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Infection with HIV is characterized by very diverse disease-progression patterns across patients, associated with a wide variation in viral set-points. Progression is a multifactorial process, but an important role has been attributed to the HIV-specific T-cell response. To explore the conditions under which different set-points may be explained by differences in initial CD4 and CD8 T-cell responses and virus inoculum, we have formulated a model assuming that HIV-specific CD4 cells are both targets for infection and mediators of a monoclonal or polyclonal immune response. Clones differ in functional avidity for HIV epitopes. Importantly, in contrast to previous models, in this model we obtained coexistence of multiple clones at steady-state viral set-point, as seen in HIV infection. We found that, for certain parameter conditions, multiple steady states are possible: with few initial CD4 helper cells and high virus inoculum, no immune response is established and target-cell-limited infection follows, with associated high viral load; when CD4 clones are initially large and virus inoculum is low, infection can be controlled by several clones. The conditions for the dependence of viral set-point on initial inoculum and CD4 T-helper clone availability are investigated in terms of the effector mechanism of the clones involved. [ABSTRACT FROM AUTHOR]

National Immunisation Programmes (NIPs) develop historically. Its performance (disease incidences, vaccination coverage) is monitored. Reviewing the schedule as a whole could inform on further optimisation of the programme, i.e., providing maximal protection with the lowest number of doses. We systematically evaluated the performance and strategies of the Dutch pathogen-specific NIP schedules through literature review, assessment of surveillance data and expert opinions. Pathogen-specific vaccinations were categorised according to their strategy of protection: I) elimination or eradication, II) herd immunity or III) 'only' individual protection. The schedule of each vaccine-component was evaluated based on fixed criteria: 1. Is the achieved protection adequate? 2. Is the intended protection achieved? 3. Does the programme include too many or too few doses? 4. Is the timing optimal or acceptable? and 5. Are there drawbacks of the NIP for (part of) the population? Identified issues were explored using surveillance data and literature. Using fixed criteria facilitated comparison between pathogens and revealed opportunities to optimise the Dutch NIP by: i. Reducing the number of polio and tetanus vaccinations; ii. prolonging the interval between diphtheria, pertussis, tetanus, polio, hepatitis B, and Hib vaccine doses for improved effectiveness; iii. Expedite the second measles vaccination from 9 to 2-4 years of age to offer unvaccinated children and primary vaccine failures an earlier chance to be protected; and iv. Delaying the second mumps vaccination to enhance protection in adolescents/young adults. No schedule adaptations were deemed necessary for the vaccines against HPV, rubella, pneumococcal disease, and meningococcal disease. Based on this evaluation the NITAG advised to move the DTaP-IPV-HBV-Hib-booster from age 11 to 12 months, the second MMR-dose from 9 to 2-4 years, replace the Tdap-IPV at 4 years with a Tdap at 5-6 years and move the dt-IPV from 9 to 14 years. Implementation of these changes is planned for 2025., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background. Scarlet fever, an infectious disease caused by Streptococcus pyogenes , largely disappeared in developed countries during the twentieth century. In recent years, scarlet fever is on the rise again, and there is a need for a better understanding of possible factors driving transmission. Methods. Using historical case notification data from the three largest cities in The Netherlands (Amsterdam, Rotterdam and The Hague) from 1906 to 1920, we inferred the transmission rate for scarlet fever using time-series susceptible-infected-recovered (TSIR) methods. Through additive regression modelling, we investigated the contributions of meteorological variables and school term times to transmission rates. Results. Estimated transmission rates varied by city, and were highest overall for Rotterdam, the most densely populated city at that time. High temperature, seasonal precipitation levels and school term timing were associated with transmission rates, but the roles of these factors were limited and not consistent over all three cities. Conclusions. While weather factors alone can only explain a small portion of the variability in transmission rates, these results help understand the historical dynamics of scarlet fever infection in an era with less advanced sanitation and no antibiotic treatment and may offer insights into the driving factors associated with its recent resurgence., (© 2022 The Authors.)

