RECOMBINOMICS

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Japan and Taiwan H1N1 Sequences Match United Kingdom (12/27/10 16:15)

Iran December H1N1 Sequences Match United Kingdom (12/26/10 20:45)

Fatal H1N1 In Previously Healthy Young Adults In UK (12/25/10 01:10)

Low UK Vaccine Uptake Raises H1N1 Pandemic Concerns (12/24/10 20:05)

H1N1 Death Cluster in Leicestershire UK Raises Concerns (12/24/10 17:25)

UK H1N1 ICU Cases Spike To 460 (12/24/10 14:45)

Australia and trH1N1 Recombinant In United Kingdom (12/23/10 19:05)

Recombination Driving H1N1 Evolution In United Kingdom (12/23/10 16:45)

Minnesota trH3N2 Is A Reassortant With PB1 E618D (12/23/10 03:05)

Alarming Rate of Severe H1N1 Cases In the UK (12/22/10 16:05)

UK ECMO Shortfalls Raise H1N1 Concerns (12/22/10 07:20)

Spike In Young ICU H1N1 Cases In UK Raises Concerns (12/21/10 19:30)

H1N1 Death Cluster In Bury Near Manchester Raises Concerns (12/21/10 17:00)

Minnesota trH3N2 Matches Wisconsin and Pennsylvania (12/21/10 00:55)

H1N1 S188T Spread To Whitechapel United Kingdom (12/20/10 19:00)

H3N2 Swine Pandemic Surveillance Concerns (12/18/10 18:20)

The Emerging H3N2 Swine Pandemic (12/17/10 22:10)

A Second trH3N2 Case In Minnesota Raises Pandemic Concerns (12/17/10 16:50)

Severe and Fatal H1N1 In Previously Healthy Young Adults (12/16/10 22:00)

Increasing Low Reactors On Novel H1N1 Genetic Background (12/16/10 17:20)

Increased Frequency of Severe and Fatal H1N1 in England (12/16/10 05:20)

Critical Escalation of Severe and Fatal H1N1 In England (12/16/10 02:50)

Spread of H1N1 Immunological Escape Via S188T (12/14/10 18:00)

Fatal H1N1 In Young UK Adults Raise Pandemic Concerns (12/11/10 22:45)

Increasing Hospitalizations in Manitoba Raise trH3N2 Concerns (12/10/10 21:40)

2010 trH3N2 Recombinant Sequence In Cameroon (12/09/10 23:25)

2010 trH3N2 Recombinant Sequence In Argentina (12/09/10 17:25)

Young Adult Deaths At Garden Hill Raise trH3N2 Concerns (12/07/10 17:25)

Spike In Garden Hills Cases Raises trH3N2 Concerns (12/06/10 19:05)

Severe Young Adult Garden Hills Cases Raise trH3N2 Concerns (12/05/10 20:15)

H3N2 Death Cluster in Garden Hills Canada Grows (12/05/10 15:45)

Details on Manitoba Cluster Increase trH3N2 Concerns (12/04/10 22:35)

Is trH3N2 Linked to Death Cluster in Manitba Canada? (12/04/10 04:05)

H3N2 Death Cluster in Manitoba Canada (12/03/10 23:05)

Genetic Linkage Between Human trH1N1 trH1N2 trH3N2 12/01/10 22:05

High H1N1 Case Fatality Rate In Lehigh County Pennsylvania (12/01/10 14:30)

Pennsylvania H1N1 Death Cluster Confirmed (12/01/10 02:45)

Pennsylvania Issues H1N1 and H3N2 Health Advisory (11/24/10 15:45)

H1N1 Death Cluster In Pennsylvania Raises Concerns (11/24/10 14:12)

Human Transmission of trH1N1 trH1N2 trH3N2 (11/23/10 22:55)

PB1 E618D Signals Emerging trH3N2 Pandemic (11/18/10 13:35)

trH3N2 Matches For All Five Patients Signal Pandemic (11/18/10 01:40)

Novel Human trH3N2 Constellation Raises Concerns (11/17/10 14:40)

Human trH3N2 / trH1N1 Matches Raise Pandemic Concerns (11/15/10 21:10)

Human trH3N2 Matches Human trH1N1 from Huron Ohio Cluster (11/15/10 19:10)

Swine trH3N2 Phylogenetic Analysis Without Sequences (11/14/10 3:10)

PB1 E618D in pH1N1 and Human H3N2 Triple Reassortant KS13 (11/13/10 17:50)

Absence of Phylogenetic Analysis on Swine H3N2 Cases (11/13/10 06:20)

CDC Fails To Show Swine To Human H3N2 Transmission (11/13/10 05:20)

Withheld Sequences from H3N2 Swine Flu Cases Raise Concerns (11/12/10 22:30)

CDC Comments On Swine H3N2 Cases In the United States (11/12/10 21:05)

WHO Silence On Swine H3N2 Case In Illinois Raises Concerns (11/11/10 18:50)

CDC Silence On Swine H3N2 Case In Illinois Raises Concerns (11/11/10 14:30)

Challenge of Surveillance of Swine H3N2 In Human (11/11/10 04:30)

Human Swine Flu Axis Generates Rapid Evolution (11/11/10 00:35)

Novel H3N2 Cases in United States Raise Pandemic Concerns (11/10/10 22:50)

H3N2 Triple Reassortants in Pennsylvania and Illinois Patients (11/10/10 21:45)

H1N1 Evolution In Thailand Raises Pandemic Concerns (11/10/10 17:57)

H1N1 Recombination and Reassortment In Swine In Thailand (11/09/10 23:45)

H3N2 Death Cluster in Akita Hospital Increases To Eight (11/09/10 17:15)

Rapid H3N2 Spread In Japan Raises Concerns (11/08/10 14:15)

Vaccine Link to H3N2 Death Cluster in Japan Hospital? (11/07/10 13:22)

High H3N2 Death Rate in Akita Japan Hospital Raises Concerns (11/06/10 22:30)

H3N2 Kills Six In Hospital In Akita Japan (11/06/10 21:10)

Worldwide H3N2 Low Reactor Sub-clade Emerges (11/02/2010 12:15)

Seasonal H1 Re-emerges in Europe (11/01/10 15:22)

Jump in Seasonal H1 Raises Pandemic Concerns (10/31/10 16:58)

80% of Influenza A in Texas is Seasonal H1 (10/31/10 5:40)

H1N1/N2 Swine/Human Reassortants Raise Pandemic Concerns (10/31/10 02:45)

H1N1/N2 Swine/Human Reassortants in Argentina (10/29/10 11:17)

H1N1 Ferret Failure Raises Pandemic Concerns (10/22/10 12:17)

D225G/N Emergence in H1N1 Variants (10/22/10 01:50)

H1N1 Vaccine Failure Raises Pandemic Concerns (10/21/10 22:17)

Worldwide Spread of H1N1 S188T Via Clonal Expansion (10/15/10 18:17)

Worldwide Spread of H1N1 Multi-Drug Resistance - XDR (10/02/10 17:17)

Spike In Pneumonia and Influenza Deaths in Week 37 (09/24/10 20:40)

Early Flu Season Start in North America (09/24/10 19:24)

S199A Emergence and Spread in H3N2 Variant (09/23/10 22:40)

Pandemic H1N1 RBD Change in Recent 2010 Isolates (09/16/10 04:26)

Kansas H1N1 is Tamiflu and Relenza Sensitive (08/26/10 16:23)

Emergence of Extensive Drug Resistant XDR-pH1N1 NOT (08/26/10 13:43)

XDR-pH1N1 Raises Pandemic Concerns NOT (08/26/10 02:22)

H1N1 Tamiflu and Relenza Resistance in Kansas Case NOT (08/25/10 23:40)

H1N1 D225G/N In Recent Australia and New Zealand Cases (08/24/10 01:11)

Hazardous WHO Pandemic Hopes and Dreams (08/10/10 12:11)

CDC Issues H3N2 Health Advisory (08/09/10 10:25)

2010 D225G Low Reactors in the United States and Russia (08/05/10 23:25)

Transmission of Low Reactor N159I H1N1 In Montana In 2010 (08/05/10 17:50)

Detailed H1N1 Case Fatality Rates In India (07/31/10 12:40)

Alarming H1N1 Case Fatality Rates In India (07/30/10 20:40)

Fatal / Severe H1N1 Cluster In India (07/26/10 14:16)

