ECDC Rapid Risk Assessment On `Drifted’ H3N2 Viruses

Credit NIAID

 

 

# 9474

 

While we often talk about seasonal strains (H1N1, H3N2, Influenza B) as if they were individual entities – in truth within each subtype there are many clades and variants - and they are all evolving over time. Geographically, these viruses can vary widely, and so the dominate strains in Europe may differ from the dominant strains in North America or Asia.

 

Over time, new, more biologically `fit’ viruses replace older strains as community immunity drives them closer to obsolesce.

 

All which makes the flu world dynamic and ever-changing, and presents a genuine challenge for vaccine manufacturers to stay ahead of. NIAID has a terrific 3-minute video that shows how influenza viruses drift over time, and why the flu shot must be frequently updated, which you can view at this link.

Over the summer it was becoming apparent that a new, `drifted’ H3N2 virus was making inroads in Europe and around the globe (see ECDC: Influenza Characterization – Sept 2014) – one that differed antigenically from this year’s H3N2 vaccine strain. 

 

In September the WHO announced a strain change for next year’s Southern Hemisphere vaccine to meet this viral challenge, but this virus emerged far too late in the year to allow changes to this fall’s Northern Hemisphere vaccine.

 

In early November, in A `Drift’ In A Sea Of Influenza Viruses, I wrote about early concerns over this year’s vaccine, and in the first week of December the CDC issued a HAN Advisory On `Drifted’ H3N2 Seasonal Flu Virus along with a warning that  Early Data Suggests Potentially Severe Flu Season.

 

Today the ECDC has issued their own Risk Assessment on this `drifted’ flu strain.

 

Rapid risk assessment: circulation of drifted influenza A(H3N2) viruses in the EU/EEA, 22 December 2014

22 Dec 2014

Available as PDF in the following languages

EN

This document is free of charge.

Abstract

Surveillance data gathered since 1 October 2014 indicate that in the first ten weeks of the 2014–15 influenza season, viruses in EU/EEA countries have been predominantly A(H3N2) rather than A(H1N1)pdm09 and type B viruses. In previous seasons, influenza A(H3N2) viruses were associated with more severe disease than A(H1N1) and type B viruses; they were also associated with several outbreaks in long-term care facilities.

These observations indicate that the 2014-15 influenza season may be associated with a greater number of cases with more severe disease, given the higher proportion of A(H3N2) strains among isolates typed to date and the early evidence of drift that is likely to be associated with reduced vaccine effectiveness.

Influenza vaccine coverage among the elderly and the risk groups in most parts of Europe is low. However, the benefits of vaccination are considerable in protecting these population groups, even if vaccine effectiveness against one of the circulating viruses may turn out to be low.

 

 

  I’ve excerpted the following from the full report:

 

Main conclusions and recommendations

Surveillance data gathered since 1 October 2014 indicate that in the first ten weeks of the 2014–15 influenza
season, viruses in EU/EEA countries have been predominantly A(H3N2) rather than A(H1N1)pdm09 and type B  viruses. In previous seasons, influenza A(H3N2) viruses were associated with more severe disease than
A(H1N1) and type B viruses; they were also associated with several outbreaks in long-term care facilities.

The recently published US CDC health alert network notification on antigenically drifted influenza A(H3N2) viruses is the first signal from a northern hemisphere country that circulating viruses will include strains that are antigenically distinct from the A(H3N2) vaccine virus, A/Texas/50/2012, which was recommended by WHO for the northern hemisphere 2014–15 season at the February 2014 strain selection meeting.

Very few influenza virus characterisations have been conducted to date in EU/EEA countries, and the majority of them have been genetic rather than antigenic. The genetic information reported so far suggests the following:

• Influenza A(H3N2) viruses circulating in EU/EEA countries this season will be antigenically distinct from the  northern hemisphere A(H3N2) vaccine virus.
• Early indications are that circulating A(H1N1)pdm09 viruses are antigenically similar to the vaccine virus.
• Too few type B viruses have been characterised to date to comment on the likely effectiveness of the B/Massachusetts/2/2012 vaccine component.
  