BackgroundSince the roll-out of COVID-19 vaccines in late 2020 and throughout 2021, European governments have relied on mathematical modelling to inform policy decisions about COVID-19 vaccination.AimWe present a scenario-based modelling analysis in the Netherlands during summer 2021, to inform whether to extend vaccination to adolescents (12-17-year-olds) and children (5-11-year-olds).MethodsWe developed a deterministic, age-structured susceptible-exposed-infectious-recovered (SEIR) model and compared modelled incidences of infections, hospital and intensive care admissions, and deaths per 100,000 people across vaccination scenarios, before the emergence of the Omicron variant.ResultsOur model projections showed that, on average, upon the release of all non-pharmaceutical control measures on 1 November 2021, a large COVID-19 wave may occur in winter 2021/22, followed by a smaller, second wave in spring 2022, regardless of the vaccination scenario. The model projected reductions in infections/severe disease outcomes when vaccination was extended to adolescents and further reductions when vaccination was extended to all people over 5 years-old. When examining projected disease outcomes by age group, individuals benefitting most from extending vaccination were adolescents and children themselves. We also observed reductions in disease outcomes in older age groups, particularly of parent age (30-49 years), when children and adolescents were vaccinated, suggesting some prevention of onward transmission from younger to older age groups.ConclusionsWhile our scenarios could not anticipate the emergence/consequences of SARS-CoV-2 Omicron variant, we illustrate how our approach can assist decision making. This could be useful when considering to provide booster doses or intervening against future infection waves.

Tuberculosis (TB) remains a public health threat in low TB incidence countries, through a combination of reactivated disease and onward transmission. Using surveillance data from the United Kingdom (UK) and the Netherlands (NL), we demonstrate a simple and predictable relationship between the probability of observing a cluster and its size (the number of cases with a single genotype). We demonstrate that the full range of observed cluster sizes can be described using a modified branching process model with the individual reproduction number following a Poisson lognormal distribution. We estimate that, on average, between 2010 and 2015, a TB case generated 0.41 (95% CrI 0.30,0.60) secondary cases in the UK, and 0.24 (0.14,0.48) secondary cases in the NL. A majority of cases did not generate any secondary cases. Recent transmission accounted for 39% (26%,60%) of UK cases and 23%(13%,37%) of NL cases. We predict that reducing UK transmission rates to those observed in the NL would result in 538(266,818) fewer cases annually in the UK. In conclusion, while TB in low incidence countries is strongly associated with reactivated infections, we demonstrate that recent transmission remains sufficient to warrant policies aimed at limiting local TB spread., Competing Interests: The authors have declared that no competing interests exist.

Objective: To quantify the impact of long-standing vaccination programmes on notified cases in the Netherlands., Design: Estimates based on model projections of historical morbidity data., Method: We collected and digitised previously unavailable monthly case notifications of diphtheria, poliomyelitis, mumps and rubella in the Netherlands over the period 1919-2015. Poisson regression models accounting for seasonality, multi-year cycles, secular trends and auto-correlation were fit to pre-vaccination periods. Cases averted were calculated as the difference between observed and expected cases based on model projections., Results: In the first 13 years of mass vaccinations, case notifications declined rapidly with 18,900 (95%-CI: 12,000-28,600) notified cases of diphtheria averted, 5100 (95%-CI: 2200-13,500) cases of poliomyelitis, and 1800 (95%-CI: 1000-3200) cases of mumps. Vaccination of 11-year-old girls against rubella averted 13700 (95%-CI: 1400-38,300) cases, while universal rubella vaccination averted 700 (95%-CI: 80-2300) cases., Conclusion: These findings show that vaccination programmes have contributed substantially to the reduction of infectious diseases in the Netherlands.

[This corrects the article DOI: 10.1371/journal.pone.0192282.].

Vaccination programmes are considered a main contributor to the decline of infectious diseases over the 20th century. In recent years, the national vaccination coverage in the Netherlands has been declining, highlighting the need for continuous monitoring and evaluation of vaccination programmes. Our aim was to quantify the impact of long-standing vaccination programmes on notified cases in the Netherlands. We collected and digitised previously unavailable monthly case notifications of diphtheria, poliomyelitis, mumps and rubella in the Netherlands over the period 1919-2015. Poisson regression models accounting for seasonality, multi-year cycles, secular trends and auto-correlation were fit to pre-vaccination periods. Cases averted were calculated as the difference between observed and expected cases based on model projections. In the first 13 years of mass vaccinations, case notifications declined rapidly with 82.4% (95% credible interval (CI): 74.9-87.6) of notified cases of diphtheria averted, 92.9% (95% CI 85.0-97.2) cases of poliomyelitis, and 79.1% (95% CI 67.1-87.4) cases of mumps. Vaccination of 11-year-old girls against rubella averted 49.9% (95% CI 9.3-73.5) of cases, while universal vaccination averted 68.1% (95% CI 19.4-87.3) of cases. These findings show that vaccination programmes have contributed substantially to the reduction of infectious diseases in the Netherlands.

