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E627K Acquisition in Swine H1N1 Raises Pandemic Concerns
Recombinomics Commentary 11:37
June 18, 2009

The recently released PB2 sequence from a patient (22F) in Shanghai (see updated map) contains E627K.  This is the first reported acquisition of this change, which is present in virtually all human influenza A isolates, including the pandemic strain from 1918. 

The current isolate, A/Shanghai/71T/2009, was collected May 31, 2009 and the sequence was deposited at Genbank on June 10, 2009.  The isolate is closely related to the swine H1N1 currently spreading worldwide, and all positions upstream from E627K match the consensus sequence, indicating the E627K was not acquired through reassortment with human PB2 or other H1N1 viruses that were not closely related to the swine H1N1 circulating in the human population.

Acquisition of E627K is a concern because it allows for optimal replication at 33 C, the temperature of a human nose in the winter, in contrast to E627, which is in the avian version of PB2 and allows for optimal replication at 41 C, the body temperature of birds.  The PB2 in the swine is of avian origin, and A/Shanghi/71T/2009 is the first public sequence from the circulating sub-clade with E627K.

In human seasonal flu, activity peaks in the winter months and only minimal levels are detected in humans over the summer.  However, the swine flu has remained active and almost all influenza A detected in the northern hemisphere at this time is swine flu.

The appearance of E627K raises concerns that the level of swine flu with E627K will markedly increase in colder months.  In 1918, the flu in the spring was mild, but the fall version of the virus, which had E627K, was much more virulent and targeted young, previously healthy adults, as previously reported for the outbreak in Mexico, and now being reported in United States and Canada, where levels are highest.  This younger population target is also being reported in other countries worldwide.

Although the current case fatality rate is low, small changes like E627K could increase viral load, leading to high cytokine levels, which are associated with many of the deaths due to the current "milder" version of the swine H1N1.  In contrast to the recent isolate from Brazil, A/Sao Paulo/1454/2009 which is identical to the HA consensus sequence, the A/Shanghi/71T/2009 has a unique change that is not found in closely related sequences. 

This change is found in other H1N1 swine sequences (see list here) and the region surrounding E627K matches H3N2 seasonal flu in circulation in 1995.  Moreover, the downstream region matches sequences found in human lethal infections in the H7N7 outbreak in the Netherlands in 2003, as well as the H5N1 outbreak in Hong Kong in 1997 (see matches here).  However, in the above outbreaks, transmission to humans was not efficient, and the number of deaths was limited. 

The only reported death in the H7N7 outbreak was a veterinarian infected with H7N7 containing E627K (and that case remains the only example of a human fatal bird flu infection not involving H5N1).  The H5N1 sequence from Hong Kong was used to show the association of E627K with increased virulence in mice.

Thus, the acquisition of PB2 E627K in the swine H1N1 is readily explain by homologous recombination with locally related sequences containing E627K, which was a concern when the swine H1N1 begun transmitting efficiently in humans .  This sustain efficient transmission lead to a phase 6 designation for the 2009 Pandemic. 

The acquisition of E627K creates concern that the virus will evolve into a more lethal agent that will be associated with an increased case fatality rate in previously healthy young adults, as was seen in the 1918 Pandemic.

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