225G Worldwide Tracking & Evaluation

This is a sticky topic.

NS1 replied

January 8, 2014, 07:17 PM
Re: 225G Worldwide Tracking & Evaluation

Gain of Function Empiriks
by
Polymorphism
pH1N1 HA 263S

Map - Active and Detailed

HA 263S: Emergent H7N9 & pH1N1 Receptor Binding Dynamic
Analytics - Polymorphism Detail

Map - Active and Detailed

More than 49% of the distinct Hemagglutinin polymorphisms found on sequences carrying the rare HA 263S are also found in H5N1.

100% of the sequences with HA 263S in 2013 also feature a Receptor Binding Variance:

HA 225G

HA 227G from H5N1
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NS1 replied

January 8, 2014, 11:05 AM
Re: 225G Worldwide Tracking & Evaluation

95 Fatalities in Texas
by
2014-01-07 *

pH1N1 Dominant Texas Fatality by County [Excel]

pH1N1 Dominant Texas Fatality by County [html/css]

Distribution of pH1N1 Influenza Fatalities in Texas [map by Al]

* 2014-01-07 Updated Stats from Jim Oliveros
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NS1 replied

January 7, 2014, 03:08 AM
Re: 225G Worldwide Tracking & Evaluation

pH1N1 Drug Resistant Low Reactor
CDC Fall 2013

Map - Active and Detailed

<div style="text-align: center;">
<hr style="width: 30%;" />46 Cases over 49 Sequences<hr style="width: 30%;" /></div>
Introduction

In the 32 days covering 2013-10-17 to 2013-11-19, the United States CDC released a total of 49 pH1N1 sequences at GISAID on 46 human cases sampled from February 2013 to October 2013. Geographic surveillance includes America, Africa, Asia, Brazil, Ecuador, Paraguay and Peru. 

The sequences in this Analytic Report describe a high level of genetic activity at the Hemagglutinin antigenic area between aa155 and aa158 with 5 amino variations and 4 silent revisions.   HA 225G is present in quasi-species on 2 American samples and as dominant form in 2 tropical countries. The Dominican Republic HA 225G Low Reactor appears on a TamiFlu Resistant strain.  Drug Resistance is also found in 2 US sequences and 1 South American case.
. . .

Read the Open-Access, Full-Text
Investigational Analytic
including Genetic Details
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NS1 replied

January 6, 2014, 05:00 AM
Re: 225G Worldwide Tracking & Evaluation

pH1N1 Child Vaccine Escape
CDC Early 2013

Map - Active and Detailed

<div style="text-align: center;">
<hr style="width: 30%;" />41 Cases over 43 Sequences<hr style="width: 30%;" /></div>
Introduction

In the 30 days covering 2013-02-28 to 2013-03-29, the United States CDC released a total of 43 pH1N1 sequences at GISAID on 41 human cases sampled from October 2012 to February 2013. Geographic surveillance includes America, Africa, Asia and Russia. Although pH1N1 in most locales during the 2012-2013 season was the minority serotype, the sequences in this Analytic Report describe a high level of human-infective diversity and an ease of avian genetic acquisition, including multiple instances demonstrating concentrated transport of High-CFR pH1N1 Upsilon polymorphisms onto single sequences.

. . .

Read the Open-Access, Full-Text
Investigational Analytic
including Genetic Details
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NS1 replied

January 6, 2014, 03:02 AM
Re: 225G Worldwide Tracking & Evaluation

71 Fatalities in Texas
by
2014-01-05 *

pH1N1 Dominant Texas Fatality by County [Excel]

pH1N1 Dominant Texas Fatality by County [html/css]

Distribution of pH1N1 Influenza Fatalities in Texas [map by Al]

* 2014-01-05 Updated Stats from Jim Oliveros
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NS1 replied

January 4, 2014, 10:33 PM
Re: 225G Worldwide Tracking & Evaluation

A <a href="http://pf11.blogspot.com/2009/11/norway-sequence-with-225g-mixture-also.html" target="_blank">flashfire</a> occurs when a <a href="http://pf11.blogspot.com/2013/12/texas-ha-225-receptor-binding-variance.html" target="_blank">minority species</a> with Hemagglutinin Receptor Binding Variance persists unacknowledged. *

pH1N1 Texas Fatality by County

* Quasi-species at key antigenic / receptor binding areas
Mixture HA 225D / HA 225G

Mixture HA 225D / HA 225N
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NS1 replied

January 3, 2014, 01:59 AM
Re: 225G Worldwide Tracking & Evaluation

Novel London pH1N1 2013 Case
Displays
Promiscuous Genetics

Introduction

On 2014-01-02, the Health Protection Agency of the United Kingdom released a pH1N1 sequence with a GISAID submission date of 2013-12-30 that was sampled in London during November of 2013. No age, gender, patient status, vaccination status or outbreak metadata was provided.
H7N9 Correlation HA 116K

H7N9 Correlation NA 48A and 321V

Host Transition HA 116K

Host Transition Potential HA 218E

Novel Hemagglutinin<o:p></o:p>

Novel Neuraminidase VISA

Clade2: 188T

On this same day, the Guardian news <a href="http://www.theguardian.com/society/2014/jan/02/uk-unprepared-flu-pandemic" target="_blank">outlet</a> asserted to no small response that the UK was not prepared for a flu epidemic. These reporters may be more accurate than they realise, but for an altogether different reason than they have developed in the filing . . .

