Approximately 60% of people ill with influenza A virus subtype H5N1 infection die [1], a case fatality rate about 25 times worse than that during the 1918 pandemic [2]. It is hard to even imagine the devastation that would result if such a virus spread widely. However, as discussed by many, the case fatality rate might decline with adaptation to transmission. Even now, H5N1 cases may be underreported (and hence the case fatality rate may be overestimated) because some infections are mild or asymptomatic. Questions about the real frequency of H5N1 infection, and thus the case fatality rate have led to seroprevalence surveys. In areas where H5N1 outbreaks have recently occurred, results show low numbers of seropositive people whose infections must have been asymptomatic or mild [3,?4].

Are such surveys missing H5N1 infections by screening only for antibody? Using antibody as a marker of infection has practical advantages but also limitations, including assay technical issues and low immunogenicity of H5 hemagglutinin (HA) for antibody responses [5]. In this issue of the Journal, the group of Tao Dong at Oxford University (Powell et al) investigated another option. They asked whether assays for T-cell immunity to H5 HA can be used to detect asymptomatic infections. In the past, large-scale population screening for T-cell responses would have been an overwhelming technical challenge. It is still a major effort, but it is now feasible to screen large numbers of human subjects for T-cell responses to overlapping peptide libraries spanning viral antigens.

Powell et al screened a Vietnamese cohort of 747 people with potential asymptomatic H5N1 exposure due to occasional avian and human H5N1 outbreaks nearby in the preceding few years. They used T-cell interferon-γ enzyme-linked immunosorbent spot (ELISPOT) assays with peptide pools …