dothedd
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Post by dothedd on Apr 11, 2011 20:56:31 GMT -5
H1N1 Blocks Speech of Venezuela's Hugo Chavez
Recombinomics Commentary 15:55 April 10, 2011
Venezuela's President Hugo Chavez suspended the transmission of program of Alo Presidente on Sunday due to the strong flu he is suffering.
"We all saw the strong flu-like symptoms that President Chavez is suffering. Tomorrow we will not broadcast Alo, Presidente ", wrote the night of Saturday the People's Minister for Communication and Information Andres Izarra, through their network user on Twitter, AVN reported.
The above translation describes the suspended broadcast of Hugo Chavez in Venezuela due to the "strong" flu, which is almost certainly the novel H1N1 circulating in Mexico and throughout Central and South America.
As noted above, it has spread to the highest levels of government in Venezuela, even though media reports describe ample levels of vaccine. However, the vaccine is directed against California/07/2009 which is quite distinct from the novel H1N1, which has acquired A189T and S165N and vaccine failure has been cited in the United States.
Moreover, one of the fatal cases in Chihuahua, Mexico had D225N, which has been cited in multiple anecdotal reports in multiple countries, including the US. This receptor binding domain change is linked to a more aggressive H1N1.
Release of 2011 US sequences as well as sequences from severe and fatal cases in Central and South America is long overdue.
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dothedd
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Post by dothedd on Apr 11, 2011 21:00:24 GMT -5
Futile H1N1 Vaccination Fences In Chihuahua Mexico
Recombinomics Commentary 17:55 April 10, 2011
Similarly, vaccination fences implements the authority to prevent the spread of the virus within 50 block radius of the infected areas where they reside, are progressing slowly, since the authority has implemented only 9 near of the 28 that yesterday would be required to perform.
"It is a process that takes time, strategy, resources and analysis? A fence can not be done overnight," justified and Undersecretary of Health, Felipe Fornelli Lafon.
Fornelli, along with the director of the Health District II, Hector Puertas Corners, noted that to date has been applied to a biological population of 5 000 318 people, who are resident within 50 square blocks of housing sick with influenza.
They stressed further that the Ministry of Health has implemented 110 000 doses of vaccine against H1N1 influenza "and is expected to arrive this week's figure of 120 thousand," he said.
The above translation describes use of vaccination “fences” to control the spread of H1N1. These approaches are destined to fail. Vaccination is most useful when administered prior to an influenza outbreak. The novel H1N1 was noted in Juarez, Chihuahua in March and has spread rapidly. Recently a red alert was issued for Tamaulipas in northern Mexico because of a spike in suspect H1N1 cases and the government announced a plan for training courses on treating H1N1 patients in the ICU.
Moreover, anecdotal reports describe emergency room patients with breathing difficulties and nose bleeds, as ICU beds fill up in Chihuahua and other states in northern Mexico, raising concerns that D225G and D225N are present, as seen in Ukraine.. The novel H1N1 is spreading rapidly and vaccination campaigns are unlikely to significantly slow the spread.
Recently released sequences reveal a novel H1N1 with changes seen in US patients were infected after vaccination. The novel H1N1 has receptor binding domain change A189T as well as S165N, which generates a new glycosylation site, which made aid in immunological escape by hiding antigenic sites. Moreover, one of the isolates from a fatal case had D225N, which is likely present in the second fatal case since the HA sequence, other than D225N was identical and the other fatality was a likely contact of the first fatal case.
Anecdotal reports describe closely related sequences in other countries, including additional sequences with D225N
The novel sub-clade is expected to continue to spread and severely tax health care delivery in northern Mexico. The reports of these outbreaks on the Texas border raise additional concerns supported by reports of linkage of initial cases to Las Cruces, New Mexico and Odessa, Texas.
Release of 2011 sequences from the United States is long overdue, as are sequences from Central and South American countries with increases in H1N1, including Venezuela where the speech of president Hugo Chavez was canceled because of “strong” influenza.
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dothedd
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Post by dothedd on Apr 11, 2011 21:05:32 GMT -5
Rapid H1N1 Spread In South America Increases Concerns
Recombinomics Commentary 23:55 April 11, 2011
The private media yet again came under fire from President Hugo Chávez, this time for the manner in which it had covered the outbreak of Swine Flu. Chávez, who late Tuesday night insisted there were no cases of the disease in Venezuela.
Venezuela's President Hugo Chavez suspended the transmission of program of Alo Presidente on Sunday due to the strong flu he is suffering.
The Governor of Monagas, José Gregorio Briceño is the sixth confirmed case of H1N1 flu in the state, as regional officials said at a news conference Monday morning.
The regional president had been detected with strong flu symptoms from several days ago.
The above translations from Venezuela contain striking examples of a lack of transparency, where President Hugo Chavez denies H1N1 presence in the country and then cancels his weekly address three days later because he has “strong” flu. That announcement was then followed by an admission that a regional president had confirmed H1N1. The high profile cases suggest H1N1 is widespread in Venezuela and provide additional evidence suggesting the vaccine has little utility because it is likely that these high ranking politicians have been vaccinated.
This lack of transparency and use of vaccines to create "fences" in Mexico also signal rapid spread of H1N1. Anecdotal reports describe patients appearing at Emergency Departments with common symptoms which include nose bleeds coupled with breathing difficulties. The patients are filling up ICU beds in northern Mexico while the death toll is said to have stopped rising. However, medical personnel are being trained in treatment of H1N1 ICU patients and vaccination drives are being launch near confirmed cases.
Initial sequence data from fatal cases identifies a novel H1N1 sub-clade with D225N. The frequent detection of D225N in this sub-clade has been anecdotally reported for multiple countries south of Mexico, once again signaling rapid spread of a novel H1N1 that has escaped the immunity provided by prior H1N1 infections and/or vaccinations.
These anecdotal reports indicate rapid spread in Argentina as well as novel H1N1 detection in Chile and Ecuador, suggesting the novel sub-clade has spread throughout South America well in advance of the start of flu season for the southern hemisphere.
This spread is not being reported by WHO, and the presence of D225N at a high frequency has not been acknowledged.
The parallels with the emergence and spread of pandemic H1N1 in 2009 is striking.
Release of 2011 H1N1 sequences from the United States as well as severe and fatal cases in Central and South America is ovedue.
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dothedd
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Post by dothedd on Apr 13, 2011 17:30:32 GMT -5
H1N1 Levels Explode in Tamaulipas Mexico Recombinomics Commentary 19:25 April 12, 2011
After confirming 12 cases of H1N1 influenza, the Epidemiologist of the Ministry of Health Alfredo Rodríguez Trujillo warned that the holiday season puts them at risk of infection in the state.
He said that so far there have been 500 suspected cases, and are the border towns of the south: Tampico, Madero and Altamira most at risk of infection.
The above translation confirms H1N1 in Tamualipas, where a red alert had been declared because of 120 suspect cases. Since the April 9 alert the suspect cases have been confirmed and the number has jumped from 120 to 500 cases primarily localized to three towns along the southern border of the state. This dramatic jump to 500 cases in a small region of one state in Mexico highlights the rapid spread of the H1N1 virus in mid-April when flu cases traditionally decline. Moreover, the spike in cases is for a novel sub-clade of H1N1 in a season that was dominated by H3N2 in Mexico. H3N2 levels have dramatically declined, allowing for the emergence of a novel sub-clade of H1N1. Spread is following the timeline of the emergence of pandemic H1N1 in 2009.
