Visualization: LM PM. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract We use age-structured models for VZV transmission and reactivation to reconstruct the natural history of VZV in Norway based on available pre-vaccination serological data, contact matrices, and herpes zoster incidence data.
Introduction The varicella zoster virus VZV is transmitted by droplets, aerosols, and direct contact, and is responsible for both varicella chickenpox and herpes zoster HZ.
Methods Data Norwegian VZV sero-prevalence data included anonymised residual sera from patients of all ages seeking both primary and hospital care during , , , and Mathematical model The age-structured model for the natural history of VZV transmission and reactivation in Norway Fig 1 , details in S1 File , comprises an MSIR sub-model for varicella transmission, plus a cascade of further compartments to account for the different episodes of exogenous boosting.
Download: PPT. Fig 1. Flow diagram of the compartmental model for VZV transmission and reactivation. Varicella force of infection, contact patterns and varicella transmission patterns By the hypothesis that the contribution of active HZ cases to the varicella FOI is negligible, the age-specific FOI of varicella in age group i at endemic equilibrium is defined as , where G represents the adopted age grouping, C ij is the average number of contacts an individual aged i has with individuals aged j per unit of time e.
Table 1. The different hypotheses about the VZV reactivation rate. Models fit to serological and zoster incidence data The different models considered were fitted to data in two sequential stages [ 32 ].
Results Transmission, force of infection and basic reproduction number of varicella For each of the three contact matrices considered synthetic, Polymod-all, Polymod-close we report the estimates for the case of age-independent transmission Q 0 , as well as the estimates for the age-dependent formulations Q 1 ,…, Q 5 over the possible choices of the cut-off age a c.
Table 2. Fig 2. VZV reactivation and the role of exogenous boosting Following the adopted two stage procedure, the alternative models for the RR Table 1 were fitted to HZ incidence data based on each of the transmission models reported in Table 2 , by retaining only the models which additionally showed a good fit to HZ. Table 4. Fig 3. Discussion The introduction of varicella vaccination is a debatable subject in European public health. Supporting information. S1 File. The mathematical model for VZV transmission and reactivation, and further results.
References 1. Heininger U, Seward JF. Lancet ;— The comparative sero-epidemiology of varicella zoster virus in 11 countries in the European region. Vaccine ;— BMC medicine , Oxman MN. Herpes zoster pathogenesis and cell-mediated immunity and immunosenescence.
J Am Osteopath Assoc. View Article Google Scholar 5. Hope-Simpson RE. The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med.
Exposure to varicella boosts immunity to herpes-zoster: implications for mass vaccination against chickenpox. Contacts with varicella or with children and protection against herpes zoster in adults: a case-control study. Lancet ; : — Exploring the impact of exposure to primary varicella in children on varicella zoster virus immunity of parents. Viral Immun. View Article Google Scholar 9. Integrating between-host transmission and within-host immunity to analyze the impact of varicella vaccination on zoster.
Elife ; 4, e View Article Google Scholar Protection against varicella with two doses of combined measles-mumps-rubella-varicella vaccine versus one dose of monovalent varicella vaccine: a multicentre, observer-blind, randomised, controlled trial. Varicella vaccination: a laboured take-off. Clinical Microbiology and Infection ;— The epidemiology of varicella—zoster virus infections: the influence of varicella on the prevalence of herpes zoster.
Epidemiology and infection, ; 03 , — Modeling the effects of varicella vaccination programs on the incidence of chickenpox and shingles. Bulletin of Mathematical Biology ;— Modelling the impact of immunization on the epidemiology of varicella zoster virus. Epidemiol Infect.
Modelling the impact of varicella vaccination on varicella and zoster. Modelling the impact of a combined varicella and zoster vaccination programme on the epidemiology of varicella zoster virus in England. EBioMedicine ; 2 10 —9. Varicella-zoster virus susceptibility and primary healthcare consultations in Norway.
BMC Infectious Diseases ; Infectious diseases of humans: dynamics and control. Oxford: Oxford University Press; The pre-vaccination epidemiology of measles, mumps and rubella in Europe: implications for modelling studies.
Inferring the structure of social contacts from demographic data in the analysis of infectious diseases spread. PLoS Comput Biol. Social contacts and mixing patterns relevant to the spread of infectious diseases. PLoS Med , 5 3 , e Estimating infectious disease parameters from data on social contacts and serological status. Appl Statist ; 59 2 : — The social contact hypothesis under the assumption of endemic equilibrium: Elucidating the transmission potential of VZV in Europe.
Epidemics , 11, 14— Last access May Epidemiol ; — Seiler HE. A study of herpes zoster particularly in its relationship to chickenpox. J Hyg. Inverse correlation between varicella severity and level of anti-Varicella Zoster Virus maternal antibodies in infants below one year of age, Hum Vaccin.
