Prof. Peter Doherty On Influenza’s Threat

 

 

 

# 5953

 

 

Last August in Professor Peter Doherty On Bird Flu I wrote about an Australian Life Scientist Magazine  interview with world renown 1996 Nobel Prize winning scientist Professor Peter Doherty, who discussed the pandemic potential of the H5N1 avian virus.

 

Today, The Conversation – which is a combined journalistic effort by a number of Australian Universities – has the first of a two-part article by Professor Doherty on influenza.

 

Rather than try to excerpt or summarize his views, I’ll simply provide a link so you can read the entire article.

 

 

Author

Peter C. Doherty
Laureate Professor at University of Melbourne

10 November 2011, 2.36pm AEST

Global efforts against flu evolving in the face of continuing threat

Influenza is never off the news agenda for long. If it’s not the flu season (and it always is in one hemisphere) and the attendant calls for vaccinations, it’s news about vaccines causing problems or new ones that will imbue immunity to all variants and mutations of the virus.

 

In this first of a two-part series on influenza and the future of vaccines for it, Peter Doherty discusses how these viruses mutate and how we monitor them to create effective vaccines.

(Continue . . . )

Tomorrow’s article will look at the feasibility of developing a “universal” flu vaccine.

»» Read More

H5N1: An Increasingly Complex Family Tree

 

 

# 5921

 

My thanks to Crof at Crofsblog for picking up this morning on the publication by the World Health Organization of their:

 

Updated unified nomenclature system for the highly pathogenic H5N1 avian influenza viruses

 

While many of you will want to follow the above link to read the report in its entirety, this document basically identifies and updates the known clades of the H5N1 virus that have emerged since the detection of the A/goose/Guangdong/1996 H5N1 virus strain back in the mid 1990s.

 

`Clades’ are essentially branches on the virus’s family tree. Each new branch has a clearly identifiable lineage from its parental strain, but has mutated far enough away to become a new strain.

 

The criteria, from the report:

 

Based on criteria used to distinguish various groups of the H5 hemagglutinin (HA) gene, the system has formally identified 20 distinct clades of the virus since its inception in early 2008 [1-2]. These clades are defined as meeting the following three specific clade definition criteria developed by the WHO/OIE/FAO H5N1 Evolution Working Group:

• sharing of a common (clade-defining) node in the phylogenetic tree;
• monophyletic grouping with a bootstrap value of ≥60 at the clade-defining node (after 1000 neighbor-joining bootstrap replicates); and
• average percentage pairwise nucleotide distances between and within clades of >1.5% and <1.5%, respectively.

 

All of which means we are not watching just one H5N1 virus strain with pandemic potential, we are watching at least 20 genetically separate clades of the virus, with many minor variants of each clade thrown in the mix.

 

And over time, it is expected that even more clades will emerge as the virus mutates and/or swaps genetic material with other viruses.

 

 

To give you an idea of just how much the virus has diversified over the past 15 years, I’ve reproduced one of the WHO charts from in this report below.

 

(click to load larger image)

 

 

In WHO Report : Antigenic & Genetic Characteristics of H5N1 & H9N2 Viruses from last month we looked at some of this viral evolution including the spread of the 2.3.2.1 clade of the virus – which was the subject of an FAO announcement (see FAO Warns On Bird Flu) at the start of September.

 

Scientists at the WHO must occasionally select candidate viruses for the production of human vaccines. Should a pandemic erupt, having a candidate vaccine already in hand could save weeks in the time it would take to produce and deploy an emergency vaccine.

 

This `new’ 2.3.2.1 clade differs antigenically from the poultry vaccines currently being used in many Asian countries, and the concern is that a new wave of bird flu may spread through poultry this winter.

 

While newer 2.3.2.1 clade samples reacted well against a couple of candidate vaccines already selected, the 2.3.4.2 clade out of Bangladesh does not.

 

Therefore, the development of a new clade 2.3.4.2 candidate vaccine virus is proposed.

 

For more on the ongoing evolution of avian influenza, you may wish to revisit:

 

Variations On A Bird Flu Theme

What Goes Around, Comes Around

EID Journal: H5N1 Branching Out

»» Read More

Updating Hong Kong’s Scarlet Fever Outbreak

 

 

# 5652

 

 

From Hong Kong’s Centre For Health Protection (CHP) this morning, we’ve updated numbers as of mid-day Monday on their Scarlet Fever outbreak.

 

Over the 72 hours of the weekend, 71 new cases have been reported. The number of fatalities (2) remains unchanged from last week.

 

 

While accurate numbers have been impossible to come by, local reporting indicates that scarlet fever is spreading on the mainland of China as well.

 

The number being reported in the media today (9,000 cases) is the same as we heard early last week, suggesting that surveillance and reporting from the mainland is less than robust.

 

In a long and informative Associated Press report by Margie Mason, we learn some new details regarding the two antibiotic resistant strains circulating in this outbreak.

 

Mutated scarlet fever fuels Hong Kong outbreak

By MARGIE MASON , 06.27.11, 03:30 AM EDT

 

 

The gist being that two mutated strains of group A Streptococcus that are causing this outbreak both show signs of increased resistance to erythromycin and clindamycin, long considered the standard treatment for the illness. 

 

Fortunately, they remain susceptible to penicillin and some newer drugs of last resort. 

 

Once a common scourge of children, scarlet fever has been largely controlled by the use of modern antibiotics. What happens should this new strain develop penicillin resistance as well is a major concern of scientists.

 

 

According to Kwok-yung Yuen - head of Hong Kong University's microbiology department -  the more dominant of the two strains has undergone a genetic mutation that appears to make it more contagious as well.

 

(Source CDC Scarlet Fever Webpage)

For some background on Scarlet Fever this morning, we’ve a 5 minute CDC Podcast on the illness from last February.

 

Scarlet Fever

Katherine Fleming-Dutra, pediatrician, discusses scarlet fever, its cause, how to treat it, and how to prevent its spread. Created: 6/9/2011 by National Center for Immunization and Respiratory Diseases (NCIRD). Date Released: 6/9/2011. Series Name: CDC Featured Podcasts.

More info on this topic

(click image to load page)

Running time = 5:09

To save the Podcast, right click the "Save this file" link below and select the "Save Target As..." option.

Save This File (5MB) [right click]

 

For now, even with the availability of antibiotics, prevention of the disease is the best course of action.  To that end, the CDC recommends:

 

Preventing Infection: Wash Those Hands

The best way to keep from getting infected is to wash your hands often and avoid sharing eating utensils, linens, towels or other personal items. It is especially important for anyone with a sore throat to wash his or her hands often. There is no vaccine to prevent strep throat or scarlet fever.

»» Read More

Eurosurveillance: A `Mildly’ Resistant Strain of H1N1 Emerges

 

 

# 5919

 

 

The acquisition of antiviral resistance by influenza strains is a constant worry, given their long history of eventually finding their way around our pharmaceutical defenses. 

