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Updating the H1N1 Update

Updating the H1N1 Update

EM of swine influenza (H1N1) virus particles (virions), determined to be the cause of the

Watching and Waiting
Tamiflu Resistance
Dr. Niman vs. WHO, ECDC and CDC

by Ilene with guest expert Dr. Henry Niman at Recombinomics

Watching and Waiting

While the numbers of new cases of swine flu have been declining in many regions, including the United States, it is too early to know whether or not there will be subsequent waves of disease.

"Based on my experience with new diseases and the lessons learned from past pandemics, I think we should remain cautious and observe the evolution of the pandemic over the next six to 12 months before declaring victory," World Health Organization Director General Margaret Chan tells Swiss newspaper Le Temps. (World Health Official Says Swine Flu Still a Threat)

Although the WHO is remaining "cautious," changes in the virus’s genome that increase its virulence and resistance to Tamiflu are becoming more common.  Dr. Henry Niman, expert in flu virus evolution, believes another wave of illnesses will occur in early 2010.  In addition, he believes resistance to Tamiflu will become "fixed," similarly to how this genetic change evolved in the seasonal H1N1 virus.  (See Flu Update: Tamiflu resistance and Ukraine update, and Efficacy of Roche’s Flu Drug Tamiflu In Doubt, by David Phillips.)

WHO: H1N1 swine flu pandemic will stick around for another year

The World Health Organization warned government health authorities to remain vigilant on the H1N1 swine flu pandemic, saying the virus could mutate before vaccines can help it dissipate.

The World Health Organization is confident that the H1N1 swine flu pandemic will be under control in a year’s time – however, WHO officials warned global governments to remain vigilant for any mutations in the troublesome bug.

Dr. Niman believes this wave will be more severe than the previous two--but not due to random mutations. Rather, this will result from the process of recombination. Due to recombination, increasingly greater transmission of aggressive variants (D225G, D225E and D225N) and Tamiflu-resistant viruses will occur.


I’ve reprinted two recent articles at Recombinomics, with my comments in blue.

The WHO Surprise on D225G / D225N H1N1 Fatalities, Recombinomics Commentary

After considering the current available virological, epidemiological and clinical findings and following discussions on an earlier draft with WHO and its European-based Collaborating Centre ECDC has come to a preliminary formulation namely that the G222D/N variants exist in a small proportion of sporadic severe, as well as mild cases of 2009 pandemic influenza A(H1N1) infection and that these represents natural variation of the virus with no special association with severity of the disease course. As such and while they do not transmit they should have a minimal impact on public health and pandemic response. Current data suggests that the cases involving variant viruses in different parts of the world are unrelated and the underlying mutation events probably occurred independently from each other in the infected individuals as a consequence of the natural variability of influenza viruses and their inability to correct random coding errors. However because of that inherent variability and ability to surprise the 2009 A(H1N1) will need on-going combined virological, epidemiological and clinical surveillance and study.

The above comments in the latest ECDC report confirm attempts by WHO consultants to explain the strong association of D225G and D225N (aka D222G and D222N) with fatal and severe H1N1 cases as "random coding errors" even though the WHO regional lab in Mill Hill found D225G in four of four fatal cases, while the WHO region lab in Atlanta (CDC) found D225N in two of two additional cases, which were almost certain fatal cases also. 

D225G and D225N are rare and have been reported in about 1% of H1N1 HA sequences, yet they have a 100% case fatality rate in sequences from Ukraine… 

My comment:  Dr. Niman means that fatal cases in Ukraine, for which genetic analysis has been performed, have shown non-wild type variations at codon 225, e.g. D225G or D225N. He is not saying that all cases in which D225G or D225N is found are fatal. The proportions of all cases and non-fatal cases with the D225G and/or D225N markers are not known. 

Although there were a few mild cases with D225G in the US at the start of the pandemic last spring, including the vaccine target California/7, mild cases are common at the start of a pandemic because there is little immunity in the target population, and infections and symptoms can be caused by low viral loads which are effectively contained by a weak host response.  The association of D225G and D225N in severe and fatal cases since the summer has been remarkable, especially since the vast majority of pandemic H1N1 infections are mild and resolve without treatment.  In contrast, nearly 100% of recent cases with D225G, D225N, or both have been fatal or severe…

I think this is confusing and that Dr. Niman means the reverse--fatal and severe cases are consistently showing variations in the D225 position (either or both D225G and D225N) of the receptor binding protein.  However, the percent of all and mild cases with D225G and/or D225N markers is not known. In other words, not all cases with D225G or D225N are fatal or severe, but the proportion of viruses circulating, with various changes in their receptor binding domains, is unknown. 