H1N1 D225G Transmission in Singapore (07/26/10 16:50)

H1N1 G158E and D225G Transmission in Nanjing China (07/26/10 15:20)

Emergence of Novel H1N1 Raises Pandemic Concerns (07/22/10 20:25)

Emergence of Novel H1N1 in American Swine (07/22/10 9:11)

Critical H1N1 In India (07/15/10 23:53)

H1N1 In Kirovograd Ukraine Approaches Epidemic Levels (07/15/10 13:13)

H1N1 G158E and D225G In Nanjing China (07/15/10 12:20)

Clonal Spread of G158E Duplication in Illinois Swine (07/07/10 16:50)

Parallel H1N1 Pandemics In 2010? (07/07/10 03:50)

Recombination and G158E Duplication in 2010 Iowa Swine (07/06/10 16:50)

Community Transmission of Tamiflu Resistance In Israel (05/18/10 20:41)

G158E pH1N1 Transmission Between Swine in MN and IL (05/14/10 12:50)

D225G and Swine Acquisitions In India pH1N1 Case (05/12/10 13:50)

Fujian / Qinghai H5N1 Recombinant at Qinghai Lake (05/08/10 21:50)

Fujian / Qinghai H5N1 Recombinants in Egypt (05/07/10 19:51)

Fixing 125del In Human H5N1 In Egypt (05/06/10 22:22)

Migration of Fujian H5N1 Through Israel? (05/06/10 21:07)

Widespread pH1N1 Low Reactors in Europe (05/06/10 19:37)

Widespread pH1N1 Tamiflu Resistance in South Korea (04/25/10 16:37)

US Pneumonia & Influenza Deaths Spike To Epidemic Threshold (04/23/10 21:45)

D225G D225N G158E Pseudospecies in Japan pH1N1 Case (04/20/10 17:56)

3 BP Deletion in Donkey H5N1 Links to H1N1 (04/19/10 10:20)

3 BP Deletion in Donkey H5N1 in Egypt (04/16/10 16:10)

Polymerase Changes in pH1N1 in Georgia (04/14/10 20:45)

Selection of pH1N1 D225G in Swine Lung (04/12/10 20:17)

Hong Kong D225G Limited to Severe and Fatal pH1N1 (04/08/10 16:50)

D225G Low Reactor In Washington State (04/07/10 20:30)

All CDC Designated US pH1N1 Low Reactors Have Same Change (04/07/10 17:17)

pH1N1 D225G in 2010 North Carolina and Wyoming Sequences (04/07/10 13:24)

Rapid pH1N1 Death In Texas Raises Concerns (04/05/10 20:24)

Excessive pH1N1 Deaths Escalate Pandemic Concerns (04/05/10 17:20)

Serious CDC Pneumonia & Influenza Death Problem (04/05/10 00:49)

Rapid Death In Malaysia H1N1 Cluster Linked to D225G/N? (04/04/10 19:55)

Malaysia Denies H1N1 Cause In Melaka Death Cluster (04/03/10 16:15)

H1N1 Death Cluster In Malaysia Raises Pandemic Concerns (04/03/01 13:45)

CDC Concedes Week 12 P&I Above Epidemic Threshold (04/02/10 21:55)

More Similarities Between 1918 and 2009 H1N1 (04/02/10 16:45)

2009 Pandemic Anniversary In the United States (04/02/10 12:45)

Severe pH1N1 Cases In West Georgia Raise Pandemic Concerns (04/02/10 11:25)

Pneumonia and Influenza Deaths Exceed Epidemic Threshold (04/01/10 23:45)

GA pH1N1 Hospitalizations Not Linked To Vaccination Coverage (04/01/10 18:35)

pH1N1 Tamiflu Resistant 2010 Sequences in Nagasaki (04/01/10 13:30)

D225G/N In Georgia Fatalities? (03/31/10 23:40)

Georgia Under-count On pH1N1 Fatalities Raises Concerns (03/31/10 17:30)

Georgia H1N1 Surveillance Raises Pandemic Concerns (03/31/10 15:55)

Spike In Atlanta Georgia Deaths Raises Pandemic Concerns (03/30/10 19:13)

CDC Investigates Spike In H1N1 Hospitalizations In Georgia (03/29/10 23:00)

M230I In pH1N1 In Southeastern Wisconsin (03/28/10/18:46)

Fixing Tamiflu Resistance In pH1N1 In Japan (03/27/10 20:35)

Transmission Linked To Rapid Appearance of Tamiflu Resistance (03/27/10 15:35)

Alarming Spike In H1N1 Hospitalizations and Deaths in Georgia (03/25/10 13:40)

H1N1 D225G Transmission Destroys WHO's Hypothesis (03/24/10 18:50)

H1N1 D225G Transmission In Duke Death Cluster (03/24/10 11:50)

Silent Spread of H1N1 D225G In India (03/23/10 21:23)

PB2 E627K In Experimental H1N1 Raises Concerns (03/18/10 20:57)

Record Jump In H1N1 Hospitalizations In Georgia (03/18/10 17:57)

Fixing PB2 E627K In Pandemic H1N1 (03/17/10 02:24)

H1N1 E627K In India Raises Pandemic Concerns (03/16/10 14:44)

H1N1 PB2 E627K In Three Patients In India (03/16/10 5:40)

Swine To Swine Transmission of Pandemic H1N1 In MN IL IA (03/15/10 17:40)

Potential Pandemic H1N1 Mismatches Raise Concern (03/15/10 11:45)

Spike In H1N1 In Texas and Alabama Raises Concerns (03/14/10 13:01)

Widespread H1N1 Low Reactor G158E In US Raises Concerns (03/12/10 13:50)

Low Reactor G158E In 2010 H1N1 Swine Pandemic H1N1 (03/11/10 12:50)

H1N1 Greek and Russian D225G Sequences Identical (03/10/10 16:50)

H1N1 Low Reactor G158E In Athens Greece (03/10/10 11:15)

H1N1 Tamiflu Resistance and D225G In 2010 Greek Case (03/10/10 9:48)

G158E H1N1 Low Reactor in South Korea (03/09/10 23:54)

Low Reactor Tamiflu Resistance H1N1 Recombinant In Japan (03/09/10 18:44)

H1N1 Low Reactor G158E D225N Japan Recombinant (03/09/10 07:35)

H1N1 G158E Low Reactors In Japan Raise Vaccine Concerns (03/09/10 6:58)

CDC Comments Raise H1N1 D225G/N Surveillance Concerns (03/08/10 15:48)

CDC In Denial On H1N1 D225G/N Significance (03/07/10 23:10)

CDC Reliance On Negative D225G/N Data Raises H1N1 Concerns (03/07/10 19:30)

CDC On D225G In Egg Isolates Raises H1N1 Vaccine Concerns (03/07/10 14:58)

Jump In H1N1 Low Reactors In the United States Raises Concerns (03/05/10 20:58)

Norway H1N1 D225G Publication Refutes WHO Position (03/05/10 16:30)

Association of D225G/N With Severe H1N1 Cases in Norway (03/04/10 22:00)

Sloppy Surveillance Raises H1N1 Pandemic Concerns (03/02/10 19:31)

Vaccine Failure In Severe H1N1 Cases (03/02/10 15:45)

H1N1 Vaccine Failure In Europe (03/02/10 13:30)

H1N1 H274Y Tamiflu Resistance in Italian Recombinant (02/28/10 18:30)

Widespread and Common Tamiflu Resistance in Japan (02/26/10 19:29)

High School Absenteeism Linked to H1N1 Phase 3 Start (02/25/10 21:15)

More Signals on H1N1 Phase 3 Start in United States (02/25/10 02:02)

H1N1 Low Reactor Recombinants Raise Pandemic Concerns (02/23/10 13:20)

H1N1 G158E and D225G Low Reactors Recombine in Italy (02/22/10 08:33)

H1N1 G158E and D225G Low Reactors Recombine in Russia (02/22/10 07:15)

H1N1 G158E Low Reactors in Germany Raise Vaccine Concerns (02/21/10 23:01)

H1N1 Low Reactors Raise Vaccine Selection Concerns (02/19/10 19:17)

WHO H1N1 Vaccine Target Selection Failure (02/19/10 12:01)

WHO H1N1 Vaccine Target Lacks D225G (02/19/10 00:36)

WHO H1N1 Vaccine Target Raises Pandemic Concerns (02//18/10 23:18)

