The observed similarity S O of pairs of experimentally verified cross-reactive epitopes (x,y) is to be compared to unrelated peptides (z i ) which retain the sequence identity of (x,y) but have an otherwise random amino acid on non-identical positions. The procedure to compute the ''unrelated'' or ''baseline'' expected similarity is best illustrated by an example: The HLA-A2 epitopes x = GLCTLVAML and y = GILGFVFTL from EBV and influenza-A share 3 identical positions: G1, V6 and L9. We first compute the observed similarity S O = S(x,y) between epitopes x and y using Eq. (2). Then we generate a set of N = 10.000 random peptides, z 1 , z 2 , L, z N , with the same identical positions, i.e. we have z i = G......V...L where a dot can be any amino acids avoiding identity with x at that position. The expected similarity between the primary (original) epitope (x) and the unrelated but semi-identical artificial peptides z is then defined as the average similarity to the ensemble of unrelated peptides as: S E~1 N P N i~1 S x,z i ð Þ.