This "random mutation" paradigm constantly produces "surprises", for which the above "experts" readily acknowledge on a very regular basis.  They were surprised and baffled by H274Y Tamiflu resistance in patients infected with seasonal H1N1, and will again be surprised and baffled by the same result in pandemic H1N1.

WHO’s reliance on consultants who try to use random mutation to explain these examples of 100% case fatality rates in multiple countries is cause for increasing concern.

Ukraine Fatalities Spike to 675 – Two Day Total 42, (Dec. 29) Recombinomics Commentary

[Numbers updated by Ukraine Fatalities Spike to 698 - One Day Total 23 (Dec. 30)]

3,669,751 3,722,314 Influenza / ARI

207,013 210,136 Hospitalized

675 698 Dead

The above figures are from the Ukraine Ministry of Health and represent a spike of 42 fatalities in the past 48 hours…

A preliminary report by WHO and ECDC has suggested that the presence of D225G and D225N in the fatal cases is due to random copy errors, even though the cases in Ukraine involve two different changes, which represent the only non-synonymous HA differences between the fatal and recovered cases,…

The recent surge in fatal cases should allow for additional sample collection over a two moth time frame to allow for more extensive analysis, which will highlight the failure of random mutations to explain the dangerous polymorphisms, D225G and D225N… 

My comment: the random mutation theory fails to account for the quickly spreading changes in the H1N1 virus as well as the recombination theory.  See Swine Flu Virus: Changes and Consequences:

Flu viruses, including the H1N1 varieties, are known for quickly changing genetically. Recombination is the driver of rapid molecular evolution, a process whereby small bits of genetic information pass between viruses so a virus may quickly acquire a genetic variation that has previously evolved and already exists in the viral reservoir (the pool of viruses circulating in a population). Unlike sporadic mutations, recombination reflects the acquisition of genetic material that has withstood the Darwinian test of time. Compared to sporadic mutation, recombination is a quicker, non-random mechanism for genetic change.

Changes in the H1N1 viral genome are natural. The viral reservoir consists of wild-type viruses (the predominant viruses) and low levels of variants carrying a variety of different sequences called “polymorphisms.” While recombination is not the currently favored theory regarding how flu viruses evolve, Dr. Niman believes it is the correct theory. The theory of recombination as a mechanism for genetic change has led to accurate predictions about how the flu virus would evolve as infection rates increase. As the size of the viral reservoir continues to expand, viruses with genetic differences, “polymorphisms,” become more evident.

Ukraine Fatalities Spike to 698 – One Day Total 23

…The increase of 23 dead in the past 24 hours is similar to the prior two days, bringing the three day total for this week to 65, which is similar to the rate at the beginning of the outbreak in October… Although cases and deaths are decline across much of the northern hemisphere, the high death rate in Ukraine provides support for another wave of H1N1 in early 2010… 

[High death rate associated] with either or both of these receptor binding domain changes raises concerns of the emergence of the changes at a higher frequency…


According to the WSJ, Retailers Jockey to Market Swine-Flu Shots:  

Pharmacies, supermarkets and other retailers are jockeying to become the go-to provider for swine-flu vaccinations, in a bid to attract more customers and, in many cases, promote their in-store health clinics.

With the vaccine becoming more widely available, Rite Aid Corp. is placing signs that read, "Protect Yourself: H1N1 Vaccinations Are Available," on the front doors of its drugstores and hanging similar banners inside. Kroger Co. is promoting its H1N1 flu shots on the cover of the grocery chain’s weekly ad circulars. Starting next year, Walgreen Co. plans to advertise its supply of the vaccine in television spots and on its Web site…

"We clearly see potential opportunity" in the vaccinations, says Brian Dowling, a spokesman for grocer Safeway Inc., which runs Dominick’s, Von’s and Tom Thumb stores. "The vast majority of our pharmacy customers shop the rest of the store."

Indeed, retailers are hoping the H1N1 shots will spark a jump in sales of other flu-prevention products, such as hand sanitizer. 

