question: BackgroundThe public and scientific discourse on how to mitigate the COVID-19 pandemic is often focused on the impact of individual protective measures, in particular on vaccination. In view of changing virus variants and conditions, however, it seems not clear if vaccination or any other protective measure alone may suffice to contain the transmission of SARS-CoV-2. MethodsHere, we investigate the effectiveness and synergies of vaccination and non-pharmaceutical interventions like masking, distancing & ventilation, testing & isolation, and contact reduction as a function of compliance in the population. Our new analysis accounts for the practical compliance in the population and for both droplet transmission and aerosol transmission. FindingsFor realistic conditions, we find that it would be difficult to contain highly contagious SARS-CoV-2 variants by any individual measure. Instead, we show how multiple synergetic measures have to be combined to reduce the effective reproduction number (Re) below unity for different basic reproduction numbers ranging from the SARS-CoV-2 ancestral strain up to measles-like values (R0 = 3 to 18). For R0 = 5 as reported for the Delta variant and [~]70% vaccination rate, the synergies of masking and distancing & ventilation with compliances around 30% appear sufficient to keep Re < 1. In combination with 2-3 tests per week, this would work also at lower vaccination rates, e.g., in schools. InterpretationIf the Omicron variant were to reach R0 = 8, it could still be contained with the synergetic measures outlined above. In case of measles-like transmissibilities (R0 = 12 to 18), higher compliances and testing rates or additional measures like general contact reductions would be required. The presented findings and approach can be used to design and communicate efficient strategies for mitigating the COVID-19 pandemic. FundingMax Planck Society. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSStudies on how to mitigate the COVID-19 pandemic are often focused on the impact of individual protective measures, in particular on vaccination. The effectiveness of non-pharmaceutical interventions (NPIs) like masking or distancing & ventilation are often under debate due to a lack of understanding of different transmission pathways (droplet versus aerosol transmission) and protective measures, in particular for the efficacy of masking and contrasting randomized trial results under different conditions (virus-limited vs. virus-rich) and at different levels of practical compliance. Thus, in view of more contagious variants such as Delta or Omicron, it is not clear if vaccination or any other protective measure alone may suffice to contain the transmission of SARS-CoV-2. Added value of this studyOur analysis explicitly accounts for both droplet and aerosol transmission as well as for practical compliance in the population, which is the main reason for divergent results on the effectiveness of the same NPIs in different regions. This was not fully considered before and may have led to misunderstandings and misinformation about the actual effects of preventive measures. For realistic conditions, we find that it would be difficult to contain highly contagious SARS-CoV-2 variants by any individual measure. Instead, we show that combining multiple synergetic measures with realistic compliances can reduce Re below unity without lockdown. Implications of all the available evidenceOur findings and the presented scientific approach can be used to design and communicate efficient strategies for mitigating the COVID-19 pandemic for specific environments like schools as well as on a population level.