These observations indicate that the 2014-15 influenza season may be associated with a greater number of cases with more severe disease, given the higher proportion of A(H3N2) strains among isolates typed to date and the early evidence of drift that is likely to be associated with reduced vaccine effectiveness.

Despite the expected low vaccine effectiveness (VE) of the A(H3N2) vaccine virus component in the vaccines administered for protection in the 2014–15 influenza season, the current tri- and quadrivalent vaccines are likely to provide protection against infection by other currently circulating influenza viruses. Even with low VE of the A(H3N2) vaccine virus components, the vaccine may ameliorate or shorten the duration of influenza disease in infected individuals and is likely to reduce the number of severe outcomes and mortality. Influenza  vaccination remains the most effective measure to prevent illness and possibly fatal outcomes.

The circulating viruses are susceptible to the antiviral drugs oseltamivir and zanamivir. Physicians should therefore always consider treatment or post-exposure prophylaxis with antivirals when treating influenza infected patients and exposed individuals in risk groups.

Influenza vaccine coverage among the elderly and the risk groups in most parts of Europe is low.

However, the benefits of  vaccination are considerable in protecting these population groups, even if vaccine effectiveness against one of the circulating viruses may turn out to be low.

CDC HAN Advisory On `Drifted’ H3N2 Seasonal Flu Virus

# 9408

 

Late yesterday the CDC issued a HAN Advisory for clinicians on the possibility of seeing `drifted’ H3N2 virus infections during this year’s flu season, along with a reminder on the appropriate and timely use of antivirals. 

 

If this sounds familiar, we looked at this possibility at some length a little over a month ago in A `Drift’ In A Sea Of Influenza Viruses.

 

But briefly, over the summer – and since this year’s flu vaccine components were selected last February – a new, antigenically drifted H3N2 virus has begun to circulate more widely.

 

The rise of this new strain has already prompted  WHO to recommend a strain change for next year’s Southern Hemisphere vaccine formulation from the current A/Texas/50/2012 (H3N2)-like virus to a new A/Switzerland/9715293/2013 (H3N2)-like virus.

 

The most recent FluView report (week 47) shows that of the 85 H3N2 viruses tested since October 1st, 41 (48%) are a good match to the vaccine strain, while 52% were not.  This `mismatch’ is expected to reduce the vaccine’s effectiveness against this drifted strain, although some protection or a reduction in the severity of illness may still result.

 

With this year shaping up to be an H3N2-dominant year, and a possible vaccine `mismatch’ in the works, the CDC is reminding clinicians of value of prescribing neuraminidase inhibitor antiviral medications for severe influenza, or for patients with co-morbidities that raise their risk of seeing serious complications.

 

Despite the constant excoriation of Tamiflu ® and other NI antiviral medications in the press – based primarily on a series of Cochrane reports (see Revisiting Tamiflu Efficacy (Again)) – there are demonstrable benefits to using these medications, particularly when given early and for severe influenza (see The CDC Responds To The Cochrane Tamiflu Study).

Earlier this summer we saw a review in the journal Clinical Infectious Disease that suggested a serious Under Utilization Of Antivirals For At Risk Flu Patients, and a month ago we saw the UK’s PHE reiterate their Influenza Antiviral Recommendations.

 

Although you can never be sure what kind of flu season we will have until it is over, years in which H3N2 viruses have dominated tend to be rougher for the elderly, and the very young,  than years when H1N1 or influenza B dominate. 

 

Despite the expected reduced effectiveness of this year’s flu shot, there are still benefits to getting the vaccine if you haven’t done so already. 

• There are two other strains (H1N1 & Influenza B) covered by the shot,
• Half the H3N2 viruses tested so far are still a `match’  to the vaccine strain
• There may still be some degree of cross-protection afforded against this new strain.