Read the Open-Access, Full-Text
Investigational Analytic
including Genetic Details
Leave a comment:
NS1 replied

December 27, 2013, 07:47 PM
Re: 225G Worldwide Tracking & Evaluation

Gain of Function Empiriks
by
Polymorphism
pH1N1 HA 142D

Map - Active and Detailed

Clinical and Genetic Features

HA 142D: pH1N1 Vaccine Escape Diversity
Analytics - Polymorphism Detail

Map - Active and Detailed

Features - Clinical and Genetic

Bolivia [EPI467387]
2013_07_31

HA 166I

HA 225Y

Puerto Rico [EPI465455]
2013_06_14

13 Year Old Female

HA 166I

HA 225G

Argentina [EPI465453]
2013_06_04

HA 166I

HA 225G

HA 324A mix wt

HA syn326S (TCc) mix wt

Singapore [EPI385418]
2010_06_03

HA 225G

HA 233H

HA syn537S (AGc)

Singapore [EPI385172]
2010_04_26

HA 225G

HA 233H

HA syn537S (AGc)
Leave a comment:
NS1 replied

December 27, 2013, 02:27 PM
Re: 225G Worldwide Tracking & Evaluation

Gain of Function Empiriks
by
Polymorphism
pH1N1 HA 46R

Map - Active and Detailed

Clinical and Genetic Features

HA 46R: pH1N1 Vaccine Escape & Child Dynamic
Analytics - Polymorphism Detail

Map - Active and Detailed

Features - Clinical and Genetic

Brazil Goias [EPI335496]
2009_08_21

HA 225G

Fatal
Leave a comment:
NS1 replied

December 27, 2013, 06:36 AM
Re: 225G Worldwide Tracking & Evaluation

Brazil 2013

Map - Active and Detailed

Clinical and Genetic Features

Brazil 2013: pH1N1 Extreme Variant and Infant Vaccine Escape
Sao Paulo Ribeirao Preto [EPI484749]
2013_10_05

Hospitalised

HA 225G

HA 263S (GoF·E) - Emergent H7N9
Leave a comment:
NS1 replied

December 26, 2013, 09:10 PM
Re: 225G Worldwide Tracking & Evaluation

Russia 2013

Map - Active and Detailed

Emergent H7N9 Homology in Fatal Human pH1N1 Case Near Caspian Sea

Rospotrebnadzor of Moscow, Russia released a set of human pH1N1 sequences without age or gender at GISAID.

Fatal - Count 06
HA 225G
[EPI471832] Volgograd

[EPI471828] Moscow
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alert replied

January 17, 2013, 08:03 PM
Re: 225G Worldwide Tracking & Evaluation

Published Date: 2013-01-17 17:10:27
Subject: PRO/EDR> Influenza (08): (Norway) emergence of D222G variant & severity
Archive Number: 20130117.1503366

INFLUENZA (08): (NORWAY) EMERGENCE OF D222G VARIANT AND SEVERITY
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Date: Thu 17 Jan 2013
Source: Eurosurveillance, Volume 18, Issue 3 [summarised & edited]

Eurosurveillance | Within-patient emergence of the influenza A(H1N1)pdm09 HA1 222G variant and clear association with severe disease, Norway

http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20369

The association between a particular mutation in the HA1 subunit of the influenza virus haemagglutinin, D222G, and severe and fatal disease in cases of influenza A(H1N1)pdm09 in Norway during the 2009 pandemic was investigated using pyrosequencing. The prevalence of the variant among fatal cases was 8/26 and among severe non-fatal cases 5/52. No D222G mutations were found among the 381 mild cases. This difference could not be attributed to sampling differences, such as body location of sampling, or duration of illness. In cases with mutant virus where clinical specimens from different days of illness were available, transition from wild-type to mutant virus was commonly observed (4/5), indicating that the mutant virus emerged sporadically in individual patients. In patients with paired samples from both the upper and lower respiratory tract (n=8), the same viral genotypes were detected in both locations. In most of the D222G cases (11/13), the mutant virus was found as a quasispecies.

Title: Within-patient emergence of the influenza A(H1N1)pdm09 HA1 D222G variant and clear association with severe disease, Norway. By: Rykkvin R, Kilander A, Dudman SG, Hungnes O. At: Department of Virology, Norwegian Institute of Public Health, Oslo, Norway

Summary
--------
The association between a particular mutation in the HA1 subunit of the influenza virus haemagglutinin, D222G, and severe and fatal disease in cases of influenza A(H1N1)pdm09 in Norway during the 2009 pandemic was investigated using pyrosequencing. The prevalence of the variant among fatal cases was 8/26 and among severe non-fatal cases 5/52. No D222G mutations were found among the 381 mild cases. This difference could not be attributed to sampling differences, such as body location of sampling, or duration of illness. In cases with mutant virus where clinical specimens from different days of illness were available, transition from wild-type to mutant virus was commonly observed (4/5), indicating that the mutant virus emerged sporadically in individual patients. In patients with paired samples from both the upper and lower respiratory tract (n=8), the same viral genotypes were detected in both locations. In most of the D222G cases (11/13), the mutant virus was found as a quasi-species.

Introduction
----------
Infection with the pandemic influenza A(H1N1) virus that emerged in 2009 led to mild disease in the vast majority of cases; however, there was also an unusual occurrence of viral pneumonia, severe disease and death in younger age groups than commonly observed for seasonal influenza [1]. In a large proportion of severe cases, conditions predisposing for severe disease have been identified [2], and host factors, therefore, appear to strongly influence the clinical outcome of infection. On the other hand, this novel virus of zoonotic origin differed from the previous seasonal A(H1N1) virus in the resulting disease profile; thus, viral determinants of pathogenicity must also be involved, e.g. it has been shown to be more pneumotropic than seasonal A(H1N1) virus in a ferret model [3]. It is important to understand better what viral and host-related factors determine the observed dichotomous pathogenicity profile.

The 1st cases of influenza A(H1N1)pdm09 virus infection in Norway were recorded in early May 2009, shortly after emergence in Mexico, but cases were few and scattered across the country until mid-summer [2009]. A limited influenza epidemic took place in late July/early August 2009, followed by a comparatively calm period leading up to a major epidemic that surpassed all previous peaks recorded in the current surveillance system. The epidemic reached its highest point in early November 2009, and by the end of 2009, it had mostly subsided.

