1918 Influenza Pandemic and Highly Conserved Viruses with Two Receptor-Binding Variants

Spanish influenza pandemic swept the globe in the autumn and winter of 1918-19, and resulted in the deaths of approximately 40 million people. Clinically, epidemiologically , and pathologically, the disease was remarkably uniform, which suggests that similar viruses were causing disease around the world. To assess the homo-geneity of the 1918 pandemic influenza virus, partial hemagglutinin gene sequences have been determined for five cases, including two newly identified samples from London, United Kingdom. The strains show 98.9% to 99.8% nucleotide sequence identity. One of the few differences between the strains maps to the receptor-binding site of hemagglutinin, suggesting that two receptor-binding configurations were co-circulating during the pandemic. The results suggest that in the early stages of an influenza A pandemic, mutations that occur during replication do not become fixed so that a uniform " consensus " strain circulates for some time. T he 1918–19 influenza pandemic began, in some parts of the world, with mild outbreaks in the spring of 1918. In the fall of that year, a lethal wave swept the globe. Outbreaks occurred in early September in North America, Europe, and Africa and spread rapidly, so that the disease had peaked and declined worldwide by the end of December (1–4). Many areas had an additional wave of the disease in the early months of 1919. In most communities, the fall wave of the pandemic lasted approximately l month, with 25% to 30% of the population experiencing symptomatic disease. Clinically, epidemiologically, and pathologically, the disease was remarkably uniform, suggesting that similar viruses were causing disease worldwide (5). To assess the homogeneity of the 1918 pandemic influenza virus, partial hemagglutinin (HA) gene sequences were determined for strains from five cases, including two newly identified samples from London, United Kingdom. The strains show 98.9% to 99.8% nucleotide sequence identity. One of the few differences between the strains maps to the receptor-binding site of HA, which suggests that two receptor-binding configurations were co-circulating during the pandemic. Influenza A virus is capable of rapid genetic change in mammals (6–8). Its polymerase complex lacks proofreading capability, such that one in five virus particles produced is likely to contain a change at one of its approximately 13,500 nt (9). If such a change provides the virus with a competitive advantage, that strain quickly replaces its predecessor. In humans, the need to escape preexisting immunity exerts positive selection pressure on changes in amino acids comprising the …