Pseudotyped Influenza A Virus as a Vaccine for the Induction of Heterotypic Immunity

There is a need for vaccines that can protect broadly across all influenza A strains. We have produced a pseudotyped influenza virus based on suppression of the A/PR/8/34 hemagglutinin signal sequence (S-FLU) that can infect cells and express the viral core proteins and neuraminidase but cannot replicate. We show that when given by inhalation to mice, S-FLU is nonpathogenic but generates a vigorous T cell response in the lung associated with markedly reduced viral titers and weight loss after challenge with H1 and H3 influenza viruses. These properties of S-FLU suggest that it may have potential as a broadly protective A virus vaccine, particularly in the setting of a threatened pandemic before matched subunit vaccines become available. Experimental infection and recovery from influenza A virus in-fection confer partial protection fromdistantly relatedA strain viruses, in the absence of detectable cross-neutralizing antibodies (reviewed in references 14 and 20). Protection is typically associ-ated with 10- to 100-fold reduction in viral replication in the lungs, milder pathology, and improved survival, even after chal-lenge with highly pathogenic H5N1 viruses (5). Schulman and Kilbourne coined the term “partial heterotypic immunity ” for this phenomenon (46), which was first observed soon after the isola-tion of human influenza in the 1930s when ferrets that had recov