Hong Kong’s Extended Flu Season

 

 

 

# 6393

 

 

As previously mentioned in this blog (see Hong Kong: Flu Activity Continues To Rise), while influenza activity in most the Northern Hemisphere (excluding the tropics) is practically non-existent right now, Hong Kong continues to see an unusual level of flu activity.

 

Today, the Hong Kong government released a brief statement suggesting that a `genetic change’ to the flu virus circulating in Hong Kong may be behind this season’s persistence.

 

While this may sound a bit ominous, there may be less to this story than it first suggests.

 

We’ve been aware of small, antigenic changes occurring in the H3N2 flu virus for a number of months now, a trend which prompted a change to next fall’s flu vaccine (see WHO: Northern Hemisphere 2012-2013 Flu Vaccine Composition).

 

Unfortunately, today’s story provides no real detail on the `genetic changes’ being observed in Hong Kong, making it difficult to draw any comparisons to the antigenic changes seen elsewhere.

 

First the news statement from NEWS.GOV.HK, then I’ll be back with a little more.

 

 

 

Flu season may be longer

June 18, 2012

A genetic change of virus may lengthen this year's peak flu season. Centre for Health Protection Controller Dr Thomas Tsang issued the warning today, saying the flu pattern this year is unusual.

 

Local influenza activity remained high from January to June. From the last week of May to the first week of June there were 1,100 flu cases.

 

The number of influenza detections dropped to about 600 last week, but is still high compared with the average of 100 cases per week in recent years.
He said the flu strain this year has changed slightly in genetic make up.

 

More than 170 people have died of influenza since January, 90% of them being elderly, Dr Tsang said, urging the public and institutions to be alert as the school holidays approach.

 

About 30 enterovirus infections are being reported in childcare centres every week, he added, including seven serious cases.

 

 

Flu viruses are constantly changing and evolving, and so minor changes to the virus are to be expected. Over time enough changes can accrue that they change the behavior or activity of the virus.  

 

Late last month, in a letter to doctors, the Centre For Health Protection mentioned that the seasonal H3N2 virus being seen in Hong Kong had drifted away from the vaccine strain. 

 

An excerpt from that letter reads:

 

The current circulating influenza A(H3N2) virus is antigenically related but not identical to the current vaccine strain, A/Perth/16/2009 (H3N2)-like virus.
Separately, the circulating influenza B viruses belonged to two lineages, the Victoria and Yamagata lineage.

 

The latest laboratory data showed that the Yamagata lineage accounts for around 70-80% of the circulating influenza B viruses. As compared with influenza B viruses of Victoria lineage,  influenza B viruses of the Yamagata lineage are antigenically less similar to the current vaccine strain B/Brisbane/60/2008-like virus. Though the match is less than optimal, studies have demonstrated some degree of cross protection with the available influenza vaccine against current circulating strains.

 

The most recent Flu Express report from the CHP (June 14th) indicates that by far, the bulk of the flu activity being detected right now are seasonal H3.

 

 

While this year’s flu season in Hong Kong remains atypical, the good news is, that there is probably no place on the planet better equipped to analyze changes to the flu virus than Hong Kong.

 

Hopefully we’ll get a more detailed report on what these `genetic changes’ might be in the near future.

»» Read More

NIAID Video: Antigenic Drift

 

 

# 6288

 

 

NIAID, part of the NIH, has just released a short (3 minute) video that nicely illustrates how flu viruses change antigenically over time, and eventually mutate so that the current flu vaccine no long is effective.

 

 

 

As the seasonal H3N2 virus that has been covered in the flu vaccine over the past 3 years has begun to accumulate changes like the ones discussed in this video, in the fall a new H3N2 strain will be incorporated in the flu shot.

 

There are currently 18 videos on the NIAID Youtube site, and links to others on other channels.

Well worth taking a look.

»» Read More

M Is For Mutation

 

 

 

# 5812

 

 

I usually try to avoid using the word `Mutant’ or `Mutation’ in my blog titles about flu because, strictly speaking . . .

 

All influenza viruses are the product of mutation.

 

Flu viruses are inherently unstable (in particularly, influenza A), and are constantly evolving and changing. Mutating. Which explains why scientists must adjust the flu vaccine nearly every year.

