Publications by authors named "Michiel van Boven"

61 Publications

High infection secondary attack rates of SARS-CoV-2 in Dutch households revealed by dense sampling.

Clin Infect Dis 2021 Apr 2. Epub 2021 Apr 2.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

Background: Indoor environments are considered one of the main settings for transmission of SARS-CoV-2. Households in particular represent a close-contact environment with high probability of transmission between persons of different ages and with different roles in society.

Methods: Complete households with a laboratory-confirmed SARS-CoV-2 positive case in the Netherlands (March-May 2020) were included. At least three home visits were performed during 4-6 week of follow-up, collecting naso- and oropharyngeal swabs, oral fluid, feces and blood samples for molecular and serological analyses of all household members. Symptoms were recorded from two weeks before the first visit through to the final visit. Infection secondary attack rates (SAR) were estimated with logistic regression. A transmission model was used to assess transmission routes in the household.

Results: A total of 55 households with 187 household contacts were included. In 17 households no transmission took place, and in 11 households all persons were infected. Estimated infection SARs were high, ranging from 35% (95%CI: 24%-46%) in children to 51% (95%CI: 39%-63%) in adults. Estimated transmission rates in the household were high, with reduced susceptibility of children compared to adolescents and adults (0.67; 95%CI: 0.40-1.1).

Conclusion: Estimated infection SARs were higher than reported in earlier household studies, presumably owing to our dense sampling protocol. Children were shown to be less susceptible than adults, but the estimated infection SAR in children was still high. Our results reinforce the role of households as one of the main multipliers of SARS-CoV-2 infection in the population.
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http://dx.doi.org/10.1093/cid/ciab237DOI Listing
April 2021

Associations between measures of social distancing and SARS-CoV-2 seropositivity: a nationwide population-based study in the Netherlands.

Clin Infect Dis 2021 Mar 27. Epub 2021 Mar 27.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan, MA Bilthoven, the Netherlands.

This large nationwide population-based seroepidemiological study provides evidence on the effectiveness of physical distancing (>1.5m) and indoor group size reductions on SARS-CoV-2 infection. Additionally, young adults may play an important role in viral spread, opposed to children up until 12 years of age with whom close contact is permitted.
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http://dx.doi.org/10.1093/cid/ciab264DOI Listing
March 2021

Persistence of antibodies to SARS-CoV-2 in relation to symptoms in a nationwide prospective study.

Clin Infect Dis 2021 Feb 24. Epub 2021 Feb 24.

Centre for Immunology of Infectious Diseases and Vaccines , National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

Background: Assessing the duration of immunity following infection with SARS-CoV-2 is a first priority to gauge the degree of protection following infection. Such knowledge is lacking especially in the general population. Here, we studied changes in Immunoglobulin (Ig) isotype seropositivity and IgG binding strength of SARS-CoV-2-specific serum antibodies up to 7 months following onset of symptoms in a nationwide sample.

Methods: Participants from a prospective representative serological study in the Netherlands were included based on IgG seroconversion to the Spike S1 protein of SARS-CoV-2 (N=353), with up to three consecutive serum samples per seroconverted participant (N=738). IgM, IgA and IgG antibody concentrations to S1, and increase in IgG avidity in relation to time since onset of disease symptoms, were determined.

Results: While SARS-CoV-2-specific IgM and IgA antibodies declined rapidly after the first month post onset of disease, specific IgG was still present in 92% (95% confidence interval, CI, 89-95) of the participants after 7 months. The estimated 2-fold decrease of IgG antibodies was 158 days (95% CI 136-189). Concentrations sustained better in persons reporting significant symptoms compared to asymptomatic persons or those with mild upper respiratory complaints only. Similarly, avidity of IgG antibodies for symptomatic persons showed a steeper increase over time compared with persons with mild or no symptoms (p=0.022).

Conclusion: SARS-CoV-2-specific IgG antibodies persist and show increasing avidity over time, indicative of underlying immune maturation. These data support development of immune memory against SARS-CoV-2 providing insight into protection of the general unvaccinated part of the population.
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http://dx.doi.org/10.1093/cid/ciab172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929058PMC
February 2021

Nationwide seroprevalence of SARS-CoV-2 and identification of risk factors in the general population of the Netherlands during the first epidemic wave.

J Epidemiol Community Health 2020 Nov 28. Epub 2020 Nov 28.

Centre for Infectious Disease Control, RIVM, Bilthoven, Netherlands

Background: We aimed to detect SARS-CoV-2 serum antibodies in the general population of the Netherlands and identify risk factors for seropositivity amidst the first COVID-19 epidemic wave.

Methods: Participants (n=3207, aged 2-90 years), enrolled from a previously established nationwide serosurveillance study, provided a self-collected fingerstick blood sample and completed a questionnaire (median inclusion date 3 April 2020). IgG antibodies targeted against the spike S1-protein of SARS-CoV-2 were quantified using a validated multiplex-immunoassay. Seroprevalence was estimated controlling for survey design, individual pre-pandemic concentration, and test performance. Random-effects logistic regression identified risk factors for seropositivity.

Results: Overall seroprevalence in the Netherlands was 2.8% (95% CI 2.1 to 3.7), with no differences between sexes or ethnic background, and regionally ranging between 1.3 and 4.0%. Estimates were highest among 18-39 year-olds (4.9%), and lowest in children 2-17 years (1.7%). Multivariable analysis revealed that persons taking immunosuppressants and those from the Orthodox-Reformed Protestant community had over four times higher odds of being seropositive compared to others. Anosmia/ageusia was the most discriminative symptom between seropositive (53%) and seronegative persons (4%, p<0.0001). Antibody concentrations in seropositive persons were significantly higher in those with fever or dyspnoea in contrast to those without (p=0.01 and p=0.04, respectively).