However, D225N is frequently found in this novel sub-clade, which may be associated with anecdotal reports of patients in northern Mexico presently at Emergency Departments with nose bleeds and breathing difficulties. These patients are filling up ICU beds and Mexico has launched training programs for care of H1N1 patients in ICU’s.
Additional anecdotal reports indicate this sub-clade with D225N is rapidly spreading throughout South America, well in advance of the flu season in the southern hemisphere. Moreover, data from surveillance of the US military and dependents identifies this novel sub-clade in patients who were previously vaccinated, casting serious doubts on the success of efforts to contain the H1N1 spread with vaccination fences.
The rapid increasing in confirmed and suspect H1N1 cases raises additional concerns that the presence of D225N will lead to more severe and fatal cases.
Release of sequences from the United States as well as severe and fatal cases in countries south of Mexico is now overdue.
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dothedd
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Post by dothedd on Apr 15, 2011 7:39:50 GMT -5
H1N1 D225G In Upper Respiratory Tract in Chihuahua Mexico
Recombinomics Commentary 19:25 April 14, 2011
The Laboratorio de Genoma de Patogenos,Instituo de Diagnostico y Referencia Epidemiologicos in Mexico has released eight more HA sequences from Chihuahua, Mexico. Five of the eight sequences were the novel sub-clade, and one, A/Mexico/InDRE2195/2011, was a pharyngeal sample from a patient, (41M) who was likely a severe or fatal case, which had a mixture of D225G and D225N, as expected. This combination was frequently detected in autopsy lung samples in Ukraine in late 2009, which demonstrated phylogenetic and geographic clustering. However, these combinations were not detected in upper respiratory tract collections.
The detection of this combination in an upper respiratory tract sample signals transmission at a high concentration, which is supported by detection of D225N in an upper respiratory tract collection from a fatal case. Anecdotal reports indicate D225N has been found in additional upper respiratory tract samples in Mexico and South America in isolates representing the same novel sub-clade. The partial sequence from the above sample had the same series of synonymous (G386A, T462A, C681T) and non-synonymous (K149N, S165N, A189T) markers seen in the other novel sequences, with D225N and D225G appended onto this genetic background. The presence of different combinations at position 225 (one sample in Ukraine had three markers, D225G, D225N, D225A), one the same background supports recombination, as does the presence of the same RBD changes in Chihuahua as seen in Ukraine.
Thus, in contrast to WHO claims that D225G did not cluster phylogenetically or geographically, the data out of Chihuahua, Mexico once again demonstrates that the WHO claims are false (which was also demonstrated by the detection of D225G and D225N in the Duke Medical center death cluster).
The presence of D225G and D225N in the upper respiratory tract may also explain anecdotal reports of patients with nose bleeds and breathing difficulties in Chihuahua and Nuevo Leon in northern Mexico and raises additional concerns that this novel sub-clade with D225N and D225G will produce a high frequency in severe and fatal cases.
The CDC has released 2011 sequences from the United States, and although the novel sub-clade was present, the recent sequences did not contain D225G or D225N, although an earlier novel sequence, A/Pennsylvania/07/2010) did have D225G. The results from Chihuahua suggest that a more aggressive effort, including deep sequencing, may be required to get a true picture of the virulence of this sub-clade.
Sequences from countries in Central and South America would be useful.
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dothedd
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Post by dothedd on Apr 15, 2011 7:44:00 GMT -5
Clustering of D225G In Novel H1N1 In Spain In 2010 Recombinomics Commentary 11:10 April 15, 2011
So far, There have been nine severe flu cases confirmed with AnH1N1 between weeks 19-25/2010 The above translation is from a week 25, 2010 report from the Galicia Public Health Department in Spain and describes severe H1N1 cases between May 9 and June 26, 2010. Recently partial sequences from Galicia, Spain collected in the above time frame were deposited at GISAID by the Instituto de Salud Carlos III in Majdahonda, and one isolate, A/Galicia/RR6669/2010, was collected April 11, 2009 from a 56 year old male. This sequence was related to the novel sub-clade currently circulating in Chihuahua, Mexico, and has D225G (as a mixture). Anecdotal reports indicate addition sequences identified D225G in five patients and D255N in another, signaling transmission.
This earlier sub-clade also had S165N, A189T, and V275I, which matched the sequence from A/Pennsylvania/07/2010, collected in August, 2010 and the novel sub-clade in Chihuahua, Mexico. Anecdotal reports describe D225N in the same sub-clade (in late 2010 or 2011) in the United States and multiple countries in South America. Moreover, the recently released partial sequence from Chihuahua, Mexico from a 41M, A/Mexico/InDRE2195/2011, also has D225G (as a mixture) in a sample collected from the upper respiratory tract. The presence of D225G and D225N was also seen in autopsy lung samples from the Ukraine in 2009, as well as the Duke Medical Center death cluster, demonstrate the ability of this combination to jump from one genetic background to another, signaling recombination. Moreover, anecdotal reports describe the detection of D225A in Chihuahua, Mexico, which was also identified in the Ukraine cluster.
However, the current outbreak of the novel sub-clade includes detection of D225G and D225N in pharyngeal swabs, signaling more efficient transmission, which is supported by a much wider distribution in North and South America where the flu season is ending in North America and has not begun in South America.
The prior history of this sub-clade in Spain, and more efficient spread in the current outbreak continues to increase pandemic concerns.
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dothedd
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Post by dothedd on Apr 18, 2011 20:08:10 GMT -5
Spread of Chihuahua Novel H1N1 Across the United States Recombinomics Commentary 20:00 April 16, 2011
The CDC has released a series of 2011 H1N1 sequences at GISAID, which includes a subset that is closely related to the sequences from Chihuahua, Mexico. In addition, The instituto de Diagnostico y Referencia Epidemiologicos has released partial HA sequence from 8 additional isolates in Chihuahua, Mexico, which includes five isolates (A/Mexico/InDRE2222/2011, A/Mexico/InDRE2200/2011, A/Mexico/InDRE2197/2011, A/Mexico/InDRE2195/2011, A/Mexico/InDRE2192/2011) that matched the three isolates (A/Mexico/InDRE1947/2011, A/Mexico/InDRE1946/2011, A/Mexico/InDRE1945/2011) released earlier.
All eight of the above sequences from Mexico have the rare marker, K149N, as well as a rare synonymous marker, T462A, and the eight sequence above are the only sequences at Genbank with both markers. These two markers were also found in five sequences at GISAID (A/Maryland/04/2011, A/Oregon/03/2011, A/Pennsylvania/02/2011, A/Texas/07/2011,and A/Utah/08/2011) demonstrating the close relationship between the dominant sub-clade in Chihuahua and the five sequences in the United States. Moreover, full sequences of two of the US isolates (PA/02 and MD/04) were released, demonstrating the absence of reassortment. The eight gene segments in these two isolates were closely related to an earlier full sequence (A/Texas/03/2010).
In addition MD/04 had H274Y, signaling Tamiflu resistance. Moreover, the recent sequences confirm the presence of the novel sub-clade in Texas.
