Appropriate relaxation of non-pharmaceutical interventions minimizes the risk of a resurgence in SARS-CoV-2 infections in spite of the Delta variant (preprint)

We analyze the relaxation of non-pharmaceutical interventions (NPIs) under an increasing number of vaccinations in Germany. For the spread of SARS-CoV-2 we employ a SIR-type model that accounts for age-dependence and includes realistic contact patterns between age groups. The implementation of NPIs occurs on changed contact patterns, improved isolation, or reduced infectiousness when, e.g., wearing masks. We account for spatial heterogeneity and commuting activities in between regions in Germany, and the testing of commuters is considered as a further NPI. We include the ongoing vaccination process and analyze the effect of the B.1.617.2 (Delta) variant, which is considered to be 40% − 60% more infectious then the currently dominant B.1.1.7 (Alpha) variant. We explore different opening scenarios under the ongoing vaccination process by assuming that local restrictions are either lifted in early July or August with or without continued wearing of masks and testing. Our results indicate that we can counteract the resurgence of SARS-CoV-2 despite the Delta variant with appropriate timing for the relaxation of NPIs. In all cases, however, school children are hit the hardest. Author summary One of the greatest challenges within the Covid-19 pandemic is to identify the timing and amount of non-pharmaceutical interventions (face masks, travel bans, school closures, etc). In the year 2021 more and more people are getting vaccinated. When can we finally lift all restrictions and stop wearing masks? In order to provide more insights to this question, we use a mathematical model which is capable of simulating the effects of non-pharmaceutical interventions in Germany while accounting for age-dependent factors as well as commuting activities between regions. We include the vaccination process and analyze the much more infectious Delta coronavirus variant. We simulate scenarios that consider the timing of the return to pre-pandemic contacts as well as when to suspend wearing masks and testing. Our results show that a later opening by 1 August in combination with masks and testing reduces the chance of a further infection wave considerably. From the retrospective view of the revision, we see that the rise in infections at the end of summer could have been well predicted by our scenarios that considered lifting of NPIs in July as it happened in many places. In all of our scenarios, the infection manifests in the younger age groups.

Regional opening strategies with commuter testing and containment of new SARS-CoV-2 variants in Germany (preprint)

Background Despite the vaccination process in Germany, a large share of the population is still susceptible to SARS-CoV-2. In addition, we face the spread of novel variants. Until we overcome the pandemic, reasonable mitigation and opening strategies are crucial to balance public health and economic interests. Methods We model the spread of SARS-CoV-2 over the German counties by a graph-SIR-type, metapopulation model with particular focus on commuter testing. We account for political interventions by varying contact reduction values in private and public locations such as homes, schools, workplaces, and other. We consider different levels of lockdown strictness, commuter testing strategies, or the delay of intervention implementation. We conduct numerical simulations to assess the effectiveness of the different intervention strategies after one month. The virus dynamics in the regions (German counties) are initialized randomly with incidences between 75-150 weekly new cases per 100,000 inhabitants (red zones) or below (green zones) and consider 25 different initial scenarios of randomly distributed red zones (between 2 and 20 % of all counties). To account for uncertainty, we consider an ensemble set of 500 Monte Carlo runs for each scenario. Results We find that the strength of the lockdown in regions with out of control virus dynamics is most important to avoid the spread into neighboring regions. With very strict lockdowns in red zones, commuter testing rates of twice a week can substantially contribute to the safety of adjacent regions. In contrast, the negative effect of less strict interventions can be overcome by high commuter testing rates. A further key contributor is the potential delay of the intervention implementation. In order to keep the spread of the virus under control, strict regional lockdowns with minimum delay and commuter testing of at least twice a week are advisable. If less strict interventions are in favor, substantially increased testing rates are needed to avoid overall higher infection dynamics. Conclusions Our results indicate that local containment of outbreaks and maintenance of low overall incidence is possible even in densely populated and highly connected regions such as Germany or Western Europe. While we demonstrate this on data from Germany, similar patterns of mobility likely exist in many countries and our results are, hence, generalizable to a certain extent.