WHO Approves H1N1 Vaccine Inventory Control (02/18/10 13:40)

Vaccine Failure and Severe H1N1 Cases in Wyoming (02/17/10 17:20)

H1N1 Spread in North Carolina (02/16/10 20:02)

H1N1 D225E Conversion to D225G in Egypt (02/16/10 18:40)

Adamantane Sensitive H1N1 in Houston Texas (02/15/10 18:18)

Duke D225G/N Death Data Destroys Random Mutation Paradigm (02/15/10 11:39)

Negative Duke D225G/N Death Data Raise Concerns (02/14/10 21:20)

Dramatic H1N1 CFR Spike In Mexico Raises Concerns (02/12/10 15:59)

Spike In H1N1 Fatalities In Mexico Raise Concerns (02/11/10 12:48)

13 Recent H1N1 Deaths In Michigan Raise Concerns (02/11/10 10:28)

Recombination Drives Duke D225G/N Death Transmission (0210/10 11:28)

WHO's Fake H1N1 Pandemic (02/09/10 15:38)

More Severe H1N1 Increases In Mississippi (02/08/10 16:38)

Pandemic H1N1 Disinformation Raises Concerns (02/07/10 21:15)

US Wave 3 Start Confirmed by H1N1 Increases in Region 4 (02/0510 23:03)

H1N1 D225G D225N H274Y Mixtures in Duke Death Cluster (02/05/10 15:50)

Six Pediatric H1N1 Deaths in California Raise Concerns (02/05/10 10:10)

Wave 3 Start Signaled By H1N1 Increases In North Carolina (02/0510 8:40)

WHO H1N1 D225G Transmission Omissions (02/04/10 21:22)

WHO Obsolete Report on H1N1 D225G Raises Concerns (02/03/10 22:03)

H1N1 Increases on North Carolina College Campuses (02/03/10 17:50)

Recombination Driving D225G and H274Y Spread (02/02/10 20:10)

Conversion of H1N1 D225E to D225G in Rome Italy (02/02/10 12:40)

Widespread High Frequencies of H1N1 D225E In Italy (02/01/20 14:41)

Severe H1N1 Cases in North Carolina Raise Concerns (02/01/10 10:05)

Ukraine H1N1 D225G in North Carolina (02/01/10 07:26)

D225G/N H1N1 Linkage By Recombination in Australia US China (01/31/10 23:55)

Mystery Spike in US Pneumonia and Influenza Deaths (01/31/10 23:19)

Spike In US Pneumonia and Influenza Deaths (01/29/10 20:09)

H1N1 D225E Converted To D225G in Japan (01/29/10 16:50)

Independent H1N1 D225G Introductions in California (01/29/10 13:40)

D225G/N in Fatal H1N1 in Chernihiv Ukraine (01/2810 13:20)

H1N1 Fatality Rate in Memphis Children Raises Concerns (01/2710 21:21)

Spike in Severe H1N1 In Memphis Tennessee Children (01/27/10 16:20)

Fujian H5N1 In Israel? (01/27/10 16:05)

D225G/N H1N1 Clustering Raises Concerns (01/27/10 14:20)

D225G In First 2010 H1N1 Sequence (01/27/10 03:40)

H1N1 Duke Death Cluster With H274Y and D225G/N (01/26/10 17:15)

H1N1 School Closings in Donetsk Ukraine (01/25/10 23:20)

D225G/N Widespread in Ukraine Fatal Cases (01/25/10 14:50)

Initial H1N1 Attack Rate Raises Pandemic Concerns (01/22/10 22:55)

Nepal Fatal Cluster Raises Concerns (01/2010 16:40)

Ukraine Dead Top 1000 - Donetsk Fatalities Grow (1/20/10 13:45)

Q226R In Fatal H1N1 Infection of Oregon Cat (01/20/10 12:49)

Fatal H1N1 D225G In India Raises Concerns (01/20/10 10:59)

Confirmed H1N1 D225G Transmission in Italian Family (01/17109 20:50)

Spike in H1N1 D225G Cases In Spain Raises Concerns (01/16/10 23:35)

Swine H3N2 in Iowan Lacking Swine Exposure (01/15/10 21:30)

Spike in H1N1 Fatalities in Romania Raises Concerns (01/14/10 23:15)

New Ukraine Sequences Raise Pandemic Concerns (01/13/10 19:05)

H1N1 D225G in India (01/13/09 13:23)

Caracal Cluster Pandemic Panic Likely Linked to D225G (01/13/09 12:40)

D225G Link to Fatal H1N1 Caracal Cluster in Romania? (01/13/10 03:30)

Ukraine Fatalities Jump to 940 - Over 4 Million Infected (01/12/10 22:35)

Fatal H1N1 Cluster in Romania Raises Concerns (01/12/10 19:40)

Transmission of Fatal H1N1 D225G/N Accelerates Concerns (01/11/10 19:05)

Identical H1N1 D225G Fatal Sequences in Brazil and Ukraine (01/11/10 14:40)

H1N1 D225G in Nasopharyngeal Swab from Fatal Brazil Case (01/10/10 16:50)

H1N1 D225G and D225N in Moldova Patient (01/10/10 14:20)

Ukraine Fatalties Jump to 882 - D225A/G/N in Kyiv (01/09/10 01:50)

H1N1 D225G D225N D225A in Ukraine Lungs (01/08/09 23:40)

H1N1 Re-Infections Confirmed (01/06/09 13:50)

Ukraine Fatalities Jump to 827 - 100K New Cases in One Day (01/06/09 13:20)

D225E and D225N RBD H1N1 Changes in Turkey (01/05/09 21:25)

Ukraine Fatalities Spike to 805 - One Day Record of 38 (01/04/09 22:10)

Fatal H1N1 RBD Change S188N in Hunan China? (01/03/09 15:40)

Ukraine Fatalities Jump to 759 - Two Day Total 32 (01/03/10 05:20)

Spreading H1N1 Sequences in Russia Raise Concerns (01/02/10 22:45)

H1N1 D225G and D225N in Russian Cases Near Ukraine (01/02/10 02:12)

Ukraine Fatalities Spike to 727 - One Day Total 29 (12/31/09 23:55)

Tamiflu Resistance Continues to Expand in the United States (12/31/09 23:05)

H1N1 D225G in Lungs of Patients Across Russia (12/31/09 21:21)

Ukraine Fatalities Spike to 698 - One Day Total 23 (12/30/09 23:55)

Fatal D225G/D225N H1N1 Co-Infections Raise Concerns (12/30/09 15:28)

Fatal H1N1 Tamiflu Resistance in New Brunswick Canada (12/30/09 02:20)

H1N1 Tamiflu Resistance Lesson Not Learned (12/30/09 00:15)

Ukraine Fatalities Spike to 675 - Two Day Total of 42 (12/29/09 20:10)

The WHO Surprise on D225G / D225N H1N1 Fatalities (12/29/09 17:48)

D225G / D225N H1N1 in Case from Sweden (12/28/09 23:55)

H1N1 Tamiflu Resistance in UK Jumps Higher (12/25/01 10:15)

D225G / D225N H1N1 Fatal Cluster in San Luis Potosi Mexico (12/24/09 23:55)

H1N1 RBD D225G and D225N in Mexican Swine (12/24/09 17:53)

Emergence and Evolution of Pandemic Tamiflu Resistance (12/22/09 12:35)

Lab Confirmed H1N1 in New York Dog (12/22/09 03:30)

Widespread Transmission of H1N1 Tamiflu Resistance (12/21/09 16:45)

German H1N1 Tamiflu Resistance Cluster Raises Concerns (12/20/09 17:35)

Japan H1N1 Tamiflu Resistance Levels Raise Concerns (12/20/09 12:25)

Ukraine Cases Top 3 Million - 21 New Fatalities (12/20/09 04:37)

Japan Tamiflu Resistance Sequences Signal Fixing Start (12/19/09 02:19)

US Spike in H1N1 Tamiflu Resistance Signals Fixing Start (12/18/09 23:55)

First Fatal Tamiflu Resistant Case in South Korea (12/17/09 18:15)

Silent Spread of Tamiflu Resistance in Texas (12/16/09 17:41)

Ukraine H1N1 Cases Explode - 507 Dead (12/15/09 21:25)

Rapid H1N1 Evolution in Beijing Raises Concerns (12/15/09 13:25)

