understand how respiratory infections might spread. They recruited 7,290 people from eight European countries (Belgium, Germany, Finland, Great Britain, Italy, Luxembourg, The Netherlands, and Poland) to participate in their study. They asked the participants to fill out a diary that documented their physical and nonphysical contacts for a single day. Physical contacts included interactions such as a kiss or a handshake. Nonphysical contacts were situations such as a two-way conversation without skin-to-skin contact. Participants detailed the location and duration of each contact. Diaries also contained basic demographic information about the participant and the contact.
They found that these 7,290 participants had 97,904 contacts during the study, which averaged to 13.4 contacts per day per person. There was a great deal of diversity among the contacts, which challenges the idea that contact rates alone provide a complete picture of transmission dynamics. The researchers identified varied types of contacts, duration of contacts, and mixing patterns. For example, children had more contacts than adults, and those living in larger households had more contacts. Weekdays resulted in more daily contacts than Sundays. More intense contacts (of longer duration or more frequent) tended to be physical. Approximately 70% of contacts made on a daily basis lasted longer than an hour, whereas three-quarters of contacts with people who were not previously known lasted less than 15 minutes. While mixing patterns were very similar across the eight countries, people of the same age tended to mix with each other.
Analyzing these contact patterns and applying mathematical and statistical techniques, the researchers created a model of the initial phase of a hypothetical respiratory infection epidemic. This model suggests that 5- to 19-year-olds will suffer the highest burden of respiratory infection during an initial spread. The high incidence of infection among school-aged children in the model results from these children having a large number of contacts compared to other groups and tending to make contacts within their own age group.
What Do These Findings Mean?
This work provides insight about contacts that can be supplemental to traditional measurements such as contact rates, which are usually generated from household or workplace size and transportation statistics. Incorporating contact patterns into the model allowed for a deeper understanding of the transmission patterns of a hypothetical respiratory epidemic among a susceptible population. Understanding the patterning of social contacts—between and within groups, and in different social settings—shows how diverse contacts and mixing between individuals really are. Physical exposure to an infectious agent, the authors conclude, is best modeled by taking into account the social network of close contacts and its patterning.
Additional Information.
Please access these Web sites via the online version of this summary at doi:10.1371/journal.pmed.0050074..
Wikipedia has technical discussions on the assumptions used in mathematical models of epidemiology (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Plans for pandemic influenza are explained for the Government of Canada, the United Kingdom's Health Protection Agency, and the United States Department of Health and Human Services
PMCID: PMC2270306  PMID: 18366252
10.  Invasiveness of Serotypes and Clones of Streptococcus pneumoniae among Children in Finland  
Infection and Immunity  2005;73(1):431-435.
Streptococcus pneumoniae (the pneumococcus) causes diseases from otitis media to life-threatening invasive infection. The species is extremely antigenically and clonally diverse. We wished to determine odds ratios (ORs) for serotypes and clones of S. pneumoniae that cause invasive disease in Finland. A total of 224 isolates of S. pneumoniae from cases of invasive disease in children <2 years of age in Finland between 1995 and 1999 were serotyped, and sequence types (STs) were determined by multilocus sequence typing. These STs were compared with a previously published carriage data set. STs from invasive disease were significantly less diverse than those from carriage (invasive disease, 0.038 ± 0.01; carriage, 0.019 ± 0.005). The ORs of serotypes 14, 18C, 19A, and 6B were significantly greater than 1, indicating association with invasive disease. The ORs of 6A and 11A were significantly less than 1. The difference between 6A and 6B is significant, which suggests that relatively subtle changes in the capsule may have a dramatic effect upon disease potential. We found that ST 156, the Spain9V-3 clone which mainly expressed serotype 14 in Finland, is strongly associated with invasive disease (OR, 10.1; 95% confidence interval, 1.3 to 79.5). Significant associations with invasive disease were also detected for STs 482, 191, 124, and 138, and associations with carriage were detected for STs 485 and 62. These results demonstrate the invasive phenotype of the serotype 14 variant of the Spain9V-3 clone and differences between members of the same serogroup in invasive disease potential.
PMCID: PMC538975  PMID: 15618181
11.  Ability of Pneumococcal Serotypes and Clones To Cause Acute Otitis Media: Implications for the Prevention of Otitis Media by Conjugate Vaccines  
Infection and Immunity  2004;72(1):76-81.
The relative abilities of pneumococcal serotypes and strains (clones) to cause acute otitis media (AOM) were investigated by comparing the serotypes and genotypes of pneumococci recovered from cases of AOM (n = 149) in children <2 years of age with those from nasopharyngeal carriage (n = 288) in age-matched controls from the same region. The odds ratio (OR) for association of pooled vaccine serotypes with AOM was found to be slightly elevated over unity, although this was not significantly different from that of pooled nonvaccine or vaccine-related serotypes. Comparing individual serotypes, 19F and 23F had 2- to 2.5-fold higher ORs, although these were not markedly different from the ORs of nonvaccine serotypes. None of the major clones had an OR that was significantly greater than the average, and the differences in ORs among serotypes and clones were much less than those for invasive disease, suggesting little variation in their ability to cause AOM. We conclude that serotype replacement may reduce the long-term efficacy of these vaccines against AOM.
PMCID: PMC343969  PMID: 14688083

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