The article discusses the immunological principles and challenges in developing effective COVID-19 vaccines. It highlights the importance of understanding natural immunity and vaccine-induced immunity, particularly the role of trained immunity and T cell-mediated immunity. The article reviews the current landscape of COVID-19 vaccine candidates, including live attenuated viruses, recombinant viral vectors, inactivated viruses, protein subunits, virus-like particles, and nucleic acid-based vaccines. It emphasizes the need for a multi-platform approach due to the complexity of the virus and the potential for different immune responses. The article also addresses safety considerations, such as the risk of antibody-dependent enhancement (ADE) and the importance of preclinical animal models. Finally, it outlines the potential strategies for vaccine design, including the selection of antigens, vaccine platforms, and vaccination routes, and discusses the progress and challenges in clinical trials.The article discusses the immunological principles and challenges in developing effective COVID-19 vaccines. It highlights the importance of understanding natural immunity and vaccine-induced immunity, particularly the role of trained immunity and T cell-mediated immunity. The article reviews the current landscape of COVID-19 vaccine candidates, including live attenuated viruses, recombinant viral vectors, inactivated viruses, protein subunits, virus-like particles, and nucleic acid-based vaccines. It emphasizes the need for a multi-platform approach due to the complexity of the virus and the potential for different immune responses. The article also addresses safety considerations, such as the risk of antibody-dependent enhancement (ADE) and the importance of preclinical animal models. Finally, it outlines the potential strategies for vaccine design, including the selection of antigens, vaccine platforms, and vaccination routes, and discusses the progress and challenges in clinical trials.