As part of the intensified surveillance carried out during the 2009 influenza pandemic, the national reference laboratory for human influenza at the Norwegian Institute of Public Health received a large number of respiratory specimens from confirmed and possible cases of influenza A(H1N1)pdm09. In late November 2009, we noticed that a particular amino acid substitution -- aspartic acid (D) to glycine (G) in the viral haemagglutinin (HA) glycoprotein subunit HA1 at position 222 (D222G) -- appeared in fatal cases, while we did not find it in the numerous mild cases analysed. Realising that a similar pattern seemed to be taking place in the Ukraine (R. Daniels, personal communication, November 2009) and given that the mutation had been shown to influence viral receptor specificity in another influenza A(H1N1) virus [4], it was decided to notify international public health authorities and other national authorities about this possible pathogenicity determinant to expedite assessment of it [5]. A preliminary review in January 2010 of D222G amino acid substitution in the HA of influenza A(H1N1)pdm09 viruses from the World Health Organization (WHO) stated that mutations, including those leading to the D222G substitution in the HA, had appeared sporadically since the 1st emergence of influenza A(H1N1)pdm09 viruses and that the substitutions in HA had been reported in viruses obtained from cases of mild to severe to fatal illnesses but that such viruses had neither formed distinct phylogenetic clustering nor been associated with consistent changes in virus antigenicity [6].

Since the 1st account of our findings in Norway [7], investigations into the occurrence of this mutation resulted in an increasing number of reports [8-28]. While the prevalence of this mutation varied between the reporting countries, in most studies, the 222G mutation is primarily found in severe and fatal cases. One of the 1st larger studies came from a group in Hong Kong, who analysed this amino acid position in severe and non-severe cases of influenza A(H1N1)pdm09 [13]. Nine (4.1 percent) of 219 severe or fatal cases of pandemic influenza had the mutation in contrast to none of 239 non-severe cases.

Data from these reports indicated that the D222G mutation was absent or uncommon in viruses that were in sustained circulation. However, one case of transmission of a 222G virus was reported [9], but the transmitted virus in this case had acquired an additional mutation that may have influenced receptor binding characteristics.

To further investigate the sporadic occurrence of the 222G mutant influenza virus, we performed a more in-depth analysis of an expanded data set. Our original data set [7] included 266 cases, while the expanded set comprised 462 cases. The present study included assessment of the majority of the fatal cases in Norway as well as of a larger number of samples from severe non-fatal and mild cases collected throughout the pandemic.

We studied the prevalence of HA1 222 mutations within different clinical outcome groups, in serially collected specimens, in upper versus lower respiratory tract and in early versus late specimens. We also analysed age and sex distribution and examined the characteristics of the fatal cases.

We further compared the mutant viruses phylogenetically and looked for the presence of mutant quasi-species and oseltamivir resistance.

[Interested readers should access the original document via the source URL to view the full text describing the methods, figures, the tabulated data, and references.]

Discussion
---------
In the present study, we provide further epidemiological evidence of the association between the D222G mutation in HA1 of influenza A(H1N1)pdm09 virus and severe or fatal clinical course. Furthermore, we present evidence that the mutated viruses emerge in individual patients after the onset of illness and demonstrate the presence of mutant virus in both the upper and lower respiratory tract. We also address some potential biases that could conceivably confound the analysis. The Norwegian cases of infection with HA1 222G genotype viruses have occurred sporadically and do not cluster epidemiologically or in phylogenetic analysis.

As observed by others, the D222G substitution has been observed to occur sporadically in the laboratory when specimens containing predominantly wild-type virus are subjected to virus isolation in eggs or mammalian cell lines [6,13,35].We therefore based our analysis on viral sequences obtained from the primary clinical specimens.

The 222G viruses appear to be rare among circulating strains, but are still quite frequent in patients with severe disease, who are not epidemiologically linked. A likely explanation is that the presence of mutant viruses in these particular individuals experiencing severe disease is due to selective upgrowth of mutant genomes during infection. In all 4 222G cases where we could analyse both early and late specimens, we observed a transition from wild-type to mutant virus, which lends support to the hypothesis that the presence of the mutant is due to sporadic emergence rather than widespread circulation.

In our analysis, we could not distinguish between upgrowth from a rare quasi-species, which may be present at inapparent levels in many more cases, and upgrowth from de novo mutation events. The 222G genotype appears to occur as sporadic mutations with no or little onward transmission, rather than through persistence as a circulating variant. If this is the case, the likelihood of finding mutant viruses is expected to increase during the course of infection. Conceivably, since the severe cases, including those that were fatal, tended to be sampled later in their course of illness than mild cases, the higher occurrence of mutations could alternatively be explained purely as a sampling artifact and not as a marker of virulence. But if the occurrence of the mutation was merely a function of time since infection, there should be no difference in the frequency of 222G mutant in specimens from mild versus severe cases, if taken equally late in infection. Our results show that the significant difference remained even when all early specimens were excluded: thus the difference in sampling day can be ruled out as an alternative explanation for the pattern observed.

In several of the cases, simultaneous specimens were available from different body locations. In all of these pairs/sets, the same genotypes were observed, but with differences in the ratio of mutant versus wild type in patients harbouring quasi-species. Other studies have identified D222G quasi-species mainly in endotracheal aspirate or broncheoalveolar lavage (BAL) samples and less frequently in nasopharyngeal aspirate samples [12,14,20]. This discrepancy could be due to the use of different analytical methods. Lower rates of mutant versus wild type in nasal swabs may not have been revealed by conventional sequencing. This was demonstrated by Baldanti et al [14]. In D222G/N cases with available paired nasal swabs and BAL samples, the authors found D222G/N in only one of 4 cases using direct sequencing, but this proportion increased to 3 of 4 cases using clonal analysis. From our study, we cannot exclude the possibility that the occurrence of the mutation as a quasi-species, together with the wild-type, is due to a complementary function of the wild-type. This phenomenon might change if the mutant virus were to develop another fitness-compensatory mutation that permits the mutant to replicate and spread in pure form. This possibility needs to be further studied.