The two markers exclusively shared between the eight sequences from Chihuahua and the five sequences from the US signal a rapid emergence and evolution of this novel sub-clade. All 13 sequences were from samples collected in 2011, and 2 of the 8 sequences from Chihuahua had D225N, in samples collected from the upper respiratory tract, signaling efficient transmission, and raising concerns that this novel sub-clade will spread worldwide and produce a high frequency of severe and fatal cases.
Anecdotal reports cite closely related sequences in South America, where cases are beginning to increase, in advance of the flu season in the southern hemisphere.
The rapid spread of the novel sub-clade, with frequently detected D225N in samples from the upper respiratory tract, continues to increase pandemic concerns.
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dothedd
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Post by dothedd on Apr 18, 2011 20:12:58 GMT -5
Frequent Detection of D225N In Chihuahua H1N1 Recombinomics Commentary 22:50 April 16, 2011
The instituto de Diagnostico y Referencia Epidemiologicos has released partial HA sequence from 8 additional isolates in Chihuahua, Mexico bring the total number of recent HA sequences to 11. Five of the eight ((A/Mexico/InDRE2222/2011, A/Mexico/InDRE2200/2011, A/Mexico/InDRE2197/2011, A/Mexico/InDRE2195/2011, A/Mexico/InDRE2192/2011) were closely related to the three isolates (A/Mexico/InDRE1947/2011, A/Mexico/InDRE1946/2011, A/Mexico/InDRE1945/2011) released earlier., indicating this Chihuahua sub-clade is dominant in Chihuahua, Mexico. One of the five sequences had D225G and D225N, which is a combination that was frequently seen in autopsy lung samples from Ukraine in 2009.
The detection of D225N in 2 of 8 sequences from the Chihuahua sub-clade is striking because it is generally detected a frequencies lower than D225G, and much lower than D225E. In sequences recently released by the CDC, sequences very closely related to those in Mexico were found in five isolates that were spread across the country (MD, PA, TX, UT, OR) which were in addition to other related sequences released earlier from the Air Force, although 2011 H1N1 sequences from Brooks Air Force Base have not been released.
The above sequences confirm a rapid spread of this sub-clade. Anecdotal reports indicate a large series of sequences from Mexico with D225N have yet to be released. These additional sequences will confirm a high frequency of D225N in this sub-clade, which is unusual. None of the 2010 sequences at Genbank habe D225N, and the frequency is also low in sequences deposited at GISAID in 2010.
The levels of D225N are even more striking, because like the Chihuahua sequences already released, the H1N1 is from pharyngeal swabs (collected from the upper respiratory tract). The frequent detection of D225N in Ukraine was from autopsy lung samples (lower respiratory tract).
The presence of D225N in the upper respiratory tract may explain presentations with bloody noses, which was been stated in additional anecdotal reports. The D225N levels in the upper respiratory tract may explain the spread of fatal infections in the Juarez traffic department, which increased concerns that the novel sub-clade with D225N in the upper respiratory tract will lead to a higher frequency of severe and fatal cases.
Mexico has tried to stem the spread with vaccination “fences”, but isolation of the novel sub-clade from vaccinated hosts suggest such vaccination campaigns will have limited success.
Additional sequences from severe and fatal cases throughout North and South America would be useful.
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dothedd
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Post by dothedd on Apr 18, 2011 20:17:44 GMT -5
trH3N2 Genetic Match In Cases In Wisconsin and Pennsylvania Recombinomics Commentary 23:30 April 17, 2011
Today, Sunday, April 17, 2011 the CDC released a full set of sequences, A/Pennsylvania/40/2010, for a Pennsylvania H3N2 triple reassortant (trH3N2) from a patient (3F) who developed symptoms September 6, 2010. This case had been announced February 5, 2011. The delay was attributed to difficulty in isolating a virus from the patient.
Previously, WHO had issued a pager alert on two US trH3N2 cases from Illinois and Pennsylvania followed by the description of the sequences (A/Wisconsin/12/2010 and A/Pennsylvania/14/2010) from the patients (Wisconsin and Pennsylvania) who developed symptoms on September 8, 2011 and October 24, 2010, respectively. The notification was accompanied by a comment that the two sequences had differences, ruling out a common source.
However, the sequences released today from the other Pennsylvania case, , from a direct sequence of the sample indicated that the two cases, who developed symptoms two days apart, were infected by trH3N2 viruses that were virtually identical, signaling human to human transmission (see timeline here).
Although additional cases in Pennsylvania have not been reported, Pennsylvania has reported an unusually high number of unsubtypable cases in late 2010 and 2011 and has issued weekly reports to physicians raising awareness of the two prior Pennsylvania cases has created serious concerns that additional cases are under investigation and have not been announced.
An explanation of the weekly announcements and the high number of unsubtypable cases is long overdue.
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dothedd
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Post by dothedd on Apr 18, 2011 20:20:47 GMT -5
trH3N2 Transmission In Pennsylvania? Recombinomics Commentary 17:05 April 18, 2011
In addition to seasonal viruses, two unrelated infections with a swine origin influenza A/H3N2 virus have been identified in Pennsylvania with onset dates in September 2010 and October 2010. In recent years this virus has also produced human illness elsewhere in the country, generally in association with direct contact with ill pigs. It has not been associated with person-to-person transmission. Clinicians should remain alert to the possibility of infection with this virus in persons with influenza-like illness who have a history of recent exposure to swine populations, and collect appropriate diagnostic specimens.
The above alert and request concerning patients infected with an H3N2 triple reassortant (trH3N2) began appearing in weekly influenza reports from Pennsylvania at week 6. However, the sequences released yesterday, Sunday, April 17, 2011 are inconsistent with multiple points implied by the above alert because the recently released sequence, A/Pennsylvania/40/2010 from the September case (3F) described above, is virtually identical to the September case (10 month M) from Wisconsin, A/Wisconsin/12/2010, which was the subject of the WHO pager alert on the Wisconsin September case and the Pennsylvania October case (46M), A/Pennsylvania/14/2010.
Thus, the above alert, as well as comments on the pager alert, are misleading because neither address the identity between the September cases, in Wisconsin and Pennsylvania, and instead compares the September cases to the October case (the pager alert compares the Wisconsin case to the later Pennsylvania case, while the Pennsylvania alert compares the two Pennsylvania cases).
As a result, both alerts claim that the September cases are linked to swine rather than each other, to maintain the claim that there is no human to human transmission of trH3N2. Consequently, the above announcement requests samples from patients exposed to swine, leading to a strong bias against trH3N2 cases linked to human to human transmission, such as children like the two September cases, who would be most vulnerable to trH3N2, which have human H and N sequences from the 1990's. Moreover, the trH3N2 sequences have D225G, and all of the recent cases have PB1 E618D.
In Pennsylvania there have been a large number of unsubtypable cases, and Pennsylvania leads the nation in reported influenza deaths.
Detection of trH3N2 in Pennsylvania is difficult, because as noted for the September case, it sub-typed as seasonal H3N2 and the 5 month delay in reporting the case was associated with the initial misdiagnosis coupled with a failure to isolate the virus. The sequence released yesterday, 7 months after the fact, was from direct sequencing of the clinical samples. However, it was released on a Sunday, absent the customary note citing the fact that the sequence was from a triple reassortant, which was included in the later case from Pennsylvania as well as the Wisconsin case (and all other human trH3N2 sequences).