Potential benefits of delaying the second mRNA COVID-19 vaccine dose (preprint)

Vaccination against COVID-19 with the recently approved mRNA vaccines BNT162b2 (BioNTech/Pfizer) and mRNA-1273 (Moderna) is currently underway in a large number of countries. However, high incidence rates and rapidly spreading SARS-CoV-2 variants are concerning. In combination with acute supply deficits in Europe in early 2021, the question arises of whether stretching the vaccine, for instance by delaying the second dose, can make a significant contribution to preventing deaths, despite associated risks such as lower vaccine efficacy, the potential emergence of escape mutants, enhancement, waning immunity, reduced social acceptance of off-label vaccination, and liability shifts. A quantitative epidemiological assessment of risks and benefits of non-standard vaccination protocols remains elusive. To clarify the situation and to provide a quantitative epidemiological foundation we develop a stochastic epidemiological model that integrates specific vaccine rollout protocols into a risk-group structured infectious disease dynamical model. Using the situation and conditions in Germany as a reference system, we show that delaying the second vaccine dose is expected to prevent deaths in the four to five digit range, should the incidence resurge. We show that this considerable public health benefit relies on the fact that both mRNA vaccines provide substantial protection against severe COVID-19 and death beginning 12 to 14 days after the first dose. The benefits of protocol change are attenuated should vaccine compliance decrease substantially. To quantify the impact of protocol change on vaccination adherence we performed a large-scale online survey. We find that, in Germany, changing vaccination protocols may lead to small reductions in vaccination intention. In sum, we therefore expect the benefits of a strategy change to remain substantial and stable.

Assessment of effective mitigation and prediction of the spread of SARS-CoV-2 in Germany using demographic information and spatial resolution (preprint)

Non-pharmaceutical interventions (NPIs) are important to mitigate the spread of infectious diseases as long as no vaccination or outstanding medical treatments are available. We assess the effectiveness of the sets of non-phar\-ma\-ceu\-ti\-cal interventions that were in place during the course of the Coronavirus disease 2019 (Covid-19) pandemic in Germany. Our results are based on hybrid models, combining SIR-type models on local scales with spatial resolution. In order to account for the age-dependence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we include realistic pre-pandemic and recently recorded contact patterns between age groups. The implementation of non-pharmaceutical interventions will occur on changed contact patterns, improved isolation, or reduced infectiousness when, e.g., wearing masks. In order to account for spatial heterogeneity, we use a graph approach and we include high-quality information on commuting activities combined with traveling information from social networks. The remaining uncertainty will be accounted for by a large number of randomized simulation runs. Based on the derived factors for the effectiveness of different non-pharmaceutical interventions over the past months, we provide different forecast scenarios for the upcoming time.

In Vitro Safety Clinical Trial of the Cardiac Liability of Hydroxychloroquine and Azithromycin as COVID19 Polytherapy (preprint)

Despite global efforts, there are no effective FDA-approved medicines for the treatment of SARS-CoV-2 infection. Potential therapeutics focus on repurposed drugs, some with cardiac liabilities. Here we report on a preclinical drug screening platform, a cardiac microphysiological system (MPS), to assess cardiotoxicity associated with hydroxychloroquine (HCQ) and azithromycin (AZM) polytherapy in a mock clinical trial. The MPS contained human heart muscle derived from patient-specific induced pluripotent stem cells. The effect of drug response was measured using outputs that correlate with clinical measurements such as QT interval (action potential duration) and drug-biomarker pairing. Chronic exposure to HCQ alone elicited early afterdepolarizations (EADs) and increased QT interval from day 6 onwards. AZM alone elicited an increase in QT interval from day 7 onwards and arrhythmias were observed at days 8 and 10. Monotherapy results closely mimicked clinical trial outcomes. Upon chronic exposure to HCQ and AZM polytherapy, we observed an increase in QT interval on days 4-8. Interestingly, a decrease in arrhythmias and instabilities was observed in polytherapy relative to monotherapy, in concordance with published clinical trials. Furthermore, biomarkers, most of them measurable in patients serum, were identified for negative effects of single drug or polytherapy on tissue contractile function, morphology, and antioxidant protection. The cardiac MPS can predict clinical arrhythmias associated with QT prolongation and rhythm instabilities. This high content system can help clinicians design their trials, rapidly project cardiac outcomes, and define new monitoring biomarkers to accelerate access of patients to safe COVID-19 therapeutics.