In addition to its possible biological importance, the fact that the majority of the cases with 222G mutants carried a mixture of 222D- and 222G-encoding viral genomes, usually with predominance of the wild-type 222D, makes it likely that many influenza A(H1N1)pdm09 cases worldwide carrying D222G mutant viruses could have been missed in analyses that are not sensitive to minor nucleic acid species or where only the majority nucleotide is recorded in the published sequence.

Selleri et al analysed influenza A(H1N1)pdm09 viral quasi-species and the polymorphism at codon 222 by ultra-deep pyrosequencing [28]. Codon 222 polymorphism was detected in 40.7 percent of patients by ultra-deep pyrosequencing and in only 7.1 percent by conventional sequencing. They found that the frequency of polymorphism was significantly higher in samples collected from patients with severe manifestations than in those patients with moderate-mild manifestations. The D222G/N/A mutations were detected as either minor or predominant variants only in severe cases, whereas D222E was equally represented in severe and moderate-mild infections.

The question of whether the presence of mutant viruses in lower airways is underestimated due to lack of sampling in the lower respiratory tract was investigated by Baldanti et al [14]. Paired nasal swabs and BAL samples from patients admitted to intensive care units for mechanical ventilation or extracorporeal membrane oxygenation were compared with samples from patients with pneumonia not requiring mechanical ventilation and from community patients. By combining data from nasal swabs and BAL samples, the frequency of D222G/N mutants in patients with severe infections increased to 43 percent, as compared with 7.8 percent and 0 percent in patients with moderate and mild infections, respectively [14]. Baldanti et al also showed that the viral RNA levels were significantly higher in BAL samples than those in nasal swabs [14]. Piralla et al. described the same finding, suggesting higher virus replication in the lower respiratory tract [20].

Watanabe et al. have characterised 2 of the Norwegian virus isolates included in our study, namely A/Norway/3568/2009 (Norway3568) and A/Norway/3487-2/2009 (Norway3487) [34]. The viruses were isolates from a fatal case (Norway3487) and a mild case (Norway3568): the viruses differ by only 10 amino acids, and none of the amino acid changes known to affect virulence were found in PB2, PB1-F2, HA, or NS1, except for an amino acid change to 222G in HA1, in Norway3487. More efficient viral replication in cultured cells and delayed virus clearance from ferret respiratory organs was observed for Norway3487 virus (isolated from a severe case), as compared with Norway3568 (isolated from a mild case). To some extent, Norway3487 virus caused more severe lung damage in non-human primates than did Norway3568 virus. Moreover, the authors found that PB2 derived from Norway3487 contributed to higher polymerase activity, possibly leading to more efficient viral replication in vitro and in vivo, which in turn also could play a role in the increased lung damage.

In our analysis, all cases with detectable 222G mutant viruses had severe illness, and the prevalence of 222G increased with the degree of severe outcome. If the conditions for virus growth in lower airways are favourable to 222G mutants and the likelihood of upgrowth of mutant virus increases with duration of infection, it follows that individuals who fail to limit infection to upper airways and fail to eliminate the infection rapidly stand a greater risk of acquiring mutant viruses. Regardless of virulence, such a mechanism may contribute to the observed pattern of mutants being found primarily in severe cases. However, if the mutant viruses are also more virulent, an increased probability of emergence in patients who already have a long-lasting infection involving the lower respiratory tract probably constitutes a vicious circle phenomenon, which underscores the importance of treatment that helps persons with elevated risk to clear the infection rapidly.

The concept of D222G being a determinant of virulence is supported by a growing body of evidence from in vitro and animal studies including non-human primates [36-45]. Increased tropism of D222G mutant virus for type II pneumocytes [44] may result in more efficient infection, reducing the availability of progenitor cells for essential lung functions and regeneration and thus leading to severe pulmonary impairment. Increased viral titres in the lungs also trigger stronger inflammatory responses, augmenting tissue damage and delaying healing in the infected lungs [44].

While one instance of transmission of 222G mutant virus has been documented [9], the transmitted virus in this case had acquired an additional mutation, (G155E) that may have counteracted the putative 222G-induced receptor-binding changes [46], and there are no indications that effective sustained transmission has taken place. In our data set, one of the patients with mutant viruses was the likely source of infection of a healthcare worker. However, this occurred early in the course of illness: virus from an early specimen, as well as the virus collected from the healthcare worker, was wild type.

In light of the fact that 222G mutant viruses are and remain substantially less transmissible than corresponding wild-type viruses, their immediate public health impact is limited to the individual cases in whom such mutants occur and the fact that they may possibly contribute to the severity of illness. Similar to the apparent situation with avian influenza A(H5N1) virus infection in humans, tropism of 222G mutant viruses for lung cells may contribute to both increased virulence and impaired transmissibility, which may thus be linked traits [47]. On the other hand, when the H275Y neuraminidase mutation conferring oseltamivir resistance in seasonal influenza A(H1N1) viruses was 1st identified, this mutation also correlated with impaired viral fitness [48], a situation that was abruptly changed with the global emergence of high-fitness resistant viruses during the 2007/08 influenza season [49]. Similarly, further adaptation of the newly emerged A(H1N1)pdm09 virus to humans as host species may conceivably lead to compensatory mutations that render the 222G mutants more transmissible, or lead to other changes that influence pathogenicity. The evolution of these viruses, therefore, needs to be closely monitored in a framework that ensures that virological and clinical data are taken into account.

--
Communicated by:
ProMED-mail from HealthMap alerts
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[This study shows that 222G viruses appear to be rare among circulating strains but are still quite frequent in patients with severe disease who are not epidemiologically linked. A likely explanation is that the presence of mutant viruses in these particular individuals experiencing severe disease is due to selective upgrowth of mutant genomes during infection. In all 4 222G cases where the authors could analyse both early and late specimens, they observed a transition from wild-type to mutant virus, which lends support to the hypothesis that the presence of the mutant is due to sporadic emergence rather than widespread circulation. However, the observations that 222G mutant viruses are and remain substantially less transmissible than corresponding wild-type viruses suggest that their immediate public health impact is limited to the individual cases in whom such mutants occur. - Mod.CP
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sharon sanders replied

January 27, 2011, 01:05 PM
Re: 225G Worldwide Tracking & Evaluation

hat tip Michael Coston -

Eurosurveillance: Debating The D222G/N Mutation In H1N1

# 5263

For well over a year there has been considerable debate among virologists, and other researchers, over the impact of an amino acid substitution seen in a small percentage of 2009 H1N1 samples.