The failure of the CDC to address the identity between the two September cases, coupled with the technical issues associated with detection, and biased alerts, such as the one listed above for Pennsylvania, continue to increase trH3N2 pandemic concerns.
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Post by dothedd on Apr 18, 2011 20:23:39 GMT -5
CDC Silence On trH3N2 Match Is Deafening Recombinomics Commentary 23:30 April 18, 2011
Initial testing of the specimen indicated a seasonal influenza A (H3N2) virus and the specimen was submitted to CDC as a routine surveillance sample. The delay from onset to detection occurred because attempts to culture the virus were unsuccessful. RT-PCR testing confirmed swine-origin influenza A (H3N2).
No epidemiologic links between this case and any of the other cases of swine-origin H3N2 infection have been identified and the viruses from all seven cases have genetic differences indicating different sources of infection.
There is no evidence of human-to-human transmission with this virus; however, early identification and investigation of all human infections with novel influenza A viruses is critical to evaluate the extent of the outbreak and possible human-to-human transmission.
The above comments are from the week 4 FluView, and as noted attempts to culture the virus were unsuccessful and no sequence data was presented or described. Therefore, the CDC was able to claim “no evidence of human-to-human transmission”. However, yesterday on Sunday, April 18 the CDC deposited the full sequence from this isolate, A/Pennsylvania/40/2010, at GISAID (lacking a trH3N2 designation), and the sequence for all 8 gene segments was virtually identical with one of the seven isolates cited above, A/Wisconsin/12/2010 proviing clear evidence of human-to-human transmission in unreported hosts.
The sequence was deposited more the seven months after the patient (3F) developed symptoms on September 6, 2010.
Thus, the only real source of “evidence of human-to-human transmission” is the sequence, which matches the isolated collected from a patient in Wisconsin, who developed symptoms two days later on September 8, 2010.
The silence of the CDC on this match is deafening.
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dothedd
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Post by dothedd on Apr 30, 2011 11:55:31 GMT -5
Commentary
US Air Force H1N1 Herald Wave Raises Pandemic Concerns Recombinomics Commentary 01:10 April 29, 2011
The military recruits, again, a captive population, essentially 100 percent immunized and, for the purposes of this slide, 100 percent immunized with the LAIV. Two sites that did receive TIV were excluded from this analysis.
We had a very remarkable increase in infections with pandemic H1N1 in recent weeks in our recruits. That is very unusual for us. Highly vaccinated, we do see influenza in that highly vaccinated population. We take those seriously, in case they are breakthroughs to see if there is drift of the circulating strains from the vaccine. But this is very unusual to see so many of late.
The above comments are from the Air Force presentation at the February 25, 2011 Vaccine Advisory Committee meeting to determine targets for the 2011/2012 flu season in the United States. Although the presenter did not characterize the H1N1 generating the significant vaccine breakthrough, in February the Air Force did release 2011 sequences from military dependents who had been vaccinated. One series was from dependents in Korea, but a second series was from dependents in the United States. Both of the sequences from the United States were the Chihuahua sub-clade, raising concerns that the data presented above represents a “herald wave” predicting the dominant sub-clade in the next flu season. The sudden 2011 appearance of the sub-clade in military samples was also seen in recently released 2011 H1N1 sequences by the CDC.
Moreover, the recent WHO 2011 pandemic alert described an H1N1 outbreak in Ecuador at the beginning of 2011 followed by outbreaks in Mexico and Venezuela in March 2011. Public sequences from Mexico, as well as anecdotal reports indicate the dominant H1N1 in all three countries, was the Chihuahua sub-clade with D225N in severe and fatal cases.
Unfortunately, the vaccine committee voted 15-0, with one abstention, to leave the H1N1 vaccine target, A/California/07/2009, unchanged. The lone abstention, Dr Vicki Debold with the National Vaccine Information Center, expressed concerns about the efficacy of the H1N1 vaccine using A/California/07/2009 as the target.
The Air Force testimony, coupled with the detection of the Chihuahua sub-clade in vaccinated hosts, raise serious concerns about the current vaccine, as well as the vaccine recently shipped to the southern hemisphere, as well as the vaccine being prepared for the 2011/2012 season in the northern hemisphere, since all of the above use A/California/07/2009 as the target for all approved vaccines, worldwide.
The current vaccine selection for WHO and the United States is heavily dependent on an antigen characterization test, which has only identified one US low reactor for the entire 2010/2011 season. Similarly, the only US isolates designated as low reactors in the 2009/2010 season had changes at the same position, 159.
These small numbers of low reactors is in marked contrast various sub-clades identified in multiple studies citing vaccine breakthroughs, including the examples presented by the Air Force, which are likely linked to the Chihuahua sub-clade.
Ignoring these important studies and relying on an antigen characterization with serious sensitivity and reproducibility issue jeopardizes the world’s health.
More information on the isolates linked to the dramatic vaccine failures described to the 2010/2011 vaccine selection committee would be useful. www.recombinomics.com/News/04291101/H1N1_AF_Herald.html
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Post by dothedd on May 2, 2011 20:38:37 GMT -5
Brazil President In Hospital With Pneumonia / Flu-like Symptoms Recombinomics Commentary 15:10 May 2, 2011
Brazilian President Dilma Rousseff is in hospital suffering from pneumonia, her spokesman Rodrigo Baena says.
Ms Rousseff had been admitted to a hospital in Sao Paulo on Saturday after suffering from severe flu symptoms for several days, he said.
He added that the president would stay a second night for further tests.
Ms Rousseff, 63, had to cancel her participation at the World Economic Forum in Rio de Janeiro on Friday because she felt ill.
The above report describes the likely infection of the President of Brazil with H1N1. It also highlights the limitation of vaccination campaigns when H1N1 is circulating. The President was vaccinated on April 25, 2011.
However, the transcript of the 2011/2012 vaccine selection meeting in the United States details H1N1 infections in vaccinated US military, as reported by the Air Force. Release of sequences from US vaccinated cases identified the Chihuahua sub-clade, adding additional support for vaccine escape by the sub-clade reported in Mexico in public reports, and in South America in anecdotal reports which icluded additional examples with D225N in severe or fatal cases, leading to WHO announced pandemic alert.
Moreover, President Rousseff was diagnosed in early 2011 with H1N1, providing further support for evolution away from prior H1N1 sub-clade, as well as the current vaccine used on April 25, 2011.
The above cases follow similar reports for the President of Venezuela, Hugo Chavez, who was also forced to cancel a public address due to “heavy flu” last month.
The above reports support the transmission of H1N1 at the highest levels in South American governments and raise serious concerns about the efficacy of aggressive 2011 H1N1 vaccine campaigns with a vaccine target from early 2009.
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Post by dothedd on May 6, 2011 8:53:45 GMT -5
Frequent Low Reactors in H1N1 S188T Sub-clade In Japan Recombinomics Commentary 22:50 May 3, 2011
NIID released 33 HA sequences, which were largely from 2011. All 33 sequences had S188T, once again demonstrating the dominance of that sub-clade in early 2011 throughout the northern hemisphere.