 

Not so long ago Amantadine (an M2 ion channel blocker) was the preferred influenza antiviral.  It was cheap, plentiful, and effective.

 

But by the mid 2000s Amantadine began to lose its ability to combat the H3N2 seasonal flu virus along with some strains of the H5N1 bird flu.

 

It has been suggested that the prophylactic use of Amantadine by Chinese poultry farmers (who supposedly included it in their chicken feed for several years) may have contributed to this sudden resistance.

 

But whatever the cause, by January of 2006 the CDC had issued a warning to doctors not to rely on Amantadine (or Rimantadine) to treat influenza.

 

Oseltamivir (Tamiflu) – a newer neuraminidase (NA) inhibitor drug  introduced in 1999 - while far more expensive, became the new treatment standard.

 

But by 2008 seasonal H1N1 began to show growing resistance to Oseltamivir as well (although H3N2 remained sensitive).

 

By the spring of 2009, - in the space of just about a  year – seasonal H1N1 had gone from almost 100% sensitive to the drug to nearly 100% resistant.

 

The arrival of the novel 2009 H1N1 pandemic virus was a game changer, in that it – unlike seasonal H1N1 – was still sensitive to oseltamivir (but not Amantadine).

 

Since then, we’ve been watching to see if – like its seasonal cousin – A/H1N1/2009 learns to evade oseltamivir and/or zanamivir as well.

 

So far, the news has been generally good.

 

Only 1%-2% of samples tested have shown the most common mutation known to convey oseltamivir resistance; H275Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275.

 

(Note: some scientists use 'N2 numbering' (H274Y) and some use 'N1 numbering' (H275Y))

 

 

Of course, resistance to antivirals is usually a matter of degree. A virus may become strongly resistant, rendering an antiviral all but useless, or just mildly resistant, which may simply reduce the drugs effectiveness.

 

We’ve a report appearing in Eurosurveillance this week which looks at the emergence of an H1N1 mutation that is mildly resistant to oseltamivir and zanamivir due to a different sort of  mutation; S247N (serine (S) to asparagine (N)) mutation at the neuraminidase position 247.

 

This emerging mutation has been appearing with some frequency in Australia, Brunei and Singapore.

 

 

Eurosurveillance, Volume 16, Issue 23, 09 June 2011

Rapid communications

 

Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation

 

A C Hurt, R T Lee, S K Leang, L Cui, Y M Deng, S P Phuah, N Caldwell, K Freeman, N Komadina, D Smith, D Speers, A Kelso, R T Lin, S Maurer-Stroh, I G Barr

 

A novel influenza A(H1N1)2009 variant with mildly reduced oseltamivir and zanamivir sensitivity has been detected in more than 10% of community specimens in Singapore and more than 30% of samples from northern Australia during the early months of 2011.

 

The variant, which has also been detected in other regions of the Asia-Pacific, contains a S247N neuraminidase mutation. When combined with the H275Y mutation, as detected in an oseltamivir-treated patient, the dual S247N+H275Y mutant had extremely high oseltamivir resistance.

 

In and of itself, this mutation may not be enough to produce clinical resistance to oseltamivir and zanamivir, as the reduction in sensitivity observed was just 6 fold and 3 fold respectively.

 

But when combined with the better known H275Y mutation, a virus with the S247N mutation proved 10 times more resistant than with the H275Y mutation alone.

 

The concern is that this mutation, which appears to be biologically fit and easily transmissible, may team up with other mutations known to produce varying degrees of resistance – and together they could prove far more problematic.

 

While the entire article is well worth reading, the authors conclude with:

 

If the S247N variant spreads globally, the greatest concern is that other NA mutations which may have previously caused only mild reductions in NAI susceptibility (e.g. mutations at the I223 residue) could instead cumulatively decrease NAI sensitivity to levels that may be clinically significant and affect treatment efficacy.

 

Laboratories should consider screening currently circulating specimens and isolates for the S247N NA mutation to determine whether the variant is spreading into other regions.

 

 

Although our antiviral arsenal remains largely effective against the new H1N1 virus, over time, that could change.

 

All of which points towards the wisdom of getting a flu shot every year. While not 100% protective, the yearly influenza vaccine can significantly reduce your chances of catching the flu.

 

After all, it is nearly always better to try to prevent an illness, than to have to treat one.   

»» Read More

Growing Diversity Of The H1N1 Virus

 

 

 

# 5531

 

 

When the 2009 H1N1 virus emerged just over two years ago, the assumption was that it would begin to evolve (or mutate) fairly rapidly.

 

There were real concerns that it might quickly pick up oseltamivir (Tamiflu) resistance, and even some worries it might hook up (reassort) with the H5N1 avian flu and produce some kind of Frankenswine Virus.

 

Instead, for the first 12 months or so, we received assurances from the CDC and the World Health Organization (WHO) that the virus was unusually stable.

 

What few variations that were seen were reportedly antigenically very similar to the A/California/7/2009 H1N1 virus that the vaccine was based upon. 

 

But of course, some changes, and variations, were observed.

 

There were a handful of oseltamivir resistant cases reported – most (but not all) appeared to have developed spontaneously in a patient actually taking the drug.

 

During a 14-month period (April 2009-June 2010) 6,740 H1N1 samples were submitted to US surveillance systems for testing, and of those, only 37 (.5%) proved resistant to oseltamivir.

 

This kind of resistance is usually caused by a mutation (H275Y) where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at neuraminidase position 275.

 

*          *         *          *           *           *

 

The D225G `Norway’ mutation made headlines in November of 2009, but it was observed in both mild and severe cases, and so it wasn’t at all clear what the clinical significance was (see Eurosurveillance: Debating The D222G/N Mutation In H1N1).

 

 

But with millions of infected hosts (people/birds/pigs) replicating trillions of copies of the virus every day, mutations were inevitable, and viral evolution was bound to take hold.

 

Many were `flashes in the pan’, and due to inferior biological fitness, failed to propagate well.  But by the middle of 2010, we began to see some subclades of the 2009 H1N1 virus that had exhibited some traction. 

 

Notably the A/Hong Kong/2213/2010 and the A/Christchurch/16/2010 (highlighted by D222N) subgroups.

 

In September of 2010, the WHO Influenza Centre in London released an analysis of the evolution of the H1N1 and seasonal viruses to be used in deciding the makeup of the Southern Hemisphere 2011 flu vaccine.  

 

They acknowledged these new subgroups (and others), but stated (bolding mine):

 

The A(H1N1) pandemic 2009 viruses propagated at NIMR remain antigenically similar to the vaccine virus A/California/7/2009.  Fewer low reactors have been detected in 2010 than was observed in 2009.