I’ve only posted the summary, so follow the link below to read the full HAN advisory, and the recommendations of antiviral use.

 

CDC Health Advisory Regarding the Potential for Circulation of Drifted Influenza A (H3N2) Viruses

 

CDC HEALTH ADVISORY

Distributed via the CDC Health Alert Network
December 3, 2014, 16:00 ET (4:00PM ET)
CDCHAN-00374

CDC is reminding clinicians of the benefits of influenza antiviral medications and urging continued influenza vaccination of unvaccinated patients this influenza season.

Summary

Influenza activity is currently low in the United States as a whole, but is increasing in some parts of the country. This season, influenza A (H3N2) viruses have been reported most frequently and have been detected in almost all states.

During past seasons when influenza A (H3N2) viruses have predominated, higher overall and age-specific hospitalization rates and more mortality have been observed, especially among older people, very young children, and persons with certain chronic medical conditions compared with seasons during which influenza A (H1N1) or influenza B viruses have predominated.

Influenza viral characterization data indicates that 48% of the influenza A (H3N2) viruses collected and analyzed in the United States from October 1 through November 22, 2014 were antigenically "like" the 2014-2015 influenza A (H3N2) vaccine component, but that 52% were antigenically different (drifted) from the H3N2 vaccine virus. In past seasons during which predominant circulating influenza viruses have been antigenically drifted, decreased vaccine effectiveness has been observed. However, vaccination has been found to provide some protection against drifted viruses. Though reduced, this cross-protection might reduce the likelihood of severe outcomes such as hospitalization and death. In addition, vaccination will offer protection against circulating influenza strains that have not undergone significant antigenic drift from the vaccine viruses (such as influenza A (H1N1) and B viruses).

Because of the detection of these drifted influenza A (H3N2) viruses, this CDC Health Advisory is being issued to re-emphasize the importance of the use of neuraminidase inhibitor antiviral medications when indicated for treatment and prevention of influenza, as an adjunct to vaccination.

The two prescription antiviral medications recommended for treatment or prevention of influenza are oseltamivir (Tamiflu®) and zanamivir (Relenza®). Evidence from past influenza seasons and the 2009 H1N1 pandemic has shown that treatment with neuraminidase inhibitors has clinical and public health benefit in reducing severe outcomes of influenza and, when indicated, should be initiated as soon as possible after illness onset. Clinical trials and observational data show that early antiviral treatment can:

• shorten the duration of fever and illness symptoms;
• reduce the risk of complications from influenza (e.g., otitis media in young children and pneumonia requiring antibiotics in adults); and
• reduce the risk of death among hospitalized patients.

(Continue . . .)

 

A `Drift’ In A Sea Of Influenza Viruses

P&I Mortality Surveillance by Week & Year - CDC

 

# 9278

 

There is always a degree of folly attached to trying to predict the kind of flu season we will have ahead.  The variability in influenza severity can be easily demonstrated by the wide range in the CDC’s mortality estimates, as described in the  August 27, 2010 MMWR report entitled “Thompson MG et al. Updated Estimates of Mortality Associated with Seasonal Influenza through the 2006-2007 Influenza Season. MMWR 2010; 59(33): 1057-1062.”

 

CDC estimates that from the 1976-1977 season to the 2006-2007 flu season, flu-associated deaths ranged from a low of about 3,000 to a high of about 49,000 people.

 

In other words, even across a span of three decades without seeing an influenza pandemic, there was as much as a 12-fold difference in mortality between flu seasons.  

 

Over the past several years, we’ve seen a huge spread in severity as well, with the 2011-12 flu season perhaps the mildest in three decades (see  2011-2012 Flu Season Draws to a Close), while the following year (2012-13) was deemed moderate-to-severe. 

 

Surprisingly, both were H3N2  dominated seasons, which tend to produce more severe flu seasons – particularly among the elderly (see MMWR Influenza Activity — United States, 2012–13 Season and Composition of the 2013–14 Influenza Vaccine) – proving that `rules of thumb’ don’t always work.