Inferring the effect of interventions on COVID-19 transmission networks (preprint)

Countries around the world implement nonpharmaceutical interventions (NPIs) to mitigate the spread of COVID-19. Design of efficient NPIs requires identification of the structure of the disease transmission network. We here identify the key parameters of the COVID-19 transmission network for time periods before, during, and after the application of strict NPIs for the first wave of COVID-19 infections in Germany combining Bayesian parameter inference with an agent-based epidemiological model. We assume a Watts-Strogatz small-world network which allows to distinguish contacts within clustered cliques and unclustered, random contacts in the population, which have been shown to be crucial in sustaining the epidemic. In contrast to other works, which use coarse-grained network structures from anonymized data, like cell phone data, we consider the contacts of individual agents explicitly. We show that NPIs drastically reduced random contacts in the transmission network, increased network clustering, and resulted in a change from an exponential to a constant regime of newcases. In this regime, the disease spreads like a wave with a finite wave speed that depends on the number of contacts in a nonlinear fashion, which we can predict by mean field theory. Our analysis indicates that besides the well-known transitionbetween exponential increase and exponential decrease in the number of new cases, NPIs can induce a transition to another, previously unappreciated regime of constant new cases.

COVID-19 in Italy: targeted testing as a proxy of limited health care facilities and a key to reducing hospitalization rate and the death toll. (preprint)

The novel Coronavirus SARS-CoV-2 (CoV) has induced a worldwide pandemic, notably in Italy, one of the worst-hit countries in Europe, which witnessed a death toll unseen in the recent past. There are potentially many factors, such as infections from undetected index cases, early vs late testing strategies, limited health care facilities etc., that might have aggravated the COVID-19 situation in Italy. We developed a COVID-19 specific infection epidemic model composed of susceptible (S), exposed (E), carrier (C), infected (I), recovery (R) and dead (D) (SECIRD), specifically parameterized for Italy to disentangle the impact of these factors and their implications on infection dynamics to help planning an effective control strategy for a possible second wave. Our model discriminates between detected infected and undetected individuals who played a crucial role in the disease spreading and is not well addressed by classical SEIR-like transmission models. We first estimated the number of undetected infections through a Bayesian Markov Chain Monte Carlo (MCMC) framework, which ranges from ~7 to ~22 fold higher than reported infections, depending upon regions. We exploited this information to evaluate the impact of the undetected component on the evolution of the pandemic and the benefits of an enhanced testing strategy. In high testing regions like Veneto, 18% of all infections resulted in hospitalization, while for Lombardia and Piemonte, it is 25% and 27%, respectively. We investigated the impact of an overwhelmed health care system upon death toll by applying hospital and intensive care unit (ICU) capacities in the SECIRD model, and we estimated a 10% reduction in death in Lombardia, the worst hit region, if a higher number of hospital facilities had been available since the beginning. Adopting a combined strategy of rapid early and targeted testing (~10 fold) with increased hospital capacity would help in avoiding bottlenecks affecting the health care system. Our results demonstrate that the early testing would have a strong impact on the overall hospital accessibility and, hence, upon death toll (~20% to 50% reduction) and could have mitigated the lack of facilities at the crucial middle stage of the epidemic.

The foreshadow of a second wave: An analysis of current COVID-19 fatalities in Germany (preprint)

A second wave of SARS-CoV-2 is unfolding in dozens of countries. However, this second wave manifests itself strongly in new reported cases, but less in death counts compared to the first wave. Over the past three months in Germany, the reported cases increased by a factor five or more, whereas the death counts hardly grew. This discrepancy fueled speculations that the rise of reported cases would not reflect a second wave but only wider testing. We find that this apparent discrepancy can be explained to a large extent by the age structure of the infected, and predict a pronounced increase of death counts in the near future, as the spread once again expands into older age groups. To re-establish control, and to avoid the tipping point when TTI capacity is exceeded, case numbers have to be lowered. Otherwise the control of the spread and the protection of vulnerable people will require more restrictive measures latest when the hospital capacity is reached.