Receptor Binding Domain Changes in Texas (12/14/09 11:15)

Tamiflu Resistance Spike in the US Raises Transparency Concerns (12/14/09 02:18)

D225G and H274Y in Illinois Case (12/13/09 18:18)

D225G and D225N Confirmed in Fatal Utah Case (12/11/09 22:22)

Fixing Fatal Tamiflu Resistance in Pandemic H1N1 (12/11/09 18:55)

Fatal Tamiflu Resistant Cases Spike in the Netherlands (12/11/09 12:50)

D225G and D225N in Fatal Utah Case? (12/10/09 21:07)

Hidden Transmission of H1N1 Tamiflu Resistance (12/10/09 16:45)

H5N1 H1N1 Cluster in Dien Bien Vietnam (12/10/09 03:52)

High Attack Rate in Tamiflu Resistant Cluster in Vietnam (12/10/09 00:25)

Fatal Tamiflu Resistance in Delaware (12/09/09 18:50)

D225N in Ukraine Raises Pandemic Concerns (12/09/09 00:05)

Ukraine Cases Spike - D225G and D225N Found (12/08/09 21:36)

Fatal Tamiflu Resistant H1N1 in the Netherlands (12/08/09 13:55)

D225G and D225N in Utah Patient Raises Pandemic Concerns (12/06/09 23:55)

WHO in Denial on Tamiflu Resistance and RBD Changes (12/05/09 21:21)

H1N1 Tamiflu Resistant Cluster in Pennsylvania (12/05/09 17:40)

H1N1 Tamiflu Resistance Crosses Tipping Point (12/04/09 15:01)

Transmission of Fit Tamiflu Resistant H1N1 in Maryland (12/04/09 03:07)

Tamiflu Resistance in Ukraine Sub-clade in Spain and US Georgia (12/03/09 20:05)

446 Dead in Ukraine - D225G and Deaths Spread (12/03/09 02:35)

Tamiflu Resistant Cluster in Maryland and Virginia USA (12/02/09 22:45)

Transmission of Novel H1N1 D225G in Norway and Sweden (12/02/09 12:55)

Fit Hong Kong Tamiflu Resistant H1N1 Is a Mixture (12/01/09 19:54)

H1N1 Evolution Outpacing Vaccine and Host Defenses (11/30/09 13:32)

H1N1 RBD Changes at 225 Create Vaccine Mismatch Concerns (11/29/09 14:24)

Week 46 Sets Record Number of H1N1 US Pediatric Fatalities (11/28/09 18:29)

WHO Weather Report on Ukraine H1N1 D225G Required (11/28/09 17:10)

WHO Silence on D225G Vaccine Mismatch Confuses Media (11/28/09 15:31)

WHO Confirms D225G Vaccine Failure (11/28/09 03:45)

WHO Mis-statements on D225G and H274Y Raise Concerns (11/27/09 21:31)

D225G and H274Y in Fatal Infection in France (11/27/09 17:30)

WHO Silence on D225G Immune Escape Raises Concerns (11/27/09 13:20)

D225G Evades Immune Response (11/27/99 08:20)

Worldwide Transmission of D225G (11/27/09 06:45)

D225G Ukraine Norway Link and China Spread (11/25/09 14:15)

H1N1 Re-infections Raise Pandemic Concerns (11/25/09 02:30)

Ukraine Dead Approach 400 - D225G Spreads (11/24/09 23:35)

H1N1 RBD Changes D225E and D225G in Norway (11/24/09 17:39)

Spontaneous Mutation Media Myth (11/24/09 7:41)

Fatal H1N1 Cluster in Texas Raises Pandemic Concerns (11/23/09 22:55)

Explosion of Swine Flu Tamiflu Resistance in the United States (11/23/09 13:30)

1918 RDB D225G in Lung Cases in the United States (11/23/09 10:27)

1918 RBD D225G in Lung Cases in Ukraine and Norway (11/21/09 13:02)

Evidence on D225G in Lung Cases in Norway and Ukraine (11/21/09 11:40)

WHO Confirms D225G in Lung Cases in Norway and Ukraine (11/20/09 23:55)

D225G in Fatal H1N1 Lung Cases in Norway and Ukraine (11/20/09 19:05)

Large Tamiflu Resistant Cluster in Wales UK (11/20/09 17:50)

H1N1 D225G in Russia Raises Pandemic Concerns (11/20/09 15:05)

D225G in Fatal H1N1 Cases in Norway? (11/20/09 15:19)

Ukraine Dead Increase to 354 - Fatal H1N1 Cases Have D225G (11/20/09 13:38)

D225G Lung Tropism Driving H1N1 False Negatives? (11/19/9 21:17)

Media Myths Cloud Joint Hearings on Pandemic Vaccine (11/19/09 17:17)

All Fatal Ukraine H1N1 Cases at GISAID Have RBD D225G (11/19/09 14:17)

Ukraine Dead Increase to 344 - Sequences Released (11/18/09 22:45)

RBD Change D225G in Ukraine Lung Raises Concerns (11/18/09 21:55)

Receptor Binding Domain Change D225G Confirmed in Ukraine (11/18/09 18:35)

RBD D225G in China and Australia Raise Ukraine Concerns (11/18/09 14:41)

Ukraine Dead Increase to 328 - Still No Sequences (11/17/09 19:17)

Ukraine H1N1 Sequence Changes Raise Concerns (11/17/09 13:17)

Ukraine Dead Increase to 315 -Still No Sequences (11/16/09 19:17)

Record Number of Lab Confirmed H1N1 Pediatric Deaths in the US (11/16/09 16:09)

Cluster of Tamiflu Resistance Near Edinburgh Scotland (11/16/09 13:45)

Ukraine Dead Increase to 299 - Still No Sequences (11/15/09 22:55)

WHO Evades Ukraine Sequence Questions at News Conference (11/15/09 12:25)

Ukraine Dead Increase to 282 - Still No Sequences (11/15/09 07:32)

Ukraine Dead Increase to 239 - Still No Sequences (11/12/09 20:21)

CDC Estimate of US H1N1 Pediatric Deaths Raised to 540 (11/12/09 19:45)

Ukraine Dead Increase to 213 - Still No Sequences (11/11/09 21:14)

Media Myths on Swine Flu in Ukraine Raise Concerns (11/11/09 13:40)

WHO Appeals to Ukraine for Help with Hemorrhagic Pneumonia (11/11/09 11:40)

Belarus Reports Almost 1/4 Million Flu Cases (11/10/09 23:35)

189 Deaths Reported in Ukraine - Belarus to 223K Cases (11/10/09 21:35)

Suspect H1N1 Death in Romania Near Ukraine Border (11/10/09 15:06)

Timeline on WHO Silence on H1N1 Sequences (11/09/09 23:21)

Pneumonia Death of Belarus Doctor Near Ukraine Border (11/09/09 20:46)

WHO Silence on Ukraine Sequences Raise Pandemic Concerns (11/09/09 19:01)

Reported Cases in Ukraine Top One Million - 174 Fatalities (11/09/09 18:41)

Over 2000 Health Care Workers Ill in Ukraine (11/09/09 14:35)

Total Destruction of Lungs in Ukraine Fatal H1N1 Cases (11/09/09 12:59)

1918 RBD Polymorphism in Ukraine H1N1? (11/09/09 04:32)

Reported Ukraine Fatalities Increase To 155 (11/09/09 02:09)

H1N1 Genetic Changes in RBD Raise Pandemic Concerns (11/08/09 19:09)

Reported Ukraine Cases Approach One Million (11/08/09 18:08)

H1N1 Jumps to Pets Raise Pandemic Concerns (11/07/09 23:24)

National H1N1 Epidemic Declared in Bulgaria (11/07/09 8:45)

Withheld Ukraine Sequences Raise Pandemic Concerns (11/07/09 02:20)

Reported Cases in Ukraine Double Again To 871,037 (11/06/09 22:54)

Reported Cases in Ukraine Double in Two Days (11/04/09 14:34)

Clusters on Hemorrhagic H1N1 Pneumonia in Ukraine (11/04/09 11:54)

WHO Targets Hemorrhagic H1N1 Cases in Lviv Ukraine (11/03/09 19:47)

Belarus H1N1 Deaths Raise Concerns (11/03/09 16:47)

Ukraine H1N1 Hospitalizations and Deaths Spike Higher (11/02/09 21:54)

Hospitalized Students at Romanian Convention Raise Concerns (11/02/09 7:22)

