Killed vaccinia virus does not induce antibodies against proteins that trigger smallpox, forcing researchers to look for alternative strategies. Xu et al. considered designing vaccines that target virulence proteins that mute the immune response. They reasoned that a vaccine that did not include the entire virus would be safer, while antibodies against virulence proteins, known as immune response modifiers (IRMs), would prevent disease even if they did not neutralize the virus.

The group now identifies an IRM that is the major target of protective antibodies in a mouse model of smallpox. This IRM prevents the antiviral cytokine interferon- from activating its receptor on immune cells. Deletion of the IRM from the mousepox virus, the group found, caused a 10⁷-fold decrease in its virulence and prevented lethality.

Mice that were injected with the IRM alone were protected against a later challenge with the wild-type virus. The IRM, the type I interferon binding protein, is well-conserved among poxviruses that infect mice and men, so the hope is that the recombinant IRM protein might be an effective poxvirus vaccine for humans as well.