High SARS-CoV-2 Seroprevalence in Children and Adults in the Austrian Ski Resort Ischgl (preprint)

Background: Early March 2020, a SARS-CoV-2 outbreak in the ski resort Ischgl in Austria initiated the spread of SARS-CoV-2 throughout Austria and Northern Europe. Methods: Between April 21 and 27, a cross-sectional epidemiologic study targeting the full population of Ischgl (n= 1867), of which 79% could be included (n=1473, incl. 214 children), was performed. For each individual, the study involved a SARS-CoV-2 PCR, antibody testing and structured questionnaires. A mathematical model was used to help understand the influence of the determined seroprevalence on virus transmission. Findings: The seroprevalence was 42.4% (95% CI 39.8-44.7). Individuals under 18 showed a significantly lower seroprevalence of 27.1% (95% CI 21.3-33.6) than adults (45%; 95% CI 42.2-47.7; OR of 0.455, 95% CI 0.356-0.682, p<0.001). Of the seropositive individuals, 83.7% had not been diagnosed to have had SARS-CoV-2 infection previously. The clinical course was generally mild. Over the previous two months, two COVID-19-related deaths had been recorded, corresponding to an infection fatality rate (IFR) of 0.25% (95% CI 0.03-0.91). Only 8 (0.5 %) individuals were newly diagnosed to be infected with SARS-CoV-2 during this study. Interpretation: Ischgl was hit early and hard by SARS-CoV-2 leading to a high local seroprevalence of 42.4%, which was lower in individuals below the age of 18 than in adults. Mathematical modeling suggests that a drastic decline of newly infected individuals in Ischgl by the end of April occured due to the dual impact from the non-pharmacological interventions (NPIs) and a significant immunization of the Ischgl population. Funding: Helmholtz Association, European Union's Horizon 2020 research and innovation program, German Research Foundation (DFG), state Tyrol.

The Common Interests of Health Protection and theEconomy: Evidence from Scenario Calculations ofCOVID-19 Containment Policies (preprint)

Several countries use shutdown strategies to contain the spread of the COVID-19 epidemic, at the expense of massive economic costs. While this suggests a conflict between health protection and economic objectives, we examine whether the economically optimal exit strategy can be reconciled with the containment of the epidemic. We use a novel combination of epidemiological and economic simulations for scenario calculations based on empirical evidence from Germany. Our findings suggest that a prudent opening is economically optimal, whereas costs are higher for a more extensive opening process. This rejects the view that there is a conflict with health protection. Instead, it is in the common interest of public health and the economy to relax non-pharmaceutical interventions in a manner that keeps the epidemic under control.

Estimate of the development of the epidemic reproduction number Rt from Coronavirus SARS-CoV-2 case data and implications for political measures based on prognostics (preprint)

The novel Coronavirus SARS-CoV-2 (COVID-19) has induced a world-wide pandemic and subsequent non-pharmaceutical interventions (NPI) in order to control the spreading of the virus. NPIs are considered to be critical in order to at least delay the peak number of infected individuals and to prevent the health care system becoming overwhelmed by the number of patients to treat in hospitals or in intensive care units (ICUs). However, there is also increasing concern that the NPIs in place would increase mortality because of other diseases, increase the frequency of suicide and increase the risk of an economic recession with unforeseeable implications. It is therefore instrumental to evaluate the necessity of NPIs and to monitor the progress of containment of virus spreading. We used a data-driven estimation of the evolution of the reproduction number for viral spreading in Germany as well as in all its federal states. Based on an extended infection-epidemic model, parameterized with data from the Robert Koch Institute and, alternatively, with parameters stemming from a fit to the initial phase of COVID-19 spreading in different regions of Italy, we found that the reproduction number was decreased to a range below 1 in all federal states. The development in Germany suggests that NPIs can be partially released based on an established new culture of social distancing, face masks and mutual care within the population. However, any release of measures delays reaching low incidence numbers. The strategy to reduce daily new cases to a sufficiently low level to be controlled by contact tracing and testing turned out to work in Germany. This requires a responsible behaviour of the population, optimised contact tracing techniques and extended testing capacities in contact clusters. Author summaryAs of mid-June Germany was able to control the pandemic to an extent that the health care system was not overwhelmed and the daily new reported infections appear under control. We analysed the evolution of the reproduction number during the epidemic in Germany and the efficiency of non-pharmaceutical interventions (NPIs) in containing viral spread. The results suggest that the cultural change induced by NPIs in interpersonal interactions and distancing allows for a partial release of political measures. However, this requires a functional case isolation and contact tracing of new cases by local health departments, early identification of contact clusters and consequent isolation of those clusters.