Vaccines that provide long-lasting protection against influenza, coronaviruses and respiratory syncytial virus (RSV) are difficult to develop. In a new review article in Cell Host & Microbe, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, explore the challenges and outline approaches to improved vaccines. Anthony S. Fauci, M.D., former NIAID director, is an author along with Jeffery K. Taubenberger, M.D., PhD, and David M. Morens, M.D. Unlike the respiratory viruses that cause measles, mumps and rubella — for which vaccination or recovery from illness provides decades-long protection against future infection — flu, RSV, SARS-CoV-2 and ‘common cold’ coronaviruses share several characteristics that enable them to cause repeated re-infections. These include very short incubation periods, rapid host-to-host transmission and replication in the nasal mucosa rather than throughout the body. This last feature — non-systemic replication — means these viruses do not stimulate the full force of the adaptive immune response, which typically takes a week or more to mount. A next generation of improved vaccines for mucosa-replicating viruses will require advances in understanding on several fronts, the authors say.