While tuberculosis (TB) represents a significant disease burden worldwide, low-incidence countries strive to reach the WHO target of pre-elimination by 2035. Screening for TB in immigrants is an important component of the strategy to reduce the TB burden in low-incidence settings. An important option is the screening and preventive treatment of latent TB infection (LTBI). Whether this policy is worthwhile depends on the extent of transmission within the country, and introduction of new cases through import. Mathematical transmission models of TB have been used to identify key parameters in the epidemiology of TB and estimate transmission rates. An important application has also been to investigate the consequences of policy scenarios. Here, we formulate a mathematical model for TB transmission within the Netherlands to estimate the size of the pool of latent infections, and to determine the share of importation-either through immigration or travel- versus transmission within the Netherlands. We take into account importation of infections due to immigration, and travel to the country of origin, focusing on the three ethnicities most represented among foreign-born TB cases (after exclusion of those overrepresented among asylum seekers): Moroccans, Turkish and Indonesians. We fit a system of ordinary differential equations to the data from the Netherlands Tuberculosis Registry on (extra-)pulmonary TB cases from 1995-2013. We estimate that about 27% of Moroccans, 25% of Indonesians, and 16% of Turkish, are latently infected. Furthermore, we find that for all three foreign-born communities, immigration is the most important source of LTBI, but the extent of within-country transmission is much lower (about half) for the Turkish and Indonesian communities than for the Moroccan. This would imply that contact investigation would have a greater yield in the latter community than in the former. Travel remains a minor factor contributing LTBI, suggesting that targeting returning travelers might be less effective at preventing LTBI than immigrants upon entry in the country.

Setting and Objective: In low-incidence countries, most tuberculosis (TB) cases are foreign-born. We explored the temporal relationship between immigration and TB in first-generation immigrants between 1995 and 2012 to assess whether immigration can be a predictor for TB in immigrants from high-incidence countries., Design: We obtained monthly data on immigrant TB cases and immigration for the three countries of origin most frequently represented among TB cases in the Netherlands: Morocco, Somalia and Turkey. The best-fit seasonal autoregressive integrated moving average (SARIMA) model to the immigration time-series was used to prewhiten the TB time series. The cross-correlation function (CCF) was then computed on the residual time series to detect time lags between immigration and TB rates., Results: We identified a 17-month lag between Somali immigration and Somali immigrant TB cases, but no time lag for immigrants from Morocco and Turkey., Conclusion: The absence of a lag in the Moroccan and Turkish population may be attributed to the relatively low TB prevalence in the countries of origin and an increased likelihood of reactivation TB in an ageing immigrant population. Understanding the time lag between Somali immigration and TB disease would benefit from a closer epidemiological analysis of cohorts of Somali cases diagnosed within the first years after entry.

Background: While the burden of community-acquired pneumonia and invasive pneumococcal disease (IPD) is still considerable, there is little insight in the factors contributing to disease. Previous research on the lagged relationship between respiratory viruses and pneumococcal disease incidence is inconclusive, and studies correcting for temporal autocorrelation are lacking., Objectives: To investigate the temporal relation between influenza-like illnesses (ILI) and IPD, correcting for temporal autocorrelation., Methods: Weekly counts of ILI were obtained from the Sentinel Practices of NIVEL Primary Care Database. IPD data were collected from the Dutch laboratory-based surveillance system for bacterial meningitis from 2004 to 2014. We analysed the correlation between time series, pre-whitening the dependent time series with the best-fit seasonal autoregressive integrated moving average (SARIMA) model to the independent time series. We performed cross-correlations between ILI and IPD incidences, and the (pre-whitened) residuals, in the overall population and in the elderly., Results: We found significant cross-correlations between ILI and IPD incidences peaking at lags -3 overall and at 1 week in the 65+ population. However, after pre-whitening, no cross-correlations were apparent in either population group., Conclusion: Our study suggests that ILI occurrence does not seem to be the major driver of IPD incidence in The Netherlands., (© 2016 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

The elimination of tuberculosis (TB) is threatened by an apparent increase in the level of resistance in Mycobacterium tuberculosis. In the Netherlands, where the majority of TB patients are migrants, resistance may also be increasing. We conducted a retrospective study, using 18,294 M. tuberculosis isolates from TB cases notified between 1993 and 2011. We investigated the trends in antituberculosis drug resistance, focusing on the country of birth of the patients and whether resistance had developed during treatment or was the result of transmission of resistant M. tuberculosis strains. For both scenarios, we determined whether this had happened in or outside the Netherlands. Antituberculosis drug resistance was found in 13% of all cases analysed and showed an increasing trend among patients who had been born in the Netherlands (p<0.001) and a decreasing trend among foreign-born (p=0.02) over the study period. Since 2005, the proportion of M. tuberculosis resistant strains among all strains tested has increased in both groups (p=0.03 and p=0.01, respectively). Overall, we found a significantly increasing trend when excluding streptomycin resistance (p<0.001). The trend was most markedly increased for isoniazid resistance (p = 0.01). Although resistance was mainly due to transmission of resistant strains, mostly outside the Netherlands or before 1993 (when DNA fingerprinting was not systematically performed), in some cases (n=45), resistance was acquired in the Netherlands. We conclude that antituberculosis drug resistance is increasing in the Netherlands, mostly related to migration from high TB-incidence countries, but also to domestic acquisition.