Conclusions: In the midst of the first epidemic wave, 2.8% of the Dutch population was estimated to be infected with SARS-CoV-2, that is, 30 times higher than reported. This study identified independent groups with increased odds for seropositivity that may require specific surveillance measures to guide future protective interventions internationally, including vaccination once available.
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http://dx.doi.org/10.1136/jech-2020-215678DOI Listing
November 2020

Estimating Transmission Parameters for Respiratory Syncytial Virus and Predicting the Impact of Maternal and Pediatric Vaccination.

J Infect Dis 2020 10;222(Suppl 7):S688-S694

Centre for Infectious Disease Control, National institute for Public Health and the Environment, Bilthoven, the Netherlands.

Background: Respiratory syncytial virus (RSV) is a leading cause of respiratory tract illness in young children and a major cause of hospital admissions globally.

Methods: Here we fit age-structured transmission models with immunity propagation to data from the Netherlands (2012-2017). Data included nationwide hospitalizations with confirmed RSV, general practitioner (GP) data on attendance for care from acute respiratory infection, and virological testing of acute respiratory infections at the GP. The transmission models, equipped with key parameter estimates, were used to predict the impact of maternal and pediatric vaccination.

Results: Estimates of the basic reproduction number were generally high (R0 > 10 in scenarios with high statistical support), while susceptibility was estimated to be low in nonelderly adults (<10% in persons 20-64 years) and was higher in older adults (≥65 years). Scenario analyses predicted that maternal vaccination reduces the incidence of infection in vulnerable infants (<1 year) and shifts the age of first infection from infants to young children.

Conclusions: Pediatric vaccination is expected to reduce the incidence of infection in infants and young children (0-5 years), slightly increase incidence in 5 to 9-year-old children, and have minor indirect benefits.
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http://dx.doi.org/10.1093/infdis/jiaa424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751153PMC
October 2020

Respiratory Syncytial Virus-Associated Hospital Admissions in Children Younger Than 5 Years in 7 European Countries Using Routinely Collected Datasets.

J Infect Dis 2020 10;222(Suppl 7):S599-S605

Centre for Global Health, University of Edinburgh, Edinburgh, United Kingdom.

Background: Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infection (RTI) in young children. Registries provide opportunities to explore RSV epidemiology and burden.

Methods: We explored routinely collected hospital data on RSV in children aged < 5 years in 7 European countries. We compare RSV-associated admission rates, age, seasonality, and time trends between countries.

Results: We found similar age distributions of RSV-associated hospital admissions in each country, with the highest burden in children < 1 years old and peak at age 1 month. Average annual rates of RTI admission were 41.3-112.0 per 1000 children aged < 1 year and 8.6-22.3 per 1000 children aged < 1 year. In children aged < 5 years, 57%-72% of RTI admissions with specified causal pathogen were coded as RSV, with 62%-87% of pathogen-coded admissions in children < 1 year coded as RSV.

Conclusions: Our results demonstrate the benefits and limitations of using linked routinely collected data to explore epidemiology and burden of RSV. Our future work will use these data to generate estimates of RSV burden using time-series modelling methodology, to inform policymaking and regulatory decisions regarding RSV immunization strategy and monitor the impact of future vaccines.
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http://dx.doi.org/10.1093/infdis/jiaa360DOI Listing
October 2020

Impact of delays on effectiveness of contact tracing strategies for COVID-19: a modelling study.

Lancet Public Health 2020 08 16;5(8):e452-e459. Epub 2020 Jul 16.

Julius Center for Health Sciences and Primary Care, Utrecht University, Utrecht, Netherlands; Department of Medical Microbiology, Utrecht University, Utrecht, Netherlands.

Background: In countries with declining numbers of confirmed cases of COVID-19, lockdown measures are gradually being lifted. However, even if most physical distancing measures are continued, other public health measures will be needed to control the epidemic. Contact tracing via conventional methods or mobile app technology is central to control strategies during de-escalation of physical distancing. We aimed to identify key factors for a contact tracing strategy to be successful.

Methods: We evaluated the impact of timeliness and completeness in various steps of a contact tracing strategy using a stochastic mathematical model with explicit time delays between time of infection and symptom onset, and between symptom onset, diagnosis by testing, and isolation (testing delay). The model also includes tracing of close contacts (eg, household members) and casual contacts, followed by testing regardless of symptoms and isolation if testing positive, with different tracing delays and coverages. We computed effective reproduction numbers of a contact tracing strategy (R) for a population with physical distancing measures and various scenarios for isolation of index cases and tracing and quarantine of their contacts.

Findings: For the most optimistic scenario (testing and tracing delays of 0 days and tracing coverage of 100%), and assuming that around 40% of transmissions occur before symptom onset, the model predicts that the estimated effective reproduction number of 1·2 (with physical distancing only) will be reduced to 0·8 (95% CI 0·7-0·9) by adding contact tracing. The model also shows that a similar reduction can be achieved when testing and tracing coverage is reduced to 80% (R 0·8, 95% CI 0·7-1·0). A testing delay of more than 1 day requires the tracing delay to be at most 1 day or tracing coverage to be at least 80% to keep R below 1. With a testing delay of 3 days or longer, even the most efficient strategy cannot reach R values below 1. The effect of minimising tracing delay (eg, with app-based technology) declines with decreasing coverage of app use, but app-based tracing alone remains more effective than conventional tracing alone even with 20% coverage, reducing the reproduction number by 17·6% compared with 2·5%. The proportion of onward transmissions per index case that can be prevented depends on testing and tracing delays, and given a 0-day tracing delay, ranges from up to 79·9% with a 0-day testing delay to 41·8% with a 3-day testing delay and 4·9% with a 7-day testing delay.