 

Last year we saw the `return’ of the H1N1 strain – which never really went away, but had been dominated by H3N2 since the 2009 pandemic ended. 

 

As is common with H1N1 strains, younger people were more severely impacted than we normally see with H3N2 (see Influenza Activity — United States, 2013–14 Season and Composition of the 2014–15 Influenza Vaccines), prompting a CDC HAN Advisory On Early pH1N1 Influenza Activity to be issued in late December.

 

As far as vaccines are concerned, the 2009 H1N1 component has remained remarkably antigenically stable since it emerged more than five years ago.  We keep expecting to see it drift away from its original form, but so far, it hasn’t.

Less stable have been the H3N2 viruses, which continue to drift and form antigenically diverse clades, which constantly bump shoulders as they seek susceptible hosts. The most recent ECDC: Influenza Characterization – Sept 2014 describes 7 distinct genetic groups detected since 2009, making vaccine strain selection more problematic.

 

Since the fall 2014 vaccines strains were selected last February, surveillance has begun to detect a rise in the number of antigenically drifted H3N2 isolates, prompting the WHO to recommend a strain change for next year’s Southern Hemisphere vaccine formulation from an A/Texas/50/2012 (H3N2)-like virus to an A/Switzerland/9715293/2013 (H3N2)-like virus.

 

According to the CDC’s latest FluView report – while this new, drifted H3N2 strain has begun to show up in North America, for now, this year’s vaccine strain (A/Texas/50/2012(H3N2)) remains dominant  among the limited number of H3N2 viruses tested.

 

CDC has antigenically characterized 10 influenza A (H3N2) viruses collected since October 1, 2014. This is the first antigenic characterization data available for H3N2 viruses collected in the United States since October 1, 2014.

• Seven (70%) of the 10 influenza A (H3N2) viruses tested have been characterized as A/Texas/50/2012-like. This is the influenza A (H3N2) component of the 2014-2015 Northern Hemisphere influenza vaccine. Three (30%) H3N2 viruses were antigenically similar to A/Switzerland/9715293/2013, the H3N2 virus selected for the 2015 Southern Hemisphere influenza vaccine.

Additionally, early surveillance suggests we may be looking at an H3N2-centric flu season.

 

Influenza A (H3N2), 2009 influenza A (H1N1), and influenza B viruses have all been identified in the U.S. this season. During the week ending October 25, 237 (74.1%) of the 320 influenza-positive tests reported to CDC were influenza A viruses and 83 (25.9%) were influenza B viruses. Of the 82 influenza A viruses that were subtyped, 96% were H3 viruses and 4% were 2009 H1N1 viruses.

 

Again, flu seasons don’t always end up the way they start out. 

 

But for now, it looks as if we may be looking at a flu season dominated by H3N2, and with two antigenically divergent clades in circulation.  One `covered’ by the this year’s vaccine, and the other – well, probably not so much.

 

None of which is to suggest that this year’s flu vaccine isn’t worth getting (I’ve already gotten mine), or that a mismatched vaccine offers no protection against an antigenically divergent virus.   The CDC explains:

 

What if there is a mismatch between circulating viruses and the vaccine viruses?

A “mismatch” is said to occur when the viruses in the vaccine are significantly different from those circulating in the community. In years when the vaccine strains are not well matched to circulating strains, vaccine effectiveness can be reduced. However, even when the viruses in the vaccine and circulating viruses are not well matched, a vaccine may still offer some protection against circulating viruses.

