Saturday, May 24, 2014

EID Journal: H7N9 As A Work In Progress


Schematic Diagram of Novel A(H7N9) Generation- Credit Eurosurveillance


# 8660


It is axiomatic that the only constant with influenza viruses is that they continually change.  And that makes sense, as most hosts develop post-infection antibodies which provide a fair degree of immunity against future infection.  


If flu viruses didn’t change over time, they’d eventually run out of susceptible hosts and die out.


Most often, change comes about gradually, through a process called antigenic drift.


This is the evolutionary process that creates small, incremental changes in the virus over time. Drift is the standard evolutionary path of influenza viruses, and comes about due to replication errors that are common with single-strand RNA viruses (see NIAID Video: Antigenic Drift).


More abrupt changes come from antigenic shift, also called reassortmentFor shift to happen, a host (human, swine, bird) must be infected by two influenza different viruses at the same time.  Shift occurs when one virus swap out chunks of their genetic code with gene segments from another virus.



The H7N9 virus which emerged in the spring of 2013 was born out of a series of reassortments between H7 avian viruses and avian H9N2.  This process essentially led to the creation of a new flu strain – one that has since infected hundreds of people in Eastern China.

While not as common as antigenic drift, reassortment often leads to big changes in how a flu virus behaves.


The good news is, most reassortant viruses are evolutionary failures.  They die out quickly because they are not as biologically `fit’ as the viruses they must compete with.  Occasionally, one hits the evolutionary lottery, and the pandemics of 2009, 1968, and 1957 are all believed to have been sparked by reassortant flu viruses. 


Earlier this year, we saw the emergence of another avian reassortment - H5N8 -  several variants of which rapidly spread across South Korea’s poultry operations.  This year China also reported a pair of H10N8 infections – again from a reassortant virus  (see Lancet: Clinical & Epidemiological Characteristics Of A Fatal H10N8 Case). 


The three avian flu viruses we are watching with particular interest – H5N1, H7N9, and H10N8 – all  share several important features (see Study: Sequence & Phylogenetic Analysis Of Emerging H9N2 influenza Viruses In China)::

    • They all first appear to emanate from Mainland China
    • They all appear to have come about through viral reassortment in poultry
    • And most telling of all, while their HA and NA genes differ - they all carry the internal genes from the avian H9N2 virus

What we are finding is that the relatively benign and ubiquitous H7N9 virus, is actually fairly promiscuous; bits and pieces of it keep turning up in new reassortant viruses.


In the past, we’ve looked at the propensity of this H9N2 virus to reassort with other avian flu viruses (see PNAS: Reassortment Of H1N1 And H9N2 Avian viruses & PNAS: Reassortment Potential Of Avian H9N2) which have shown the H9N2 capable of producing `biologically fit’ and highly pathogenic reassortant viruses. And in 2010 (see Study: The Continuing Evolution Of Avian H9N2) we looked at computer modeling (in silica) that warned the H9N2 virus has been slowly evolving towards becoming a `more humanized’ virus.


All of which serves as prelude to an EID journal letter, published yesterday, that finds that the H7N9 avian virus continues to reassort with local H9N2 viruses, making the H7N9 viruses that circulated in wave 2 genetically distinct from those that were seen during the 1st wave.


Volume 20, Number 9—September 2014

Genetic Changes of Reemerged Influenza A(H7N9) Viruses, China

Article Contents

To the Editor: From March 30, 2013, through April 8, 2014, a total of 401 human infections with novel avian influenza A (H7N9) virus were reported in China (1). In the initial wave from February through May 2013, cases were laboratory confirmed for 133 patients (45 died), mainly in eastern China. From June through early October 2013, only 2 laboratory-confirmed cases were reported in China. One of these, identified on August 10, 2013, was the first case of influenza A(H7N9) virus infection in Guangdong Province (strain A/Guangdong/HZ-01/2013). However, a second wave of influenza A(H7N9) virus infection began on October 14, 2013 (2). As of April 8, 2014, a total of 266 laboratory-confirmed cases had been reported, mainly in Zhejiang Province in eastern China (92 cases, 37 deaths) and Guangdong Province in southern China (99 cases, 30 deaths).

Previous sequencing studies suggested that 6 of the 8 influenza A(H7N9) virus RNA segments were acquired from influenza A(H9N2) virus. This acquisition process involved at least 2 steps of sequential reassortment; the most recent event most likely occurred in the Yangtze River Delta area of eastern China (35). To date, nearly all analyses have been performed by using sequences obtained from viruses isolated during the first wave of infection; changes associated with viruses isolated during the second wave are largely unknown (6). We therefore conducted phylogenetic analyses of whole-genome sequence data for 15 influenza A(H7N9) viruses isolated from human patients in Guangdong from November 4, 2013, through January 15, 2014.


This study provides evidence that influenza A(H7N9) viruses isolated during the second wave of influenza in Guangdong differ genetically (in 5 of the 8 RNA segments) from that of influenza A(H7N9) viruses isolated during the first wave. High similarity of these 5 segments with those of locally circulating subtype H9N2 viruses suggests that rapid and continued reassortment with circulating subtype H9N2 viruses occurred during the second wave of the influenza A(H7N9) virus epidemic. Because reassortment and genetic changes can contribute to host fitness and infection capacity of reemerged influenza A(H7N9) viruses, studies of pathogenicity and transmission, to reveal the exact role of each genetic alteration, are needed.

Jing Lu1, Jie Wu1, Dawei Guan1, Lina Yi, Xianqiao Zeng, Lirong Zou, Lijun Liang, Hanzhong Ni, Xin Zhang, Jinyan Lin, and Changwen KeComments to Author

Author affiliations: Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, China


Continued antigenic shift (reassortment) is no guarantee that the H7N9 virus will someday adapt more readily to human physiology, but it keeps that door open a bit wider than would antigenic drift alone.  Making it imperative to continue to monitor these new variants closely.


The generation of a pandemic virus is admittedly an exceedingly rare event.


But as any virologist will tell you . . . Shift happens.

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