Interpretation: In our model, minimising testing delay had the largest impact on reducing onward transmissions. Optimising testing and tracing coverage and minimising tracing delays, for instance with app-based technology, further enhanced contact tracing effectiveness, with the potential to prevent up to 80% of all transmissions. Access to testing should therefore be optimised, and mobile app technology might reduce delays in the contact tracing process and optimise contact tracing coverage.

Funding: ZonMw, Fundação para a Ciência e a Tecnologia, and EU Horizon 2020 RECOVER.
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http://dx.doi.org/10.1016/S2468-2667(20)30157-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365652PMC
August 2020

Trade-off between local transmission and long-range dispersal drives infectious disease outbreak size in spatially structured populations.

PLoS Comput Biol 2020 07 6;16(7):e1008009. Epub 2020 Jul 6.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, The Netherlands.

Transmission of infectious diseases between immobile hosts (e.g., plants, farms) is strongly dependent on the spatial distribution of hosts and the distance-dependent probability of transmission. As the interplay between these factors is poorly understood, we use spatial process and transmission modelling to investigate how epidemic size is shaped by host clustering and spatial range of transmission. We find that for a given degree of clustering and individual-level infectivity, the probability that an epidemic occurs after an introduction is generally higher if transmission is predominantly local. However, local transmission also impedes transfer of the infection to new clusters. A consequence is that the total number of infections is maximal if the range of transmission is intermediate. In highly clustered populations, the infection dynamics is strongly determined by the probability of transmission between clusters of hosts, whereby local clusters act as multiplier of infection. We show that in such populations, a metapopulation model sometimes provides a good approximation of the total epidemic size, using probabilities of local extinction, the final size of infections in local clusters, and probabilities of cluster-to-cluster transmission. As a real-world example we analyse the case of avian influenza transmission between poultry farms in the Netherlands.
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http://dx.doi.org/10.1371/journal.pcbi.1008009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365471PMC
July 2020

Short- and long-term impact of vaccination against cytomegalovirus: a modeling study.

BMC Med 2020 07 2;18(1):174. Epub 2020 Jul 2.

Center for Infectious Disease Control, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.

Background: Infection with cytomegalovirus (CMV) is highly prevalent worldwide and can cause severe disease in immunocompromised persons and congenitally infected infants. The disease burden caused by congenital CMV infection is high, especially in resource-limited countries. Vaccines are currently under development for various target groups.

Methods: We evaluated the impact of vaccination strategies and hygiene intervention using transmission models. Model parameters were estimated from a cross-sectional serological population study (n=5179) and a retrospective birth cohort (n=31,484), providing information on the age- and sex-specific CMV prevalence and on the birth prevalence of congenital CMV (cCMV).

Results: The analyses show that vertical transmission and infectious reactivation are the main drivers of transmission. Vaccination strategies aimed at reducing transmission from mother to child (vaccinating pregnant women or women of reproductive age) can yield substantial reductions of cCMV in 20 years (31.7-71.4% if 70% of women are effectively vaccinated). Alternatively, hygiene intervention aimed at preventing CMV infection and re-infection of women of reproductive age from young children is expected to reduce cCMV by less than 2%. The effects of large-scale vaccination on CMV prevalence can be substantial, owing to the moderate transmissibility of CMV at the population level. However, as CMV causes lifelong infection, the timescale on which reductions in CMV prevalence are expected is in the order of several decades. Elimination of CMV infection in the long run is only feasible for a vaccine with a long duration of protection and high vaccination coverage.

Conclusions: Vaccination is an effective intervention to reduce the birth prevalence of cCMV. Population-level reductions in CMV prevalence can only be achieved on a long timescale. Our results stress the value of vaccinating pregnant women and women of childbearing age and provide support for the development of CMV vaccines and early planning of vaccination scenarios and rollouts.
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http://dx.doi.org/10.1186/s12916-020-01629-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331215PMC
July 2020

High varicella zoster virus susceptibility in Caribbean island populations: Implications for vaccination.

Int J Infect Dis 2020 May 26;94:16-24. Epub 2020 Feb 26.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan 9, 3720 MA Bilthoven, The Netherlands. Electronic address:

Objectives: Varicella zoster virus (VZV) infection is reported regularly among adolescents and adults in Caribbean island populations. The disease more often runs a severe course among these populations, causing a substantial burden. The aim of this sero-epidemiological study was to obtain an insight into VZV susceptibility and its determinants in island populations of the Caribbean Netherlands (CN).

Methods: Participants from Bonaire, St. Eustatius, and Saba (n = 1829, aged 0-90 years) donated a blood sample and completed a questionnaire. VZV-specific IgG antibodies were determined using a bead-based multiplex immunoassay. Risk factors were analysed using a logistic regression model.

Results: Overall seroprevalence in CN was 78%, being lowest on St. Eustatius (73%) and highest on Bonaire and Saba (79%). Seropositivity increased gradually with age, with 60% and 80% at ages 10 years and 30 years, respectively, and ranging between 80% and 90% thereafter. Higher odds for VZV seronegativity were seen among persons who were born in CN or had resided there since early childhood, and among single-person households.