 

Of course, the media loves the word `Mutation’ – I suspect because it conjures up vivid images in the minds of their readers. And to the public, mutations are almost universally perceived as `bad’. 

 

Earlier this week we saw a plethora of `Mutant’ headlines, including:

 

New bird flu virus mutation threatens Vietnam -Thanh Nien Daily

No vaccine yet for mutant bird flu ...  - The Straits Times

Mutant Bird-Flu Strain Spreads in Asia - The Daily Beast

Mutant bird flu strain in Asia prompts call for scrutiny - MSNBC

 

 

While the emergence of this (relatively) new strain of H5N1 is a big story, so far we’ve seen no evidence to suggest that this `mutation’ poses any greater threat to humans than do any of the other dozen or so clades of the bird flu virus.

 

But that isn’t the sort of lede that sells newspapers.

 

Since the `M’ word seems to be on the lips of many people this week, today seems like a good day to go over how influenza viruses mutate.

 

Don’t worry. 

 

I’ll keep this layman simple, mostly so I – a non-scientist - can understand it.  Real scientists, however, may wish to avert their eyes.

 

The genetic sequence of the influenza virus can be represented by a chain of letters identifying the hundreds of amino acids that make up the viral genome.

 

A tiny sub-section of that chain might have an amino acid sequence that looks something like:

 

MKAILVVMLYTFATA

 

As the virus inhabits a cell, and begins to replicate, it makes thousands of copies of itself which then burst out of the cell after a few hours and go on to infect other cells.

 

Those cells, in turn, make copies that go forth to infect more cells and repeat the process.

 

But being a single-strand RNA virus, the influenza virus tends to be sloppy in making copies of itself. As it replicates millions of times, tiny errors sometimes creep in. If in the process of making copies it mixes up just a single amino acid, we can end up with a mutated virus.

 

MKAILVVMLYTFATA

MKAILVVMLYTFATA

MKAIFVVMLYTFATA      -  Voila! A mutation

MKAIFVVMLYTFATA

MKAIFVVMLYTFATA

 

Above, I’ve swapped out the amino acid leucine (L) at position 5 for phenylalanine (F), simulating a replication error.

Assuming the result is a `biologically fit’ and competitive virus (most aren’t), then it may go on to infect other cells, and conceivably, other hosts.

 

Of course, that doesn’t mean it will make the virus more dangerous.  A mutation can make the virus less virulent or less transmissible.

 

Or it may simply have no effect at all.

 

These small mutations in the virus are called drift, and over time the flu virus can accumulate enough changes so that last year’s vaccine is no longer effective.

 

And that is essentially the story behind this new 2.3.2.1 clade of the H5N1 virus. Enough antigenic changes have accumulated in its genome to allow it to evade the poultry vaccines currently in use.

 

Of course, mutations like these are also capable of bringing about other changes, including antiviral resistance, or perhaps increasing the virulence or transmissibility of the virus.

 

So while not necessarily alarming, this week’s bird flu news is certainly worthy of our attention.

 

Bigger changes in the influenza virus generally come about through a process known as reassortment or shift.

 

Reassorted viruses can result when two different flu strains inhabit the same host (human or otherwise) at the same time. Under the right conditions, they can swap one or more gene segments and produce a hybrid virus.

 

 

While far less common than drift, shift can produce dramatic changes in how a virus behaves, and has been responsible for the creation of pandemic viruses in the past. 

 

Again this week, we’ve received news of a pair of `reassortant’ swine H3N2 flu viruses detected in children from two different states (see MMWR: Swine-Origin Influenza A (H3N2) Virus Infection in Two Children).

 

For those of us who were covering the earliest reports of a novel swine flu outbreak in April of 2009, this week’s report admittedly has a tinge of deja flu.

 

But it is important to remember that over the past 5 years (excluding the 2009 H1N1 virus) nearly 2 dozen similar novel swine flu viruses have been detected across the country. It is also probable that a number of other novel infections have escaped notice – yet so far none has been shown to spread efficiently from human-to-human.

 

That could change, of course - as each reassortant is  a new roll of the genetic dice - and so the CDC quite understandably is encouraging enhanced local flu surveillance, and would mount a vigorous response if more cases were to start to appear. 

