Despite being considered one of the greatest achievements of modern medicine, vaccination is often limited by poor responses in a significant fraction of the general population. For example, influenza vaccine is clinically effective in most young adults, but it is clinically ineffective in the majority of elderly individuals. Improved understanding of vaccine immunology and identification of new biomarkers for vaccine efficacy are required to guide the optimization of immunization strategies and the development of new vaccines. Here we report hypoleptinemia as an important risk factor for poor vaccine responses. We found that low leptin was strongly associated with low antibody responses to influenza and hepatitis B virus (HBV) vaccines in different age groups. Similarly, leptin receptor-deficient mice showed impaired antibody responses after influenza virus infection or immunization. In a more physiological setting, fasting mice failed to mount vaccination-mediated protection to influenza infection, but this was largely rescued by leptin replacement. Mechanistic studies revealed that leptin promotes both mouse and human follicular helper T (TFH) cell differentiation and IL-21 production in a Stat3-dependent manner. TFH cells are specialized CD4+ T cell subset that is essential for supporting vaccine-induced antibody responses. Our results for the first time identify the "satiety hormone" leptin as a natural regulator of both mouse and human TFH cells and a biomarker of vaccine responses.