 

New genetic sub-clades have been detected but they do not appear antigenically distinct from the majority of A(H1N1) pandemic 2009 viruses collected since the start of the pandemic.

 

Not quite the same thing as saying that all of the viruses collected are antigenically close to the vaccine strain.  But we live in an imperfect world.

 

Herein lies the dilemma for those who must choose which virus strains to include in a vaccine 6 months before it can be deployed.  

 

The influenza virus is a constantly moving target.

 

And unlike a school of fish, that all change direction at  at the same time, flu viruses go their own way.   It’s very messy.   And very difficult to predict.

 

Worse, it is entirely possible that you can have a field of viruses circulating with enough antigenic diversity that not all of them can be covered by the vaccine.  The best you can hope for is to include the most prevalent strains.

 

Hence the occasional reports of `vaccine escapes’, and `low reactors’.  

 

Actually we see a similar situation every year when the vaccine committees choose one of the two B viruses (Yamagata or Victoria strain) to include in the vaccine. Some people who take the flu vaccine will be unlucky enough to catch the strain not included that year. 

 

Flu vaccines, most years, are pretty good.  But they aren’t perfect.  And some years they miss the mark badly.

 

As I tell people, if you want a guarantee . . . buy a Craftsman.

 

By late 2010 another subgroup A/England/142/2010 began to spread widely across Europe.  

 

By the end of the 2010-2011 flu season (week 16), at least in the European theatre – its prevalence had nearly equaled the number of A/California/7/2009-like isolates detected.

 

Chart based on data from Euroflu Report Week 16 : 18/04/2011-24/04/2011

 

In other parts of the world, the A/Hong Kong and A/Christchurch strains had much larger shares of the influenza pie.

 

As far as antiviral resistance goes (again from the WHO surveillance of Europe) we find that it is only slowly increasing, with the overwhelming majority of isolates tested still showing sensitivity to Tamiflu. 

 

 

But as we move further downrange from the emergence of the 2009 H1N1 virus, the odds are that we’ll see more diversity in the subgroups, more `low reactors’, and more antiviral resistance.

 

If a virus – which leaves behind immunity in the host – fails to evolve into a new antigenically different strain, it will eventually die out due to a lack of susceptible hosts.

 

Survival demands that the virus evolve. 

 

And in recent months we’ve seen reports – particularly out of Europe – suggesting that may be happening, as the effectiveness of the seasonal flu vaccine over the 2010-2011 flu season had dropped.  

 

CIDRAP covered this report in late March.

 

Preliminary studies show lower flu-shot effectiveness in Europe

Robert Roos News Editor

Mar 21, 2011 (CIDRAP News) – Preliminary studies suggest that this year's trivalent seasonal flu vaccine used in Europe was less effective against the 2009 H1N1 virus than last year's monovalent H1N1 vaccine was, possibly because of some degree of mutation in the virus, according to recent reports in Eurosurveillance.

(Continue . . . )

 

 

Which brings us to an interesting report, mentioned by CIDRAP last night in their news roundup, coming from the US Department of Defense (DoD).

 

It states that recent outbreaks of H1N1 in Venezuela and Mexico's Chihuahua state need to be monitored because they has been linked to severe infections and deaths, including some patients who had received the vaccine.

 

Initial analysis are suggesting that the Mexico group (inDRE1945) of H1N1 does not fall into previously characterized  A/England/142/2010, A/Christchurch/16/2010 (highlighted by D222N), or A/Hong Kong/2213/2010 subclades.

 

 

http://airforcemedicine.afms.mil/idc/groups/public/documents/afms/ctb_152827.pdf

 

 

These outbreaks have been well monitored for more than a month by the newshounds on the flu forums, including in this thread on FluTrackers, which has more than 250 entries.  

 

But what to make of all this is less than clear.

 

Sub clades of circulating influenza viruses emerge all the time.  Some disappear almost immediately, others linger in the background for awhile, sputter and die. 

 

A very few take off like a rocket.

 

It is a case of survival of the fittest. The virus that evades acquired immunity the best, replicates well, and transmits the most efficiently usually wins the race.  

 

At least for a while.

 

In the world of influenza viruses, nothing is permanent, the status quo never lasts for long, and the only constant is change.

 

Obviously, anything that increases the virulence, or moves the virus away from our acquired immunity (through prior infection or vaccines), is of concern.

 

But whether this suspected branch in H1N1’s evolution in Mexico & Latin America proves to have `legs’, remains to be seen.

 

It is possible that after a relatively mild second year of A/H1N1/2009, we could see a more severe flu season come the fall due to evolution of the virus.  

 

It’s happened before.

 

In 1957, the Asian Flu pandemic seemed to disappear completely for more than a year, only to return in 1959 and again after a two year lull during the 1962-63 flu season.  

 

NEJM 2009

 

With the Northern Hemisphere’s flu season at an end, we’ll be looking to the events south of the equator over the next six months to give us some hint of what may be in store for next fall.

Stay tuned.

»» Read More

PLoS One: A Single Mutation That Enhances H1N1 Transmission

 

 

 

# 5362

 

 

By just about any standard, we dodged a bullet with the pandemic of 2009. Despite hundreds of thousands of hospitalizations and tens of thousands of deaths (far more than were officially counted), it could have been far worse.

 

But we may not be out of the woods just yet.

 

It isn’t lost on scientists that in 1957, the Asian Flu pandemic seemed to disappear completely for more than a year, only to return in 1959 and again after a two year lull during the 1962-63 flu season.  

 

NEJM 2009

 

Influenza viruses are – as we’ve said before – unpredictable.

 

 

Two things we look for in an emerging virus are its pathogenicity – its ability to cause disease, and its transmissibility in humans – often measured by its R0 (pronounced `R nought’)  or basic reproductive number.

 

This R0 number describes the average number of new cases caused by one infectious person entering a totally susceptible population If less than 1.0,  outbreaks are likely to sputter and die out. 

 

With an R0 greater than 1.0, an outbreak has `legs’, and can spread through a community.

 

Determining the R0 of a virus can only be done in retrospect, and that number may vary considerably from one community to another.  The best researchers can usually come up with is an estimated range.

 

For the 2009 H1N1 virus, that number has usually been pegged at between 1.4 and 1.6.   Fairly low for a pandemic virus, but sufficient to ensure its survival and spread. 

 

The 1918 pandemic virus, in comparison, has been estimated to have an R0 between 2.0 and 3.0.  There are some estimates that run even higher.

 

 

In order to spread efficiently, a virus must be able to bind to human receptor cells – preferably those found in the upper airway.  While H1N1 does bind to human α2,6 receptor cells, it appears to do so more weakly than do many other flu viruses.

 

Additionally, in 2009 researchers at MIT and the CDC found that a portion of the PB2 gene – which is normally found in efficiently transmitted influenza viruses – was missing.

 

From MIT News,  July 3rd 2009.