Conclusions: VZV susceptibility is relatively high among adolescents and adults in CN. In order to reduce the burden of VZV-related disease in these populations, routine varicella vaccination is recommended. As data are scarce, the study findings can serve as a blueprint for the epidemiology in tropical regions.
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http://dx.doi.org/10.1016/j.ijid.2020.02.047DOI Listing
May 2020

Case of seasonal reassortant A(H1N2) influenza virus infection, the Netherlands, March 2018.

Euro Surveill 2018 04;23(15)

Department Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands.

A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general practitioner participating in the routine sentinel surveillance of ILI in the Netherlands. The patient recovered fully. Further epidemiological and virological investigation did not reveal additional cases.
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http://dx.doi.org/10.2807/1560-7917.ES.2018.23.15.18-00160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836195PMC
April 2018

Infectious reactivation of cytomegalovirus explaining age- and sex-specific patterns of seroprevalence.

PLoS Comput Biol 2017 Sep 26;13(9):e1005719. Epub 2017 Sep 26.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

Human cytomegalovirus (CMV) is a herpes virus with poorly understood transmission dynamics. Person-to-person transmission is thought to occur primarily through transfer of saliva or urine, but no quantitative estimates are available for the contribution of different infection routes. Using data from a large population-based serological study (n = 5,179), we provide quantitative estimates of key epidemiological parameters, including the transmissibility of primary infection, reactivation, and re-infection. Mixture models are fitted to age- and sex-specific antibody response data from the Netherlands, showing that the data can be described by a model with three distributions of antibody measurements, i.e. uninfected, infected, and infected with increased antibody concentration. Estimates of seroprevalence increase gradually with age, such that at 80 years 73% (95%CrI: 64%-78%) of females and 62% (95%CrI: 55%-68%) of males are infected, while 57% (95%CrI: 47%-67%) of females and 37% (95%CrI: 28%-46%) of males have increased antibody concentration. Merging the statistical analyses with transmission models, we find that models with infectious reactivation (i.e. reactivation that can lead to the virus being transmitted to a novel host) fit the data significantly better than models without infectious reactivation. Estimated reactivation rates increase from low values in children to 2%-4% per year in women older than 50 years. The results advance a hypothesis in which transmission from adults after infectious reactivation is a key driver of transmission. We discuss the implications for control strategies aimed at reducing CMV infection in vulnerable groups.
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http://dx.doi.org/10.1371/journal.pcbi.1005719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630159PMC
September 2017

Variation in loss of immunity shapes influenza epidemics and the impact of vaccination.

BMC Infect Dis 2017 09 19;17(1):632. Epub 2017 Sep 19.

National Institute for Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, Bilthoven, 3721 MA, The Netherlands.

Background: Protective antibody immunity against the influenza A virus wanes in 2-7 years due to antigenic drift of the virus' surface proteins. The duration of immune protection is highly variable because antigenic evolution of the virus is irregular. Currently, the variable nature of the duration of immunity has had little attention in analyses of the impact of vaccination, including cost-effectiveness studies.

Methods: We developed a range of mathematical transmission models to investigate the effect of variable duration of immunity on the size of seasonal epidemics. The models range from simple conceptual to more realistic, by distinguishing between infection- versus vaccination-induced immunity, by inclusion of primary vaccine failure, by assuming a leaky vaccine, and by the inclusion of age-dependent contact patterns.

Results: We show that annual variation in the duration of immunity causes large variation in the size of epidemics, and affects the effectiveness of vaccination. Accumulation of susceptible individuals in one or more mild seasons results in a disproportionately large outbreak in a subsequent season. Importantly, variation in the duration of immunity increases the average infection attack rate when the vaccination coverage is around the outbreak threshold. Specifically, in a tailored age-stratified model with a realistic reproduction number (R = 1.4) and vaccination coverage of 25%, we find that the attack rate in unvaccinated children (<10 years old) is negligible if the duration of immunity is constant, while on average 2.8% (2.5-97.5% percentiles: 1.8-4.1%) of the children are infected if the duration of immunity is variable. These findings stem from the buildup of susceptibility over multiple seasons by waning of immunity, and the nonlinear relation between susceptibility and infection attack rates.

Conclusions: The models illustrate that variation in the duration of immunity impacts the long-term effectiveness of vaccination, and that vaccine effectiveness cannot be judged for each year in isolation. Our findings have implications for vaccination strategies that aim to maximize the vaccination coverage while extending the age range of persons eligible for vaccination.
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http://dx.doi.org/10.1186/s12879-017-2716-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606000PMC
September 2017

Heterosubtypic cross-reactivity of HA1 antibodies to influenza A, with emphasis on nonhuman subtypes (H5N1, H7N7, H9N2).

PLoS One 2017 17;12(7):e0181093. Epub 2017 Jul 17.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

Epidemics of influenza A vary greatly in size and age distribution of cases, and this variation is attributed to varying levels of pre-existing immunity. Recent studies have shown that antibody-mediated immune responses are more cross-reactive than previously believed, and shape patterns of humoral immunity to influenza A viruses over long periods. Here we quantify antibody responses to the hemagglutinin subunit 1 (HA1) across a range of subtypes using protein microarray analysis of cross-sectional serological surveys carried out in the Netherlands before and after the A/2009 (H1N1) pandemic. We find significant associations of responses, both within and between subtypes. Interestingly, substantial overall reactivity is observed to HA1 of avian H7N7 and H9N2 viruses. Seroprevalence of H7N7 correlates with antibody titers to A/1968 (H3N2), and is highest in persons born between 1954 and 1969. Seroprevalence of H9N2 is high across all ages, and correlates strongly with A/1957 (H2N2). This correlation is most pronounced in A/2009 (H1N1) infected persons born after 1968 who have never encountered A/1957 (H2N2)-like viruses. We conclude that heterosubtypic antibody cross-reactivity, both between human subtypes and between human and nonhuman subtypes, is common in the human population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181093PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513445PMC
September 2017

Space-time analysis of pneumonia hospitalisations in the Netherlands.