Epub May 1. Using social contact data to estimate age-specific transmission parameters for infectious respiratory spread agents. Whether or not steroids should be used to treat herpes zoster remains controversial. Concerns about the use of intravenous acyclovir include the side effects of renal and central nervous system dysfunction and the possibility of emergence of resistant viral strains.
None of these concerns has proved to be an impediment to successful treatment of immunocompromised patients. The major future challenge is to find an optimal way to treat varicella zoster virus infections with oral formulations of acyclovir or its congeners. Moreover, this phenomenon is difficult to assess due to the presence of confounding effects, such as the increase in HZ incidence observed in various settings prior to the introduction of varicella vaccination see e.
Therefore, it is critical, before decisions about immunisation against varicella and HZ are taken, to carefully characterise the local VZV epidemiology, and the consequent potential impact of different immunisation programmes. In this study we have used mathematical models for VZV transmission and reactivation in combination with available age-structured data on contact patterns, varicella sero-prevalence and herpes zoster incidence, to reconstruct the natural history of VZV in Norway.
Results about varicella transmission indicate a somewhat large variation in R 0 between 3. As for varicella force of infection the resulting differences are more neatly ascribable to the structural differences in the contact matrices considered. On the one hand, synthetic matrices yield a marked peak during the pre-school period ages 3—5 , with a rapid decline thereafter and a relapse during the childbearing period.
On the other hand, Polymod-type [ 26 ] matrices yield a much lower peak but the FOI persists at a high level during the overall pre-school and primary school period age 3—12 years ; moreover the peak during childbearing is higher than implied by synthetic matrices and more well-defined.
As regards VZV reactivation, the progressive immunity mechanism [ 32 ] explains Norway age-specific HZ incidence data far better than concurring models. This result brings population-level evidence about the magnitude of exogenous boosting, particularly about the conjecture that a certain degree of CMI boosting must exist although not necessarily at the same rate as the force of infection [ 10 ], as instead commonly postulated in the modelling literature [ 14 , 15 , 16 , 20 ].
The use of the reproduction numbers of boosting proposed here, allows to quantify the importance of boosting, indicating that when the boosting magnitude is supposed to be maximal i. Compared to other modeling studies of the natural history of VZV, the present results indicate that varicella transmission in Norway is slower than in the Netherlands and Belgium, but faster than in Central and Southern Europe countries, and the UK [ 2 , 28 ].
Compared to Finland, the varicella FOI in Norway seems to be higher during pre-school age 3—5 years , lower during primary school 6—12 years , and essentially aligned thereafter. The relapse of the FOI during childbearing, which seems to be a robust phenomenon of varicella transmission across Europe [ 28 ], is confirmed for Norway in the present study as well as by independent estimates based on mixture modelling of antibodies data [ 44 ].
Overall, estimates of varicella FOI for Norway based on Polymod-type matrices are consistent with those found by studies using Polymod matrices for other European countries [ 28 ]. As for HZ, the estimates of reactivation parameters by the progressive immunity model are broadly consistent with those found for Finland [ 32 ].
This might be suggestive of the presence of a higher exogenous boosting intensity as a specific feature of Nordic countries, as also consistent with the above-described finding on varicella transmission. Our estimates of varicella transmission and reactivation will be taken, jointly with available contact matrices, as inputs of VZV dynamic models to be used to evaluate the impact of different vaccination options, in order to inform the current discussion on the introduction of varicella and HZ immunization in Norway.
In relation to this, our results indicate some issues that will need careful consideration during modelling of vaccination strategies. On one hand, there is evidence of a non-negligible proportion of varicella susceptible individuals among adults, who are at risk of serious varicella disease and congenital varicella syndrome in their offspring [ 45 ], especially in consideration of the increasing force of infection during childbearing ages.
On the other hand, the predicted higher level of the FOI during the childbearing period jointly with the present findings on re-exposure, suggest that childbearing ages might be important for CMI boosting, so that the suppressive effect due to varicella immunisation should be carefully considered. Concerning the limitations of this work, the present reconstruction of VZV natural history in Norway was based on serological data documenting past experience of varicella infection, and HZ incidence data, using mathematical modelling relying on available contact matrices.
As for the latter point, we compared the results provided by synthetic contact matrices, available for Norway after [ 25 ], with those based on diary-informed contact matrices [ 26 ], by borrowing Polymod type contact matrices from Finland.
The resulting differences for the predicted shape of the force of infection across age are indicative of the presence of model-based uncertainty in transmission which is larger than the statistical uncertainty surrounding estimates from a given matrix, and therefore worth considering in the modeling of the impact of vaccination. Similarly, though the progressive immunity model allows an excellent fit of HZ data, our analyses indicate the possibility of substantial uncertainty about the magnitude of exogenous boosting, which also will be worth considering in future dynamic modeling.
