Using directed attenuation to enhance vaccine immunity

Abstract

Many viral infections can be prevented by immunizing with live, attenuated vaccines. Early methods of attenuation were hit-and-miss, and these are now much improved by genetic engineering. But even current attenuation methods operate on the principle of genetic harm, reducing the viruss ability to grow, which in turn limits the host immune response below that of infection by wild-type. We use mathematical models of the dynamics of virus and its control by innate and adaptive immunity to explore the tradeoff between attenuation of virus growth and the generation of immunity. Our analysis suggests that directed attenuation that disables key viral defenses against the host immune responses may attenuate viral growth without compromising, and potentially even enhancing the generation of immunity. We explore which immune evasion pathways should be attenuated and how attenuating multiple pathways could lead to robust attenuation of pathology with enhancement of immunity. Author summaryLive attenuated virus vaccines are among the most effective interventions to combat viral infections. Historically, the mechanism of attenuation has been one of genetically reduced viral growth rate, often achieved by adapting the virus to grow in a novel cells. More recent attenuation methods use genetic engineering but also are thought to impair viral growth rate. These classical attenuations typically result in a tradeoff whereby attenuation depresses the within-host viral load and pathology (which is beneficial to vaccine design), but reduces immunity (which is not beneficial). We use models to explore ways of directing the attenuation of a virus to avoid this tradeoff. We show that directed attenuation by interfering with (some) viral immune-evasion pathways can yield a mild infection but elicit higher levels of immunity than of the wild-type virus.