H1N1 Doctor Deaths in Ukraine Raise Concerns (11/01/09 22:22)

H1N1 Attack Rate Explodes in Ukraine (11/01/09 16:47)

WHO Team to Investigate Ukraine H1N1 Outbreaks (10/30/09 23:47)

Ukraine Orders Mobile Military Labs for H1N1 Caseload (10/30/09 18:50)

H1N1 Fatalities in Ukraine Generate Travel Restrictions (10/30/09 15:47)

US Emergency Declarations Raise Pandemic Concerns (10/29/09 22:47)

H1N1 in Swine in Iceland Raises Pandemic Concerns (10/29/09 21:27)

School Undercounts Raise Pandemic Concerns (10/26/09 17:34)

Pandemic H1N1 Spread in Swine Raises Pandemic Concerns (10/19/09 21:20)

H1N1 Attack Rate Raises Pandemic Concerns (10/15/09 22:12)

Weak Immune Response In Mild Cases Driving Re-Infections? (10/10/09 16:02)

Buffalo School Outbreaks Raise H1N1 Re-Infection Concerns (10/08/01 12:45)

Silent Spread of E627K in Pandemic H1N1 in Patients (09/29/09 14:01)

www.recombinomics.com/whats_new.html

[dothedd]

Severe H1N1 Cases Threaten UK Health Care Delivery
Recombinomics Commentary 19:30
December 29, 2010


Geoff Martin, chairman of Health Emergency, said: "We are getting reports of intensive care units in London where up to a quarter of the beds are filled with swine flu cases and the crisis is getting worse by the day. Cuts in recent years to bed and staff numbers have left the NHS dangerously exposed and there is no doubt that many ITUs will soon have to close to new admissions, putting hundreds of lives at risk."

The above comments increase concerns that the continuing increases of severe H1N1 cases will significantly impact health care delivery in the UK. Last week the number of severe cases rose to 460, compared to a peak of 180 last season. Although the number of severe cases has not been updated, the ILI rate has risen to 124 from 86 last week. Many of the severe cases need EMCO machines to oxygenate their blood, but only 20 such machines exist for the entire country, and each patient requires 5 days to 3 weeks of use.

The situation is compounded by an abysmal vaccine uptake rate. Agency reports have focused on the 43% rate in those at risk under 65, but most of the severe cases do not have an underlying condition, and the vaccine uptake in those patients is likely to be much lower. One reported cited a rate of 19% in pregnant women without additional risk factors and one hospital reported a rate of 7.1% among its staff. The rate for the general population under 65 and without risk factors is likely lower than the above abysmal rates.

The recent sequence data suggests that the vaccine may be far from ideal because it uses California/7 which was isolated in the spring of 2009. Recent sequence data from the UK, as well as Iran, Japan, and Taiwan demonstrates an evolution away from last season’s strain. Novel sequences generated by recombination are clearly present in the small number of sequences released, which leads to vaccine escape and spikes in cases, as described above. However, there will be no new vaccines this season, so the current vaccine is the only viable prevention measure that directly attacks the H1N1 causing the severe cases in young adult patients without risk factors.

The rapid rise in recent cases will blunt vaccine efforts because the vaccine works best when taken weeks in advance of infection.

The low vaccine uptake was almost certainly impacted by WHO pronouncements of the end of the H1N1 pandemic, which was not scientifically based. Pandemics always produce an ebb and flow of cases, and a return of a more virulent strain in the second season is not unusual.

[dothedd]

UK H1N1 ICU Cases Spike To 738
Recombinomics Commentary 17:30
December 30, 2010


Last week there were 460 people in intensive care, which has now jumped to 738. There are more than 3,600 intensive care beds with contingency plans in place to double this if necessary.

The above comments reflect the serious nature of the H1N1 outbreak in the UK. Last season, the peak number was 180, and at that level there was a shortage of ECMO machines. The jump to 460 last week raised serious questions about the ability to deliver appropriate health care to the severe cases. There are only 20 machines in the entire country, and each patient requires 5 days to three weeks, so on average about 2 machines become available each day. However, the jump from 302 severe cases on December 20 to 460 on December 24, to 738 on December 30 indicates the freeing of 2 machines per day, falls far short of the need.

Similarly, these increases severely impact ICU beds, which are undoubtedly full at this time with the exploding numbers of flu cases, in addition to other conditions and procedures that require ICU beds. Thus the necessity for doubling the ICU beds is already abundantly clear, but the plans to increase ECMO machines are not.

Moreover, the latest HPA report cites increases in Tamiflu resistance, which will undoubtedly increase the number of severe and fatal cases.
Initial sequence data from four patients demonstrate an evolution via recombination away from the current vaccine, as well as immunity elicited toward H1N1 from last season.

The earlier data on fatal cases indicated a majority did not have pre-existing conditions, and the vaccination uptake in those under 65 who do not have risk factors is abysmal. Similarly, the latest series of agency comments, which ignore the increasing number of severe and fatal cases in previously healthy young adults. increases concerns that the serious nature of the current situation is being lost in sound bites and head pats.

www.recombinomics.com/whats_new.html

[dothedd]

NOT GOOD NEWS!

H1N1 Deaths Of Healthy UK Adults Raise Pandemic Concerns
Recombinomics Commentary 20:15
December 30, 2010


HPA is receiving reports of fatal influenza cases from various sources (clinicians, laboratory reports and death certificates). These reports have been reconciled and verified with clinicians. These will not represent all influenza-related deaths.

Twenty-three of the 38 fatal cases with available information (61%) were in one of the CMO-defined clinical risk groups for vaccination.

The above data is from the latest report by the HPA and indicate that 39% of reported H1N1 fatalities had no broadly defined underlying condition. Although this level is slightly lower than the more than 50% reported last week, the reported cases will be heavily biased towards those with underlying conditions, who are the focus of almost every agency statement coming out of the UK. As noted above, the 38 fatal cases do not represent all H1N1 deaths. Many have not been confirmed and many will not be reported because of a lack of testing.


The high percentage of fatal and severe cases with no underlying conditions is severely straining health care delivery in the UK. The latest spike in severe cases to 738 is well above the peak of 180 cases reported last season, and well above the 460 reported last week. Many of these severe cases will need ECMO machines, which are already stretched to the limit. There are only 20 such machines in the entire country, and on average only two become free each day, so the demand far outstrips the supply leading to needless deaths.

However, the severe pressure on ICU beds and staff will exacerbate the crisis, as more patients are denied care and become more critically ill and/or die.


The latest report also describes an increase in Tamiflu resistance, which will also increase the number of severe cases and deaths, which will create additional concerns.


These problems can be traced to poor planning linked to misguided statements on the end of the pandemic and an associated relaxation of preparedness, which is compound by agency comments attempting to downplay the significance of the crisis, which is spreading to Europe and will soon impact the entire northern hemisphere.


The signal began to appear in Australian and New Zealand where a new sub-clade emerged which was drifting away from last years strain. Ferret antibodies against the new sub-clade had significantly low antibody titers against last year’s vaccine target, California/7, and the sequences in the UK show additional drift driven by recombination, as seen in the first four sets of sequences released by the Health Protection Agency. Additional sequences from Iran and Asia demonstrate additional recombination, which will create additional problems.


Such changes are not unexpected. The pandemic H1N1 initial spread because of a lack of immunity, particularly in those under 65. As the population developed immunity, the levels fell and the WHO made its declaration on the end of the pandemic phase, even though H1N1 was killing young adults in India and Australia.


However, pandemic always show such a decline as new variants emerge, and there are no assurances that the new variants will produce a milder disease.


Pandemic H1N1 is a swine influenza which jumped species, as happened in 1918, and excessive deaths in the following year, as seen in 1919, was not unexpected. Indeed, increased travel and population density set the stage for an aggressive re-emergence, as is being seen in the UK, where the proportion of severe and fatal cases in previously healthy young adults is on the rise, and the current vaccine targets the H1N1 isolates in the spring of 2009.


Aggressive actions in the UK and on the vaccine front are long overdue, as are additional sequences from fatal and severe cases in the UK as well as other countries like Egypt and Sri Lanka.

[dothedd]

H1N1 Death Cluster In Greater Manchester Increases To 12
Recombinomics Commentary 15:50
December 31, 2010


A man from Trafford, a patient from Tameside, and a teenage boy, from Oldham, have died after suffering from swine flu and health bosses believe it also contributed to the death of a younger child, from Bury.