 

MIT, CDC find H1N1 flu virus ill-suited for rapid transmission

But researchers say new strain bears watching, could mutate

(EXCERPT)

Recent studies have shown that a viral RNA polymerase known as PB2 is critical for efficient influenza transmissibility. (RNA polymerase controls the viruses' replication once they infect a host.) The new H1N1 strain does not have the version of the PB2 gene necessary for efficient transmission.

 

 

While we’ve been relatively fortunate so far, the question becomes, what would it take to make the 2009 pandemic virus more dangerous?

 

While there is probably more than one answer to that question, once again researchers from MIT and the CDC have been investigating, and have recently presented the results of a laboratory generated single point mutation that confers enhanced transmissibility to the H1N1 virus (at least in ferrets).

Ferrets are often used in influenza studies because their respiratory physiology, and susceptibility to influenza viruses, is close to that of humans.

 

The study, which appears in the March 2nd edition of Plos One, is called:

A Single Base-Pair Change in 2009 H1N1 Hemagglutinin Increases Human Receptor Affinity and Leads to Efficient Airborne Viral Transmission in Ferrets

Akila Jayaraman, Claudia Pappas, Rahul Raman, Jessica A. Belser, Karthik Viswanathan, Zachary Shriver, Terrence M. Tumpey, Ram Sasisekharan

 

The 2009 H1N1 influenza A virus continues to circulate among the human population as the predominant H1N1 subtype. Epidemiological studies and airborne transmission studies using the ferret model have shown that the transmission efficiency of 2009 H1N1 viruses is lower than that of previous seasonal strains and the 1918 pandemic H1N1 strain.

 

We recently correlated this reduced transmission efficiency to the lower binding affinity of the 2009 H1N1 hemagglutinin (HA) to α2→6 sialylated glycan receptors (human receptors). Here we report that a single point mutation (Ile219→Lys; a base pair change) in the glycan receptor-binding site (RBS) of a representative 2009 H1N1 influenza A virus, A/California/04/09 or CA04/09, quantitatively increases its human receptor-binding affinity.

 

The increased human receptor-affinity is in the same range as that of the HA from highly transmissible seasonal and 1918 pandemic H1N1 viruses. Moreover, a 2009 H1N1 virus carrying this mutation in the RBS (generated using reverse genetics) transmits efficiently in ferrets by respiratory droplets thereby reestablishing our previously observed correlation between human receptor-binding affinity and transmission efficiency. These findings are significant in the context of monitoring the evolution of the currently circulating 2009 H1N1 viruses.

 

 

For a less technical take on all of this, MIT News has an article describing the ramifications of this discovery. 

 

 

Keeping an eye on H1N1

MIT scientists identify a mutation that could allow the flu virus to spread much more easily.

 

 

Despite all of our technology, and an unprecedented two-year focus on the 2009 H1N1 virus, scientists are just beginning to unravel the secrets of the internal workings of flu viruses.

We can readily observe changes to the virus’s structure, but only rarely can we predict what those changes may mean in terms of virulence or transmissibility.

 

We know, for instance, that the H275Y mutation confers oseltamivir resistance, and although we’ve been watching the D225G `Norway’ mutations around the globe for more than a year, the jury is still out on its clinical significance (see Eurosurveillance: Debating The D222G/N Mutation In H1N1).

 

It isn’t enough to simply observe mutations occurring in the influenza virus.  

 

We need to know that they mean.

 

To that end, this research has identified a potentially dangerous single point mutation that – should it begin appearing in the wild – could signal the start of a new wave of illness. 

 

While that may not happen with the 2009 H1N1 virus, knowing what to look for gives us a decided advantage when tracking the evolution of this – and any other – influenza virus.

»» Read More

Egyptian MOH:`No Mutation’ Of Flu

 

 

# 5217

 

 

Invariably, when a new or novel influenza virus makes an appearance on the world stage, the concern is that over time it will mutate to a more formidable viral foe.

 

Mutating is, after all, what viruses do. 

 

And influenza viruses are particularly adept at acquiring changes – either through small incremental changes (called `drift’), or via a reassortment or swapping of genetic material with another virus, called `shift’.

 

And as any virologist will tell you, Shift Happens.

 

Yet, despite the stigma attached to the word `mutation’, viruses can also mutate into a less dangerous strains. 

 

Over the past few days we are seeing public reassurances from some public health agencies that the swine flu virus has not `mutated’ into a more virulent strain.

 

Last week, scientists from the UK’s HPA, writing in Eurosurveillance (see Eurosurveillance: Analysis Of Fatal H1N1 Cases In The UK) stated that: so far no unique mutations have been associated with severe or fatal cases of influenza A(H1N1)2009, but further comprehensive analysis is required.

 

That isn’t to say that mutations haven’t shown up.  They have, and will no doubt continue to do so.  

 

But so far, none of these changes is viewed by these HPA researchers as particularly alarming, linked to fatal cases, or indicative of a fundamental change in the H1N1 virus.

 

Today, similar assurances from the Egyptian Ministry of Health, on both H1N1 and H5N1 `bird flu’.

 

(Note: I realize there may not be universal agreement over the significance of some of the mutations that have been seen to date. Since I’m not a virologist, I’ll have to leave it to others to debate that issue.)

 

A double hat tip to Twall and Shiloh on FluTrackers for links to the Arabic and English versions of the following report.

 

No mutation of the avaian flu with swine flu, says health minister

Minister of Health asks citizens to take flu seriously but denies presence of mixed mutation of avian flu with swine flu

Ahram Online, Monday 10 Jan 2011

Egyptian Minister of Health Hatem El-Gabaly denied the presence of any mixed mutation of avian flu with swine flu (H1N1). He did, however, warn citizens against taking the flu threat lightly.

(Continue . . . )

 

 

When a novel flu virus like H5N1 co-circulates with a human-adapted influenza like H1N1 or H3N2, the concern is that the two will infect the same host at the same time, swap genetic material, and produce a new hybrid strain with the worst qualities (virulence and transmissibility) of both parent viruses.

 

We know reassortments like this can happen, as they has happened in the past. 

 

But it obviously doesn’t happen often, or easily, else we’d be hip deep in reassorted flu viruses every year.

 

Of course, it only takes one good hookup between compatible viruses, in the right host at the right time and in the right place to spark another global flu crisis.

 

 

In her keynote speech last night at Duke University, Assistant Surgeon General Dr. Anne Schuchat reminded her audience that had the 2009 novel H1N1 virus been detected just a few weeks sooner (it was already circulating), it could have been incorporated into that year’s seasonal flu shot.

 

That would have saved billions of dollars over the production of a separate pandemic jab, and would have gotten the vaccine into the arms of millions of people months sooner.

 

A step that would likely have saved many lives and billions more in health care costs.

 

Which is why surveillance, analysis, and reporting on any changes to influenza viruses circulating in humans and animals around the world remains a high priority.

