Discussion
The three North American 1918 influenza strains sequenced previously were isolated from patients separated by nearly 2 months in time and almost 4,000 miles in distance.[27] Two nucleotide differences were found among these three strains, one of which resulted in an amino acid substitution in the receptor-binding site.[15] All three cases likely derived from the initial introduction of the fall wave into the United States, believed to have occurred in Boston in early September 1918. The virus then spread rapidly from Camp Devens, Massachusetts, the first U.S. army base to experience the epidemic, which then reached army bases throughout the eastern United States within 2 weeks.[2] Influenza probably reached Brevig Mission, Alaska, via Seattle, Washington. The pandemic reached Camp Lewis, Washington, in mid-September, following the arrival of a troop ship from Philadelphia, Pennsylvania,[1,2] and spread to Seattle by late September. After careful screening to exclude sick passengers, a ship left Seattle for Nome, Alaska, in mid-October, but days after its arrival local residents began falling ill.[1] An account of the pandemic as it occurred in Brevig Mission reports that visitors from Nome brought the disease to the village in November.[28] This chain of events suggests that the Alaskan outbreak was not the result of a separate introduction of the 1918 influenza from Asia to the West Coast of the United States.
The spring wave of the 1918 epidemic was widespread in France and Spain during April and May but did not reach England until June. The fall wave also arrived somewhat later in England than in continental Europe and the United States; peak mortality in London occurred during the first 2 weeks of November.[2] A second peak occurred in the third week of February 1919. One strain from each of these peaks was sequenced for this study.
Our results show that strains separated by over 7,500 miles (Brevig Mission, Alaska, to London, United Kingdom) and several months (September 26, 1918, to February 15, 1919) share a sequence identity of 99%. This level of genetic homogeneity is slightly higher than that seen for the available 1957 and 1968 pandemic strains, but the 1957 and 1968 strains were not sequenced directly from clinical material. Sequences from different passages of the same strain were sometimes as different from each other as they were from other strains,[29] suggesting that sequence heterogeneity observed was the result of culture adaptation, making it impossible to determine how homogeneous the pandemic viruses actually were. Even so, the 1957 and 1968 pandemic strains show >97% identity between strains. Similar levels of genetic homogeneity were seen in strains from case-patients isolated from a drift epidemic in 1997. Thus, influenza viruses circulating during a single outbreak, whether epidemic or pandemic, show levels of sequence identity consistent with the uniformity of the 1918 cases.
Despite the uniformity of the 1918 strains, one of the variable sites is an amino acid known to be important in receptor binding.[21] At a subset of amino acids critical for receptor binding, avian strains differ from swine H1s at only one amino acid, E190D.[15] At these amino acids, two of the cases (A/New York/1/1918 and A/London/1/1919) are identical to that of A/sw/Iowa/1976/31 (a classical swine strain). The other 1918 cases have an additional change from the avian consensus at amino acid 225. Since swine viruses with the same receptor site as A/sw/Iowa/1976/31 bind both SAa2,3Gal and SAa2,6Gal,[14] A/New York/1/1918 and A/London/1/1919 probably also had the capacity to bind both receptors. Because two of five 1918-19 analyzed fall wave strains from case-patients have the swine-like receptor-binding pattern, the E190D change alone is apparently sufficient to allow viral replication in the human respiratory tract. However, the existence of three strains with the additional G225D change shows that both receptor-binding variants were co-circulating throughout the pandemic. The current evidence does not suggest progression from one receptor-binding pattern to the other during the pandemic, since the two variants are present, on both continents, both early and late in the pandemic. Since residue 225 has also been identified as part of the Ca antigenic site,[19] the co-circulating strains possibly differed in antigenic reactivity as well as receptor-binding characteristics.
This study is the first to examine the genetic homogeneity of a pandemic influenza virus directly from clinical material. The results suggest that in the early stages of a pandemic, mutations that occur during replication do not become fixed so that a uniform consensus strain circulates for some time. Studies of influenza strains circulating after 1919 should provide insight into how pandemic viruses evolve after the initial waves through immunologically vulnerable populations. In terms of pandemic planning, our results indicate that a specific antiviral drug or vaccine would have a uniform effect during the important and often lethal first wave of a pandemic.[30,31]
This work was supported by a grant from the National Institute of Allergy and Infectious Diseases (R01 AI50619-01) to J.K.T. and by the intramural funds of the Armed Forces Institute of Pathology. J.S.O., C.L.B., and R.S.D. gratefully acknowledge financial support from the Wellcome Trust and the Ian Heap fund.
Jeffery K. Taubenberger, Armed Forces Institute of Pathology, Department of Cellular Pathology and Genetics, 1413 Research Blvd., Building 101, Room 1057, Rockville, MD 20850-3125, USA; fax: 1-301-295-9507; email: taubenbe@afip.osd.mil
Emerging Infectious Diseases. 2003;9(10) © 2003 Centers for Disease Control and Prevention (CDC)
Cite this: 1918 Influenza Pandemic Caused by Highly Conserved Viruses with Two Receptor-Binding Variants - Medscape - Oct 01, 2003.