Scientists are now equipped with a more detailed picture of the human immune system's response to influenza vaccination, thanks to the results of a new investigation. They say their findings could help guide better vaccine development, because understanding the cellular basis for protective immunity is critical for creating effective immunizations. Even though influenza vaccination is well-established as the most effective strategy to prevent people from becoming sickened with seasonal flu, many details about how the immune system fends off the virus and protects the body remain mysterious. Here, Marios Koutsakos and colleagues closely examined how different types of immune cells respond to vaccines. They analyzed blood samples from 35 healthy adults at several time-points during a three-year period following immunization. Beginning one week after vaccination, Koutsakos et al. noted a marked increase in antibody-producing B cells programmed to fight against specific components of the corresponding year's flu shots. A similar pattern emerged for another group of cells called circulating T follicular helper cells (cTfh) - providing new insight about their ability to generate long-lasting immune memory. The presence of pre-existing anti-flu antibodies prior to vaccination in study participants' blood dampened B cell responses. After one year, flu-specific B cells were no longer detected in the blood - prompting the researchers to analyze tissues from deceased organ donors (which allowed them to track down memory B cells in the lungs, tonsils, spleens, and lymph nodes). The authors speculate that the migration of flu-specific B cells to different tissues could have implications for the ideal inoculation route, and that intranasal vaccination might be more effective than injections.