With the ongoing COVID-19 pandemic, many healthcare workers, as well as scientists are pressured by external expectations to find effective approaches that would prevent the spread of the virus within a short period of time including, possible cures, different types of prevention and vaccines. Indeed, the vaccines may have been produced within an appropriate amount of time during the pandemic. However, throughout the processes taken in preventing the spread of the virus, many steps were overlooked. Thus, the efficacy of these vaccines is not at their fullest potential. Here, we discuss a hypothesis emerging from the studies below, regarding the human microbiome influence on the overall efficacy of COVID-19 vaccines. The microbiota’s crucial role in modulating vaccine immune responses is further explained through other immune processes that require the help of the microbiota as well as factors that help strengthen or weaken the relationship between the human immune responses and the microbiota itself.