PLoS One 2017 13;12(7):e0180797. Epub 2017 Jul 13.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

Community acquired pneumonia is a major global public health problem. In the Netherlands there are 40,000-50,000 hospital admissions for pneumonia per year. In the large majority of these hospital admissions the etiologic agent is not determined and a real-time surveillance system is lacking. Localised and temporal increases in hospital admissions for pneumonia are therefore only detected retrospectively and the etiologic agents remain unknown. Here, we perform spatio-temporal analyses of pneumonia hospital admission data in the Netherlands. To this end, we scanned for spatial clusters on yearly and seasonal basis, and applied wavelet cluster analysis on the time series of five main regions. The pneumonia hospital admissions show strong clustering in space and time superimposed on a regular yearly cycle with high incidence in winter and low incidence in summer. Cluster analysis reveals a heterogeneous pattern, with most significant clusters occurring in the western, highly urbanised, and in the eastern, intensively farmed, part of the Netherlands. Quantitatively, the relative risk (RR) of the significant clusters for the age-standardised incidence varies from a minimum of 1.2 to a maximum of 2.2. We discuss possible underlying causes for the patterns observed, such as variations in air pollution.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509219PMC
September 2017

Different cross protection scopes of two avian influenza H5N1 vaccines against infection of layer chickens with a heterologous highly pathogenic virus.

Res Vet Sci 2017 Oct 8;114:143-152. Epub 2017 Apr 8.

Faculty of Veterinary Medicine, Department of Farm Animal Health, Utrecht University, Yalelaan 7, 3584 CL Utrecht, The Netherlands.

Avian influenza (AI) virus strains vary in antigenicity, and antigenic differences between circulating field virus and vaccine virus will affect the effectiveness of vaccination of poultry. Antigenic relatedness can be assessed by measuring serological cross-reactivity using haemagglutination inhibition (HI) tests. Our study aims to determine the relation between antigenic relatedness expressed by the Archetti-Horsfall ratio, and reduction of virus transmission of highly pathogenic H5N1 AI strains among vaccinated layers. Two vaccines were examined, derived from H5N1 AI virus strains A/Ck/WJava/Sukabumi/006/2008 and A/Ck/CJava/Karanganyar/051/2009. Transmission experiments were carried out in four vaccine and two control groups, with six sets of 16 specified pathogen free (SPF) layer chickens. Birds were vaccinated at 4weeks of age with one strain and challenge-infected with the homologous or heterologous strain at 8weeks of age. No transmission or virus shedding occurred in groups challenged with the homologous strain. In the group vaccinated with the Karanganyar strain, high cross-HI responses were observed, and no transmission of the Sukabumi strain occurred. However, in the group vaccinated with the Sukabumi strain, cross-HI titres were low, virus shedding was not reduced, and multiple transmissions to contact birds were observed. This study showed large differences in cross-protection of two vaccines based on two different highly pathogenic H5N1 virus strains. This implies that extrapolation of in vitro data to clinical protection and reduction of virus transmission might not be straightforward.
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http://dx.doi.org/10.1016/j.rvsc.2017.04.005DOI Listing
October 2017

An Evidence Synthesis Approach to Estimating the Proportion of Influenza Among Influenza-like Illness Patients.

Epidemiology 2017 07;28(4):484-491

From the Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

Background: Estimation of the national-level incidence of seasonal influenza is notoriously challenging. Surveillance of influenza-like illness is carried out in many countries using a variety of data sources, and several methods have been developed to estimate influenza incidence. Our aim was to obtain maximally informed estimates of the proportion of influenza-like illness that is true influenza using all available data.

Methods: We combined data on weekly general practice sentinel surveillance consultation rates for influenza-like illness, virologic testing of sampled patients with influenza-like illness, and positive laboratory tests for influenza and other pathogens, applying Bayesian evidence synthesis to estimate the positive predictive value (PPV) of influenza-like illness as a test for influenza virus infection. We estimated the weekly number of influenza-like illness consultations attributable to influenza for nine influenza seasons, and for four age groups.

Results: The estimated PPV for influenza in influenza-like illness patients was highest in the weeks surrounding seasonal peaks in influenza-like illness rates, dropping to near zero in between-peak periods. Overall, 14.1% (95% credible interval [CrI]: 13.5%, 14.8%) of influenza-like illness consultations were attributed to influenza infection; the estimated PPV was 50% (95% CrI: 48%, 53%) for the peak weeks and 5.8% during the summer periods.

Conclusions: The model quantifies the correspondence between influenza-like illness consultations and influenza at a weekly granularity. Even during peak periods, a substantial proportion of influenza-like illness-61%-was not attributed to influenza. The much lower proportion of influenza outside the peak periods reflects the greater circulation of other respiratory pathogens relative to influenza.
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http://dx.doi.org/10.1097/EDE.0000000000000646DOI Listing
July 2017

Estimation of age-specific rates of reactivation and immune boosting of the varicella zoster virus.

