Feline panleukopenia virus (FPV) is a parvovirus that causes severe disease in cats, as well as in a variety of wild carnivores or animals in zoos - including many endangered animals. In the absence of vaccination virtually all cats will be infected by FPV within the first year of life. In kittens older than about 5 weeks the virus may cause a severe enteritis due to virus replicating in and killing the dividing stem cells that regenerate the intestinal epithelium. If kittens are infected during the neonatal period (or perhaps in utero) they may develop cerebellar hypoplasia resulting in permanent ataxia. A modified live FPV is a component of all of the standard (core) feline vaccines. However, it appears that the viral strains in most of the vaccines in the USA were collected over 50 years ago, and there has been variation in the viruses since those were collected. Recent widespread outbreaks of FPV-disease around the world have raised the possibility that the vaccines are not as effective as they were previously, or that there are changes in the virulence or tropism of the viruses. In this study we will therefore analyze the sequence variation of FPV viruses from the USA and from current commercial vaccines, and will compare those to sequences of viruses from other countries. From our related work on canine parvovirus (CPV) we have determined the structures of the viral capsids, identified the binding site of the host receptor, and the binding sites of many antibodies against the capsid. We will therefore map the variation in the entire viral genome, identify changes that may alter functional sites on the capsids, and determine the structures of some viruses that contain key mutations using cryo-electron microscopy (cryoEM). We will also analyze the antigenic reactivity of viruses by HA inhibition, ELISA and neutralization assays with feline sera from vaccinated or naturally infected cats. We will also compare the reactions of capsids with a panel of monoclonal antibodies generated against FPV or CPV capsids. Finally, we will examine the binding sites and patterns of feline antibodies to the FPV capsids using cryoEM of capsids complexed with polyclonal antibody-derived Fabs. Our overall goals are to understand the natural history and genetic variation of the FPV-like viruses, to reveal their antigenic structure and variation, to identify mutations that influence host receptor binding, and to determine whether there are differences between vaccine viruses and contemporary circulating virus strains.