However, these sequences frequently had changes at positions 156, 157, 158, 159 (1, 3, 5, 1 respectively) which are within the antigenic site most commonly linked to low reactors (the 5 coded for G158E). Moreover, all 10 changes were mixtures with wild type, allowing for rapid dominance of the "low reactor" genotype within the patient, if subjected to selection pressure. Thus, these “low reactors” may be more dangerous, since the wild type component reduces the likelihood that the isolates would register as low reactors, leading to a gross underestimate of the true level of low reactors in circulation. This gross under-estimate can be affected further through lab manipulation of isolates and anti-sera used in the antigenic characterization tests used to identify low reactors. Results generated by the CDC have produced intra-lab and inter-lab inconsistencies. Inter-lab differences were discussed at the recent vaccine selection meeting regarding the higher number of low reactors identified by Mill Hill. The CDC claimed that the low reactors were identified because of the cell line used, and suggested that Mill Hill change cell lines to identity fewer low reactors, which is a recurring CDC theme.
Other WHO regional centers like NIID in Japan also has identified increasing numbers changes associated with low reactors as indicated above, yet the CDC argues for use of a cell line that is less sensitive for detection of such changes.
These low numbers are seen in data produced by the CDC. Last season the CDC only identified 6 low reactors in the United States out of 1847 tested and all six had a change at position 159. This year the CDC has identified an even lower frequency (1 out of 490 tested) even though the above sub-clade is now dominant throughout the northern hemisphere, including the United States.
This denial of low reactors is consistent with similar positions on the linkage of D225G or D225N changes with severe and fatal cases, as well as the decision to designate isolates with H274Y below 50% as Tamiflu sensitive.
The pattern of discounting important changes associated with immunological escape, increased virulence, or anti-viral resistance continues to be hazardous to the world’s health, which has been exacerbated by the decision to leave the H1N1 unchanged once again (in spite of compelling reports on vaccine breakthroughs) and to discount the clinical significance of D225N detected at high frequency in the Chihuahua sub-clade, which has generated a WHO pandemic alert. www.recombinomics.com/whats_new.htmlwww.issapharma.org/blog,frequent-low-reactors-in-h1n1-s188t-sub-clade-in-japan,991575904.html
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dothedd
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Post by dothedd on May 6, 2011 8:58:09 GMT -5
CDC Test and Isolation Bias Raises H1N1 Pandemic Concerns Recombinomics Commentary 14:20 May 4, 2011
DR. GELLIN: I am always impressed by what a body of work that is. Two questions. One of them, you had mentioned about the low reactors and the biological issues at the lab in London, is that the same issue for the H1 as well as the H3? Because they showed, I think, that there was a higher percentage of H1 low reactors in the London lab, as well. The question really is that a lab problem or does that signal some other evolution, since they have had more H1 this year?
DR. COX: Yes. What we know for H1N1 viruses is that if you isolate them in a particular cell line, you tend to get more of the variance with changes within that region that I mentioned -- the 153 to 158 region. They had been using the particular cell line that pulls out that particular variant or that selects for that particular variant.
They have subsequently switched to normal MDCK cells. I think what they are seeing is a combination of the two phenomena. Plus, they receive a lot of viruses that have been isolated COT, the special kind of MDCK cells. I think it is a combination of they are receiving viruses with changes that cause that reduction in activity and then having some additional low reactors, but they are scattered throughout the tree.
The above comments from the 2011/2012 vaccine advisory meeting provides additional data supporting a emphasis on using cell lines that reduce the likelihood of identifying low reactors, which explains the failure of the CDC to report H1N1 low reactors in US isolates from the 2009/2010 and 2010/2011 seasons. The above comments do not claim that the “normal” MDCK cells produce isolates that are reflective of the H1N1 in the patient, and in fact the data released in weekly FluViews for the past two seasons strongly suggests extreme bias in the CDC data.
The antigen characterization test can be heavily influenced by the isolation procedures for the test virus, as well as the creation and use of the ferret reference sera. CDC data has been internally and externally inconsistent with data produced by the CDC other WHO regional centers, including Mill Hill, as described above. These inconsistencies involve the antigenic site described above, as well as receptor binding domain changes, including D225G and D225N.
The data bias and inconsistencies for the antigenic reason are best demonstrated by G158E (H3 numbering), which has been demonstrated to be an important change associated with low reactor status via multiple approaches by multiple labs, including the CDC. One of the first H1N1 low reactors identified by the CDC, A/Bayern/69/2009, was an isolate from Germany that had G158E. This result was supported by Mill Hill, who characterized another G158E isolate from Germany, A/Bayern/62/2009, as a low rector. This designation was supported by data from MedImmune who had characterized various clones from California/07/2009 (CA/07), the H1N1 vaccine target. One clone had G158E and grew well in chicken eggs and therefore was a vaccine candidate. However, antisera directed against wild type CA/07 had a dramatically reduced titer against the G158E clone, so the clone was not selected. Similarly, escape mutants that evaded monoclonal antibodies directed agains CA/07 also had G158E, providing another line of evidence supporting the role of G158E in the generation of low reactors.
However, the assay used by the CDC subsequently failed to identify isolates with G158E as low reactors. One dramatic example was an isolate from Ukraine, A/Lviv/N6/2009, which had D225G. Mill Hill designated this isolate as a low reactor. However, the CDC isolated a virus from this patient that had D225G and G158E, yet did not designate the isolate as a low reactor. This isolate subsequently was used as a control in antigen characterization tests and data published by the Health protection Agency in the UK as well as the WHO regional center in Australia used the target and clearly showed a dramatic reduction in titer against a number of ferret anti-sera generated against various targets, including CA/07.
The lack of sensitivity in the CDC is reflected in FluView reports. Although other labs report the frequent detection of G158E, the CDC reported only 6 low reactors out of 1847 tests of 2009/2010 isolates and all six involved changes at position 159. Thus, the CDC found no examples of low reactors in US isolates with G158E. The frequency of low reactors in the 2010/2011 season is even lower, with only one reported example out of 490 tests. Recent sequences from Germany and Japan have high frequencies of changes at positions 156-159, with G158E being the most common change.
This failure of the CDC to identify isolates with G158E, as well as the failure to classify isolates with G158E as low reactors raises serious issues of bias in the nCDC isolation procedures as well as the sensitivity of the antigen characterization test.
This selection bias extends to the recent emergence of the Chihuahua sub-clade with D225N and associated 2011 pandemic alert issued by WHO. D225N is a raely reported receptor binding domain change, yet it was found in 2 of 11 Chihuahua sub-clade sequences from sever or fatal cases in Mexico. These data were generated by direct sequencing of the clinical sample (pharyngeal swab). Similarly, when the CDC released data from direct sequencing of their first two samples from Ukraine, both had D225N, which was also seen at a high frequency in direct sequences generated by Mill Hill of Ukraine autopsy lung samples.
Recently, the CDC has release 8 sequences from 2011 US samples that are closely related to the D225N sequences from Mexico, but none of the CDC sequences have D225N. However, none are direct sequences, raising concerns that this important change is also being selected against by CDC isolation procedures.
