Without a cure, vaccine, or proven long-term immunity against SARS-CoV-2, test-trace-and-isolate (TTI) strategies present a promising tool to contain its spread. For any TTI strategy, however, mitigation is challenged by pre- and asymptomatic transmission, TTI-avoiders, and undetected spreaders, which strongly contribute to ”hidden" infection chains. Here, we study a semi-analytical model and identify two tipping points between controlled and uncontrolled spread: (1) the behavior-driven reproduction number $${R}_{t}^{H}$$RtH of the hidden chains becomes too large to be compensated by the TTI capabilities, and (2) the number of new infections exceeds the tracing capacity. Both trigger a self-accelerating spread. We investigate how these tipping points depend on challenges like limited cooperation, missing contacts, and imperfect isolation. Our results suggest that TTI alone is insufficient to contain an otherwise unhindered spread of SARS-CoV-2, implying that complementary measures like social distancing and improved hygiene remain necessary.

Mass vaccination offers a promising exit strategy for the COVID-19 pandemic. However, as vaccination progresses, demands to lift restrictions increase, despite most of the population remaining susceptible. Using our age-stratified SEIRD-ICU compartmental model and curated epidemiological and vaccination data, we quantified the rate (relative to vaccination progress) at which countries can lift non-pharmaceutical interventions without overwhelming their healthcare systems. We analyzed scenarios ranging from immediately lifting restrictions (accepting high mortality and morbidity) to reducing case numbers to a level where test-trace-and-isolate (TTI) programs efficiently compensate for local spreading events. In general, the age-dependent vaccination roll-out implies a transient decrease of more than ten years in the average age of ICU patients and deceased. The pace of vaccination determines the speed of lifting restrictions; Taking the European Union (EU) as an example case, all considered scenarios allow for steadily increasing contacts starting in May 2021 and relaxing most restrictions by autumn 2021. Throughout summer 2021, only mild contact restrictions will remain necessary. However, only high vaccine uptake can prevent further severe waves. Across EU countries, seroprevalence impacts the long-term success of vaccination campaigns more strongly than age demographics. In addition, we highlight the need for preventive measures to reduce contagion in school settings throughout the year 2021, where children might be drivers of contagion because of them remaining susceptible. Strategies that maintain low case numbers, instead of high ones, reduce infections and deaths by factors of eleven and five, respectively. In general, policies with low case numbers significantly benefit from vaccination, as the overall reduction in susceptibility will further diminish viral spread. Keeping case numbers low is the safest long-term strategy because it considerably reduces mortality and morbidity and offers better preparedness against emerging escape or more contagious virus variants while still allowing for higher contact numbers (freedom) with progressing vaccinations. In this work, we quantify the rate at which non-pharmaceutical interventions can be lifted as COVID-19 vaccination campaigns progress. With the constraint of not exceeding ICU capacity, there exists only a relatively narrow range of plausible scenarios. We selected different scenarios ranging from the immediate release of restrictions to more conservative approaches aiming at low case numbers. In all considered scenarios, the increasing overall immunity (due to vaccination or post-infection) will allow for a steady increase in contacts. However, deaths and total cases (potentially leading to long covid) are only minimized when aiming for low case numbers, and restrictions are lifted at the pace of vaccination. These qualitative results are general. Taking EU countries as quantitative examples, we observe larger differences only in the long-term perspectives, mainly due to varying seroprevalence and vaccine uptake. Thus, the recommendation is to keep case numbers as low as possible to facilitate test-trace-and-isolate programs, reduce mortality and morbidity, and offer better preparedness against emerging variants, potentially escaping immune responses. Keeping moderate preventive measures in place (such as improved hygiene, use of face masks, and moderate contact reduction) is highly recommended will further facilitate control.

Test-trace-and-isolate and moderate contact restrictions offer sustainable exit strategies complementary to vaccination.