For example, in a study among persons 50-64 years of age during the 2003-04 influenza season, when the vaccine strains were not optimally matched, inactivated influenza vaccine effectiveness against laboratory-confirmed influenza was 60% among persons without high-risk conditions, and 48% among those with high risk conditions. However, vaccine effectiveness was 90% against laboratory-confirmed influenza hospitalization (Herrera, et al Vaccine 2006). A study in children during the same year found vaccine effectiveness of about 50% against medically diagnosed influenza and pneumonia without laboratory confirmation (Ritzwoller, Pediatrics 2005). Still, in some years when vaccine and circulating strains were not well-matched, no vaccine effectiveness may be able to be demonstrated (Bridges, JAMA 2000). It is not possible in advance of the influenza season to predict how well the vaccine and circulating strains will be matched, and how that may affect vaccine effectiveness. For more information, see Vaccine Effectiveness - How Well Does the Flu Vaccine Work?

 

Although a partially mismatched vaccine, and an H3 heavy year may suggest a severe flu season ahead, how all of this will play out, is unknown. Which is why the CDC issues a mid-season and end-of-season reports rather than a forecast.

 

As I’ve written here often , flu vaccines are considered very safe – and most years provide a moderate level of protection against influenza. Their VE (vaccine effectiveness) can vary widely between flu shot recipients, and is often substantially reduced among those older than 65 or with immune problems.

 

While the vaccine can’t promise 100% protection, it – along with practicing good flu hygiene (washing hands, covering coughs, & staying home if sick) – remains your best strategy for avoiding the flu (and other viruses) this winter.

Study: Sequence & Phylogenetic Analysis Of Emerging H9N2 influenza Viruses In China

Poultry Vaccination - Photo Credit OIE

 

# 8425

 

Among the avian flu viruses we watch with concern, the H5N1 and H7N9 viruses have gained the most notoriety.  Yet, behind each of these rising stars is an unindicted co-conspirator – the ubiquitous, but little noticed H9N2 avian virus – which has lent crucial internal genes to both of these emerging threats.

We looked at these contributions six weeks ago in The Lancet: H9N2’s Role In Evolution Of Novel Avian Influenzas, but briefly - H5N1, H7N9, and the recently observed H10N8 – all share several important features:

• 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

Since H9N2 rarely causes serious illness in humans, and as it is already pretty much widespread in Asian poultry, it tends to fly below the radar.  Unlike H5 and H7 avian viruses, it isn’t considered enough of a threat by the OIE to be reportable, and vaccination – not culling – is the standard practice to prevent its spread.

Yet, some researchers view it with concern.

 

Last January, The Lancet carried a report entitled Poultry carrying H9N2 act as incubators for novel human avian influenza viruses by Chinese researchers Di Liu a, Weifeng Shi b & George F Gao that warned:

 

Several subtypes of avian influenza viruses in poultry are capable of infecting human beings, and the next avian influenza virus that could cause mass infections is not known. Therefore, slaughter of poultry carrying H9N2—the incubators for wild-bird-origin influenza viruses—would be an effective strategy to prevent human beings from becoming infected with avian influenza.

We call for either a shutdown of live poultry markets or periodic thorough disinfections of these markets in China and any other regions with live poultry markets.

 

In the past, we’ve looked at the propensity of the 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.

 

And while we have only seen a handful of human infections with this virus (see Hong Kong: Isolation & Treatment Of An H9N2 Patient), it is also true that in areas where this virus is most common, testing and surveillance for the virus is extremely limited.  Like so many other novel viruses, we can only guess at is true burden in the human population.

 

All of which brings us to a new study, which appears in the journal Virus Genes, that takes a look at H9N2 viruses collected from two regions in China (Zhejiang & Guangdong Provinces) between October & December 2011,  where poultry vaccination is practiced (Note: an inactivated H9N2 vaccine was introduced in China in 1998).

 

What they found was an array of viruses that have evolved antigenically away from the vaccine strain, with a majority of isolates (14 out of 18) showing an amino acid change in the receptor binding site suggestive of an enhanced ability to bind to human receptor cells.

