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Bird Flu Genetic Changes Leading to Thai Binh Clusters

Recombinomics Commentary
March 14, 2005

l>>  Scientists believe the greatest risk from H5N1 lies in adaptive mutation, a process whereby avian H5N1 could progressively adapt to new mammalian hosts -- including humans -- until it becomes efficient at infecting humans and at being transmitted from human-to-human. <<

H5N1 has been increasing its pandemic potential by gradually changing genetically.  These changes have increased its host range and tissue tropism.  The virus has been evolving steadily.  It has not swapped avian for mammalian genes, but has gradually accumulated genetic changes. These genetic changes ultimately are due to replication errors, but there is strong evidence for recombination driving the rapid year to year changes.

Regardless of the mechanism driving the incremental changes, commonly called antigenic drift, the H5N1 genes are clearly changing.  Associated with these changes is an ability to infect mammals.

The frequency of isolating H5N1 that can readily grow in mice has increased over the past few years.  Similarly, many of these isolates can also grow in neurological tissues producing fatal or paralytic disease.  H5N1 can grow in both mice and ferrets in the lab, and has also been shown to infect domestic cats in the lab.  Moreover the infection can be transmitted cat to cat.  Similarly, H5N1 can also infect and transmit between wild cats and it has also been isolated from pigs.  In the past two seasons it has also infected and killed people in Vietnam, Thailand, and Cambodia.

For the past two seasons H5N1 has also had the ability to transmit between people.  The much cited example in Thailand is unique in its clarity.  It was easy to prove daughter to mother transmission because the mother was not exposed to poultry, and was in another city when her daughter was infected.

However, the other aspects of the familial cluster are very similar to 10 other familial clusters. All of the clusters were bimodal involving disease onset dates that were 1-2 weeks apart.  In each cluster the index case died and at least one family member was confirmed to be H5N1 positive.  In addition to the bimodal distribution, the gender of the index cases was evenly split between male and female, while the secondary cases were predominantly female.  The gender difference correlated with traditional roles of females as caregivers to family members.

There is evidence for genetic change in the human H5N1 isolates.  In the first reported Thai Binh cluster in early 2004 the two sisters of the index case were H5N1 positive.  They had both cared for him before he died. Although the time course of the disease from onset of symptoms until death was identical for each sister, the clinical presentation was different.  One sister had a respiratory disease while the other had a gastrointestinal illness.  Moreover, the sequences of the genes in the two isolates were different.

Further genetic change was seen this season.  The 2005 isolates have undergone antigenic drift.  One of the nine isolates from the south is distinct from the other eight.

The current concern centers on larger clusters that are being identified at higher frequencies.  There have been several cases this year in Thai Binh.  Moreover, there have been three Thai Binh familial clusters this year.  The most recent is the only documented cluster in the current outbreak that includes at least one health care worker.  The confirmed case and the suspect case extend the cluster beyond the family, and extend the chain of the clusters.  Each person infected had a later disease onset date.

Also associated with the increase in size and frequency of the clusters in Thai Binh is a decreased case fatality rate. This season there have been no reported discharges of patients in the south, but most of the reported outcomes in the north have been discharges.

The decreased fatality rate associated with more efficient transmission suggests that further incremental genetic change has increased the pandemic potential of H5N1.

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