Their deaths are expected to bring the death toll from H1N1 in Greater Manchester to twelve out of 36 nationally.

And 27 people, with serious complications caused by flu, are fighting for life in intensive care or high dependency wards in the region's hospitals.

This is putting pressure on the region's hospitals – at times this week there have been no intensive care beds available at some of the region's flagship hospitals including the Manchester Royal Infirmary and the Royal Manchester Children’s Hospital.

The above comments describe four more H1N1 deaths in the Greater Manchester area, increasing the number of reported H1N1 deaths to 12, or 1/3 of the UK total. Moreover, there are 27 additional patients with severe disease. This type of cluster signals a more aggressive H1N1, and sequences from such patients would be useful.

The number of severe cases has spiked to 738, from 460 a week ago, and as indicated above, this has significantly pressured health care for H1N1 patients.

The sequences from these patients are critical. Earlier sequences released by the Health Protection Agency demonstrated drift linked to recombination, and raised serious questions regarding vaccine escape.

Moreover, Tamiflu resistance was in the rise, which would add to the increasing burden associated with severe and fatal case.

ECMO machines are already stretched to the limit, and the dramatic increases in severe cases signal a major pandemic concern that requires aggressive action.

[dothedd]

Rising H1N1 Tamiflu Resistance In The UK
Recombinomics Commentary 19:25
December 31, 2010



Of 336 influenza H1N1 (2009) viruses reported as tested for antiviral susceptibility at RVU (not including regional labs) since week 40 2010, six have been found to carry the H275Y mutation which confers resistance to the antiviral drug oseltamivir.

The above comments are from the HPA influenza report for week 52. In the week 51 report there were three cases out of 402. The drop in the number tested was due to the exclusion of data from regional labs, suggesting that the number of sequences with H274Y was higher than the six at RVU. This rise in cases with resistance raises concerns that the trend will continue and expand as Tamiflu use becomes more widespread. H274Y is widely circulating as a minor sub-population, which is more easily seen in samples collected after the start of treatment. The emergence of H274Y can have a significant effect on the number of severe and fatal cases, which will increase the strain on ICU beds and ECMO machines.

The increase in H274Y effects will led to an increased use of Relenza, zanamivir. However, resistance to Relenza has also been reported, and sequential use of Tamiflu and Relenza will likely lead to an increase in resistance to both neuraminidase inhibitors.

The resistance level for the adamantines is already hear 100%, raising concerns that all approved antivirals may be of limited value, as the number of cases expands.

[dothedd]

Severe H1N1 Cases Force UK Black Alerts
Recombinomics Commentary 22:45
December 31, 2010


NHS pressure group Health Emergency said a number of hospitals in East Anglia were on black and red alert, meaning the NHS was struggling to cope as the outbreak worsened.

Chairman Geoff Martin said the James Paget University Hospital in Great Yarmouth had declared a "black alert" yesterday - the most severe status level.

He added that the Norfolk and Norwich University Hospital was on "red alert" - one step below black.

He said: "We warned that hospitals would be forced on to black alert as the flu cases fill the available beds - now it's happening and we do not believe that the chaos is restricted to East Anglia.

The above comments increase concerns that health care delivery in the UK is being taxed by the spike in severe H1N1 cases. The cases in East Anglia and the Greater Manchester area suggest that the H1N1 will soon significantly impact London, where reports cite a 25% occupancy rate of severe H1N1 cases in ICU beds. Moreover, these high levels may be blunted by GP offices closed over the holiday week, and a re-opening of those offices coupled with a return to school may create additional problems next week, including a shortage of ECMO machines.

The number of severe cases has increased from 460 to 738, suggesting triple digits next week, compared to a peak of 180 last season.

The current crisis is exacerbated by a rising number of Tamiflu resistant cases, as well as shortages of anti-virals and vaccines.

The deteriorating situation may lead to more aggressive measures in the upcoming days.

[dothedd]

UK Vaccine Shortage Increases H1N1 Pandemic Concerns
Recombinomics Commentary 07:00
January 1, 2011


Doctors have run out of flu jabs amid one of the worst outbreaks of the illness in more than a decade.

Many surgeries failed to order sufficient doses earlier this winter and some admit they have no idea when extra supplies will arrive.

Pregnant women, the elderly and those with chronic illnesses such as asthma and diabetes are being refused appointments or told to call back in a few weeks. Doctors have been urging these high-risk cases to come in for jabs.

The above comments confirm the shortage of vaccine in the UK, which adds to the concerns relating to a health care delivery failure. This shortage helped explain the emphasis on vaccination of “at risk” patients when half of the severe and fatal cases do not have underlying conditions. This shortage would also explain the decision to not launch an under 5’s vaccination campaign amid increasing deaths, ECMO shotages, and Tamiflu resistance.

Media reports have suggested the peak of the flu season will be reached in a week or two, but such expectations are largely based on wishful thinking. Although the number of cases has exploded in recent weeks, many areas, including London, have only recently seen a dramatic jump in cases, which began a few weeks ago in the midlands. Moreover, flu season traditionally peaks in February, so the support for an early end to the flu season is lacking.

The above comments reflect the effects of a more virulent and recombinant H1N1 which has increased severe cases to 738 from 460 a week ago. These levels are strikingly higher than the peak for last season of 180, which has contributed to the strain on health care delivery.

Hospitals have been placed on red and black alerts, which have created a health care crisis that is still in its early stages. The re-opening of GP offices next week, as well as the return to school, will generate more pressure on an over-taxed health care system.

This failure to prepare for the current outbreak is linked to the ill advised decision to declare an end to the pandemic phase, which reduced vaccine uptake and significantly impacted pandemic preparedness.

The current crisis in the UK will undoubtedly spread to the rest of Europe in the upcoming weeks.

[dothedd]

The 2011 H1N1 Pandemic Fiasco
Recombinomics Commentary 14:50
January 1, 2011


Despite three people in East Yorkshire already dying from swine flu this year, Jim Deacon, assistant director of emergency planning for the NHS in the Humber region, insisted the threat is no greater than in the past.

Swine flu is the most predominant strain of flu this winter and is classed as part of seasonal flu.

Mr Deacon said deaths from seasonal flu are not as high as previous years and the fact the most common strain this year is swine flu is "not significant".

"But you would expect something like 2,000 deaths nationally from flu by this time of year and it is about 400 so far.

The above comments encapsulate the 2011 pandemic fiasco, an abject failure to control the spread of H1N1 in 2011, which is well represented by the health care crisis in the United Kingdom.

The fiasco really traces back to the SARS pandemic, when laboratory confirmation was used to define and quantify SARS coronavirus infections. There was a clear need for an accurate number of cases because of the significant financial, political, and social impacts of infections, and shortly after the mysterious disease began to spread internationally, a laboratory test based on the novel coronovirus was in place and distributed worldwide.

However, the testing requirements provided a convenient mechanism for gaming the system by simply limiting testing. Prior to the test China limited knowledge of the disease by simply not reporting cases. They subsequently lowered the case fatality rate by increasing the number of mild cases tested. However, Taiwan was the country that aggressively lowered its number of SARS cases by cremating bodies prior to sample collection and classifying these cases, which clinically matched SARS confirmed cases, as SARS-related cases, thereby cutting the number of SARS confirmed cases in half.

This manipulation of confirmed cases was quickly extended to influenza in general and H5N1 in particular. The most effective way of limiting the spread of confirmed H5N1 cases was to simply not test. Consequently, the H5N1 index cases for Cambodia, Indonesia, and China were not counted because samples were not collected, and the first confirmed cases in each country were contacts of the index cases. The “not testing” approach was also widely applied to outbreaks in poultry and wild birds, initially in Asia, but subsequently in Europe, the Middle East, and Africa.

The testing requirement and associated gross undercounts were eventually applied to the 2009 H1N1 pandemic, leading to major misconceptions about the spread and gravity of the outbreak. Infections in schools were underplayed because only lab confirmed cases were cited and the vast majority of infected students were not tested. This allowed schools to remain open and the high levels of H1N1 undisclosed. It also created a gross undercount of cases, which extended to severe and fatal cases.

The gross undercount was magnified by comparisons to historic levels of seasonal flu deaths. In the United States the annual number was 36,000, but these were deaths of the frail and elderly who were estimated by death certificates and clinically defined cases, not lab confirmation.