 

H9N2 influenza viruses isolated from poultry in two geographical regions of China

Yu Xue, Jing-Lan Wang, Zhuan-Qiang Yan, Guang-Wei Li, Shun-Yan Chen, Xiang-Bin Zhang, Jian-Ping Qin, Hai-Yan Li, Shuang Chang, Feng Chen, Ying-Zuo Bee, Qing-Mei Xie

Abstract

Subtype H9N2 avian influenza viruses (AIVs) circulating in China have aroused increasing concerns for their impact on poultry and risk to public health. The present study was an attempt to elucidate the phylogenetic relationship of H9N2 AIVs in two geographically distinct regions of China where vaccination is routinely practiced.

A total of 18 emerging H9N2 isolates were identified and genetically characterized. Phylogenetic analysis of hemagglutinin (HA) and neuraminidase (NA) genes confirmed that the isolates belonged to the Y280 lineage. Based on the HA genes, the isolates were subdivided into two subgroups. The viruses from Zhejiang Province were clustered together in Group I, while the isolates from Guangdong Province were clustered together in Group II.

Antigenic characterization showed that the tested viruses were antigenically different when compared to the current used vaccine strain. It was notable that 14 out of total 18 isolates had an amino acid exchange (Q→L) at position 216 (226 by H3 Numbering) in the receptor-binding site, which indicated that the virus had potential affinity of binding to human like receptor.

These results suggest that the emerging viruses have potential risk to public health than previously thought. Therefore, continuous surveillance studies of H9N2 influenza virus are very important to the prognosis and control of future influenza pandemics.

Yu Xue, Jing-Lan Wang, and Zhuan-Qiang Yan have contributed equally to this study.

One of the concerns with long-term vaccination schemes, such as China has employed over the past 16 years, is that the widespread use of vaccines can sometimes drive the development of new viral strains. And a failure to continually update the vaccines being used to match these new strains can further exacerbate the problem, as a poorly matched vaccine may mask symptoms without actually preventing infection.

 

Last year, in the Journal Clinical and Experimental Vaccine Research, Dong-Hun Lee and Chang-Seon Song penned a study called H9N2 avian influenza virus in Korea: evolution and vaccination, where they wrote:

 

Compared to human influenza virus, the antigenicity of AIV is relatively stable, which may be due to the lack of immune pressure. However, as large-scale and long-term vaccinations against AIV have been performed in several countries, AIVs have also undergone antigenic drift due to the presence of immune pressure [48].

<SNIP>

Concluding Remarks

Wide use of AIV vaccine in animal population could enhance the immune pressure and drive the mutation resulting in rapid antigenic drift at the antigenic sites [52]. Therefore, improved vaccination strategies and periodic updates of vaccine seed strains are required to increase immunogenicity and cross protective efficacy in chicken farms. These strategies could include: the selection of highly immunogenic vaccine seed strains, the use of effective adjuvants for chickens, and the use of new technology vaccines. Several studies reported that the recent Korean LPAI H9N2 virus underwent antigenic drift and could escape from vaccine protection.

Thus, continued active surveillance of poultry farms and LBMs to reveal new variant LPAI H9N2 viruses in Korea and analyzing appropriate vaccine seed viruses should be considered to prevent new outbreaks.

 

The use of vaccines to control avian viruses in poultry is not without controversy.  The OIE has repeatedly warned that vaccines are a short-term solution to avian flu problem, and that countries should have an `exit strategy’ away from vaccines.  This from the H7N9 FAQ issued last year:

 

Does OIE recommend vaccination of animals to control the disease?

When appropriate vaccines are available, vaccination aims to protect the susceptible bird populations from potential infection. Vaccination reduces viral excretions by animals and the virus’ capacity to spread. Vaccination strategies can effectively be used as an emergency effort in the face of an outbreak or as a routine measure in an endemic area. Any decision to use vaccination must include an exit strategy, i.e. conditions to be met to stop vaccination.

Careful consideration must be given prior to implementing a vaccination policy and requires that the recommendations from the World Organisation for Animal Health (OIE) on vaccination and vaccines are closely followed (http://www.oie.int/downld/AVIAN INFLUENZA/Guidelines on AI vaccination.pdf).