»» Read More

Eurosurveillance On Recently Isolated H1N1 Mutations

 

#4998

 

 

 

That the novel H1N1 virus would begin to show signs of changing over time comes as no surprise.  Indeed, many experts expected to see changes begin last fall and winter in the northern hemisphere, and were surprised at how stable the virus remained.

 

Small changes were detected, in what appeared to be widely scattered mutations.  

 

The D22G – or Norway mutation – garnered a good deal of press beginning in November of 2009.   It failed, however, spread widely and in any event, the feared pathogenic changes that came with that mutation were inconsistent. 

Some cases were more severe, while others remained mild.  For more, see:

 

Study: Receptor Binding Changes With H1N1 D222G Mutation

CIDRAP Report On The H1N1 Mutation Debate

WER Review: D222G Mutation In H1N1

 

 

Similarly, a relative handful of H275Y mutations which conveyed Oseltamivir resistance have been reported. But once again, there was little evidence to suggest it was spreading widely.

 

 

NIH: Rapid Development Of Antiviral Resistance In Two Cases

WER Review: Oseltamivir Resistance In Pandemic H1N1

 

So called `low reactor’ viruses – those that appeared to be less well matched to the current pandemic H1N1 component to the flu vaccine – have also been reported in a few scattered instances around the world.  

But overall, the virus has remained antigenically close to the A/California/7/2009-like strain included in the vaccine.

 

Today Eurosurveillance has a major report on the detection of a growing number of `drifted’ H1N1 virus isolates from Singapore, Australia, and New Zealand over the winter of 2010.

 

The important points here are that right now, despite some reported vaccine `breakthroughs’ and some reported fatal cases with this mutation, it doesn’t appear that these changes render the existing vaccine ineffective, and pending further information there is scant evidence that they make the virus more dangerous.

 

A less positive note is that this `mutated’ virus appears to be relatively biologically `fit’, and capable of competing with the original virus, and spreading throughout the human population.

 

What this does tell us is that the virus is picking up changes, and that it must be closely watched as it slowly evolves during its run in through the northern hemisphere.

 

 

Eurosurveillance, Volume 15, Issue 42, 21 October 2010

---

Barr IG, Cui L, Komadina N, Lee RT, Lin RT, Deng Y, Caldwell N, Shaw R, Maurer-Stroh S. A new pandemic influenza A(H1N1) genetic variant predominated in the winter 2010 influenza season in Australia, New Zealand and Singapore. Euro Surveill. 2010;15(42):pii=19692.

Date of submission: 14 September 2010

---

Pandemic H1N1 influenza virus is of global health concern and is currently the predominant influenza virus subtype circulating in the southern hemisphere 2010 winter. The virus has changed little since it emerged in 2009, however, in this report we describe several genetically distinct changes in the pandemic H1N1 influenza virus.

 

These variants were first detected in Singapore in early 2010 and have subsequently spread through Australia and New Zealand.

 

At this stage, these signature changes in the haemagglutinin and neuraminidase proteins have not resulted in significant antigenic changes which might make the current vaccine less effective, but such adaptive mutations should be carefully monitored as the northern hemisphere approaches its winter influenza season.

 

The always dependable Maggie Fox, science and health editor of Reuters, has a report on all of this which you can access at:

 

New strain of swine flu emerges - report

Maggie Fox, Health and Science Editor

 

The bottom line:  The impact of these mutational changes is unclear at this time, but this reinforces the need to monitor the antigenic changes of this – and any other – circulating flu virus.

»» Read More

Study: Receptor Binding Changes With H1N1 D222G Mutation

 

 

 

# 4909

 

 

Although it’s nestled behind a pay wall at the Journal of Virology, the abstract from a study published ahead of print this week in the Journal of Virology gives us a tantalizing glimpse at research conducted on the D222G mutation that has been found in some isolates of the pandemic H1N1 (pdmH1N1) virus.

 

While we’ve discussed the D222G mutation before, this is an obscure enough subject as to make a review helpful.  I’ll keep it simple (essential so that I can follow, as well), so real scientists may wish to skim or skip ahead.

 

The `Norway’ or D222G (D225G in influenza H3 Numbering) mutation first announced by Norwegian Scientists last November has sparked repeated speculation that it might be associated with increased virulence.

 

This mutation had actually been detected months earlier, and in many other countries, but Norway was the first country to announce a possible link between that mutation and greater virulence.

 

This mutation involves a single amino acid change in the HA1 gene at position 222 from aspartic acid (D) to glycine (G).

 

The World Health Organization’s take on this mutation has been pretty consistent.  It is worth following, and studying, but there is no evidence (as yet) that it poses a substantial public health hazard.

 

In January, in a blog entitled WER Review: D222G Mutation In H1N1, I quoted the latest WHO report that stated:

 

`Based on currently available virological, epidemiological and clinical information, the D222G substitution does not appear to pose a major public health issue.’

 

This view is not universally held, however. There are some who have maintained that that the WHO is underestimating the impact of this mutation.

 

In March of this year, researchers from the Norwegian Institute of Public Health in Oslo reported that they found the mutation in 11 of 61 severe illness cases that they analyzed, but that it was not found in any of the 205 mild cases they looked at  (see CIDRAP Report On The H1N1 Mutation Debate).

 

The WHO WER Review reported that the overall prevalence of D222G was <1.8% (52 detections among >2755 HA sequences) in contrast to a rate of 7.1% in fatal cases. The WHO paper also reported on the occurrence of  two other mutations at this amino acid position, D222E and D222N, although their significance is unclear.

 

While this may sound like fairly damning evidence, it should be noted that mild cases have been detected with this D222G mutation in other studies, and most of the severe and fatal cases of pandemic H1N1 that have been examined did not have this mutation.

 

Which brings us to today’s study, which features an impressive pedigree and some very familiar names including Ab Osterhaus and  Ron Fouchier of the Erasmus Medical Center in Rotterdam.

 

This study was also supported by researchers from the Mt. Sinai School of Medicine in New York, the NIH, the University of Cambridge, the University of Maryland . . . among others.

 

First the abstract (hat tip Tetano on FluTrackers) slightly reformatted for readability, then a little discussion.

 

Virulence-associated substitution D222G in hemagglutinin of 2009 pandemic influenza A(H1N1) virus affects receptor binding.

Chutinimitkul S, Herfst S, Steel J, Lowen AC, Ye J, van Riel D, Schrauwen EJ, Bestebroer TM, Koel B, Burke DF, Sutherland-Cash KH, Whittleston CS, Russell CA, Wales DJ, Smith DJ, Jonges M, Meijer A, Koopmans M, Rimmelzwaan GF, Kuiken T, Osterhaus AD, Garcia-Sastre A, Perez DR, Fouchier RA.