These very different approaches in estimating seasonal and pandemic H1N1 deaths led to false comparisons, including media reports claiming the H1N1 was an infection that was much milder than seasonal flu, when lab confirmed deaths in young adults were compared to estimates of deaths of patients who were well over 65 years of age and battling long term health problems.

The public and in some cases agency perceptions of the false comparisons were compounded by the WHO proclamation on the end of pandemic phase of the 2009 H1N1 pandemic in August of 2010. Although a new sub-clade was emerging in Australia and previously healthy young adults were dying in Australia and India, the pandemic phase was declared over because the seasonal H3N2 influenza A as well as influenza B began to re-emerge while pandemic H1N1 levels were low in the northern hemisphere. However, and decline in the pandemic strain is the norm, which is due to the target population developing immunity. However, the pandemic strain develops variants which can escape from the immune response, which produces a new wave, as is currently seen in the UK.

The UK H1N1 includes the sub-clade that was emerging in Australia when the WHO issued its August proclamation. This sub-clade and other variants continue to evolve away from the 2009 vaccine target as well as immune responses generated against the H1N1 circulating last season, including the vaccine target A/California/7/2009, which is again the target for this season.

California/7 was not the ideal target. Although it was circulating in southern California in early April of 2009, it had multiple HA differences with the sub-clade that was much more widespread. Consequently, there were a few single amino acid changes that could produce low reactors, isolates that had a four fold or greater reduction in titer.

One such change was G158E, which was present in one of the first low reactors identified by the CDC, an isolate from Germany. This association was not a surprise because Mill Hill had designated another isolate from Germany as a low reactor and both had D158E. Moreover, escape mutants also had D158E, and MedImmune found that clones with D158E grew well in chicken eggs, but reacted poorly with anti-sera generated against California/7.

However, when D158E began to appear in US isolates, the CDC changed its assay, which no longer classified H1N1 isolates with G158E as low reactors. Moreover, an isolate from the Ukraine, A/Lviv/N6/2009 had another change D225G, which Mill Hill designated as a low reactor. The CDC published a sequence from that patient that had both G158E and D225G, but they still failed to designate that isolate as a low reactor. The WHO regional center in Australia subsequently published antigenic characterization data which showed a sharp reduction in titer for A/Lviv/N6/2009, adding to the uncertainty about the CDC assay.

Indeed, the only low reactors from the United States identified by the CDC were those with changes at the adjacent position, 159, raising further doubt about the sensitivity of the CDC assay.

The change at position D225G also was critical in vaccine production. Isolates with D at position 225 produce a low viral yield when grown in chicken eggs. MedImmune used a clone with D225G and had a vaccine spray delivered weeks ahead of the vaccine shot because of differences in viral yield. The delay in the shot was significant because the spike in fall H1N1 was early and had passed its peak by the time the vaccine shot shipped in quantity. Thus, vaccine uptake in late 2009 / early 2010 was very low and the vaccine target for 2010/2011 was unchanged.

This initial low uptake was compounded by the WHO August proclamation on the pandemic phase. The announcement of its end led to low vaccine uptake in the fall of 2010, as well as a relaxing of pandemic preparedness.

This reduction in preparedness has led to the current fiasco in the UK, which is now starting to appear in Europe, where H1N1 is the dominant strain in circulation and vaccine uptake is low.

The low vaccine uptake is compounded by the evolution of the H1N1, which was most obvious in Australia over the summer of 2010. A new sub-clade emerged which was associated with vaccine breakthrough and severe cases.

The recently released sequences from the UK showed that this sub-clade has migrated to the UK, along with additional sub-clades that are drifting away from California/7 via recombination, which has reduce the effectiveness of the current vaccine, as well immunity generated against the H1N1 circulating last season.

These genetic changes have led to an explosion of severe H1N1 cases in the UK which is straining health care delivery. A vaccine shortage has focused attention on patients with underlying conditions, even though approximately half of severe and fatal H1N1 cases have no underlying conditions. These previously healthy young adults have a very low vaccine uptake and they are filling up ICU beds and crating an ECMO shortage.

The spike in severe cases has appeared early in the season and may increase dramatically in 2011, when more GP offices open and children return to school. This health care delivery strain seen in the UK will almost certainly spread to Europe in the upcoming weeks, where vaccine uptake is also low and the new sub-clades of H1N1 will also target previously healthy young adults.

The above sequence of events will produce a 2011 pandemic fiasco where the emerging H1N1 will severely strain health care delivery throughout the northern hemisphere.

[dothedd]

UK H1N1 Children's Epidemic Predicted
Recombinomics Commentary 21:40
January 1, 2011


The flu outbreak gripping Britain is set to become a "children's epidemic" as new figures show that the number of under-fives being brought into doctors' surgeries with the illness doubled over the Christmas period.

With schools beginning to reopen this week after the Christmas and New Year break, experts believe the spread of the virus will escalate, taking the number of cases to epidemic level within the next week to 10 days.
Only 23% of healthy children aged under five who are eligible for free flu vaccinations have taken them.

Across England the highest incidence of flu is in the under-four age group – 184 cases per 100,000 babies and infants.

The above suggest a “children’s epidemic will begin the UK in the next 1-2 weeks, as children head back to school with H1N1 in circulation with a 23% vaccine uptake rate. The return to school will almost certainly send the rate of infection markedly higher, as children are crowded together on buses and in classrooms as the start of the traditional flu season begins in earnest.

The level in the under four group is near epidemic levels (which is 200 cases per 100,000), and the outbreak, which was concentrated in the midlands, begins to spread into larger cities to the south, including London.

Vaccine shortages for the at risk population have already been reported and Tamiflu resistance is starting to rise.

The poor pandemic preparedness will accelerate and expand the 2011 H1N1 pandemic fiasco.

[dothedd]

UK H1N1 Cases Raise ECMO Usage To 100%
Recombinomics Commentary 17:25
January 3, 2011


Over the past month the National Health Service has increased fourfold the number of special machines that treat critical flu victims.

A portable Ecmo machine was flown by Prince William in a RAF helicopter to treat a young woman who developed swine flu just weeks after giving birth, but she later died in North Manchester General Hospital.

Ecmo is now on offer at seven hospitals around England, with referrals taking place at the country’s main Ecmo centre in Glenfield Hospital, Leicester. Those offering the treatment, which requires the use of increased numbers of doctors and nurses, have been told to postpone planned operations.

All 21 beds are now in use, although there is no suggestion that patients are being turned away. But as more patients continue to be considered for Ecmo, health bodies are preparing to buy even more of the £40,000 machines and install them in more centres.

“Although Ecmo is a highly specialised treatment, expert clinicians who perform cardiac surgery and provide critical support to patients in intensive care use many of the same skills and technology required for Ecmo.

“SHAs have been asked to identify appropriate cardiac surgery centres (whose staff do not normally provide the Ecmo services) so that these hospitals can also be authorised to provide a limited Ecmo service. Hospitals will only perform Ecmo if staff are appropriately qualified with the right level of experience. Hospitals will operate to strict clinical protocols and receive advice and support from clinicians at other centres.”

The above comments describe the availability of ECMO machines in England. As noted above, one was flown to Manchester in a failed effort to save the life of a young H1N1 patient. The number of critical cases has since risen and was up to 738 last week, compared to 460 a week earlier.

Although the 21 machines is higher than the 12 available last season, they are in full use and it is far from clear that machines are readily available for all of the critical H1N1 patients, which is undoubtedly higher than the 738 announced last week and is likely to grow in part due to the start of school and return to work after the holidays.

Each machine cost £40,000 and more may be ordered, but the current situation raises health care delivery concerns. These concerns extend to children, who have filled ICU beds and an increase associated with the start of school is expected.

[dothedd]

H1N1 Vaccine Breakthrough In Sweden
Recombinomics Commentary 20:25
January 3, 2011


Since the start of the season in week 40, with 65 cases of A (H1N1) reported in 2009. A large proportion of patients (46 pc) were not vaccinated against the influenza pandemic, 16 were missing data on vaccination status and only three patients reported that they were vaccinated.

The above week 51 data from Sweden includes at least three cases of vaccine breakthrough for pandemic H1N1. Since the above data is incomplete, the number of categorized cases does not equal the total number of confirmed case, and a large portion of the categorized cases have an unknown vaccination status, the frequency of breakthrough is unclear, which is also true for the UK, where at least one case has been reported.