In short, vaccination should be implemented when culling policies cannot be applied either because the disease is endemic and therefore widely present, or the infection in affected animals is too difficult to detect.

 

Unfortunately, after 16 years of use, there are no signs that an exit strategy is likely to be proffered by the Chinese anytime soon.

 

A legitimate concern due to growing evidence that the use of (particularly mismatched)  vaccines can drive potentially dangerous evolutionary changes in the very viruses they are designed to prevent.

 

All of which means that while we watch H7N9, H5N1, or H10N8 for signs of pandemic potential, we can’t afford to ignore the evolving threat posed by the H9N2 virus – which either directly or indirectly – could play a substantial role in generating the next pandemic virus.

EID Journal: The Expanding Variants Of H5N1

Photo Credit NIAID

# 7957

 

 

Influenza A subtypes are categorized by two proteins they carry on their surface; their HA (hemagglutinin) and NA (neuraminidase). There are 17 known HA proteins, and 10 known NAs, making many different subtype combinations possible, although only a few are known to infect humans. 

 

While we talk about H1N1 or H3N2 seasonal flu as if each were a single entity, in truth, there can be much variation within each subtype.  Within each subtype, there are often genetic groupings called clades, and within each clade- subclades - and within these even smaller genetic variations.

 

The ECDC’s most recent Influenza Virus Characterisation Report (Sept. 2013) found that the 2009 H1N1 virus HA genes have morphed into eight different genetic groups (clades), with a ninth ‘outlier’ group largely restricted to countries of west Africa.  Similarly, the H3N2 viruses circulating over the past year fall into 3 groups (3, 5, 6), with three subgroups (3A, 3B, 3C) and subgroup 3C has 3 subsets (3C.1, 3C.2, 3C.3).

 

This expanding variety in each strain is due to antigenic drift, which comes about when errors are made in the replication of the virus.  Over a period of a few hours, millions of copies of a virus can be produced in a single host, and invariably some of these copies are `flawed’, and contain amino acid substitutions somewhere in the virus’s genetic code.

 

Most of the time, these changes either do nothing, or make the virus less viable.  With millions of copies being generated, a few `duds’ hardly makes a difference to the virus, or the host.

 

But every once in awhile, out of millions of failures, a more biologically `fit’ virus will emerge.  One that replicates better than either its parents or its siblings - and if it is also easily transmissible - it can take off as a new, emerging variant or (if it is genetically distinct enough) as a new clade. 

These new clades can change the virus antigenically (evading existing immunity), can convey resistance to antivirals, and can even change the virulence of the virus.

This is why the flu vaccine must be updated nearly every year. Flu viruses mutate constantly, and over time new clades (and sometimes, entirely new strains) appear. Even more abrupt changes can come from Antigenic Shift or reassortment (see Because, Sometimes Shift Happens).

 

And, as you might expect, the same is true with avian and swine influenza viruses.  

 

Since the H5N1 virus was first identified in 1996 it has expanded into more than 20 different clades and subclades, and various versions of the virus now circulate in different parts of the world. You can see the evolution of the virus through 2011 in the chart below.

 

NOTE: Not all of these clades continue to circulate.

 

Clade 2.3.2 (and now 2.3.2.1) are very common in South East Asia, clades 2.2.1 and 2.2 are endemic in Egypt and clades 2.1.1, 2.1.2. and 2.1.3 are found in Indonesia.

 

As you might imagine, as new clades emerge, it complicates the vaccine picture enormously, for humans and for poultry. A vaccine designed for clade 1.0 probably won’t prove very effective against clade 2.2. 

 

Last month (see WER: Antigenic & Genetic Comparisons Of Zoonotic Flu Viruses And Development Of Vaccine Candidates)  the WHO proposed that 4 new candidate vaccine viruses be developed.