Abstract

The clinical impact of the 2009 pandemic influenza A(H1N1) virus (pdmH1N1) has been relatively low. However, amino acid substitution D222G in the hemagglutinin of pdmH1N1 has been associated with cases of severe disease and fatalities.

 

Here, D222G was introduced in a prototype pdmH1N1 by reverse genetics, and the effect on virus receptor binding, replication, antigenic properties, and pathogenesis and transmission in animal models was investigated.

 

pdmH1N1 with D222G caused ocular disease in mice without further indications of enhanced virulence in mice and ferrets. pdmH1N1 with D222G retained transmissibility via aerosols or respiratory droplets in ferrets and guinea pigs.

 

The virus displayed changes in attachment to human respiratory tissues in vitro, in particular increased binding to macrophages and type II pneumocytes in the alveoli and to tracheal and bronchial submucosal glands.

 

Virus attachment studies further indicated that pdmH1N1 with D222G acquired dual receptor specificity for complex α2,3- and α2,6-linked sialic acids. Molecular dynamics modeling of the hemagglutinin structure provided an explanation for the retention of α2,6 binding.

 

Altered receptor specificity of the virus with D222G thus affected interaction with cells of the human lower respiratory tract, possibly explaining the observed association with enhanced disease in humans.

 

 

Testing here was done on mice, ferrets, guinea pigs, and on human cells in vitro, and each demonstrated (sometimes small) pathogenic differences between the D222G-engineered and regular pdmH1N1 virus.

 

In mice and ferrets, the D222G virus showed no increase in virulence with the exception of `ocular disease’ in mice (I’m guessing conjunctivitis, but without access to the full article, I can’t be certain).

 

Given the low incidence of the D222G mutation in the wild (less than 1.8%), it has been suggested that this mutation might render the virus less contagious, but ferret and guinea pig studies showed it retained transmissibility via aerosols and respiratory droplets.

 

The increased binding to type II pneumocytes in the alveoli (in vitro) is a particularly interesting finding, given that this was also observed in the Baskin Study of H5N1 vs human H1N1 viruses.

 

Seasonal H1N1 viruses, when they invade the lungs, are more likely to attack type I pneumocytes which handle the gas exchange (02 and C02) between the lungs and the blood stream.  

 

Type II pneumocytes are responsible for the production of surfactant with antimicrobial, immunomodulatory, and anti-inflammatory properties, and are the lung’s primary mechanism for repairing damaged cells.

 

Damaging them can significantly degrade the lung’s ability to recover from injury.

 

Which brings us to the last major finding, that D222G acquired dual receptor specificity for complex α2,3- and α2,6-linked sialic acids.

 

Familiar territory to regular readers of this blog, but at the risk of repeating myself:

 

A virus’s ability to bind to specific cells is controlled by its RBD or Receptor Binding Domain; an area of its genetic code that allows it to attach to, and infect, specific types of host cells.

 

(Very Simplified Illustration of RBDs)

 

Like a key into a padlock, the RBD must `fit’ in order to open the cell to infection.

 

Avian adapted influenza viruses bind preferentially to Alpha 2,3 receptor cells, which are commonly found in the digestive tract of birds.

 

Human adapted viruses have an affinity for the alpha 2,6 receptor cell, which populate the upper airway and lungs.

 

Humans have some avian-like alpha 2,3 receptor cells, particularly deep in the lungs. 

 

This has been suggested as the reason that when humans contract H5N1, it is usually a deep lung infection.  It has also been postulated that H5N1’s deeper lung infections may reduce human-to-human transmission, as sneezing is a less common symptom.   

 

This duel receptor affinity with the D222G mutation may help explain why some patients that contract it also develop more serious lung infections.

 

The operative word here being `may’. 

 

The bottom line here is that so far, whatever pathogenic differences this mutation may spark, it has had a relatively small effect on the overall mortality and morbidity of this virus. 

 

That could change, of course, if this mutation were to become more common, or if complementary concurrent changes to the genetic structure of the virus were to further enhance its virulence.

 

All in all, a fascinating piece of research, and one that advances our knowledge of this mutation considerably.  No, it doesn’t answer the `big question’, of whether this mutation will end up becoming a significant public health threat.

 

But scientific knowledge is gained incrementally. 

 

So stay tuned.

 

 

For more on the Baskin Study (Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus by Carole Baskin et. al.  that appeared PNAS), which looked at the comparative pathogenesis of seasonal H1N1, a 1918-like H1N1, and the H5N1 virus, you may enjoy my 3-part series available at the following links:

 

 

Dissecting the Influenza Pathogenesis Study Pt. 1

Dissecting the Influenza Pathogenesis Study Pt. 2

Dissecting the Influenza Pathogenesis Study Pt. 3

»» Read More

Fitness Of Oseltamivir-Resistant A/H1N1/2009

 

 

 

# 4952

 

 

Last night CIDRAP posted a summary of a PLoS Pathogens study in their nightly newsscan that has the potential, at some point, to become a significant story.

 

A brief excerpt, followed by some comments on my part.

 

Study: Tamiflu-resistant 2009 H1N1 passes fitness tests

Trials to assess the pathogenicity and transmissibility of oseltamivir-resistant 2009 H1N1 viruses in mice and ferrets suggest that the resistant strain is as fit as counterparts that are sensitive to the drug, according to Japanese researchers. The group, which includes Dr Yoshihiro Kawaoka, a virologist from the University of Wisconsin at Madison, reported their findings in PLoS Pathogens . .  .  .

Aug 26 PLoS Pathogens abstract

 

 

The entire study is titled:

 

Characterization of Oseltamivir-Resistant 2009 H1N1 Pandemic Influenza A Viruses

Kiso M, Shinya K, Shimojima M, Takano R, Takahashi K, et al. (2010) Characterization of Oseltamivir-Resistant 2009 H1N1 Pandemic Influenza A Viruses. PLoS Pathog 6(8): e1001079. doi:10.1371/journal.ppat.1001079

 

And as the CIDRAP piece explained, the authors looked a the fitness (ability to replicate, compete, and transmit) of oseltamivir (Tamiflu) resistant novel H1N1 viruses compared to non-resistant strains.

 

For now, the good news is that the 2009 H1N1 virus remains overwhelmingly sensitive to Tamiflu.

 

But of course, the same could have been said about the old seasonal H1N1 virus back in 2006-2007, when 99% of isolates tested showed good sensitivity to oseltamivir.

 

Resistance is generally caused by a mutation, known as H274Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 274.

 

Back in 2007, the belief was that the mutation that made the virus resistant to Tamiflu (H274Y), also reduced its biological fitness – suggesting that mutated versions of the viruses were unlikely to spread widely.

 

But those hoped dimmed when, by the end of the 2007-2008 flu season,  nearly 13% of H1N1 isolates tested the United States were resistant to the drug.

