We know, as Dr. Palese has often pointed out, that the 1918 virus caused a W-shaped death rate. That is, if we plot the number of deaths on the Y-axis and the age groups that died on the X-axis, we find that young people died early on, and then there was a gap, and older people died much later. People between 30 and 60 years of age presumably had prior exposure to an H1-like virus. We should add that it is thought that H3 and H1 both circulated before 1918, and that there is no evidence that H5, H7, H9, or any of the highly pathogenic viruses in avian species were found in humans in those earlier times.

A question about viral archeology inevitably comes up—the sort of studies that Dr. Jeff Taubenberger has done. Such investigation is very difficult because tissues were not preserved before 1900. His work was done on formalin fixed tissues. The question was raised whether we could examine tombs in churches for examples of antibodies, but we felt that would be extremely difficult.

At the theoretical level we can continue to predict changes and the effect on antigenic epitopes. An example is the paper in the Proceedings of the National Academies of Science by evolutionary biologist Dr. Simon Levin and his group, who predicted HA clusters and antigenic evolution. Such studies should continue.

Surveillance of influenza viruses—now occurring throughout the world—should also continue, as should nucleotide sequencing of viral genomes. Ideally, we need better immunological markers. We point out that hemagglutinin inhibition tests are insensitive, and that they don't work on H5 viruses.

Question 4 addressed the studies needed to determine pandemic risk associated with antigenic characteristics. We need to determine the extent of antigenic variation that yields a pandemic strain. We need both human and animal studies to follow how much variation can occur in a strain and still lead to disease and pandemic potential.

We would like to know whether preexisting antibody to one subtype can have an effect on infection with another subtype. That is, we can look at the ability of viruses of different subtypes to infect animals such as ferret that already have antibody levels to common human viruses. If we already have some antigenic determinants to a component of any one of those viruses, might that provide some benefit against infection with another influenza virus?

Lastly, Dr. Purnell Choppin and others asked whether we need studies that ask whether human genetic changes increase or decrease susceptibility to influenza virus infection. Could such studies be coupled to the NCI cancer genome project? For the mouse, such work could easily be coupled with the huge forward genetics projects occurring at five centers in the United States for mutagenizing the mouse on a total random basis and mapping any genetic changes. Could we use those leftover mice to determine if their susceptibility to influenza had increased or decreased? Although the mouse may not be a very good model, those projects provide an avenue of research.

Our workshop’s first priority is to determine the sequences of human, animal, and avian isolates within an epidemiological framework. We want to stress the latter, because just having the sequences doesn’t help. We need to know the clinical data from human cases to accompany the sequences.

Our second major recommendation is to determine the genes and their function for transmission and pathogenicity in ferrets using qualified reagents. That one sentence



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