The COVID-19 pandemic has led to an unprecedented global response in terms of social lockdown in order to slow the spread of the virus 1,2. Currently the greatest hope is based on world-wide vaccination3,4. The expectation is that social and economic activities can gradually resume as more and more people become vaccinated. Yet, a relaxation of social distancing that allows increased transmissibility, coupled with selection pressure due to vaccination, will likely lead to the emergence of vaccine resistance 5. Here we analyze the evolutionary dynamics of COVID-19 in the presence of dynamic lockdown and in response to vaccination. We use infection and vaccination data of 6 different countries (Israel, US, UK, Brazil, France and Germany) to assess the probability and timing for the wave of vaccine resistant mutant2. For slow vaccination rates, resistant mutants will appear inevitably even if strict lockdown is maintained. For fast vaccination rates (such as those used in Israel) the emergence of the mutant can be prevented if strict lockdown is maintained during vaccination. Our mathematical results provide quantitative guidelines for a combined vaccination and lockdown policy that minimizes the probability of emergence of vaccine resistance variants for current and future vaccination programs.