Swine flu vaccines would be effective against Tamiflu-resistant variants. However, there is evidence suggesting the injectible vaccines would not provide sufficient protection against D225G variants and perhaps other viruses with changes in the receptor binding domain.  The injectible vaccines are likely to be less effective or ineffective against particularly aggressive (lung-binding) D225G subtypes of viruses. In contrast, viruses against which the Flu Mist vaccine was developed included viruses displaying the D225G marker so, theoretically, Flu Mist would be effective against viruses with this worrisome genetic variation.

Tamiflu Resistance

See Flu Update: Tamiflu resistance and Ukraine

Tamiflu (oseltamivir) has been a big seller this year, with global sales soaring 362% to $1.93 billion in the first nine months. Driven by the threats of a swine flu pandemic, governments have been stockpiling the drug to the tune of $1.32 billion. (Efficacy of Roche’s Flu Drug Tamiflu In Doubt, David Phillips): 

According to David Phillips:

Allegations have surfaced that Swiss drug maker Roche has misled governments and physicians alike on the efficacy of its popular drug Tamiflu in preventing complications, such as hospitalization from pneumonia or death, in otherwise healthy people afflicted with the flu — seasonal or the H1N1 (swine flu) version. If the company is unconvincing in refuting such claims, more than its reputation could be sullied.

Leveraging global concerns over avian and swine flu, Roche has seamlessly raised awareness of the purported need to treat the complications associated with the seasonal flu too. The company has successfully challenged conventional wisdom — that “rest and aspirin” be the preferred treatment option for seasonal flu — with marketing campaigns that resonate with reassuring efficacy claims for Tamiflu (oseltamivir)… [See Tamiflu media updates].

A scarcity of published data in the medical literature motivated the nonprofit research group Cochrane Collaboration to investigate — and verify — Tamiflu’s alleged efficacy claims, particularly on the drug’s effect on the risk of hospital admission and complications in otherwise healthy people with influenza. The Cochrane review and a linked investigation undertaken jointly by the British Medical Journal and the local Channel 4 News cast doubt on the efficacy and safety of Tamiflu — and also raises disturbing questions on the drug’s promotional and marketing activities condoned by regulators on both sides of the Atlantic.

Investigators disclosed that an often cited meta-analysis used as evidentiary support was based entirely on ten trials funded by Roche, only two of which were published in peer reviewed journals. The Cochrane reviewers could find no independently funded trials of Tamiflu for healthy adults. Troubling, too, former employees of the medical communcations company hired by Roche were alleged to have ghost written some of the manuscripts….

Continue reading Efficacy of Roche’s Flu Drug Tamiflu In Doubt here >> .

As noted in Swine Flu Virus: Changes and Consequences, the swine flu virus may be headed for greater degrees of tamiflu resistance as the genetic sequence conferring resistance (represented by the "H274Y" marker) is being passed to drug-sensitive viruses in a process called recombination. This has happened before. Tamiflu resistance was fixed in the seasonal H1N1 flu virus through this same process. This development is currently being downplayed by the CDC and WHO. According to Dr. Henry Niman, critical data is being withheld which would provide further evidence. 

Moreover, the H274Y marker is occurring along with changes in the virus’s receptor binding domain (represented by D225G, D225N or D225E genetic markers). Receptor binding domain changes appear to increase the potential severity of infection. The D225G viral variant binds to cells in the lungs rather than the more common binding of flu viruses in the upper airways.

Dr. Niman vs. WHO, ECDC and CDC

Fatal D225G / D225N H1N1 Co-Infections Raise Concerns (Dec. 30) Recombinomics Commentary

Current data suggests that the cases involving variant viruses in different parts of the world are unrelated and the underlying mutation events probably occurred independently from each other in the infected individuals as a consequence of the natural variability of influenza viruses and their inability to correct random coding errors.

The above comment from the ECDC report on D225G and D225N is false.  The current data suggests just the opposite and indicates these changes are transmitting and jumping from one genetic background via recombination.  The frequency of D225G/N in public HA sequences (about 3000) is near 1% yet in Ukraine D225G/N is in six of six isolates from fatal cases, which has a chance of a trillion to one if events are independent and random.  Moreover, the association of H225G/N with fatal or severe cases extends well beyond Ukraine. 

