Several vaccines against COVID-19 are now available, based on different techniques and made by different laboratories spread around the world. With the roll out of the vaccination process in an advanced stage in many countries, the reduced risk of hospitalization due to the Omicron variant relative to the Delta variant infection, despite the higher transmission risk of Omicron, may lead to a misinterpretation of the results, as infection by Omicron is associated with a significant reduction in severe outcomes and shorter hospitalization time than the Delta variant. We compared the in-hospital mortality due to the Omicron (Jan–Mar 2022) with Gamma (Jan 2021) and Delta (Oct–Dec 2021) variants of patients in the Brazilian public health system. This study also discusses the decrease in booster vaccine effectiveness in patients hospitalized due to the Omicron variant compared with the Delta variant. Without a remodeling of vaccines for new variants, booster doses may be necessary with a shorter time interval.