Background Different levels of control measures were introduced to contain the global COVID-19 pandemic, many of which have been controversial, particularly the comprehensive use of diagnostic tests. Regular testing of high-risk individuals (pre-existing conditions, older than 60 years of age) has been suggested by public health authorities. The WHO suggested the use of routine screening of residents, employees, and visitors of long-term care facilities (LTCF) to protect the resident risk group. Similar suggestions have been made by the WHO for other closed facilities including incarceration facilities (e.g., prisons or jails), wherein parts of the U.S., accelerated release of approved inmates is taken as a measure to mitigate COVID-19. Methods and findings Here, the simulation model underlying the pandemic preparedness tool CovidSim 1.1 (http://covidsim.eu/) is extended to investigate the effect of regularly testing of employees to protect immobile resident risk groups in closed facilities. The reduction in the number of infections and deaths within the risk group is investigated. Our simulations are adjusted to reflect the situation of LTCFs in Germany, and incarceration facilities in the U.S. COVID-19 spreads in closed facilities due to contact with infected employees even under strict confinement of visitors in a pandemic scenario without targeted protective measures. Testing is only effective in conjunction with targeted contact reduction between the closed facility and the outside world—and will be most inefficient under strategies aiming for herd immunity. The frequency of testing, the quality of tests, and the waiting time for obtaining test results have noticeable effects. The exact reduction in the number of cases depends on disease prevalence in the population and the levels of contact reductions. Testing every 5 days with a good quality test and a processing time of 24 hours can lead up to a 40% reduction in the number of infections. However, the effects of testing vary substantially among types of closed facilities and can even be counterproductive in U.S. IFs. Conclusions The introduction of COVID-19 in closed facilities is unavoidable without a thorough screening of persons that can introduce the disease into the facility. Regular testing of employees in closed facilities can contribute to reducing the number of infections there, but is only meaningful as an accompanying measure, whose economic benefit needs to be assessed carefully.

Background COVID-19 vaccines are approved, vaccination campaigns are launched, and worldwide return to normality seems within close reach. Nevertheless, concerns about the safety of COVID-19 vaccines arose, due to their fast emergency approval. In fact, the problem of antibody-dependent enhancement was raised in the context of COVID-19 vaccines. Methods and findings We introduce a complex extension of the model underlying the pandemic preparedness tool CovidSim 1.1 (http://covidsim.eu/) to optimize vaccination strategies with regard to the onset of campaigns, vaccination coverage, vaccination schedules, vaccination rates, and efficiency of vaccines. Vaccines are not assumed to immunize perfectly. Some individuals fail to immunize, some reach only partial immunity, and—importantly—some develop antibody-dependent enhancement, which increases the likelihood of developing symptomatic and severe episodes (associated with higher case fatality) upon infection. Only a fraction of the population will be vaccinated, reflecting vaccination hesitancy or contraindications. The model is intended to facilitate decision making by exploring ranges of parameters rather than to be fitted by empirical data. We parameterized the model to reflect the situation in Germany and predict increasing incidence (and prevalence) in early 2021 followed by a decline by summer. Assuming contact reductions (curfews, social distancing, etc.) to be lifted in summer, disease incidence will peak again. Fast vaccine deployment contributes to reduce disease incidence in the first quarter of 2021, and delay the epidemic outbreak after the summer season. Higher vaccination coverage results in a delayed and reduced epidemic peak. A coverage of 75%–80% is necessary to prevent an epidemic peak without further drastic contact reductions. Conclusions With the vaccine becoming available, compliance with contact reductions is likely to fade. To prevent further economic damage from COVID-19, high levels of immunization need to be reached before next year’s flu season, and vaccination strategies and disease management need to be flexibly adjusted. The predictive model can serve as a refined decision support tool for COVID-19 management.

Background Governments across the globe responded with different strategies to the COVID-19 pandemic. While some countries adopted measures, which have been perceived controversial, others pursued a strategy aiming for herd immunity. The latter is even more controversial and has been called unethical by the WHO Director-General. Inevitably, without proper control measures, viral diversity increases and multiple infectious exposures become common, when the pandemic reaches its maximum. This harbors not only a potential threat overseen by simplified theoretical arguments in support of herd immunity, but also deserves attention when assessing response measures to increasing numbers of infection. Methods and findings We extend the simulation model underlying the pandemic preparedness web interface CovidSim 1.1 (http://covidsim.eu/) to study the hypothetical effect of increased morbidity and mortality due to ‘multi-infections’, either acquired at by successive infective contacts during the course of one infection or by a single infective contact with a multi-infected individual. The simulations are adjusted to reflect roughly the situation in the USA. We assume a phase of general contact reduction (“lockdown”) at the beginning of the epidemic and additional case-isolation measures. We study the hypothetical effects of varying enhancements in morbidity and mortality, different likelihoods of multi-infected individuals to spread multi-infections and different susceptibility to multi-infections in different disease phases. It is demonstrated that multi-infections lead to a slight reduction in the number of infections, as these are more likely to get isolated due to their higher morbidity. However, the latter substantially increases the number of deaths. Furthermore, simulations indicate that a potential second lockdown can substantially decrease the epidemic peak, the number of multi-infections and deaths. Conclusions Enhanced morbidity and mortality due to multiple disease exposure is a potential threat in the COVID-19 pandemic that deserves more attention. Particularly it underlines another facet questioning disease management strategies aiming for herd immunity.