In Sao Paulo there are four examples and all four are also from fatal cases.  The published sequences have two with D225G and two with D225N.  However, recent sequences with D225G and D225N in the same sample in Sweden, Mexico, and the United States have raised the possibility that the mixture is common,…

In Mexico, two patients in San Luis Potosi have the mixed signals in isolates which were collected within a day of each other.  The WHO working hypothesis would require that both patients were independently infected by wild type H1N1 and the H1N1 in both patients would make the same two errors in adjacent positions to generate the fatal combination of D225G and D225N.  The likelihood of this happening independently in two patients in the same location at the same time is beyond remote…

The reliance of the WHO and ECDC on such an unlikely explanation of the data raises serious questions about data analysis by consultants so wedded to such an outdated view invoking random mutations, which is not supported by the data. 

This reliance is extremely hazardous to the world’s health.

H1N1 Tamiflu Resistance Lesson Not Learned (Dec. 30) Recombinomics Commentary

Dr. Nancy Cox isn’t convinced H3N2 is going away. But the head of the influenza division of the U.S. Centers for Disease Control would be happy with a one-for-one exchange, with the pandemic H1N1 replacing the seasonal virus of the same name.

That’s because seasonal H1N1 viruses are resistant to oseltamivir (Tamiflu), the main drug used to fight flu.

The pandemic H1N1 viruses are susceptible to Tamiflu, though they are resistant to two older flu drugs, amantadine and rimantadine. Those two drugs aren’t widely used anymore because resistance to them develops easily.

Swapping viruses that are immune to Tamiflu for ones the drug works against would be a bargain, Cox suggests. "Getting rid of resistance in circulating H1N1 viruses would be a real silver lining."

The above comments on replacing seasonal H1N1 where H274Y is fixed, with pandemic H1N1 where H274Y is becoming fixed, signals a lesson not learned.  H274Y in seasonal H1N1 went from 0% to 100% in one season in several countries.  In the US it went from 10% to 100%.  Although the process began in 2006 when H274Y was first identified in seasonal H1N1 in patients who had not been treated with Tamiflu.  H274Y jumped from one seasonal flu genetic background to another via recombination, as did several additional polymorphisms… 

The repeat in pandemic H1N1 may be much quicker because the widespread use of Tamiflu creates additional selection pressure for H274Y to pair with receptor binding domain changes that also drive selection…

However, most flu cases usually appear in the winter, when the virus is stable and host resistance is compromised by cold weather and other respiratory diseases.  Thus, it is likely that an influenza virus will emerge, but seasonal flu is virtually absent throughout the northern hemisphere.  Thus although swine H1N1 in the US and across the northern hemisphere is declining, there are still high levels of pandemic H1N1 in circulation.  In the US the week 50 levels of swine H1N1 were still three fold higher than seasonal flu last year, and 100 fold higher than seasonal flu this year.  In Ukraine, deaths have spiked higher raising concerns of multiple pockets of pandemic H1N1 that can fill the seasonal flu void in the upcoming months.

Thus, the potential for H274Y to become fixed in the next wave is quite real because competing seasonal flu strains are not circulating, and competing swine H1N1 that is Tamiflu sensitive is on the decline…

This, the silver-lining in the replacement of seasonal H1N1 with pandemic H1N1 may lead to a result that contains no silver lining, other than another example of influenza evolution via recombination, instead of the random mutation explanation of the detection of D225G/N on multiple H1N1 genetic backgrounds.


Dr. Henry Niman

Dr. Niman earned a PhD in biochemistry at the University of Southern California in 1978, and as a coincidence, he and I worked in the same pathology/biochemistry laboratory at USC, separated only by time. His dissertation focused on feline retroviral expression in tumors. Working on his post-doctorate at the Scripps Clinic and Research Foundation, and later accepting a staff position, Dr. Niman began looking at making monoclonal antibodies using synthetic peptides. Data generated in 1982 demonstrated that the two technologies–monoclonal antibody and synthetic peptide technologies–could be combined. His work led to the popularity of the flu monoclonal antibody, which is widely used throughout the pharmaceutical, biotech, and research industries.  He also produced a broad panel of monoclonal antibodies against synthetic peptides of oncogenes and growth factors.

Dr. Niman subsequently had a joint appointment as Instructor in Surgery at Harvard/Massachusetts General Hospital and as Research Associate at the Shriner’s Burn Center across the street from Mass General. (These were research positions – he did not teach or do surgery.) Technology developed by Dr. Niman was used to form ProgenX, a cancer diagnostic company that became Ligand Pharmaceuticals. More recently, he has been studying infectious diseases and viral evolution.


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