These isolation issues and biased antigen characterization tests can have serious consequences. At the vaccine selection meeting, the Air Force provided dramatic evidence of recent vaccine breakthrough in military recruits, consistent with release of Chihuahua sequences from vaccinated military dependents, raising serious concerns about the current utility of an H1N1 vaccine directed against CA/07. However, in spite of this compeling evidence against the efficacy of the current H1N1 target, the committee voted 15-0 with one abstention, to leave the H1N1 target unchanged, largely based on the antigen characterization data presented by the CDC.
The reliance on this heavily biased test for vaccine target selection continues to be hazardous to the world’s health.
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dothedd
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Post by dothedd on May 6, 2011 9:01:23 GMT -5
Air Force Cites H1N1 Chihuahua Vaccine Breakthrough Recombinomics Commentary 20:20 May 4, 2011
Additionally, we are learning that some cases in this group were previously vaccinated. The above comments regarding the Chihuahua sub-clade are from the Air Force week 16 infuenza report, and further supports comments made at the 2011/2012 vaccine advisory committee meeting, as well as sequences previously released b the Air Force from vaccinated hosts. These comments increase concerns that the failure of the CDC to identify low reactors in this sub-clade is tied into their heavily biased antigen characterization assay, which has only identified 7 H1N1 low reactors in the past two seasons. The Chihuahua sub-clade has a newly acquired gylcosylation site due to S165N, as well as a receptor binding domain change, A189T, which is at a position implicated in immunological escape of seasonal H1N1 in the 2009/2010 season. The vaccine breakthrough raises serious concerns regarding the emerging sub-clade, which contributed to the pandemic alert. Moreover, the high frequency detection of D225N in severe and fatal cases increases those concerns. The number of fatalities is rising in Chihuahua, Mexico and recent media reports describe the death of a social activist who was not included in the confirmed H1N1 fatalities in Chihuahua. This death increases concerns that the number of H1N1 fatalities in Mexico is markedly higher than the 5 cases in Chihuahua or 8 cases in Juarez. Similarly, the close similarity between sequences in the United States and Mexico suggests that severe and fatal cases in the United States also have D225N. Release of the sequences in Mexico with D225N, as well as additional examples in North and South America, would be useful.
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dothedd
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Post by dothedd on May 6, 2011 9:04:20 GMT -5
More US H1N1 Chihuahua Sequences Raise Concerns Recombinomics Commentary 21:20 May 4, 2011
The CDC released a series of 35 H1N1 HA sequences at GISAID which were largely from 2011 isolates in the United States. Included were three US sequences (A/Pennsylvania/04/2011, A/Texas/08/2011, A/New Jersey/05/2011) which were collected in March and were closely related to the Chihuahua sub-clade sequences from Mexico. The three US sequences were identical to each other, as well as three sequences released earlier (A/Maryland/04/2011, A/Oregon/03/2011, A/Texas/07/2011) providing further evidence for the spread of this sub-clade in the United States. Two other closely related US sequences (A/Utah/08/2011 and A/Pennsylvania/02/2011) represent the eight US sequences which are closely related to the sequences from Mexico including the presence of K149N.
Two of the sequences from severe or fatal cases in Mexico have D225N, raising concerns that the US patients also have D225N, which is not found in the viral isolates from their samples due to collection or isolation issues.
The sequences from Mexico were generated by direct sequencing of the clinical samples, while the US sequences come from virus isolated in culture. Unreleased sequences from Mexico, as well as other countries in North and South America have D225N on a Chihuahua sub-clade genetic background, raising concerns that this receptor binding domain change is widespread and in samples represented by the CDC sequences.
This emerging sub-clade with D225N has led to a pandemic alert, and recent comments from the Air Force as well as sequences from vaccinated Air Force dependents has raised concerns that massive vaccination campaigns will have limited success.
The time for a new H1N1 vaccine targeting the Chihuahua sub-clade is long overdue.
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dothedd
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Post by dothedd on May 6, 2011 9:12:35 GMT -5
H1N1 Death of Chihuahua Social Activist Raises Concerns Recombinomics Commentary 02:20 May 5, 2011
Sources close to his family Fong confirmed early yesterday that Luis K. Fong died of a pulmonary impairment caused by the H1N1 virus.
However, the death of activist Chihuahua has not been incorporated into the official report of the Ministry of Health in which only shows the death of a person in the municipality of Santa Barbara also due to the H1N1 influenza virus.
The above translation is one of many media reports on the H1N1 death of the political activist in the city of Chihuahua. As noted, his death is not included the five confirmed deaths there. The other death announced was the fifteenth confirmed cases in the state of Chihuahua, but the confirmed cases are likely to be a gross under-estimate, as suggested by media reports identifing fatalities not included in the official numbers.
Confirmed cases in Mexico are tightly controlled by lab tests done by the government, which creates delays and additional limits. Most of the suspect samples test negative, as was reported for the index case (26M) who was a Juarez traffic officer and the partner of an H1N1 confirmed fatality, who also died with H1N1 symptoms.
The report of unconfirmed fatalities raises transparency concerns, as does the withholding of sequences with H1N1. Other signs of undercounts come from the New Mexico border report on a clinic in southeastern Juarez near the cluster of cases at the eastern traffic station. That clinic, CAAPS Aguilas, had reported 355 ILI cases in the week 14 report, representing 64.3% of patient visits. In the week 15 report, the site had been removed, and totals for the border region had been revised downward, raising serious concerns about the reliability and transparency of the influenza reports.
An explanation for the removal of the CAAPS Aguilas data, as well as the release of withheld Chihuahua sequences with D225N, would be useful.
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dothedd
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Post by dothedd on May 18, 2011 19:30:21 GMT -5
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Post by dothedd on May 18, 2011 19:31:43 GMT -5
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dothedd
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Post by dothedd on May 20, 2011 18:05:49 GMT -5
Pneumonia and Influenza Death Toll In El Paso Increases To 83 Recombinomics Commentary 19:30 May 19, 2011
The week 19 Pneumonia and Influenza (P&I) deaths for El Paso, Texas increased to 15, which raised the total for the past 6 weeks to 83. Thus, in the past 6 weeks, record levels were reported for weeks 14, 15, 18 and 19. The prior record number of deaths for week 19 was 7 in 1997, so the 2011 level more than doubled the record for the past 15 years. The P&I death rate for these six weeks was 12.73%, which is more than 1.5 times the national epidemic threshold for the period.
These record numbers of deaths come at the end of the flu season, which officially ends at week 20. The number of lab confirmed H1N1 cases in the US has been declining steadily, consistent with the seasonal nature of influenza. However, the high number of deaths in El Paso supports the emergence of a new H1N1 sub-clade, as seen across the border in Chihuahua, Mexico, which caused WHO to issue a 2011 pandemic alert.
Moreover, and increase in P&I deaths has also been recorded for US Region III, which includes Delaware, where Tamiflu resistant H1N1 is transmitting, raising concerns that a more virulent H1N1 is emerging at the end of the 2010/2011 flu season.
The dramatic increase in P&I deaths in El Paso over the past 6 weeks has not been addressed by health agencies.