 

Flu viruses have been quietly mutating and reassorting for thousands of years, but only rarely does that result in a pandemic strain. The vast majority of these mutations end up in evolution’s dustbin.

 

Even though we don’t always know what they signify, today we have the surveillance tools that enable us to watch some of these genetic changes when they start to appear.

 

 

And while that means we are likely to hear about a lot of potential viral threats that never materialize, it also means we may get some invaluable advance warning about the next pandemic virus before it strikes. 

»» Read More

Review: Evolution & Adaptation Of The 2009 pdmH1N1 Virus

 

 

# 5704

 

A comprehensive review today of the history - and possible future evolution - of the 2009 H1N1 pandemic virus, by Richard J. Webby PhD, et al. from the Department of infectious Diseases at St Jude Children’s Research Hospital in Memphis, Tennessee. 

 

Dr. Webby is also Director of the World Health Organization’s  Collaborating Center for Studies on the Ecology of Influenza in Animals and Birds. 

 

This review appears in the July 15th edition of  Virus Adaptation and Treatment, a Dovepress open access, peer reviewed journal on scientific and medical research.

 

The 9-page review may be accessed at the following link.

 

Evolution and adaptation of the pandemic A/H1N1 2009 influenza virus

Review

Authors: Ducatez MF, Fabrizio TP, Webby RJ

Published Date July 2011 Volume 2011:3 Pages 45 - 53

DOI: http://dx.doi.org/10.2147/VAAT.S9656

 

 

There is so much good content packed into this review, it would be difficult to summarize it here.  Webby, et al. cover such topics as:

 

• Evolution and adaptation of A(H1N1)pdm09 viruses in human and swine
• Genetic drift
• Antigenic variation
• Reassortment in humans
• Reassortment in swine
• Reassortment in experimental models

• Replication, transmission,and virulence of pandemic A(H1N1)pdm09 viruses
• Transmission in animal models
• Molecular markers of virulence

• Drivers of future evolution and adaptation
• Evolutionary rates
• Vaccination
• Antiviral drug use

 

Fortunately, it is short enough, and readable enough – even for those with a limited background in influenza science - that it really doesn’t require a condensed version from me.

 

But briefly . . . 

 

While the first 18 months of the spread of the 2009 pdmH1N1 virus showed very little genetic diversity, over the past 6 to 8 months the WHO’s GISN has detected “increased heterogeneity”  (diversity) among H1N1 isolates tested. 

 

For now, the vaccine strains selected for this fall’s vaccination campaign in the Northern Hemisphere remain a good antigenic match to the vast majority of the influenza A viruses now in circulation.

 

Over time, history tells us that will change.

 

Since influenza viruses leave their hosts with protective antibodies, they must either evolve to evade those antibodies, or die for a lack of susceptible hosts.

 

It is also possible that changes in transmissibility and virulence may also occur as the virus adapts and evolves.

 

As the authors write in their conclusion:

 

The presence of this virus in swine, the propensity for swine to support reassortment, and the known ability, albeit limited, of viruses to move between swine and humans, create an opportunity for these substantial changes to occur.

 

For anyone with even a passing interest in the evolution of influenza viruses in general, and of the likely future of the pandemic H1N1 virus in particular, this review is highly recommended.

»» Read More

NIAID Scientists Propose New Explanation for Flu Virus Antigenic Drift

 

# 3907

 

NIH News released the following report a couple of hours ago, describing new research into how flu viruses mutate and drift antigenically.

 

The news brief below is fairly straight forward, but essentially researchers believe that more antigenic drift occurs in immunologically naïve hosts (such as unvaccinated children) than occurs in adults who have a history of building antibodies.

 

They propose that increasing the vaccination rates in children could slow the rate of antigenic drift. 

 

A fascinating report. 

 

 

---

Reference: SE Hensley et al. Hemagglutinin receptor binding avidity drives influenza A virus antigenic drift. Science. DOI: 10.1126/science.1178258 (2009).