The `Norway’ or D222G/N (D225G/Nin influenza H3 Numbering) mutation was first linked to more severe disease by Norwegian Scientists in November 2009, although patients carrying these strains can have mild illness as well.

While we’ve covered this territory a number of times over the past year, a brief (and hopefully simple) review is in order. If you are up to speed on receptor binding, and the history of the D222G/N variant, feel free to skip the next section.

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

The pdmH1N1 virus carrying this mutation appears to bind more readily to receptor cells (α2-3) found deeper in the lungs, whereas unmutated seasonal flu strains bind preferentially to the (α2-6) receptor cells found in the upper airway.

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.

(A Very Simplified Illustration of RBDs)
Like a key into a padlock, the RBD must `fit’ in order to open the cell to infection.

The evidence for the D222G/N amino acid substitution driving increased virulence has been mixed, with the World Health Organization, the CDC, and the HPA continuing to investigate.

During the first week of January, Eurosurveillance printed a study looking at fatal and non-fatal cases of influenza in the UK (see Eurosurveillance: Analysis Of Fatal H1N1 Cases In The UK).

Ellis et al. reported that almost all of the virus samples tested in fatal and non-fatal cases during the early wave of the 2010/11 influenza season showed aspartic acid (D) at position 222.

In other words, no `Norway’ mutation.

Today, Eurosurveillance published a letter from an Italian researcher who has found a high percentage of D222G/N mutations in severely ill patients (43%) – particularly when taking virus samples from the lower respiratory tract (lungs).

You can read the entire letter at the link below.
Eurosurveillance, Volume 16, Issue 4, 27 January 2011
Letters
Letter to the editor. Virological analysis of fatal influenza cases in the United Kingdom during the early wave of influenza in winter 2010/11
F Baldanti

The point being, that if the UK researchers were only taking nasal (or upper respiratory) swabs, they might be missing some D222G/N mutations.

In a reply, the authors of the original study concede that in many cases, only upper respiratory swabs were available for this analysis, and that when possible, samples from the lower respiratory system would be useful.

Eurosurveillance, Volume 16, Issue 4, 27 January 2011
Letters
Authors’ reply. Virological analysis of fatal influenza cases in the United Kingdom during the early wave of influenza in winter 2010/11
J Ellis , M Galiano, R Pebody, A Lackenby, CI Thompson, A Bermingham, E McLean, H Zhao, S Bolotin, O Dar, J M Watson, M Zambon

This scholarly debate isn’t over, of course. As Ellis et al. state in their reply:
The selection and emergence of the D222G mutation as a cause or consequence of more severe lower respiratory tract infection is still to be resolved.

Emergence of this mutant is likely to exacerbate severity of disease, but by itself, may be neither necessary nor sufficient to account for a severe disease outcome, which is invariably a balance between virus virulence factors and host immune response capability.

It will take more samples, more research, and more time to determine the truth in the matter.

And even if this mutation should eventually be linked to higher virulence, its ultimate impact on public health will ride on how just prevalent this D222G/N is among the H1N1 viruses in circulation.

Stay tuned. There’s a lot left for us to discover.
Leave a comment:

mixin replied

January 27, 2011, 01:04 PM

Re: 225G Worldwide Tracking & Evaluation

Disclaimer: I am not a scientist, researcher, programmer or file converter so there could be an occassional error.

I finally have the ability to search submissions from both GISAID and Genbank. Thanks to gs for the hours and hours he spent helping me with this.

To tell the difference between my GISAID isolates and his from Genbank, mine include the method of passage and the collection date is a little different.

This first group contains the mutations that give D225N.

Code:

R >A/Castro/12274/2010,2010/05/14,E3/E1
R >A/Moldova/351/2010,2010/01/18,clinical sample
A >A/Christchurch/16/2010,2010/07/12,E2
R >A/Hong Kong/2166/2010,2010/07/13,E1
A >A/Hong Kong/2172/2010,2010/07/12,E3
A >A/Christchurch/16/2010,2010/07/12,E2/E2
A >A/Christchurch/16/2010,2010/07/12,E2/E1
A >A/Kenya/3872/2010,2010/07/13,E3
R >A/Bangladesh/8003/2010,2010/09/16,C2/C1
A >A/Alborz/5607/2010,2010/12/01,E2/E1
A >A/YOKOHAMA/1357/2009,2009/10/06,MDCK 2 +2,
A >A/NIIGATA/1371/2009,2009/11/06,MDCK 2 +1
A >A/YAMAGATA/721/2009,2009/12/08,MDCK 1 +3
A >A/India/4725/2009,2009/06/10,X2/C2
A >A/Neimenggu-Hangjinhouqi/SWL51/2009,2009/11/02,E2
A >A/Fujian-Gulou/SWL11951/2009,2009/11/16,E2
R >A/Ukraine/01/2009,2009/10/28,Original
A >A/Ukraine/02/2009,2009/10/28,Original
R >A/Stockholm/92/2009,2009/08/27,original
R >A/Moldova/G-152/2009,2009/10/23,clinical sample
R >A/Kyiv/377/2009,2009/11/07,lung wash
R >A/Chernihiv/452/2009,2009/11/07,lung wash
R >A/Lviv/425/2009,2009/11/07,lung autopsy
R >A/Lviv/639/2009,2009/11/11,lung autopsy
R >A/Azores/13092/2009,2009/11/12,nasopharyngeal swab
R >A/Rivne/836/2009,2009/11/13,lung autopsy
R >A/Chernivtsi/842/2009,2009/11/11,lung autopsy
R >A/Lviv/420/2009,2009/11/09,lung autopsy
A >A/Lviv/646/2009,2009/11/10,lung autopsy
A >A/Lviv/638/2009,2009/11/08,lung autopsy
R >A/Azores/13091/2009,2009/11/20,bronchial wash
R >A/Ivano-Frankivsk/237/2009,2009/10/26,lung autopsy
R >A/Lviv/421/2009,2009/11/09,lung autopsy
R >A/Lviv/645/2009,2009/11/01,lung autopsy
R >A/Rivne/214/2009,2009/10/30,lung autopsy
A >A/Chernivtsi/844/2009,2009/11/11,lung autopsy
R >A/Cherkasy/744/2009,2009/11/01,lung autopsy
R >A/Chernihiv/859/2009,2009/11/14,lung autopsy
A >A/Baden-Wurttemberg/502/2009,2009/12/06,SIAT3, SIAT1
A >A/Ireland/M79555/2009,2009/11/11,pm lung
A >A/Ireland/M79556/2009,2009/11/11,pm lung
R >A/Arizona/04/2009,2009/04/27,E2
R >A/South Carolina/09/2009,2009/04/26,E2
R >A/Utah/42/2009,2009/07/24,Original
A >A/Michigan/10/2009,2009/06/03,C1-1
A >A/Michigan/10/2009,2009/06/03,C1-2
R >A/North Carolina/42/2009,2009/10/14,IR
A >A/South Carolina/47/2009,2009/11/05,E2
R >A/SYDNEY/2501/2009,2009/07/07,original specimen
A >A/VICTORIA/2125/2009,2009/11/08,Clinical Specimen
A >A/Perth/431/2009,2009/07/28,MDCK2
T >A/Monterrey/3/2009
R >A/Sw/4/Mexico/2009/04/
R >A/South Carolina/09/2009/04/26
R >A/Arizona/04/2009/04/27
A >A/Argentina/HNRG8/2009/06/11
A >A/NY/4099/2009/06/13
A >A/NY/4576/2009/07/08
A >A/Texas/43132503/2009/07/13
R >A/Utah/42/2009/07/24
A >A/Sao Paulo/53838/2009/08/01
A >A/Sao Paulo/53845/2009/08/02
A >A/Malaysia/8860/2009/08/08
R >A/Mexico/InDRE36529/2009/08/08
R >A/Nagano/RC1/2009/08/27
A >A/Nagano/RC1/2009/08/27
R >A/Bahia/15525/2009/09/05
R >A/Mexico/InDRE41741/2009/09/14
R >A/Mexico/InDRE50625/2009/10/31
A >A/Ulyanovsk/CRIE-SHTA/2009/10/31
A >A/Egypt/N14648/2009/11/
R >A/Mexico/InDRE50617/2009/11/01
A >A/Russia/100/2009/11/01
A >A/Netherlands/2457b/2009/11/07
A >A/Moscow oblast/CRIE-STV/2009/11/09
A >A/Orenburg/IIV2974/2009/11/16
R >A/Orel/CRIE-AAP/2009/11/20
R >A/Moscow/CRIE-TYD/2009/11/23
A >A/Tambov/CRIE-SPN/2009/11/24
R >A/Ivanovo/CRIE-RNA/2009/11/24
A >A/Ankara/26/2009/11/24
R >A/Tambov/CRIE-LLA/2009/11/30
A >A/Netherlands/2629/2009/12/04
A >A/Yaroslavl/IIV-198/2009/12/05
715  haall 84   -:132 A:42 G:9143 R:41 T:1

This group gives mutations for D225G

Code:

G >A/Zhejiang-Haishu/SWL1289/2010,2010/02/11,E1
G >A/Arizona/04/2010,2010/04/03,C1
G >A/Florida/04/2010,2010/03/18,E2
G >A/Florida/04/2010,2010/03/18,CX/C1
G >A/Saratov/07/2010,2010/02/01,E2
G >A/Saratov/07/2010,2010/02/01,E2/E1
G >A/St. Petersburg/204/2010,2010/02/08,E2
G >A/St. Petersburg/204/2010,2010/02/08,E2/E1
G >A/Wisconsin/04/2010,2010/02/22,E3
G >A/Kentucky/06/2010,2010/04/06,MX/C1
G >A/Brazil/8546/2010,2010/03/04,C1
R >A/Moldova/351/2010,2010/01/18,clinical sample
G >A/Belgorod/2/2010,2010/03/15,E1, E1
G >A/Victoria/502/2010,2010/06/20,E3
R >A/Montana/01/2010,2010/04/04,E2
G >A/Brazil/1394/2010,2010/03/25,C1
G >A/St. Petersburg/204/2010,2010/02/08,E2/E2
G >A/Hong Kong/2200/2010,2010/07/14,MDCK2, MDCK1
G >A/Pennsylvania/07/2010,2010/08/12,C1
G >A/SYDNEY/202/2010,2010/07/18,mdckx,mdck1
G >A/BRISBANE/209/2010,2010/08/09,MDCK4
G >A/Venezuela/27/2010,2010/01/29,C1
G >A/England/4880378/2010,2010/12/01,original
G >A/England/4940476/2010,2010/12/01,original
G >A/Kentucky/09/2010,2010/11/01,E2
G >A/Saudi Arabia/4270/2009,2009/07/28,C1
G >A/Tianjin/SWL4/2009,2009/06/11,E3
G >A/NAGANO/RC1/2009,2009/08/27,MDCK1
G >A/India/8489/2009,2009/10/20,X3/C1
R >A/KathmanduBGN/21-2/2009,2009/11/30,nasal swab
R >A/YAMAGUCHI/247/2009,2009/12/01,MDCK 2
G >A/Egypt-Vacsera/138/2009,2009/12/01,E1,E1
R >A/Laos/138/2009,2009/08/22,C2
G >A/Iran/572/2009,2009/12/01,Ex, E1
R >A/Iran/20001/2009,2009/12/01,Ex, E1
G >A/Georgia/4484/2009,2009/12/21,clinical specimen
G >A/Turkey/TR-20/2009,2009/10/31,SIAT1, SIAT3
R >A/Shanxi-Linxian/SWL323/2009,2009/11/04,C1
G >A/Guangdong-Luohu/SWL1755/2009,2009/11/05,E2
G >A/Zhejiang/SWL3/2009,2009/09/06,C2
G >A/Georgia/4484/2009,2009/12/21,SIAT4
R >A/TOKYO/99946/2009,2009/11/05,E1 +1
G >A/Lviv/N2/2009,2009/10/28,lungs
G >A/Ternopil/N10/2009,2009/10/28,lungs
G >A/Ternopil/N11/2009,2009/10/27,lungs
G >A/Lviv/N6/2009,2009/10/27,throat swab
G >A/Stockholm/48/2009,2009/07/15,original
R >A/Stockholm/92/2009,2009/08/27,original
R >A/Dnipropetrovsk/273/2009,2009/11/05,MDCK1
R >A/Moldova/G-152/2009,2009/10/23,clinical sample
V >A/Kyiv/377/2009,2009/11/07,lung wash
R >A/Chernihiv/452/2009,2009/11/07,lung wash
G >A/Ivano-Frankivsk/240/2009,2009/10/29,lung autopsy
R >A/Lviv/425/2009,2009/11/07,lung autopsy
G >A/Kyiv/251/2009,2009/11/04,lung autopsy
G >A/Ivano-Frankivsk/239/2009,2009/10/28,lung autopsy
G >A/Rivne/516/2009,2009/11/10,lung autopsy 
R >A/Lviv/639/2009,2009/11/11,lung autopsy
R >A/Zakarpatska/830/2009,2009/11/12,lung autopsy
R >A/Rivne/836/2009,2009/11/13,lung autopsy
R >A/Chernivtsi/842/2009,2009/11/11,lung autopsy
R >A/Lviv/420/2009,2009/11/09,lung autopsy
R >A/Azores/13091/2009,2009/11/20,bronchial wash
R >A/Ivano-Frankivsk/237/2009,2009/10/26,lung autopsy
R >A/Lviv/421/2009,2009/11/09,lung autopsy
R >A/Lviv/645/2009,2009/11/01,lung autopsy
R >A/Rivne/214/2009,2009/10/30,lung autopsy
R >A/Sumy/797/2009,2009/11/13,lung autopsy
R >A/Cherkasy/744/2009,2009/11/01,lung autopsy
G >A/Volin/226/2009,2009/11/05,Siat3
G >A/Rivne/214/2009,2009/10/30,Siat4
R >A/Chernihiv/859/2009,2009/11/14,lung autopsy
R >A/Chernihiv/856/2009,2009/11/13,lung autopsy
R >A/Chernihiv/855/2009,2009/11/11,lung autopsy
R >A/Chernihiv/857/2009,2009/11/14,lung autopsy
G >A/Voronezh/01/2009,2009/11/30,E1/E1
R >A/France/6808/09,2009/11/01,C1, SIAT2
G >A/Latvia/12-1488/2009,2009/12/29,MDCKx
G >A/Latvia/12-2498/2009,2009/12/07,MDCKx
G >A/Iceland/162/2009,2009/10/21,MDCK2
G >A/Iceland/176/2009,2009/11/01,MDCK2
G >A/Denmark/1900/2009,2009/12/01,MDCK3, SIAT1
G >A/Iceland/162/2009,2009/10/21,MDCK2, SIAT3
G >A/Latvia/12-1488/2009,2009/12/29,MDCKx, SIAT1
G >A/Moldova/3163/2009,2009/11/23,clinical sample
G >A/Moldova/3245/2009,2009/11/25,clinical sample
V >A/Moldova/5053/2009,2009/12/11,clinical sample
G >A/ENG/671/2009,2009/07/01,c1
G >A/ENG/94640080/2009,2009/11/04,original
G >A/ENG/93960032/2009,2009/09/10,original
G >A/SC/10/2009,2009/06/01,original
G >A/ENG/93780689/2009,2009/09/01,c1
G >A/ENG/1005/2009,2009/09/01,c1
R >A/ENG/94620048/2009,2009/10/01,original
R >A/California/07/2009,2009/04/09,E2
G >A/Mexico/3955/2009,2009/04/03,E2
G >A/New York/04/2009,2009/04/01,E2
R >A/New York/11/2009,2009/04/25,E2
R >A/New York/31/2009,2009/04/24,E2
G >A/Georgia/01/2009,2009/04/27,C1
R >A/Nebraska/02/2009,2009/04/01,E2
R >A/Texas/04/2009,2009/04/14,X/E2
G >A/Texas/11/2009,2009/04/23,E2
