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Paradigm Shift Intervention Monitoring
The 2009 H1N1 pandemic is
entering its third
wave, which is following an evolutionary course that requires
genetic changes that will target the human population that was infected
or vaccinated last season. The appearance of S188T,
a change adjacent to receptor binding position 190, raised concerns
that pandemic H1N1 would follow an evolutionary path similar to changes
seen in 2008/2009 for seasonal H1N1.
The fixing of H274Y was facilitated by that change hitchhiking on an H1N1 genetic backbone that had acquired A193T and at least one additional change at positions 187, 189, and 196. These three positions where each changed at least two times in the seasonal H1N1 sequences that emerged in the 2008/2009 season. Virtually all H1N1 sequences had this combination of changes, demonstrating how dominant and critical the changes were for the seasonal H1N1 emergence in 2008/2009. These combinations allowed frequencies of H274Y to increase from 0% to 100% in one season in many countries.
Thus, the appearance of S188T and its rapid spread led to concerns that it was driving immunological escape, and the release of four HA sequences from recent fatal cases in the United Kingdom increased those concerns. S188T was present on one of the sequences, A/England/4880374/2010, from a fatal case. The publication of a phylogenetic analysis of 41 recent sequences from the UK included 22 sequences with S188T, demonstrating its role in establishing pandemic H1N1 in the UK.
However, another sequence, A/England/118/2010, from another fatal case, had an adjacent change, S186P, and the phylogenetic analysis demonstrated this receptor binding change on 14 additional sequences.
Thus, as was seen in seasonal H1N1, two changes in this key region could be found in the vast majority (36 of the 41 sequences) of cases, demonstrating the role of these changes in the spread of pandemic H1N1 in a population that had been exposed to pandemic H1N1 in the previous season.
Of additional concern was the presence of D225G on sequences, A/England/4880378/2010 and A/England/4940476/2010, from two severe cases because both sequences were identical, signaling clonal transmission. These two sequences were on a branch that had S188T as well as D100N. D100N is on multiple genetic backgrounds. In the phylogenetic analysis it was on three backgrounds, including two that are currently co-circulating in the UK. Moreover, the branch with D100N, S188T, and D225G had seven sequences and five of the seven were from severe or fatal cases. This clustering raises concern that D225G was in additional patients, but not detected in the sample collected or virus isolated.
The transmission of D225G via a dominant gentic background could be catastrophic. Two of the five sequences from fatal cases who died in 1918 or 1919 had D225G, demonstrating its transmissibility under certain circumstances. Last season the frequency of D225G was relatively low in the overall population, but almost all sequences with D225G were from severe or fatal cases, as reported for samples from multiple countries and on multiple genetic backgrounds.
The detection of two identical sequences with D225G on a genetic background with drivers such as S188T and D100N raise concerns that the frequency of D225G could increase markedly and generate a much higher frequency of severe and fatal cases.
Currently, the level of severe and fatal cases in the UK has clearly taxed the health care delivery system, filling up ICU beds and raising use of available EMCO machines to 100%. A jump in the levels of D225G could seriously impact health care delivery and significantly increase the H1N1 case fatality rate.
More details on the two severe cases with identical sequences carrying D225G with powerful drivers like S188T and D100N would be useful.