Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is critical to controlling the coronavirus disease 2019 (COVID-19) pandemic. However, a weak response to the vaccine and insufficient persistence of specific antibodies may threaten the global impact of mass vaccination campaigns. This study summarizes the internal factors of the body that affect the effectiveness of the SARS-CoV-2 vaccine. T follicular helper (Tfh) cells support germinal center B cells to produce vaccine-specific immunoglobulins. A reduction in the Tfh cell number and a shift in the subset phenotypes caused by multiple factors may impair the production and persistence of high-affinity antibodies. Besides efficacy differences caused by the different types of vaccines, the factors that affect vaccine effectiveness by intervening in the Tfh cell response also include age-related defects, the polarity of the body microenvironment, repeated immunization, immunodeficiency, and immunosuppressive treatments. Assessing the phenotypic distribution and activation levels of Tfh cell subsets after vaccination is helpful in predicting vaccine responses and may identify potential targets for improving vaccine effectiveness.