R >A/Texas/10/2009,2009/04/23,E2
R >A/California/13/2009,2009/04/21,E2
G >A/Texas/05/2009,2009/04/15,X/E2
G >A/Illinois/10/2009,2009/07/31,C4
G >A/Indiana/09/2009,2009/04/22,E2
R >A/Massachusetts/16/2009,2009/06/15,C1
G >A/Utah/42/2009,2009/07/24,M1
R >A/Utah/42/2009,2009/07/24,Original
G >A/Costa Rica/3149/2009,2009/07/13,X1/C1
G >A/Michigan/25/2009,2009/10/14,C1
G >A/Utah/42/2009,2009/07/24,M1/C1
G >A/Mexico/3956/2009,2009/04/03,Original
R >A/North Carolina/39/2009,2009/10/15,IR
G >A/North Carolina/49/2009,2009/10/16,M1/C1
G >A/North Carolina/53/2009,2009/10/18,M1/C1
G >A/Washington/68/2009,2009/10/14,X/C2
G >A/Jamaica/6261/2009,2009/07/07,C1
G >A/Uruguay/755/2009,2009/07/22,C1
G >A/SYDNEY/2503/2009,2009/07/12,original specimen
R >A/SOUTH AUSTRALIA/2016/2009,2009/07/16,MDCKX,MDCK1
G >A/Perth/261/2009,2009/08/12,MDCKX,MDCK1
T >A/Monterrey/3/2009
G >A/Mexico/InDRE4114/2009
G >A/Mexico/InDRE4114/2009
G >A/Vladivostok/01/2009
G >A/Abakan/02/2009
G >A/Tomsk/07/2009
G >A/Salekhard/01/2009
G >A/Tomsk/08/2009
R >A/Sw/4/Mexico/2009/04/
R >A/Nebraska/02/2009/04/
G >A/NY/04/2009/04/
G >A/Mexico/3955/2009/04/02
R >A/CA/07/2009/04/09
R >A/Texas/04/2009/04/14
G >A/Texas/05/2009/04/15
R >A/CA/13/2009/04/21
R >A/Texas/10/2009/04/23
G >A/Texas/11/2009/04/23
R >A/NY/31/2009/04/24
R >A/NY/11/2009/04/25
G >A/Georgia/01/2009/04/27
G >A/Mexico city/CIA11/2009/05/02
T >A/Sw/Alberta/OTH-33-3/2009/05/03
G >A/Mexico city/CIA10/2009/05/03
R >A/Boston/109/2009/06/15
G >A/Hiroshima/201/2009/06/17
G >A/CA/VRDL7/2009/06/17
M >A/CA/VRDL31/2009/06/17
G >A/CA/VRDL27/2009/06/27
G >A/Argentina/HNRG16/2009/06/29
R >A/Texas/42291877/2009/06/29
G >A/Sao Paulo/53206/2009/07/19
G >A/Rio de Janeiro/4707/2009/07/23
R >A/Finland/614/2009/07/24
R >A/Utah/42/2009/07/24
G >A/Utah/42/2009/07/24
G >A/Rio de Janeiro/5826/2009/07/28
G >A/Catalonia/NS1706/2009/07/29
N >A/Singapore/GP2312/2009/07/31
G >A/Pune/NIV9355/2009/08/
G >A/Mum/NIV9312/2009/08/
G >A/Rio de Janeiro/7131/2009/08/01
G >A/Sao Paulo/53225/2009/08/01
G >A/Catalonia/NS2001/2009/08/03
G >A/Catalonia/NS2008/2009/08/03
G >A/Rio de Janeiro/7455/2009/08/04
N >A/Singapore/GP2641/2009/08/05
N >A/Singapore/GP2651/2009/08/05
R >A/Norway/2924/2009/08/10
G >A/Orenburg/CRIE-VNV/2009/08/16
G >A/Rio de Janeiro/14601/2009/08/24
G >A/Roma/ISS1897/2009/08/27
G >A/Roma/ISS1941/2009/08/27
R >A/Nagano/RC1/2009/08/27
G >A/Pune/NIV10278/2009/09/
G >A/Netherlands/1064b/2009/09/01
G >A/Norway/3206-3/2009/09/01
R >A/Bahia/15525/2009/09/05
G >A/South Carolina/WRSP520/2009/09/05
G >A/Zhejiang-Yiwu/11/2009/09/06
G >A/Zhejiang/DTID-ZJU02/2009/09/07
G >A/Zhejiang/DTID-ZJU03/2009/09/07
G >A/Nsk/NIV10348/2009/09/07
R >A/Mexico/InDRE43149/2009/09/28
R >A/Moscow/CRIE-BVA/2009/10/24
R >A/Mexico/InDRE50625/2009/10/31
R >A/Kaluga/CRIE-INV/2009/11/
R >A/Ivanovo/CRIE-AMV/2009/11/
G >A/Moscow oblast/CRIE-DEI/2009/11/
G >A/Egypt/N14644/2009/11/01
R >A/Mexico/InDRE50617/2009/11/01
G >A/Moscow oblast/CRIE-OAM/2009/11/02
R >A/Lipetsk/CRIE-BVV/2009/11/10
R >A/Yaroslavl/CRIE-CHMV/2009/11/10
G >A/Bryansk/IIV2971/2009/11/11
G >A/Tver/IIV2969/2009/11/14
G >A/Thessaloniki/2502/2009/11/17
G >A/Netherlands/2243/2009/11/17
C >A/Madrid/INS296/2009/11/17
G >A/Kastoria/2636/2009/11/18
G >A/Ivanovo/CRIE-BOV/2009/11/18
G >A/Ivanovo/CRIE-AIV/2009/11/18
R >A/Orel/CRIE-AAP/2009/11/20
G >A/Ivanovo/CRIE-STV1/2009/11/21
G >A/Thessaloniki/2812/2009/11/22
G >A/Moscow/CRIE-CHSN/2009/11/23
R >A/Moscow oblast/CRIE-KMA/2009/11/23
G >A/Ulyanovsk/CRIE-BAA/2009/11/23
R >A/Moscow/CRIE-TYD/2009/11/23
R >A/Ivanovo/CRIE-RNA/2009/11/24
G >A/Perm/01/2009/11/25
G >A/Tver/IIV-183/2009/11/25
R >A/Tambov/CRIE-LLA/2009/11/30
G >A/Taraz/01/2009/12/
G >A/Yaroslavl/IIV-196/2009/12/04
G >A/IIV-Anadyr/177/2009/12/04
G >A/Catalonia/NS092145684/2009/12/10
R >A/NY/7216/2009/12/21
G >A/Iran/1519/2009/12/23
G >A/CA/VRDL131/2009/12/30
G >A/Egypt/N00267/2010/01/
G >A/Karasuk/01/2010/01/04
G >A/Kavala/219/2010/01/12
G >A/Thessaloniki/206/2010/01/12
G >A/Thessaloniki/225/2010/01/13
G >A/Tunisia/1064/2010/01/18
G >A/Orenburg/IIV-13/2010/03/02
G >A/Orenburg/IIV-13/2010/03/02
R >A/Singapore/SS003/2010/04/
R >A/Singapore/SS004/2010/04/
R >A/Bahia/231/2010/04/01
G >A/Nanjing/2/2010/06/30
G >A/Nanjing/1/2010/06/30
716  haall 244   -:132 A:8983 C:1 G:159 M:1 N:3 R:76 T:2 V:2

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