The presence of multiple genetically different pathogenic variants within the same individual host is common in infectious diseases. Although this is neglected in some diseases, it is well recognized in others like malaria, where it is typically referred to as multiplicity of infection (MOI) or complexity of infection (COI). In malaria, with the advent of molecular surveillance, data is increasingly being available with enough resolution to capture MOI and integrate it into molecular surveillance strategies. The distribution of MOI on the population level scales with transmission intensities, while MOI on the individual level is a confounding factor when monitoring haplotypes of particular interests, e.g., those associated with drug-resistance. Particularly, in high-transmission areas, MOI leads to a discrepancy between the likelihood of a haplotype being observed in an infection (prevalence) and its abundance in the pathogen population (frequency). Despite its importance, MOI is not universally defined. Competing definitions vary from verbal ones to those based on concise statistical frameworks. Heuristic approaches to MOI are popular, although they do not mine the full potential of available data and are typically biased, potentially leading to misinferences. We introduce a formal statistical framework and suggest a concise definition of MOI and its distribution on the host-population level. We show how it relates to alternative definitions such as the number of distinct haplotypes within an infection or the maximum number of alleles detectable across a set of genetic markers. It is shown how alternatives can be derived from the general framework. Different statistical methods to estimate the distribution of MOI and pathogenic variants at the population level are discussed. The estimates can be used as plug-ins to reconstruct the most probable MOI of an infection and set of infecting haplotypes in individual infections. Furthermore, the relation between prevalence of pathogenic variants and their frequency (relative abundance) in the pathogen population in the context of MOI is clarified, with particular regard to seasonality in transmission intensities. The framework introduced here helps to guide the correct interpretation of results emerging from different definitions of MOI. Especially, it excels comparisons between studies based on different analytical methods.

Background: Draconic control measures were introduced to contain the global COVID-19 pandemic, many of which have been controversial, particularly the comprehensive use of diagnostic tests. Regular testing of high-risk individuals (pre-existing conditions, older than 60 years of age) has been suggested by public health authorities. The WHO suggested the use of routine screening of residents, employees, and visitors of long-term care facilities (LTCF) to protect the resident risk group. Similar suggestions have been made by the WHO for other closed facilities including incarceration facilities (e.g., prisons or jails), where in parts of the US, accelerated release of approved inmates is taken as a measure to mitigate COVID-19. Methods and findings: Here, the simulation model underlying the pandemic preparedness tool CovidSim 1.1 (http://covidsim.eu/) is extended to investigate the effect of regularly testing of employees in order to protect immobile resident risk groups in closed facilities. The reduction in the number of infections and deaths within the risk group are investigated as well as the potential economic gain resulting from savings in COVID-19 related treatment costs in comparison to costs resulting from the testing interventions. Our simulations are adjusted to reflect the situation of LTCFs in the Federal Republic of Germany. The probability is nearly one that COVID-19 spreads into closed facilities due to contact with infected employees even under strict confinement of visitors in a pandemic scenario without targeted protective measures. Regular screening of all employees by PCR tests provides a significant reduction of COVID-19 cases and related deaths in LTCFs. While the frequency of testing (testing rate) and the quality of tests have noticeable effects, the waiting time for obtaining test results (ranging from 12 up to 96 hours) hardly impacts the outcome. The results suggest that testing every two weeks with low-quality tests and a processing time of up to 96 hours yields a strong reduction in the number of cases. Rough estimates suggest a significant economic gain. Conclusions: The introduction of COVID-19 in closed facilities is unavoidable without thorough screening of persons that can introduce the disease into the facility. These measures provide an economically meaningful way to protect vulnerable risk groups characterized by an elevated risk of severe infections in closed facilities, in which contact-reducing measures are difficult to implement due to imminent unavoidable close human-to-human contacts.