Epidemics 2017 06 22;19:1-12. Epub 2016 Nov 22.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. Electronic address:

Studies into the impact of vaccination against the varicella zoster virus (VZV) have increasingly focused on herpes zoster (HZ), which is believed to be increasing in vaccinated populations with decreasing infection pressure. This idea can be traced back to Hope-Simpson's hypothesis, in which a person's immune status determines the likelihood that he/she will develop HZ. Immunity decreases over time, and can be boosted by contact with a person experiencing varicella (exogenous boosting) or by a reactivation attempt of the virus (endogenous boosting). Here we use transmission models to estimate age-specific rates of reactivation and immune boosting, exogenous as well as endogenous, using zoster incidence data from the Netherlands (2002-2011, n=7026). The boosting and reactivation rates are estimated with splines, enabling these quantities to be optimally informed by the data. The analyses show that models with high levels of exogenous boosting and estimated or zero endogenous boosting, constant rate of loss of immunity, and reactivation rate increasing with age (to more than 5% per year in the elderly) give the best fit to the data. Estimates of the rates of immune boosting and reactivation are strongly correlated. This has important implications as these parameters determine the fraction of the population with waned immunity. We conclude that independent evidence on rates of immune boosting and reactivation in persons with waned immunity are needed to robustly predict the impact of varicella vaccination on the incidence of HZ.
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http://dx.doi.org/10.1016/j.epidem.2016.11.001DOI Listing
June 2017

Long-term adaptation of the influenza A virus by escaping cytotoxic T-cell recognition.

Sci Rep 2016 09 15;6:33334. Epub 2016 Sep 15.

National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

The evolutionary adaptation of the influenza A virus (IAV) to human antibodies is well characterised. Much less is known about the long-term evolution of cytotoxic T lymphocyte (CTL) epitopes, which are important antigens for clearance of infection. We construct an antigenic map of IAVs of all human subtypes using a compendium of 142 confirmed CTL epitopes, and show that IAV evolved gradually in the period 1932-2015, with infrequent antigenic jumps in the H3N2 subtype. Intriguingly, the number of CTL epitopes per virus decreases with more than one epitope per three years in the H3N2 subtype (from 84 epitopes per virus in 1968 to 64 in 2015), mostly attributed to the loss of HLA-B epitopes. We confirm these observations with epitope predictions. Our findings indicate that selection pressures imposed by CTL immunity shape the long-term evolution of IAV.
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http://dx.doi.org/10.1038/srep33334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024124PMC
September 2016

Global trends in vaccination coverage.

Lancet Glob Health 2016 10 25;4(10):e670-1. Epub 2016 Aug 25.

National Institute for Public Health and the Environment, 3720 BA Bilthoven, Netherlands.

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http://dx.doi.org/10.1016/S2214-109X(16)30185-1DOI Listing
October 2016

A Bivariate Mixture Model for Natural Antibody Levels to Human Papillomavirus Types 16 and 18: Baseline Estimates for Monitoring the Herd Effects of Immunization.

PLoS One 2016 18;11(8):e0161109. Epub 2016 Aug 18.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

Post-vaccine monitoring programs for human papillomavirus (HPV) have been introduced in many countries, but HPV serology is still an underutilized tool, partly owing to the weak antibody response to HPV infection. Changes in antibody levels among non-vaccinated individuals could be employed to monitor herd effects of immunization against HPV vaccine types 16 and 18, but inference requires an appropriate statistical model. The authors developed a four-component bivariate mixture model for jointly estimating vaccine-type seroprevalence from correlated antibody responses against HPV16 and -18 infections. This model takes account of the correlation between HPV16 and -18 antibody concentrations within subjects, caused e.g. by heterogeneity in exposure level and immune response. The model was fitted to HPV16 and -18 antibody concentrations as measured by a multiplex immunoassay in a large serological survey (3,875 females) carried out in the Netherlands in 2006/2007, before the introduction of mass immunization. Parameters were estimated by Bayesian analysis. We used the deviance information criterion for model selection; performance of the preferred model was assessed through simulation. Our analysis uncovered elevated antibody concentrations in doubly as compared to singly seropositive individuals, and a strong clustering of HPV16 and -18 seropositivity, particularly around the age of sexual debut. The bivariate model resulted in a more reliable classification of singly and doubly seropositive individuals than achieved by a combination of two univariate models, and suggested a higher pre-vaccine HPV16 seroprevalence than previously estimated. The bivariate mixture model provides valuable baseline estimates of vaccine-type seroprevalence and may prove useful in seroepidemiologic assessment of the herd effects of HPV vaccination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161109PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990197PMC
July 2017

Distribution of Health Effects and Cost-effectiveness of Varicella Vaccination are Shaped by the Impact on Herpes Zoster.

EBioMedicine 2015 Oct 8;2(10):1494-9. Epub 2015 Aug 8.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.

Introduction: Varicella zoster virus (VZV) is the etiological agent of varicella and herpes zoster (HZ). It has been hypothesised that immune boosting of latently infected persons by contact with varicella reduces the probability of HZ. If true, universal varicella vaccination may increase HZ incidence due to reduced VZV circulation. To inform decision-making, we conduct cost-effectiveness analyses of varicella vaccination, including effects on HZ.

Methods: Effects of varicella vaccination are simulated with a dynamic transmission model, parameterised with Dutch VZV seroprevalence and HZ incidence data, and linked to an economic model. We consider vaccination scenarios that differ by whether or not they include immune boosting, and reactivation of vaccine virus.

Results: Varicella incidence decreases after introduction of vaccination, while HZ incidence may increase or decrease depending on whether or not immune boosting is present. Without immune boosting, vaccination is expected to be cost-effective or even cost-saving. With immune boosting, vaccination at 95% coverage is not expected to be cost-effective, and may even cause net health losses.

