Human hepatitis A virus (HAV) was first grown in cell cultures four and one-half years ago, enabling significant progress toward the development of HAV vaccines. Vaccine development in a number of laboratories has proceeded on three fronts: 1) live, attenuated vaccine of cell culture origin; 2) inactivated vaccine of cell culture origin; and 3) genetic recombinant vaccines. Our studies to date have focused most heavily on the development of a live, attenuated HAV vaccine, although we have also made a prototype killed HAV vaccine form infected marmoset liver which induced anti-HAV and solid immunity to infection in marmosets. HAV was attenuated in virulence for both marmosets and chimpanzees by serial passaging in fetal rhesus monkey kidney cells and human diploid embryonic lung fibroblasts. A number of variants were produced which showed different levels of virulence/attenuation in these animal models. Some variants showed desirable live vaccine-like properties (little or no induction of enzyme elevations; little or no liver histologic change; retention of anti-HAV induction capacity). Vaccinated animals were solidly immune to challenge with virulent HAV. Experimental vaccines have been prepared from several attenuated HAV variants and preliminary studies in humans are planned.