Background: The incidence of extra-pulmonary tuberculosis (EPTB) in the Netherlands shows a seasonal trend, with a peak in spring and a trough in autumn. Possible causes of this peak are winter crowding and a seasonal decrease in immune competence in spring. A third explanation may be a reporting bias., Objective: To investigate the role of winter crowding by a time-series analysis of notification data. DNA fingerprinting clustering status can differentiate between recent and remote infections. Seasonality in clustered cases would reflect enhanced transmission in winter and/or seasonally lowered immunity, while seasonality in unique cases would only reflect seasonally lowered immunity., Methods: We fitted (seasonal) auto-regressive moving average models to culture-positive TB notifications in the Netherlands (1993-2008) to assess seasonality. We then used seasonal trend Loess decompositions to derive the seasonal pattern, and compared the heights of the seasonal peaks., Results: Clustered and unique EPTB notifications showed a seasonal trend that was absent in clustered and unique PTB notifications. The seasonal peak in clustered EPTB cases was not significantly higher than in unique EPTB cases., Conclusions: The similar timing and height of the seasonal peak of clustered and unique EPTB cases suggests that winter crowding is unlikely to cause the seasonal trend in notifications.

A seasonal rise in tuberculosis (TB) notifications has been confirmed in several studies. Here, we examined one hypothesis for its cause: increased transmission of TB during wintertime due to crowding. Seasonality analysis was performed on actual and simulated notifications of clustered TB cases, which are considered to be representative of recent transmission, diagnosed from 1993 to 2004 in the Netherlands (n = 4,746). To test the hypothesis of winter crowding, notifications were simulated by adding patient delay and incubation period to an infection date randomly taken to be in winter in 80% of cases. The incubation periods were derived from frequency distributions for different TB disease localizations drawn from the literature. Seasonality analysis was performed using autocorrelation function plots and spectral analysis. Actual notifications showed strong seasonality in clustered TB and clustered extrapulmonary TB cases but not in clustered pulmonary TB cases. Analysis of simulated notifications revealed barely significant seasonality only in extrapulmonary TB cases. Our results suggest that increased transmission of TB during wintertime is unlikely to be the only cause of the seasonal peak in TB notifications. A factor closer to the notification date probably contributes to the seasonality observed in TB notifications.

Setting: The seasonality of tuberculosis (TB) incidence suggests that the risk of infection or development of disease has a seasonal component., Objective: To investigate factors associated with seasonal patterns of TB disease in the Netherlands by splitting notifications according to origin (natives vs. non-natives) and disease site (pulmonary TB [PTB] vs. extra-pulmonary TB [EPTB]). We focus on the presence of a seasonal peak, as much debate has centred on factors enhancing transmission vs. disease development., Design: Monthly notifications were derived from culture sample dates of all cases between 1993 and 2008. We fitted seasonal autoregressive integrated moving average (SARIMA) models to the time series. Seasonal decomposition revealed seasonal trends. To assess the seasonality of the peak, we repeated the analysis omitting December (trough) notifications., Results: TB notifications show a seasonal pattern, with a peak in spring and a trough in winter, which is present in both PTB and EPTB and in both natives and non-natives. However, when excluding December notifications, seasonality only holds in non-native EPTB and non-native TB notifications., Conclusion: A seasonal peak in TB notifications (March-June) is apparent in non-natives, but is absent in natives. This peak is driven by the seasonality of EPTB notifications, which are highest in June-July. The contribution of winter crowding is discussed. Vitamin D deficiency, enhancing disease development at the end of winter-early spring, seems the most likely factor explaining the yearly peak in EPTB.

The great variability in the time between infection with HIV and the onset of AIDS has been the object of intense study. In the current work, we examine a mathematical model that focuses on the role of immune response variability between patients. We study the effect of variation in both the avidity and the breadth of the immune response on within-patient disease dynamics, viral setpoint and time to AIDS. We conclude that immune response variability can explain the observed variability in disease progression to a large extent. It turns out that the avidity, more than the breadth of the immune response, determines disease progression, and that the average avidity of the five best clones is a much better correlate for disease progression than the total number of clones responding. For the design of vaccines, this would suggest that, if given the choice between stimulating a broader, but average avidity response or a narrower high-avidity response, the latter option would yield better control of virus load and consequently slow down disease progression.