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dothedd
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Post by dothedd on Jun 8, 2011 13:33:02 GMT -5
Pneumonia and Influenza Death Toll In El Paso Increases To 93 Recombinomics Commentary 19:30 June 5, 2011
The week 20 Pneumonia and Influenza (P&I) deaths for El Paso, Texas set another weekly record. The 10 deaths raised the total for the past 7 weeks to 93. Thus, in the past 7 weeks, record levels were reported for weeks 14, 15, 18, 19, and 20. Thus, even though week 20 marks the official end of the 2010/2011 flu season for the northern hemisphere, deaths in El Paso remain at double digit levels. The P&I death rate for these seven weeks continues at a rate that is above 12%, which is more than 1.5 times the national epidemic threshold for the period.
The number of lab confirmed H1N1 cases in the US has been declining steadily, consistent with the seasonal nature of influenza. However, the high number of deaths in El Paso supports the emergence of a new H1N1 sub-clade, as seen across the border in Chihuahua, Mexico, which caused WHO to issue a 2011 pandemic alert.
The record number of P&I deaths in El Paso has not been addressed by local or national agencies.www.recombinomics.com/News/06051101/El_Paso_PI_93.html
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dothedd
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Post by dothedd on Jun 8, 2011 13:35:01 GMT -5
Pneumonia and Influenza Death Toll In El Paso Increases To 106 Recombinomics Commentary 20:15 June 5, 2011
The week 21 Pneumonia and Influenza (P&I) deaths for El Paso, Texas set another weekly record. The 13 deaths raised the total for the past 8 weeks to 106. Thus, in the past 8 weeks, record levels were reported for weeks 14, 15, 18, 19, 20 and 21. Thus, even though week 21 is after the official end of the 2010/2011 flu season for the northern hemisphere, deaths in El Paso remain at record double digit levels. The P&I death rate for these eight weeks continues at a rate that is above 12%, which is more than 1.5 times the national epidemic threshold for the period.
The spike in deaths began in week 14, when the 19 reported deaths were 1 death shy of the weekly record reported for El Paso in the past 15 years at the CDC website, which maintains the weekly data fro the top 122 cities in the US over the past 15 years. The record of 20 was broken in week 15, when 24 deaths were reported. The numbers declined in weeks 16 and 17, but a new weekly record has been set for each of the past 4 weeks, even though lab confirmed cases have steadily declined to baseline levels as the flu season ended.
The record number of P&I deaths in El Paso has not been addressed by local or national agencies and these high levels are not reflected in lab confirmed cases raising concerns that the sampling and associated testing grossly under estimates the number of influenza deaths, particularly for H1N1. In the past 8 weeks the number of deaths in the 25-64 age group has been over represented, providing additional data linking the spike in deaths to unreported / undetected H1N1 infections, consistent with the linkage between the start of the increases and the outbreak of Chihuahua H1N1 across the border in Juarez, Mexico.
This outbreak lead to a pandemic alert, and the above data suggests that the cases are grossly under represented by the lab confirmed numbers. The pandemic alert was linked to the detection of the D225N receptor binding domain (RBD) change in the upper respiratory tract of severe and fatal cases, but sequences demonstrating a high frequency of D225N in Chihuahua have been withheld.
The withholding of these sequences, and the lack of comment on the record number of deaths in El Paso, continue to raise pandemic concerns.
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dothedd
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Post by dothedd on Jun 14, 2011 21:23:45 GMT -5
S246N Tamiflu Resistance - Recombination & Clonal Expansion Recombinomics Commentary 23:15 June 10, 2011
The recent Eurosuveillace rapid communication, “Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation, describes a rapidly expanding NA genetic change, (S246N – N2 numbering) that confers modest resistance to the two major influenza anti-virals, Tamiflu (oseltamivir) and Relenza (zanamivir)> This could have profound clinical significance due to the characteristics of the drugs, which are useful when used at optimal dosage, but frequently lead to further resistance when used at sub-optimal levels. Further resistance would be a problem since the genetic change at position 246 can synergize with the more common position for N1 resistance, H274Y, producing a 6000 fold increase.
The paper provided support for the spread of S246N via two mechanisms, recombination and clonal expansion. The phylogenetic tree below (larger version here) identifies isolates with S246N, including 2011 isolates in the expanded panel.
The top branch in the expanded panel contains isolates from the S188T sub-clade (labeled HA-S202T in the figure), the largest current sub-clade in circulation. This branch has three isolates with S246N (A/Singapore/KK64/11, A/Brunei/1/11, and A/Montana/03/11, but each isolate is on a separate branch, signaling the recent acquisition via recombination.
Recombination allows the same genetic change to jump from one branch to another, or one sub-clade to another. S246N is concentrated in another sub-clade with A/Singapore/TT89/11 at its base, with 17 additional isolates from Singapore or Australia with S246N. Thus, these additional 17 isolates, which were collected in 2011 or late 2010, all represent clonal expansion of an isolate containing S246N.
This jumping from genetic one genetic background to another, followed by the clonal expansion of a resistant sub-clade in the absence of drug treatment follows the pattern for the fixing of H274Y in seasonal H1N1 in the 2008/2009 season.
Concern for a repeat of this fixing of resistance is increased by recently released Pandemic H1N1 sequences from Italy. In most cases only the HA sequence was released, which matched the clonally expanding sub-clade in Singapore and Australia. The HA sequence for these isolates has E359A (labeled HA-E373A on tree) which is present in Italy (see list here and here).
The NA sequence from one Italian isolate was released. Although it did not have S246N, it was virtually identical to Singapore/TT89/11 rising concerns that the sequence with S246N has already expanded in Italy and Europe, or will rapidly expand in the southern hemisphere in the current season, and become fixed in the northern hemisphere in late 2011.www.recombinomics.com/News/06101101/H1N1_S246N.html
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dothedd
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Post by dothedd on Jun 14, 2011 21:25:19 GMT -5
S246N and H274Y Tamiflu Resistance In Fatal Australian Case Recombinomics Commentary 19:30 June 12, 2011
In Perth, Western Australia, an immunocompromised patient was found on 1 March 2011 to be infected with an influenza virus that contained the S247N NA mutation (A/Perth/30/2011) (Table). Oseltamivir treatment was commenced two days after detecting the initial S247N variant (3 March). A sputum specimen collected five days later (8 March) contained an influenza virus with both the S247N and H275Y NA mutations (A/Perth/29/2011) (Table). Despite commencement of intravenous zanamivir the patient died on 16 March from multiple organ failure. The isolate with the dual S247N and H275Y mutations had an oseltamivir IC50 nearly 6,000-fold higher than sensitive viruses and 10-fold higher than seen for influenza A(H1N1)2009 viruses with the H275Y mutation alone (Table).
The above comments from the recent Eurosurveillance rapid communication on “moderate” oseltamivir (Tamiflu) resistance due to S246N describe detection of H274Y in a sample collected five days after the start of oseltamivir treatment. The rapid appearance of H274Y strongly suggests that the polymorphism was circulating in the patient prior to treatment (although it was not present in the published sequence, A/Perth/30/2011, collected prior to treatment), and the moderate resistance (six fold), linked to S246N significantly facilitated the increase in H274Y (present in the later collection, A/Perth/29/2011), which was reported in the absence of a wild type signal at position 274.
The appearance of H274Y in patients treated sub-optimally was not unexpected. Treatment of children in Japan with sub-optimal dosing of oseltamivir was linked to the appearance of resistance at multiple positions, and clusters of H274Y have been reported in immunocompromised patients treated with Tamiflu.
