Background
Historically, attenuated live microbes have proven to be highly effective.  The advent of genomics, molecular genetics, and high through put screening methods has raised the possibility of generating safe candidate live agents---viruses for which no effective vaccine exists, bacteria, and even protozoa---that might be designed to lose virulence yet retain immunogenicity. 

Roadblock
We currently lack suitable means for testing live attenuated candidate vaccine agents capable of providing reliable and predictive information about both immunogenicity and pathogenicity, short of subjecting them to clinical trials in human subjects.

Challenge
To develop suitable model systems for testing the behavior of candidate attenuated live vaccines for residual virulence, immunogenicity relevant to protection against infection, replication capacity, cellular host range, and reversion to full virulence.  Such systems might be generated in cell or organ culture in vitro, but more likely would require adaptation of rodent or primate animal hosts by genetic means or transplantation to more closely resemble the human host for that agent with respect to replication, pathogenesis, and the immune response.

Potential Benefits

• Acceleration of the development of highly effective, stable vaccines
• Elucidation of principles to guide the development of additional live vaccines

Priority Areas

• Viruses refractory to vaccine development (such as HIV, HCV, herpes viruses, etc.)
• Pathogenic bacteria
• Selected complex pathogens (protozoa, yeasts, fungi, etc.)