Conclusions: Cost-effectiveness of varicella vaccination depends strongly on the impact on HZ and the economic time horizon. Our findings reveal ethical dilemmas as varicella vaccination may result in unequal distribution of health effects between generations.
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http://dx.doi.org/10.1016/j.ebiom.2015.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634630PMC
October 2015

Joint modelling of serological and hospitalization data reveals that high levels of pre-existing immunity and school holidays shaped the influenza A pandemic of 2009 in the Netherlands.

J R Soc Interface 2015 Feb;12(103)

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, PO Box 1, Bilthoven 3720AB, The Netherlands

Obtaining a quantitative understanding of the transmission dynamics of influenza A is important for predicting healthcare demand and assessing the likely impact of intervention measures. The pandemic of 2009 provides an ideal platform for developing integrative analyses as it has been studied intensively, and a wealth of data sources is available. Here, we analyse two complementary datasets in a disease transmission framework: cross-sectional serological surveys providing data on infection attack rates, and hospitalization data that convey information on the timing and duration of the pandemic. We estimate key epidemic determinants such as infection and hospitalization rates, and the impact of a school holiday. In contrast to previous approaches, our novel modelling of serological data with mixture distributions provides a probabilistic classification of individual samples (susceptible, immune and infected), propagating classification uncertainties to the transmission model and enabling serological classifications to be informed by hospitalization data. The analyses show that high levels of immunity among persons 20 years and older provide a consistent explanation of the skewed attack rates observed during the pandemic and yield precise estimates of the probability of hospitalization per infection (1-4 years: 0.00096 (95%CrI: 0.00078-0.0012); 5-19 years: 0.00036 (0.00031-0.0044); 20-64 years: 0.0015 (0.00091-0.0020); 65+ years: 0.0084 (0.0028-0.016)). The analyses suggest that in The Netherlands, the school holiday period reduced the number of infectious contacts between 5- and 9-year-old children substantially (estimated reduction: 54%; 95%CrI: 29-82%), thereby delaying the unfolding of the pandemic in The Netherlands by approximately a week.
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http://dx.doi.org/10.1098/rsif.2014.1244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305427PMC
February 2015

Immuno-epidemiological modeling of HIV-1 predicts high heritability of the set-point virus load, while selection for CTL escape dominates virulence evolution.

PLoS Comput Biol 2014 Dec 18;10(12):e1003899. Epub 2014 Dec 18.

Theoretical Biology and Bioinformatics, Universiteit Utrecht, Utrecht, The Netherlands.

It has been suggested that HIV-1 has evolved its set-point virus load to be optimized for transmission. Previous epidemiological models and studies into the heritability of set-point virus load confirm that this mode of adaptation within the human population is feasible. However, during the many cycles of replication between infection of a host and transmission to the next host, HIV-1 is under selection for escape from immune responses, and not transmission. Here we investigate with computational and mathematical models how these two levels of selection, within-host and between-host, are intertwined. We find that when the rate of immune escape is comparable to what has been observed in patients, immune selection within hosts is dominant over selection for transmission. Surprisingly, we do find high values for set-point virus load heritability, and argue that high heritability estimates can be caused by the 'footprints' left by differing hosts' immune systems on the virus.
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http://dx.doi.org/10.1371/journal.pcbi.1003899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270429PMC
December 2014

Discrimination of influenza infection (A/2009 H1N1) from prior exposure by antibody protein microarray analysis.

PLoS One 2014 18;9(11):e113021. Epub 2014 Nov 18.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

Reliable discrimination of recent influenza A infection from previous exposure using hemagglutination inhibition (HI) or virus neutralization tests is currently not feasible. This is due to low sensitivity of the tests and the interference of antibody responses generated by previous infections. Here we investigate the diagnostic characteristics of a newly developed antibody (HA1) protein microarray using data from cross-sectional serological studies carried out before and after the pandemic of 2009. The data are analysed by mixture models, providing a probabilistic classification of sera (susceptible, prior-exposed, recently infected). Estimated sensitivity and specificity for identifying A/2009 infections are low using HI (66% and 51%), and high when using A/2009 microarray data alone or together with A/1918 microarray data (96% and 95%). As a heuristic, a high A/2009 to A/1918 antibody ratio (>1.05) is indicative of recent infection, while a low ratio is indicative of a pre-existing response, even if the A/2009 titer is high. We conclude that highly sensitive and specific classification of individual sera is possible using the protein microarray, thereby enabling precise estimation of age-specific infection attack rates in the population even if sample sizes are small.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113021PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236143PMC
April 2016

Silent spread of highly pathogenic Avian Influenza H5N1 virus amongst vaccinated commercial layers.

Res Vet Sci 2014 Dec 19;97(3):637-41. Epub 2014 Sep 19.

Faculty of Veterinary Medicine, Department of Farm Animal Health, Utrecht University, Yalelaan 7, Utrecht 3584 CL, Netherlands.

The aim of this study was to determine whether a single vaccination of commercial layer type chickens with an inactivated vaccine containing highly pathogenic avian influenza virus strain H5N1 A/chicken/Legok/2003, carried out on the farm, was sufficient to protect against infection with the homologous virus strain. A transmission experiment was carried out with pairs of chicken of which one was inoculated with H5N1 virus and the other contact-exposed. Results showed that the majority of the vaccinated birds developed haemagglutination inhibition (HI) titres below 4log2. No clinical signs were observed in the vaccinated birds and virus shedding was limited. However, nearly all vaccinated birds showed a four-fold or higher increase of HI titres after challenge or contact-exposure, which is an indication of infection. This implies that virus transmission most likely has occurred. This study showed that a single vaccination applied under field conditions induced clinical protection, but was insufficient to induce protection against virus transmission, suggesting that silent spread of virus in vaccinated commercial flocks may occur.
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http://dx.doi.org/10.1016/j.rvsc.2014.09.013DOI Listing
December 2014

Estimation of the serial interval of pertussis in Dutch households.

