Wednesday, March 21, 2018

J. Virology: Analysis Of A Swine Variant H1N1 Virus Associated With A Fatal Outcome


Novel flu viruses (like H5N1, H5N6, H7N9, and H10N8), are particularly worrisome because - while they haven't yet figured out how to spread efficiently among humans  - when they do jump to humans they tend to have a very high mortality rate. 
But going back 130 years, we've only seen human influenza pandemics (and seasonal flu epidemics) sparked by H1, H2, and H3 viruses (see  Are Influenza Pandemic Viruses Members Of An Exclusive Club?).
Granted, we've no clue what influenza subtypes might have circulated in humans before 1890, and there is some guesswork surrounding those prior to 1918.  But based on a relatively limited sample size - H1, H2, and H3 viruses are the most likely to produce a human pandemic.
Which is why, even though they tend to produce far lower mortality than novel flu, we keep a close eye on human, avian, and swine-origin H1, H2, and H3 viruses. 
Between 2005 and the end of 2010, the CDC  documented 19 human infections by swine origin influenza viruses (SOIV) across the United States, 12 of which were trH1N1 viruses, 6 were trH3N2, and 1 was trH1N2.
During the summer of 2011 a new strain of swine influenza  - originally dubbed trH3N2 but renamed H3N2v (swine variant influenza) – was discovered to have evolved in pigs. 
What made this virus different from the earlier trH3N2 novel strains was that it was a reassortant swine H3N2 which had acquired the matrix (M) gene from the 2009 H1N1 pandemic virus. The CDC has speculated that:
`This M gene may confer increased transmissibility to and among humans, compared to other variant influenza viruses.CDC HAN 2012
The CDC’s MMWR  in November of 2011 detailed the Iowa cases in a dispatch called Limited Human-to-Human Transmission of Novel Influenza A (H3N2) Virus — Iowa, November 2011.
By then  it was pretty apparent that this swine H3N2 virus had a greater affinity to human hosts than most of the other SOIVs we’d seen in the past (excluding the 2009 H1N1pdm virus).
A few more scattered cases occurred in Minnesota and West Virginia by year's end, and the virus was given a new name WHO/FAO/OIE: Call It A(H3N2)v, which raised the total for 2011 to a dozen cases reported around the country.
This was, in all likelihood, a substantial undercount with at least one estimate putting the number 200 times greater (see CID Journal: Estimates Of Human Infection From H3N2v (Jul 2011-Apr 2012).
The following summer (2012) the floodgates opened - and while still likely badly under counted - over a little more than two months more than 300 human swine variant infections were reported across 10 states.
Again, nearly all had direct contact with pigs at state and local fairs (see CID Journal: H3N2v Outbreaks In United States – 2012).
Although the number of reported swine variant infections dropped back to single digits for each of the next three years (2013, 2014, 2015) in 2016 we saw a renewed surge of cases (20+), and last year (2017) 67 cases were reported (see FluView Wk 49: Influenza Increasing - 1 Novel H3N2v Report From Iowa).

These swine variant viruses have also continued to evolve. Eighteen months ago an MMWR: Investigation Into H3N2v Outbreak In Ohio & Michigan - Summer 2016 revealed that 16 of the 18 cases analyzed belonged to a new genotype not previously detected in humans.

While most human infections have been either mild or moderate, a couple of deaths have been reported, including a fatal case in Ohio in 2015 (see FluView Week 17: Fatal Swine Variant (H1N1v) Case In Ohio).
Often the severity and outcome of an influenza infection is based on a person's preexisting conditions, or even host genetics (see  A Genetic Predisposition To Severe Flu Infection), but sometimes a severe outcome can be due to subtle changes in the virus. 
All of which brings us to a study by researchers at the Influenza Division, National Center for Immunization and Respiratory Diseases, CDC -  published this week in the Journal of Virology - that looks at the genetics and infectivity and transmissibility (in ferrets) of the swine origin virus that caused the death of the patient in Ohio in 2015.

