viral replication—induced by one influenza A subtype that protects against another (see Epstein in Chapter 5; Epstein, 2004). It can be induced in mouse models with live, wild-type viruses or inactivated viruses given mucosally, but has not been studied for the live attenuated viruses sometimes used in influenza vaccines. Although Het-I has not been demonstrated to occur in humans, accounts of the 1957 pandemic suggest that it occurred and that additional historical epidemiological investigation would reveal further evidence of its existence.

Researchers thus reasoned that if Het-I could be induced in humans through mass or routine immunization, there is the possibility that they would gain broad cross-protection against all influenza A subtypes, which should at least reduce mortality in a pandemic until a matched vaccine became widely available (Epstein, 2004). Vaccines could be made in advance and administered to prime immunity, and they could be used “off the shelf” in the event of a pandemic to reduce symptoms until a matched vaccine became widely available. Several proteins that are relatively conserved among all subtypes have proved promising targets for such a strategy, and have been shown to induce immunity that greatly reduced morbidity and mortality in mouse influenza models (Epstein, 2004; Epstein et al., 2002). These antigens were delivered in the form of DNA vaccines, which offer several advantages: They can be preserved at ambient temperatures, removing the need for a cold chain; because they are produced in bacterial cell culture, not in eggs or mammalian cell cultures, they might eventually be cheaper or faster to produce; and they permit investigation of the roles of individual viral proteins in immunity. However, it must be stated that although a DNA vaccine strategy may be effective in addressing pandemic influenza, it is years away from clinical use because no DNA vaccine has been shown to provide effective immune protection from disease (any disease) nor has one been registered with the FDA for future approval.

Another weapon that could be aimed at broadly conserved features among influenza A strains is RNA interference (RNAi) technology, which consists of short, complementary RNA sequences that inhibit protein expression. In this case, the target proteins are necessary for influenza A replication, of which several are relatively conserved among known viral subtypes. Prior studies on this technology have examined viral systems in vitro and in vivo, but few disease models have been explored. Recently, researchers from the CBER and CDC demonstrated that RNAi could protect against lethal virus challenge by H5N1, H1N1, and H7N7 in mice (Tompkins et al., 2004). A second group from the Massachusetts Institute of Technology produced similar results in mice against H1N1 using an intranasal plasmid delivery system that could be adapted for clinical use (Ge et al., 2004).

Although these initial results appear promising, workshop participants raised important challenges that must be resolved before taking this tar-