Moreover, the hypothesis adopted here that the boosting factor is age-independent must be considered as a simplifying departure point, worth to extend in future studies, perhaps under a different framework for reactivation. Other critical points lie in the parametrization of reactivation. From this viewpoint, since the progressive immunity formulation is simple i. For example, in the progressive immunity model the relationship between the reactivation risk and the number of boosting events is represented by an exponentially declining function, therefore potentially going to zero for a large number of boosts.
This is an approximation, given that this dependency in reality must have an upper bound in VZV-specific immunity. Similarly the growth in the risk after the last boost is hardly age-independent, rather it is possibly affected by the age at which the last boost occurred. These realistic complications might be worth considering in the future, provided issues of over-parametrization can be properly handled. More important, our formulation relied on the EBH.
Though evidence in favour of the EBH from a number of different investigations, i. Moreover, negative or opposite evidence also exists [ 46 , 47 ]. Other studies [ 9 ] suggest that a key role might be played by endogenous forms of boosting, which is major knowledge gap about immunity to HZ, and for which only two modelling studies exists so far [ 9 , 48 ].
The relative importance of exogenous vs endogenous boosting might play a critical influence on the estimated impact of varicella vaccination, and undermine the usefulness of models including exogenous boosting only. Therefore, although the present work has added new population-based insight on the magnitude of exogenous boosting, further progress in modelling VZV reactivation and related implications for vaccination strategies would require substantial progress in the immunologically-based measurement of boosting, both exogenous and endogenous, an area which is still rather under-developed.
This file reports full details about the mathematical model for VZV transmission and reactivation used in the manuscript, and a number of further results.
We would like to acknowledge Arild Osen, Department of Health Data Management and Analysis, the Norwegian Institute of Public Health, for assistance during extraction and management of data on primary healthcare consultations. We warmly thank an Editor and two anonymous referees of the Journal for a number of deep and helpful suggestions which allowed to sharply improve the manuscript.
National Center for Biotechnology Information , U. PLoS One. Published online May Graciela Andrei, Editor. Author information Article notes Copyright and License information Disclaimer. Competing Interests: All the authors have declared that no competing interests exist.
Conceptualization: EF PM. Data curation: LM. Formal analysis: PM LM. Funding acquisition: EF. Methodology: PM. Project administration: EF. Resources: EF GM. Software: LM GG. Supervision: EF PM. Visualization: LM PM.
Received Oct 27; Accepted Apr This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This article has been cited by other articles in PMC. Abstract We use age-structured models for VZV transmission and reactivation to reconstruct the natural history of VZV in Norway based on available pre-vaccination serological data, contact matrices, and herpes zoster incidence data. Introduction The varicella zoster virus VZV is transmitted by droplets, aerosols, and direct contact, and is responsible for both varicella chickenpox and herpes zoster HZ.
Methods Data Norwegian VZV sero-prevalence data included anonymised residual sera from patients of all ages seeking both primary and hospital care during , , , and Mathematical model The age-structured model for the natural history of VZV transmission and reactivation in Norway Fig 1 , details in S1 File , comprises an MSIR sub-model for varicella transmission, plus a cascade of further compartments to account for the different episodes of exogenous boosting.
Open in a separate window. Fig 1. Flow diagram of the compartmental model for VZV transmission and reactivation. Table 1 The different hypotheses about the VZV reactivation rate. Models fit to serological and zoster incidence data The different models considered were fitted to data in two sequential stages [ 32 ].
Results Transmission, force of infection and basic reproduction number of varicella For each of the three contact matrices considered synthetic, Polymod-all, Polymod-close we report the estimates for the case of age-independent transmission Q 0 , as well as the estimates for the age-dependent formulations Q 1 ,…, Q 5 over the possible choices of the cut-off age a c. Fig 2. Table 3 Predicted age-specific varicella incidence. VZV reactivation and the role of exogenous boosting Following the adopted two stage procedure, the alternative models for the RR Table 1 were fitted to HZ incidence data based on each of the transmission models reported in Table 2 , by retaining only the models which additionally showed a good fit to HZ.
Fig 3. Fig 4. Table 5 Reproduction numbers of boosting. Discussion The introduction of varicella vaccination is a debatable subject in European public health. PDF Click here for additional data file.
Data Availability The dataset supporting the conclusions of this manuscript cannot be publicly shared because of the national data protection legislation. References 1. Heininger U, Seward JF. Lancet ; — The comparative sero-epidemiology of varicella zoster virus in 11 countries in the European region. Vaccine ; 25 — BMC medicine , 7
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