Antigenically diverse swine-origin H1N1 variant influenza viruses exhibit differential ferret pathogenesis and transmission phenotypes

Joanna A. Pulit-Penaloza1, Joyce Jones1, Xiangjie Sun1, Yunho Jang1, Sharmi Thor1, Jessica A. Belser1, Natosha Zanders1, Hannah M. Creager1, Callie Ridenour1, Li Wang1, Thomas J. Stark1, Rebecca Garten1, Li-Mei Chen1, John Barnes1, Terrence M. Tumpey1, David E. Wentworth1, Taronna R. Maines1# and C. Todd Davis1#


Influenza A(H1) viruses circulating in swine represent an emerging virus threat as zoonotic infections occur sporadically following exposure to swine. A fatal infection caused by an H1N1 variant (H1N1v) virus was detected in a patient with reported exposure to swine and who presented with pneumonia, respiratory failure, and cardiac arrest. 

To understand the genetic and phenotypic characteristics of the virus, genome sequence analysis, antigenic characterization, and ferret pathogenesis and transmissibility experiments were performed. 

Antigenic analysis of the virus isolated from the fatal case, A/Ohio/09/2015, demonstrated significant antigenic drift away from classical swine H1N1 variant viruses and H1N1 pandemic 2009 viruses. A substitution in the H1 hemagglutinin (G155E) was identified that likely impacted antigenicity, and reverse genetics was employed to understand the molecular mechanism of antibody escape. 

Reversion of the substitution to 155G, in a reverse genetics A/Ohio/09/2015 virus, showed that this residue was central to the loss of hemagglutination inhibition by ferret antisera raised against a prototypical H1N1 pandemic 2009 virus (A/California/07/2009), as well as gamma lineage classical swine H1N1 viruses, demonstrating the importance of this residue for antibody recognition of this H1 lineage. 

When analyzed in the ferret model, A/Ohio/09/2015 and another H1N1v virus (A/Iowa/39/2015), as well as A/California/07/2009, replicated efficiently in the respiratory tract of ferrets.
The two H1N1v viruses transmitted efficiently among cohoused ferrets, but respiratory droplet transmission studies showed that A/California/07/2009 transmitted through the air more efficiently. Pre-existing immunity to A/California/07/2009 did not fully protect ferrets from challenge with A/Ohio/09/2015.

Human infections with classical swine influenza A(H1N1) viruses that circulate in pigs continue to occur in the United States following exposure to swine.
To understand the genetic and virologic characteristics of a virus (A/Ohio/09/2015) associated with a fatal infection and a virus associated with a non-fatal infection (A/Iowa/39/2015), we performed genome sequence analysis, antigenic testing, and pathogenicity and transmission studies in a ferret model. 

Reverse genetics was employed to identify a single antigenic site substitution (HA G155E) responsible for antigenic variation of A/Ohio/09/2015 compared to related classical swine influenza A(H1N1) viruses. Ferrets with pre-existing immunity to the pandemic A(H1N1) virus were challenged with A/Ohio/09/2015 demonstrating decreased protection. 

This data illustrates the potential for currently circulating swine influenza viruses to infect and cause illness in humans with pre-existing immunity to H1N1 pandemic 2009 viruses and a need for ongoing risk assessment and development of candidate vaccine viruses for improved pandemic preparedness.

Although swine-variant infections have been reported year-round, the prime `season' appears to be from early summer and into the fall, when millions of people visit state fairs and agricultural exhibits across the country.  
While most human infections are reported in the United States, that is likely due to our relatively high level of surveillance and testing, and not due to a paucity of porcine influenza around the globe. 
For more on swine-origin influenza, and the public health risks they pose, you may wish to revisit:
oonosis & PH: Survey Of Animal Exhibitor's KAP During Swine Variant Outbreak

EID Journal: Transmission Of Swine H3N2 To Humans At Agricultural Exhibits - Michigan & Ohio 2016
J. Virol: Novel Reassortant Human-like H3N2 & H3N1 Influenza A Viruses In Pigs
J. Virology: A Single Amino Acid Change Alters Transmissability Of EAH1N1 In Guinea Pigs

I&ORV: Triple-Reassortant Novel H3 Virus of Human/Swine Origin Established In Danish Pigs

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