 

Based on the available antigenic, genetic and epidemiologic data, A/duck/Bangladesh/19097/2013-like (clade 2.3.2.1), A/duck/Viet Nam/NCVD-1584/2012-like (clade 2.3.2.1) and A/Cambodia/W0526301/2012-like (clade 1.1) candidate vaccine viruses are proposed.

 

Not all H5N1 viruses possess the same virulence, and some strains may be more readily transmissible than others. Last April we looked at a study that examined the  Differences In Virulence Between Closely Related H5N1 Strains.

 

All of which serves as prelude to a new Dispatch that appeared this week in the CDC’s EID Journal, that reports the emergence of three new variations of the H5N1 virus in Vietnam between 2009 and 2012.

 

Novel Variants of Clade 2.3.4 Highly Pathogenic Avian Influenza A(H5N1) Viruses, China

Min Gu, Guo Zhao, Kunkun Zhao, Lei Zhong, Junqing Huang, Hongquan Wan, Xiaoquan Wang, Wenbo Liu, Huimou Liu, Daxin Peng, and Xiufan Liu

Abstract

We characterized 7 highly pathogenic avian influenza A(H5N1) viruses isolated from poultry in China during 2009–2012 and found that they belong to clade 2.3.4 but do not fit within the 3 defined subclades. Antigenic drift in subtype H5N1 variants may reduce the efficacy of vaccines designed to control these viruses in poultry.

<SNIP>

Conclusions

The location of the 7 HPAI A(H5N1) virus variants in the HA gene tree (Figure) suggests that novel monophyletic subclades other than the previously identified 2.3.4.1, 2.3.4.2, and 2.3.4.3 subclades continue to emerge within clade 2.3.4. As a result of our findings, we suggest that these groups should be assigned new fourth-order clades of 2.3.4.4, 2.3.4.5, and 2.3.4.6 to reflect the wide divergence of clade 2.3.4 viruses.

 

In China, 1 of the 6 countries to which subtype H5N1 virus is endemic (7), multiple distinct clades (2.2, 2.5, 2.3.1, 2.3.2, 2.3.3, 2.3.4, 7, 8, and 9) were identified by surveillance during 2004–2009 (5). In particular, clades 2.3.2, 2.3.4, and 7 viruses have gained ecologic niches and have continued circulating by further evolving into new subclades (2). In addition, various NA subtypes of H5 viruses (H5N5, H5N8, and H5N2) bearing the genetic backbone of clade 2.3.4 A(H5N1) viruses have been detected in ducks, geese, quail, and chickens (8–12). These findings highlight the importance of periodic updates of the WHO/OIE/FAO classification of Asian A(H5N1) viruses by continuous surveillance to better understand the dynamic nature of the viral evolution.

 

Our findings have implications for the effectiveness of vaccination of chickens against HPAI A(H5N1) viruses. The results of cross-HI assays (Table 1) and vaccine efficacy experiments (Table 2) indicate antigenic drift in subtype H5N1 variants, as compared with the vaccine strain specifically designed to control the prevalent clade 2.3.4 virus infection in poultry. Although previous studies by Tian et al. (13) and Kumar et al. (14) proposed that vaccinated chickens with HI antibody titers of >4 log₂ could be protected from virus challenge, our data demonstrate that vaccine efficacy is substantially influenced by antigenic matching between the vaccine strain and circulating viruses in preventing the replication and transmission of influenza virus, especially when the induced antibodies are of moderate titers.

 

 

While we’ve been fortunate that no human-transmissible strain of H5N1 has evolved over the years, there are no guarantees that an emerging variant won’t gain that ability down the road. 

 

And, assuming the H7N9 virus doesn’t fade away on its own accord, there is little reason not to expect a similar evolutionary expansion as more hosts are infected and more copies of itself are generated, which will provide more opportunities for new successful variants to be created.

 

The only thing you can truly bank on with influenza viruses is that they continually change.  And until an effective universal vaccination can be developed against them, they will continue to pose a considerable threat to humanity.

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.

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.

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. 

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.

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. 

 

 

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

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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.