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Alarm Bells Ringing

>> On Aug 28, I warned in this column that it was not giving enough credence to the fact that viruses can evolve very rapidly through a third way, 're-combination,' where small portions of any of the eight genes in the bird flu virus are swopped with small portions of any of the eight genes in the human flu virus or an animal flu virus.<<

Since recent reports of probable human to human transmission have been given a "1 alarm bell" rating by some, I think it is worth reviewing some additional alarm bells in the past 12 months, to put the 1 alarm rating into context.  Most agree that the key event involved in turning an animal pandemic into a human pandemic will be the ability of the H5N1 virus to be easily passed from human to human.
I think that alarm bell ratings can be viewed by looking for changes that will increase the likelihood of recombination leading to an expanded mammalian host range.
The 1 alarm rating given to the recent Thai cluster should also be given to a virtually identical cluster in Vietnam in late July early August.  The difference really lies in the fact that the caregiver (mother) in Thailand was not present when her daughter was initially infected.  However, the key epidemiological clue comes from then fact that the mother's symptoms developed after caring for her ill daughter.  This was also seen in Vietnam, where the older sister (who was confirmed to be H5N1 positive) developed symptoms after her brother had already died.  Thus, the Vietnamese cluster should also be given a 1 alarm rating.  These alarms are not additive, because they are measuring the same thing, human to human transmission by a virus that is very similar to the virus isolated at the beginning of this year.  However, the Vietnamese cluster shows that the human to human transmission is an ongoing problem and again involves cluster of transmission between relatively young adults (in Vietnam the index case was 19 and his cousin and sister were in their 20's).
Since re-assortment has not been noted in the H5N1 isolates from Vietnam and Thailand, it is virtually certain that the expanded host range is associated with recombination.  Recombination requires dual infections and the evidence for dual infections is mounting.  Dual infections are easily detected via re-assortment and re-assortment is on the rise.  The 1997 Hong Kong H5N1 outbreak involved isolates with re-assorted genes, signaling dual infections.  Moreover, some other sequences appeared to be "humanized" because some of the polymorphisms detected were commonly found in mammalian isolates.  The "humanized" also developed via recombination.
H5N1 isolates from Hong Kong in 2003 also have evidence for both re-assortment and recombination.  Over half of the deposited H9N2 sequences are of genes commonly found in H5N1 isolates.  Similarly, recent H5N1 isolates from Hong Kong have genes commonly found in H9N2 isolates and these H5N1 isolates have very clear examples of recombination in most of the 8 genes.  In addition, the H5N1 swine isolate from Shandong has genes that are commonly found in H9N2 isolates.  Moreover, the H5N1 swine isolates is closely related to H5N1 avian isolates found throughout China (Shanghai, Fujian, Guangdong, Guangxi, Jilian provinces).
The H5N1 virus causing the fatal human infections in Vietnam and Thailand is also a recombinant and has recombinant sequences found in H5N1 isolates throughout Asia.  Last season these recombinant viruses generated an unprecedented incidence of H5N1 infections throughout Asia and early indications for this season indicate the recombinant viruses is causing additional fatal human infections.
The more recent H5N1 and H9N2 also have expanded host ranges.  They grow more easily in laboratory mice and can infect a wide range of tissue types, including neurological tissues.  In Thailand, infections in wild and domestic cats were noted earlier this year, and more recent results show that cats can easily transmit the virus and associated illness from cat to cat.
The H5N1 isolates from Vietnam and Thailand also have polymorphisms unique to H5N1 isolates from those two countries.  However, these polymorphisms can  be found in other serotypes, including H1N2 which is commonly found in humans and pigs, indicating the isolates in Vietnam and Thailand have undergone additional recombination.
The contribution of widespread vaccinations in Asia remains to be determined.  However, most or all vaccines in use reduce the amount of circulating viruses detected after challenge.  However, vaccines that reduce viral titers to sub clinical levels keep the virus circulating in a large number of birds that appear to be healthy.  This increased pool of H5N1 virus is a provocative target for subsequent infections, which create conditions favorable for additional re-assortment and recombination.
In summary, the bells are certainly ringing and they point to increasing recombination and associated expanded host ranges.  It seems likely that the upcoming flu season will pose some serious challenges as the influenza gene base in Asia continues to destabilize.
It should be noted that some have suggested that the 1918 pandemic was due to the emergence of a recombinant, although others have questioned the approach and indicated that the data was related to uneven rates of evolution.
The current data on recombination in recent H5N1 isolates (as well as H3N2 human isolates) is unmistakable and irrefutable, and provides a molecular basis for the pandemic described above.



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