 

Jump ahead to December of 2008, and nearly all seasonal H1N1 isolates tested around the world carried the H274Y mutation that conferred Tamiflu resistance.

 

The CDC was forced to issue major new guidance for the use of antivirals for the second time in just three years (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).   

 

The `replacement’ 2009 pandemic virus, that supplanted the largely resistant seasonal strain, was fortunately both relatively mild and sensitive to Tamiflu. 

 

But over the past 16 months, several hundred scattered cases of Tamiflu resistance have been detected, including in a couple of clusters, raising the specter that someday this new strain of H1N1 could become resistant as well.

 

Earlier this summer, part of the mystery of how the old seasonal H1N1 developed resistance and still managed to transmit efficiently was revealed when researchers identified two "pre-adaptive mutations” that helped pave the way for the H274Y strains to spread (see Caltech: How Seasonal Flu Gained Tamiflu Resistance).

 

Today’s study shows that while still limited in the wild, the mutated 2009 H1N1 virus demonstrates biological fitness, and replicates and spreads efficiently in mice and ferrets.

Post mortem exams of ferrets used in this study also show no reduction in pathogenicity of the mutated virus.

 

Leading the authors to state:

 

Our findings highlight the possibility that NA H274Y-possessing oseltamivir-resistant 2009 H1N1 pandemic viruses could supersede oseltamivir-sensitive viruses, as occurred with seasonal H1N1 viruses.

 

Since novel H1N1 is already resistant to the older amantadine-class (M2 ion channel blockers) antivirals, the loss of these newer neuraminidase (NA) inhibitors (oseltamivir and zanamivir) would be a serious blow.

But not as serious as it would have been before a vaccine was available. Today, unlike a year ago, we have the ability to substantially (not 100%, of course) protect against this virus. 

 

And it is almost always better to prevent a disease than to try to treat one.

 

Antibiotics and antivirals are fleeting victories against rapidly evolving pathogens at best, since from the minute they are introduced, nature begin to work on ways to defeat them.

 

Once again, from the study’s text:

 

The widespread administration of oseltamivir, and to a lesser extent zanamivir, will clearly contribute to the emergence of NA inhibitor-resistant viruses that retain optimal replication fitness and transmissibility in humans. 

 

The authors note that in vitro and in vivo experiments on two experimental drugs- CS-8958 and favipiravir – suggest these may be candidates to deal with 2009 H1N1 line of viruses in the future.

 

For some earlier essays on the H274Y mutation, you might wish to check out:

 

NIH: Rapid Development Of Antiviral Resistance In Two Cases

WER Review: Oseltamivir Resistance In Pandemic H1N1

NEJM: Community Cluster Of Tamiflu Resistant H1N1

»» Read More

When Viruses Don’t Read The Manual

 

 

Note: I’m still blogging from the beach, and with a slow wireless connection and using a smaller than normal netbook keyboard, so I’m keeping my blog entries relatively brief this week.

 

# 4786

 

 

An absolutely fascinating study this morning that reveals a previously unknown way for influenza viruses to adapt to, and replicate efficiently in, humans.

 

This not only helps explain the transmission of the 2009 H1N1 pandemic strain, it illuminates another way that other avian flu viruses (including H5N1) could someday become a `humanized’.

 

A little background is in order, then the study.

 

Scientists have long come to expect to find a couple of specific amino acids at two locations in an influenza virus’s polymerase PB2 protein that enable it to replicate efficiently in humans; Lysine at position 627 or asparagine at position 701.

 

The 2009 pandemic virus lacked both of these changes, yet replicated extremely well, breaking the `rules’ and greatly puzzling scientists.

 

 

Researchers have now discovered that Lysine at position 591 of the PB2 protein compensates for the lack of these other two changes.

 

Moreover, they also found by making this change to H5N1, the virus replicated efficiently in mammals and increased in virulence in mice.

 

 

 

The study, published in PLoS Pathogens is titled:

 

Biological and Structural Characterization of a Host-Adapting Amino Acid in Influenza Virus

Yamada S, Hatta M, Staker BL, Watanabe S, Imai M, et al. 2010 Biological and Structural Characterization of a Host-Adapting Amino Acid in Influenza Virus. PLoS Pathog 6(8): e1001034. doi:10.1371/journal.ppat.1001034

ABSTRACT

Two amino acids (lysine at position 627 or asparagine at position 701) in the polymerase subunit PB2 protein are considered critical for the adaptation of avian influenza A viruses to mammals.

 

However, the recently emerged pandemic H1N1 viruses lack these amino acids. Here, we report that a basic amino acid at position 591 of PB2 can compensate for the lack of lysine at position 627 and confers efficient viral replication to pandemic H1N1 viruses in mammals.

 

Moreover, a basic amino acid at position 591 of PB2 substantially increased the lethality of an avian H5N1 virus in mice. We also present the X-ray crystallographic structure of the C-terminus of a pandemic H1N1 virus PB2 protein. Arginine at position 591 fills the cleft found in H5N1 PB2 proteins in this area, resulting in differences in surface shape and charge for H1N1 PB2 proteins.

 

These differences may affect the protein's interaction with viral and/or cellular factors, and hence its ability to support virus replication in mammals.

 

This is a long, complex, but ultimately fascinating research article, and many of my readers will probably want to read it in its entirety.

 

You’ll find additional mainstream media coverage on this story in Medical News Today and in this Reuters report.

 

This study not only helps to explain how novel H1N1 moved efficiently into the human population, it also highlights a new region of avian flu viruses that need to be monitored for changes that might signify an emerging threat to humans.

»» Read More

Dial M For Mutation

 

 

 

#4771

 

 

Once again we’ve a story out of India claiming that the novel H1N1 `swine flu’ virus has `mutated’, but as in earlier media reports, we’re given very little solid information to go on.

 

First the article from the Hindustan Times, then a bit of discussion.

 

 

H1N1 virus has mutated

Mumbai: , June 24, 2010

Neha Bhayana , Hindustan Times

The H1N1 virus has undergone a slight genetic mutation and its effect on patients has also changed. But patients are still responding to anti-viral drug Tamiflu.

 

“Unlike last year, swine flu patients don’t have high fever these days. Severe sore throat and backache are the most prominent symptoms now,” said Dr G.T. Ambe, Brihanmumbai Municipal Corporation’s executive health officer.

 

He added that Tamiflu and the vaccine are still “very effective.”

 

The state Directorate of Health Services had called for a meeting of experts and officials involved in tackling swine flu on Wednesday.

 

Dr A.C. Mishra, director of the National Institute of Virology, who attended the meeting in Mumbai, shared insights about the change in antigenicity of the virus (ability to cause production of antibodies), according to sources.

 

Infectious disease specialist Dr Om Srivastav has also observed changes in the clinical manifestation of swine flu. “Fever is not a predominant feature anymore,” he said.