Epidemics 2014 Jun 18;7:1-6. Epub 2014 Feb 18.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, The Netherlands. Electronic address:

Increasing incidence has led to the re-appearance of pertussis as a public health problem in developed countries. Pertussis infection is usually mild in vaccinated children and adults, but it can be fatal in infants who are too young for effective vaccination (≤3 months). Tailoring of control strategies to prevent infection of the infant hinges on the availability of estimates of key epidemiological quantities. Here we estimate the serial interval of pertussis, i.e., the time between symptoms onset in a case and its infector, using data from a household-based study carried out in the Netherlands in 2007-2009. We use statistical methodology to tie infected persons to probable infector persons, and obtain statistically supported stratifications of the data by person-type (infant, mother, father, sibling). The analyses show that the mean serial interval is 20 days (95% CI: 16-23 days) when the mother is the infector of the infant, and 28 days (95% CI: 23-33 days) when the infector is the father or a sibling. These time frames offer opportunities for early mitigation of the consequences of infection of an infant once a case has been detected in a household. If preventive measures such as social distancing or antimicrobial treatment are taken promptly they could decrease the probability of infection of the infant.
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http://dx.doi.org/10.1016/j.epidem.2014.02.001DOI Listing
June 2014

Cost-effectiveness of targeted vaccination to protect new-borns against pertussis: comparing neonatal, maternal, and cocooning vaccination strategies.

Vaccine 2013 Nov 27;31(46):5392-7. Epub 2013 Sep 27.

Epidemiology and Surveillance Unit, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. Electronic address:

Pertussis (whooping cough) is a severe infectious disease in infants less than 6 months old. Mass vaccination programmes have been unable to halt transmission effectively. Strategies to protect new-borns against infection include vaccination of the neonate or the mother directly after birth (cocooning), or the mother during pregnancy (maternal). Here we investigate the cost-effectiveness of these three strategies in the Netherlands. Costs for health care utilization and productivity losses, as well as impact on quality of life were calculated for a 10-year vaccination programme, assuming that vaccine-induced immunity lasts 5 years. Cocooning was the most attractive option from a cost-effectiveness viewpoint (€89,000/QALY). However, both cocooning and maternal vaccination would reduce the disease burden in infants and mothers vaccinated (about 17-20 QALY/year). Specifically, with a persistent epidemic as seen in 2012, there is need for reconsidering the vaccination schedules against pertussis in order to increase protection of the vulnerable new-borns.
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http://dx.doi.org/10.1016/j.vaccine.2013.09.028DOI Listing
November 2013

Driving factors of influenza transmission in the Netherlands.

Am J Epidemiol 2013 Nov 12;178(9):1469-77. Epub 2013 Sep 12.

Influenza epidemics in temperate regions show a characteristic seasonal pattern with peak incidence occurring in winter. Previous research has shown that low absolute humidity and school holidays can both affect influenza transmission. During an epidemic, transmission is strongly influenced by the depletion of susceptibles (i.e., increase in the number of those immune). To assess how much variability in influenza transmission intensity is due to each of these driving factors, we used a long time series of the number of weekly visits to general practitioners for influenzalike illness in the Netherlands from 1970-2011 and transformed this into a time series of weekly influenza reproduction numbers, which are a measure of transmission intensity. We used statistical regression techniques to quantify how the reproduction numbers were affected by each driving factor. We found a clear ranking of importance of driving factors in explaining the variation in transmission intensity. Most of the variation (30%) was explained by the depletion of susceptibles during the season, 27% was explained by between-season effects, and 3% was explained by absolute humidity. School holidays at the Christmas period did not have a statistically significant effect on influenza transmission. Although the influence of absolute humidity was small, its seasonal fluctuations may determine when sustained influenza transmission is possible and may thus drive influenza seasonality.
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http://dx.doi.org/10.1093/aje/kwt132DOI Listing
November 2013

Estimation of vaccine efficacy and critical vaccination coverage in partially observed outbreaks.

PLoS Comput Biol 2013 2;9(5):e1003061. Epub 2013 May 2.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

Classical approaches to estimate vaccine efficacy are based on the assumption that a person's risk of infection does not depend on the infection status of others. This assumption is untenable for infectious disease data where such dependencies abound. We present a novel approach to estimating vaccine efficacy in a Bayesian framework using disease transmission models. The methodology is applied to outbreaks of mumps in primary schools in the Netherlands. The total study population consisted of 2,493 children in ten primary schools, of which 510 (20%) were known to have been infected, and 832 (33%) had unknown infection status. The apparent vaccination coverage ranged from 12% to 93%, and the apparent infection attack rate varied from 1% to 76%. Our analyses show that vaccination reduces the probability of infection per contact substantially but not perfectly ([Formula: see text] = 0.933; 95CrI: 0.908-0.954). Mumps virus appears to be moderately transmissible in the school setting, with each case yielding an estimated 2.5 secondary cases in an unvaccinated population ([Formula: see text] = 2.49; 95%CrI: 2.36-2.63), resulting in moderate estimates of the critical vaccination coverage (64.2%; 95%CrI: 61.7-66.7%). The indirect benefits of vaccination are highest in populations with vaccination coverage just below the critical vaccination coverage. In these populations, it is estimated that almost two infections can be prevented per vaccination. We discuss the implications for the optimal control of mumps in heterogeneously vaccinated populations.
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http://dx.doi.org/10.1371/journal.pcbi.1003061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3642050PMC
March 2014