Increased monitoring of immunocompromised patients is common and the increase in resistance can have clinical consequences, including death, as seen in the above patient.
The level of H274Y in circulation is under-reported because WHO collaborating groups have agreed not to publicly report H274Y levels below 50%. The resistance is reported to physicians, because as seen above, the frequency increases quickly and significantly after the start of treatment, and as indicated by the IC50 value reported above, the treatment is useless.
The recent report of efficient transmission of S246N in Singapore and Australia raises concerns that associated increases in the levels of H274Y will become increasingly common.
Release of data on H1N1 samples with H274Y levels below 50% would be useful.
The WHO agreement to withhold this data continues to be hazardous to the world’s health.
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dothedd
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Post by dothedd on Jun 14, 2011 21:28:12 GMT -5
S246N and H274Y Tamiflu Resistance Clinical Concerns Recombinomics Commentary 16:00 June 13, 2011
Pharmacokinetic data would suggest that the maximum drug levels achieved via the recommended dose easily exceed the observed IC50 values of the S247N mutant [11], and therefore the variant is unlikely to be clinically resistant.
The above comments in the recent report on the rapid clonal expansion of S246N (S247N in N1 numbering) is widely disseminated in media reports and refers Tamiflu data from a 1999 publication. However, clinical data data on actual patients treated with Tamiflu raises serious concerns about the effects of a six fold reduction in the effective dose of Tamiflu (or a corresponding 3 fold reduction in the effectiveness of Relenza).
Most of the clinical data has been on patients treated with Tamiflu, since it has been approved for a longer time period and has been used in the treatment of prevention of H5N1 as well as season and pandemic influenza.
Tamiflu is most frequently used in Japan, and earlier use of lower doses in children led to widespread resistance in seasonal H3N2 linked to genetic changes at multiple positions. Earlier in vitro studies using all nine neuraminidase serotypes indicated Tamiflu was less effective against N1, which would help explain clinical issues with H5N1, seasonal H1N1, or pandemic H1N1 associated with H274Y (H275Y in N1 numbering).
Resistance in H5N1 was initially associated with the appearance of H274Y and S296N in a contact treated prophylactically with Oseltamivir (and prophylactic treatment is used at 50% the treatment dose). This two-fold difference led to the use of Tamiflu at double the recommended dosage as well as clinical trials using Tamiflu at a double dose for H5N1.
However, data on Tamiflu treatment for seasonal and pandemic H1N1 is more extensive and clinical results again raise concerns that H1N1 (pandemic and seasonal) can effectively evade the effects of Tamiflu). For seasonal H1N1, H274Y began to appear in patients not receiving Tamiflu signaling fitness of H1N1 with H274Y. Low levels were seen for clade 1 (New Caledonia), and clade 2C (Hong Kong), but dramatic increases were seen in clade 2B (Brisbane/59) in the 2007/2008 season. High levels (above 50% were reported in northern Europe) and then the level of H274Y rose to 100% in the southern hemisphere in 2008, followed by 100% of H1N1 in the northern hemisphere in the 2008/2009.
The 2009 H1N1 pandemic displaced / replaced seasonal H1N1, but H274Y continued to be a concern. Initial cases again involved H1N1 treated prophylactically, again signaling concerns that a two difference in dosing could lead to infections. Similarly H274Y was identified in patients who had not been treated with Tamiflu, and increasing community transmission has been noted, most recently in Delaware and Maryland.
The spread of S246N, which reduces the efficacy of Tamiflu six fold, would likely accelerated the spread of H274Y, which lowers the efficacy of Tamiflu 600 fold and is additive with S246N.
Moreover, H274Y is circulating as a mixture (and levelss below 50% are not being reported), leading to rapid detection after the start of treatments as seen in the H1N1 fatal infection (40M) in Perth. The sample collected prior to treatment, A/Perth/30/2011, had S246N, while sample collected 5 days after the start of treatment, A/Perth/29/2011, has S246N and H274Y.
Thus, the 6 or 3 fold reductions in effectiveness for Tamiflu and Relenza respectively cased by S246N, can have profound and far reaching clinical effects, which cause considerable concern due to the rapid spread of S246N in Singapore and Australia.
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dothedd
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Post by dothedd on Jun 14, 2011 21:31:35 GMT -5
Widespread S246N Tamiflu Resistance Clusters Raise Concerns Recombinomics Commentary 20:15 June 13, 2011
The recent report on “moderate” Tamiflu and Relenza resistance (6 and 3 fold reductions in efficiencies) linked to S246N has raised concerns that this genetic change will become widespread and the modest reduction in efficiencies will lead to an increase in changes that have more severe consequences, such as H274Y, which reduces Tamiflu effectiveness by 600 fold, and syngergizes with S246N to generate 6000 fold reductions.
There are concerns that similar synergies will be seen in isolates with S246N and changes at position 222 (I222R or I222K) which reduce Relena effectiveness rendering the two major neuraminidase inhibitors useless.
The paper noted the increasing levels of S246N in Singapore and Australia due to rapid clonal expansion. However, the paper included a phyogentic tree showing S246N on multiple H1N1 backgrounds, signaling expansion via recombination, which appended S246N onto multiple gentic backgrounds.
However, a close examination of these additional cases, most of which were from 2009 or 2010, also formed small clusters, signaling additional clonal expansion and an absence of a selection penalty. Two identical sequences with S246N (A/Jiangxi-Donghu/SWL131/2010 and A/Jiangxi-Donghu/SWL157/2010) were collected a week apart from the same province in China. Similarly three other sequences which matched each other (A/Athens/INS342/2009, CY062875 A/Athens/INS161/2009, A/Athens/INS350/2009) were collected days apart from three patients in Athens). In other clusters the sequences were closely related to each other including three isolates from the United States (A/North Carolina/03/2010, A/North Carolina/05/2010, A/Minnesota/02/2010) or two isolates from eastern Europe (A/Croatia/18576-1/2010 and A/Slovenia/234/2011). Thus, each cluster represents an independent introduction of S246N via recombination), and the clustering in time and space presents clonal expansion of each introduction. These clusters are smaller than those reported for Singapore and Australia in part because in 2009 and 2010 there was little immunity in those under the age of 60 so novel sub-clades did not dominate.
In the 2010/2011 new and larger sub-clades began to appear such as the S188T and S186P sub-clade that were large and widespread. Another sub-clade with changes near the larger receptor binding domain, which had R208K and I219V in addition to D100N and V252L began to expand in Sweden, Iraq, and Iran in late 2010, early 2011. More evolved versions of this sub-clade were seen in large numbers in Italy (Milan and Pavia) and these sequences were very closely related to the sequences in Singapore and Australia. Most of the sequences from Italy did not include NA, so the presence or absence of S246N could not be determined for most public isolates, but S246N was not in the few NA sequences published. However, the large number of sequences from this sub-clade indicated it could spread rapidly, which happened in Singapore and Australia after S246N was acquired.
Thus, the prior history of small clusters in 2009 and 2010 on multiple genetic backgrounds, coupled with the rapid spread in Australia and Singapore after S246N was acquired raises concerns that S246N will be common in the current flu season beginning in the southern hemisphere, and this change will lead to significant clinical consequences involving additional resistance changes including H274Y and I222R/K.
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