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Paradigm Shift Intervention Monitoring
R193M and RBD
Changes In H5N1 Fatal Bali Indonesia Cluster
The above comments, regarding the receptor binding domain change R193M (H3 numbering), found in an escape mutant from A/Indonesia/05/2005, from the second confirmed H5N1 case (37F, fatal) in Indonesia, are from a paper entitled “Broad Cross-Protection against H5N1 Avian Influenza Virus Infection by Means of Monoclonal Antibodies that Map to Conserved Viral Epitopes”. A position 193 change (S193F) was associated with the fixing of adamantine resistance (S31N in M2) in seasonal H3N2, as well as the fixing of oseltamivir resistance (H274Y in NA) in seasonal H1N1, as detailed in “Emergence and Fixing of Antiviral Resistance in Influenza A Via Recombination and Hitchhiking”. Thus, the finding of R193M in all of the 2008 and 2011 human H5N1 sequences from Indonesia (see list here) signals the importance of position 193 in seasonal H3N2, seasonal H1N1, and pandemic H5N1.
The similarities between seasonal H1N1 and pandemic H5N1 are striking. In late 2007 / early 2008 oseltamivir resistance began appearing in multiple countries in the northern hemisphere in patients who had not been treated with oseltamivir (Tamiflu). All sequences were from clade 2B (Brisbane/59) and the frequencies varied (highest in northern Europe, including Norway where initial cases were reported). A subset of those cases had A193T. In the 2008 southern hemisphere flu season, the frequency of H274Y rose to 100% in South Africa and A193T was in the dominant sub-clade. Similar sequences were found in Australia, and in late 2008 the 100% frequency for H274Y spread throughout the northern hemisphere. Virtually all sequences had A193T as well as changes at two or more flanking positions (187, 189, 196). These combinations likely facilitated immunological escape, from responses to prior infections or vaccinations.
The sequences from the three Bali fatal H5N1 cases have a series of changes, D187N, A188G, R193M) that are remarkable similar to the locations and combinations of changes seen in seasonal H1N1, and likely represent similar immunological escape from human immunological response, facilitating spread and cluster formation.
Once again the Indonesian Ministry of Health is acknowledged for its rapid release of these important sequences, which highly the importance of transparency and increased surveillance.