Rationalizing the development of live attenuated virus vaccines

Since the first demonstration of the protective effects of vaccinia inoculation, vaccination has been one of the medicine’s greatest successes. The design of vaccines against viral disease has evolved considerably over the last 50 years. Classically attenuated viruses, those created by passaging a virus in cultured cells, have proven to be an effective means for preventing many viral diseases, including smallpox, polio, measles, mumps, and yellow fever. However, empiric attenuation is not a reliable approach for all viruses and there are a number of safety issues associated with the use of live, attenuated viruses (LAVs). While inactivated viruses and subunit vaccines alleviate many of these concerns, they have generally been less efficacious than their LAV counterparts. Advances in molecular virology have provided new ways of controlling viral replication and virulence, renewing interest in LAV vaccines. These rationally attenuated viruses may lead to a new generation of safer, more widely applicable LAV vaccines. Here, we review several new approaches to viral attenuation and vaccine design, including deleterious gene mutation, altered replication fidelity, codon deoptimization, and control by microRNAs or zinc finger nucleases. While each of these approaches has garnered significant attention in recent months, they are still in their infancy and require further in vitro and animal testing before progressing to clinical trials.