BackgroundCOVID-19 vaccines are approved, vaccination campaigns are launched, and worldwide return to normality seems within close reach. Nevertheless, concerns about the safety of COVID-19 vaccines arose, due to their fast emergency approval. In fact, the problem of antibody-dependent enhancement was raised in the context of COVID-19 vaccines.Methods and findingsWe introduce a complex extension of the model underlying the pandemic preparedness tool CovidSim 1.1 (http://covidsim.eu/) to optimize vaccination strategies with regard to the onset of campaigns, vaccination coverage, vaccination schedules, vaccination rates, and efficiency of vaccines. Vaccines are not assumed to immunize perfectly. Some individuals fail to immunize, some reach only partial immunity, and – importantly – some develop antibody-dependent enhancement, which increases the likelihood of developing symptomatic and severe episodes (associated with higher case fatality) upon infection. Only a fraction of the population will be vaccinated, reflecting vaccination hesitancy or contraindications.We parameterized the model to reflect the situation in Germany and predict increasing incidence (and prevalence) in early 2021 followed by a decline by summer. Assuming contact reductions (curfews, social distancing, etc.) to be lifted in summer, disease incidence will peak again. Fast vaccine deployment contributes to reduce disease incidence in the first quarter of 2021, and delay the epidemic outbreak after the summer season. Higher vaccination coverage results in a delayed and reduced epidemic peak. A coverage of 75% – 80% is necessary to prevent an epidemic peak without further drastic contact reductions.ConclusionsWith the vaccine becoming available, compliance with contact reductions is likely to fade. To prevent further economic damage from COVID-19, high levels of immunization need to be reached before next year’s flu season, and vaccination strategies and disease management need to be flexibly adjusted. The predictive model can serve as a refined decision support tool for COVID-19 management.

The introduction of genomic methods facilitated standardized molecular disease surveillance. For instance, SNP barcodes in Plasmodium vivax and Plasmodium falciparum malaria allows the characterization of haplotypes, their frequencies and prevalence to reveal temporal and spatial transmission patterns. A confounding factor is the presence of multiple genetically distinct pathogen variants within the same infection, known as multiplicity of infection (MOI). Disregarding ambiguous information, as usually done in ad-hoc approaches, leads to less confident and biased estimates. We introduce a statistical framework to obtain maximum-likelihood estimates (MLE) of haplotype frequencies and prevalence alongside MOI from malaria SNP data, i.e., multiple biallelic marker loci. The number of model parameters increases geometrically with the number of genetic markers considered and no closed-form solution exists for the MLE. Therefore, the MLE needs to be derived numerically. We use the Expectation-Maximization (EM) algorithm to derive the maximum-likelihood estimates, an efficient and easy-to-implement algorithm that yields a numerically stable solution. We also derive expressions for haplotype prevalence based on either all or just the unambiguous genetic information and compare both approaches. The latter corresponds to a biased ad-hoc estimate of prevalence. We assess the performance of our estimator by systematic numerical simulations assuming realistic sample sizes and various scenarios of transmission intensity. For reasonable sample sizes, and number of loci, the method has little bias. As an example, we apply the method to a dataset from Cameroon on sulfadoxine-pyrimethamine resistance in P. falciparum malaria. The method is not confined to malaria and can be applied to any infectious disease with similar transmission behavior. An easy-to-use implementation of the method as an R-script is provided.

Background: Governments across the globe responded with different strategies to the COVID-19 pandemic. While some countries adapted draconic measures, which have been perceived controversial others pursued a strategy aiming for herd immunity. The latter is even more controversial and has been called unethical by the WHO Director-General. Inevitably, without proper control measure, viral diversity increases and multiple infectious exposures become common, when the pandemic reaches its maximum. This harbors not only a potential threat overseen by simplified theoretical arguments in support of herd immunity, but also deserves attention when assessingresponse measures to increasing numbers of infection. Methods and findings: We extend the simulation model underlying the pandemic preparedness web interface CovidSim 1.1 (http://covidsim.eu/) to study the hypothetical effect of increased morbidity and mortality due to 'multi infections', either acquired at by successive infective contacts during the course of one infection or by a single infective contact with a multi-infected individual. The simulations are adjusted to reflect roughly the situation in the East Coast of the USA. We assume a phase of general contact reduction ('lockdown') at the beginning of the epidemic and additional case-isolation measures. We study the hypothetical effects of varying enhancements in morbidity and mortality, different likelihoods of multi-infected individuals to spread multi infections and different susceptibility to multi infectious in different disease phases. It is demonstrated that multi infections lead to a slight reduction in the number of infections, as these are more likely to get isolated due to their higher morbidity. However, the latter substantially increases the number of deaths. Furthermore, simulations indicate that a potential second lockdown can substantially decrease the epidemic peak, the number of multi-infections and deaths. Conclusions: Enhanced morbidity and mortality due to multiple disease exposure is a potential threat in the COVID-19 pandemic that deserves more attention. Particularly it underlines another facet questioning disease management strategies aiming for herd immunity