 

“There is a small change in the virus. But this is not surprising. We expect it to change further,” said Dr Srivastav, who is part of the state government’s H1N1 advisory committee.

(Continue . . . )

 

 

Although the word `mutation’ has an ominous connotation, changes in the influenza virus happen often and only rarely result in a more aggressive or dangerous flu strain.

 

Most of these mutations result in evolutionary dead ends; flawed viruses unable to compete against the existing strain.

 

In order for a mutation to become a pathogenic `player’, it has to be biologically fit, and capable of replicating reliably and efficiently. 

 

And even when that happens, the end result isn’t necessarily bad. A virus can certainly mutate into a less virulent strain.

 

This isn’t the first media story about suspected mutations in the H1N1 virus to come out of India since the pandemic started.  

 

Last March (see PB2 Mutation Detected In India) there was a brief flurry of reports about the detection of an (unspecified) change in the PB2 segment of the virus.

 

It was reported that this mutation had little clinical significance.

 

Although details were not provided, this change is thought to be similar to that which  Dutch scientists isolated last September; the E627K mutation (see ProMed Mail  INFLUENZA PANDEMIC (H1N1) 2009 (58): THE NETHERLANDS, PB2 MUTATION). 

 

The E627K mutation in novel H1N1 was widely expected to expedite viral replication in humans. The fact that it apparently doesn’t was of considerable surprise to scientists around the world.

 

And last September The Hindu printed this somewhat hyperbolic report:

 

A(H1N1) gets more virulent

Tuesday, Sep 15, 2009

HYDERABAD: The A(H1N1) virus is showing signs of getting ‘mutated’ into a more virulent form.

 

Clinical observation of experts in the State capital indicate that the genetic make up of A(H1N1) virus has ‘changed’ and is now more ‘potent’ after coming into contact with the local existing viral forms.

(Continue . . . )

 

 

Inferring a `mutation’ based on a change in clinical presentation is an `iffy’ proposition.   And despite the warnings of a `more virulent’ result, we’ve seen little evidence to support that prediction.

 

Small, often incremental changes to the H1N1 virus are to be expected.   After all, that’s what influenza viruses do. 

 

They mutate.  They evolve.

 

The significance of this most recent report is difficult to gauge, given the lack of specifics provided.

 

More information regarding the location and type of mutation and the transmissibility (and incidence) of this `mutated virus’ would be helpful.

 

For now, I consider this report interesting, but not terribly illuminating.  

»» Read More

PB2 Mutation Detected In India

 

 

# 4436

 

 

 

The `buzz’ this morning surrounds an article out of India describing the discovery of a `mutation’ in the PB2 gene segment of the H1N1 virus that has been detected in 3 patients.

 

Mutations, of course, are common with influenza viruses.  Most turn out to be of little importance. 

 

On rare occasions mutations can convey a significant biological advantage to the virus.

 

While this article is infused with an extraordinary amount of `disease geek-speak’ for a newspaper story, we get surprisingly little hard information about this reported genetic change in the virus. 

 

 

First the article, then a few comments.

 

 

 

H1N1 virus shows genetic mutation, 'but not a worry'

Umesh Isalkar, TNN, Mar 16, 2010, 07.32am IST

PUNE: The swine flu virus isolated from the throat swab samples of three H1N1-infected patients at the National Institute of Virology (NIV) has shown a small genetic mutation in the polymerase 2 (PB2) gene, NIV director A C Mishra told TOI on Monday.

 

However, Mishra said there was no cause for worry as the virus was still not resistant to oseltamivir, which is an active ingredient in Tamiflu.

 

It may be noted that a small genetic mutation was earlier detected in the haemagglutinin (HA) region of the virus as well while testing the throat swab samples of two patients who eventually succumbed to the H1N1 infection.

 

The PB2 mutation has previously been associated with increased efficiency of replication and possible virulence changes in other influenza A viruses. “However, we did not find such increased efficiency of replication or increased virulence in the isolates of the swine flu virus in which we have noticed mutation of the PB2 gene. The mutation is not very significant in that sense,” said Mishra.

 

Consulting microbiologist and immunologist Siddharth Dalvi said, “The PB gene makes a protein that is responsible for viral replication. Since this enzymic protein is not directly involved in the immune responses, point mutations in this gene may not be of immediate clinical impact. However, it may, in theory, change the way the virus replicates.”

 

Most RNA viruses (including influenza virus) replicate their genome by using the viral enzyme to make copies from the parent RNA. “This enzyme has a weak proof-reading activity, that is, checking if the right nucleotides have been incorporated in the genome. Hence, over time, point mutations are bound to happen in the genome of these viruses. In fact, we would be surprised if they don’t. The majority of these mutations may not have any significance, either for the virus, or for the host,” said Dalvi.

 

 

Left out of this reassuring virology lesson are a few key (but basic) facts that would have gone a long ways towards clarifying the significance of this story.

 

What mutation in the PB2 gene are they talking about?  (Possibly E627K, but never actually stated)

When were these samples collected?

Were these three patients epidemiologically connected in any way?

 

What of the course of illness and outcome for these three patients?

 

 

I ask these questions - not because I’m particularly concerned over the impact of this particular mutation - but simply in the interest of clear and concise reporting.

 

Saying that they found a mutation in the PB2 gene is, quite frankly, about as precise as reporting `a flood somewhere in New England’.  

 

Accurate as far as it goes, but not terribly helpful.

 

 

If this report sounds a little familiar, it may be because last September Dutch scientists reported that they had found a couple of patients with a PB2 mutation (E627K) that – to their surprise – conveyed no detectable biological advantage to the virus.

 

ProMed Mail  carried an alert on this story on September 27th , some of which is excerpted below:

 

INFLUENZA PANDEMIC (H1N1) 2009 (58): THE NETHERLANDS, PB2 MUTATION

From: Marion Koopmans
<Marion.Koopmans@rivm.nl>

We would like to report 2 patients in The Netherlands, diagnosed with influenza pandemic A(H1N1) 2009 virus infection that had a mutation (E627K) in the basic polymerase 2 (PB2) protein. This mutation has previously been associated with increased efficiency of replication and possible virulence changes in other influenza A viruses.

The investigation identified a specific geographic region in the north of The Netherlands as the place where viruses with the same genetic background have circulated between mid July and mid August [2009]. No other cases carrying the PB2 mutation have been identified.

(Continue . . . )

 

The E627K mutation in novel H1N1 was widely expected to expedite viral replication in humans. The fact that it apparently doesn’t was of considerable surprise to scientists around the world.

 

We’ll have to wait for better reporting on the Indian mutation before we can know with certainty exactly what mutation they are talking about.   

 

If it turns out to be E627K, their observations would appear to match those of the researchers out of the Netherlands last year.  

 

Obviously, we’ll keep an eye on this story in hopes of more details.

»» Read More