---

 

NIAID Scientists Propose New Explanation for Flu Virus Antigenic Drift

Influenza viruses evade infection-fighting antibodies by constantly changing the shape of their major surface protein. This shape-shifting, called antigenic drift, is why influenza vaccines — which are designed to elicit antibodies matched to each year's circulating virus strains — must be reformulated annually. Now, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have proposed a new explanation for the evolutionary forces that drive antigenic drift. The findings in mice, using a strain of seasonal influenza virus first isolated in 1934, also suggest that antigenic drift might be slowed by increasing the number of children vaccinated against influenza.

 

Scott Hensley, Ph.D., Jonathan W. Yewdell, M.D., Ph.D., and Jack R. Bennink, Ph.D., led the research team, whose findings appear in the current issue of Science.

 

“This research elegantly combines modern genetic techniques with decades-old approaches to give us new insights into the mechanisms of antigenic drift and how influenza viruses elude the immune system," says NIAID Director Anthony S. Fauci, M.D."

 

"No one is sure exactly how the antigenic drift of flu viruses happens in people," says Dr. Yewdell. According to the prevailing theory, drift occurs as the virus is passed from person to person and is exposed to differing antibody attacks at each stop. With varying success, antibodies recognize one or more of the four antigenic regions in hemagglutinin, the major outer coat protein of the flu virus. Antibodies in person A, for example, may mount an attack in which antibodies focus on a single antigenic region. Mutant viruses that arise in person A can escape antibodies by replacing one critical amino acid in this antigen region. These mutant viruses survive, multiply and are passed to person B, where the process is repeated.

 

It is not possible to dissect the mechanism of antigenic drift in people directly, notes Dr. Yewdell. So he and his colleagues turned to a classic mouse model system developed in the mid-1950s at the University of Chicago, but used rarely since. The team infected mice with a strain of seasonal influenza virus that had circulated in Puerto Rico in 1934. Some mice were first vaccinated against this virus strain and developed antibodies against it, while others were unvaccinated.

 

After infecting the vaccinated and unvaccinated mice with the 1934 influenza strain, the scientists isolated virus from the lungs of both sets of mice and passed on these viruses to a new set of mice. They did this nine times. After the final passage, the researchers sequenced the gene encoding the virus hemagglutinin protein. Of course, says Dr. Yewdell, gene sequencing was not possible in the mid-1950s, when the nature of the gene was first elucidated, and until very recently, sequencing was expensive and time-consuming. "Now, with automated gene sequencers, sequencing of dozens of isolates is easily done overnight," he says.

 

Sequencing revealed that the unvaccinated mice — which lacked vaccine-induced antibodies — had no mutated influenza viruses in their lungs. In contrast, the hemagglutinin gene in virus isolated from vaccinated mice had mutated in a way that increased the ability of the virus to adhere to the receptors it uses to enter lung cells. Essentially, says Dr. Yewdell, the virus can shield its hemagglutinin antigenic sites from antibody attack by binding more tightly to its receptor.

 

"The virus must strike the right balance, however," Dr. Yewdell says. "Excessively sticky viruses may end up binding to cells lining the nose or throat or to blood cells and may not make it into lung cells. Also, newly formed viruses must detach from infected cells before they can spread to the next uninfected cell. Viruses that have mutated to be highly adherent to the lung cell receptors may have difficulty completing this critical step in the infection cycle."

 

Next, the researchers infected a new set of unvaccinated mice with the high-affinity mutant virus strain that had emerged in the first series of experiments. In the absence of antibody pressure, the virus reverted to a low-affinity form and was once again able to easily infect cells and spread.

 

"We propose a model for antigenic drift in which high- and low-affinity influenza virus mutants alternate," says Dr. Yewdell. In adults — who have been exposed to many strains of influenza in their lifetime and, correspondingly, have a wide range of antibody responses — the virus is pressured to increase its receptor affinity to escape antibody neutralization. When such high-affinity mutants are passed to people — such as children — who have not been exposed to many influenza strains or who have not been vaccinated against flu, receptor affinity decreases. People who have not been exposed to multiple influenza virus strains or who have never been vaccinated against influenza are said to be immunologically naïve.

 

"Our model predicts that decreasing the immunologically naïve population — by increasing the number of children vaccinated against influenza, for example — could slow the rate of antigenic drift and extend the duration of effectiveness of seasonal influenza vaccines," he says.

»» Read More