However, the rapid spread of H1N1 in the UK suggests that many who are infected this season were also infected last season, demonstrating the ability of the current virus to evade the host immune system primed by last year’s virus. Some of the sequences from the UK are derived from sequences circulating in Australia, where there were also reports of vaccine breakthrough and severe cases.

This type of immunological escape is not unusual. It is part of the natural evolution of a virus that re-emerges in the following season. The immunological escape is required for a robust return as seen in the UK, which raises concerns that the use of a vaccine target from early 2009 will have limited utility against a rapidly emerging H1N1 in 2011.

This natural evolution was largely discounted in the WHO proclamation in August declaring the end of the pandemic phase, and was also discounted by “experts” who maintained that immunity generate last season would lead to a milder season in 2010/2011. The recent reports from the UK describe a more virulent H1N1 which is causing severe and fatal illness in a higher frequency of cases, which has severely strained health care delivery of ICU beds and ECMO machines.

The return of vacationing students and workers to schools and jobs raises concerns that the spike in severe and fatal cases seen during the holiday period will intensify in the upcoming weeks raising serious health care delivery issues.

The release of UK sequences from December severe and fatal cases would be useful.

[dothedd]

H1N1 Death Cluster In Liverpool Increases Concerns
Recombinomics Commentary 18:35
January 4, 2011

Olivia Rae Clee-Barnett, 17, from Wirral, Merseyside died in the early hours of Sunday morning.

Shocked friends set up a Facebook page paying tribute to the teen, nicknamed 'Livvy', who was a student at Wallasey School’s sixth form.

Her family were too devastated to comment.

It is understood the 17-year-old is the sixth person from Merseyside to lose her fight against the illness.

The above comments describe another death cluster in England. This cluster in the Liverpool area is near the death cluster of 12 described for the Manchester area. These 18 fatalities make up a large portion of the initial 36 confirmed H1N1 deaths reported in the week 52 HPA report. However, media reports describe almost 60 deaths, and the actual number of known deaths is undoubtedly considerably higher.

The severe and fatal cases have put significant pressure on ICU’s with many hospitals on red or black alerts and the situation is expected to deteriorate in upcoming days because of a post-holiday return to schools and workplaces. ECMO usage is at 100% and health care delivery is stretched to the limit.

Media reports indicate pressure is mounting in city to the south of Liverpool and Manchester, including London. Similarly, other countries, including Egypt and Israel are reporting sharp increases in H1N1 cases, suggesting a new wave of infections is beginning across the northern hemisphere.

There have already been reports of vaccine breakthroughs in the UK, Sweden, and Spain suggesting that those infected last season are vulnerable to the emerging sub-clade creating a crisis in the UK.

Release of December sequences from severe and fatal cases would be useful.

[dothedd]

H1N1 Dutch Death Cluster Raises Wave 3 Concerns
Recombinomics Commentary 20:35
January 4, 2011


Two children have died of swine flu in Nijmegen, the local health board said on Tuesday. The children were aged four and 11, and the fact they both lived in the same city is a coincidence, the health board said.

National infectious disease council RIVM said there is no reason for panic, despite the resurgence of the disease, which killed 63 people last winter.

The chance of being killed by flu is 'incredibly small', RIVM spokesman Roel Coutinho said.

The above comments describe and H1N1 death cluster in Nijmegen in The Netherlands. The flu season is just beginning to take off in The Netherland, and the report of two pediatric deaths in the same city signal clustering, as has been seen in the UK in Manchester and Liverpool. This type of clustering signals a more virulent H1N1 and in the UK the severe and fatal cases seen in Manchester and Liverpool is now heading into southern England. The same type of cluster in The Netherlands, which is adjacent to England is not surprising.

Vaccine breakthrough in England, Sweden, and Spain signal a new H1N1 sub-clade that is evading the current vaccine. Similar vaccine breakthroughs were seen over the summer in Australia and initial sequences from the UK demonstrate the migration of H1N1 in Australia into the UK.

This spread is beginning to appear in other countries, including Spain, Egypt, and Israel. The dramatic uptick in the UK signals the start of a new pandemic wave, adding further evidence of the error in the WHO proclamation that the initial pandemic phase had ended.

The current sub-clade not only is spreading rapidly, leading to the worst flu season in 20 years, but it continues to target young adults with a higher frequency of severe and fatal cases in patients without underlying conditions.

Although this change in at risk population is clear from initial data in the UK and Spain, agency announcements continue to target at risk populations identified in the waves in 2009. Moreover, these agencies continue to claim that the immunity generated against the H1N1 in waves one and two will offer protection in wave three, but accumulating data indicate those vaccinated against California/7, as well as those infected in 2009 are still vulnerable to H1N1 infection in 2011.

Sequence data from recent severe and fatal cases in the UK, Spain, Sweden, Israel, Egypt, and The Netherlands would be useful.

[dothedd]

H1N1 Death Cluster In Montgomery County Pennsylvania
Recombinomics Commentary 22:45
January 4, 2011


A two-year-old Lower Merion boy, 32-year-old Upper Merion woman and a 24-year-old Norristown man are the first three people in Montgomery County to succumb to influenza this season.

The above comments are from a press release issued by the Montgomery County Department of Health in Pennsylvania, which also requested that residents get the current flu vaccine. Although the serotypes are not given, the ages of the fatal cases strongly suggests that they are due to H1N1. Montgomery County is just south of Lehigh County and just northwest of Philadelphia. The Pennsylvania Department of Health previously announced an H1N1 outbreak in Lehigh Valley and two previously healthy young adults (45M and 28M) died within days of each other at Lehigh Valley Hospital, which represented the first two confirmed fatalities in Pennsylvania. Two more deaths were announced shortly after the first two, suggesting all four were from the Lehigh area.

In the week 52 report from Pennsylvania, the death toll has risen to eight. Although the location of the fatal cases are not given, virtually all confirmed H1N1 cases are in the above counties or adjacent regions concentrated in the eastern portion of the state.

This clustering of deaths in young adults and children raise concerns that a virulent H1N1 is emerging in a pandemic third wave. Recent death clusters have been reported in Manchester and Liverpool in the United Kingdom, as well as Niijmejen in The Netherlands.

These clusters, coupled with reports of vaccine breakthroughs suggest a new H1N1 wave has begun in the northern hemisphere.

More information on these Pennsylvania deaths, as well as sequence data on the Pennsylvania cases, as well as recent fatal and severe cases in the UK, Spain, Sweden, Israel, Egypt, and The Netherlands would be useful.

[dothedd]

H1N1 Death Cluster(s) In Pennsylvania Raise Concerns
Recombinomics Commentary 12:30
January 5, 2011


This season's flu has hit the Philadelphia region, killing two adults and a child in Montgomery County, officials reported Tuesday.

A 32-year-old Upper Merion woman died on Christmas, a 24-year-old Norristown man died Jan. 3, and a 2-year-old Lower Merion child died Dec. 21, said Harriet Morton, spokeswoman for the county Health Department.

She said that because of the fatalities, the department was advising all members of the public older than 6 months to go for a flu shot.

"If you have not gotten the flu vaccine, it is important, and this is why," Morton said.

In Pennsylvania thus far, there have been eight deaths, including the three in Montgomery County. Two occurred in Lehigh County, and one each in Westmoreland, Erie, and Lancaster Counties, said Holli Senior, press secretary for the state's Health Department and health communications.

The ages of the victims ranged from 2 to 65, Senior said. Three of the fatalities were due to the type A/H3N2 strain, two were due to A/H1N1, and three others have not been typed, Senior said

The above comments provide additional information on the recent cluster of deaths in Montgomery County, as well as the earlier five deaths in Pennsylvania. The two deaths in Lehigh county were the two cases with confirmed H1N1. It is likely that the three recent deaths in Montgomery County are the three that have not been sub-typed, but the age of the victims (2M, 32F, 24M), coupled with the clustering, strongly suggests that they are also H1N1. Earlier the Pennsylvania Department of Health issued an advisory on an H1N1 outbreak in Lehigh County that was associated with deaths and severe illness. Montgomery county is just south of Lehigh county and virtually all confirmed H1N1 cases in Pennsylvania are in the counties with the five deaths described above, as well as the adjacent counties. The region with the highest number of confirmed H1N1 cases in Pennsylvania is Philadelphia, with five, and as noted, the confirmed cases represent a small fraction of the total number of influenza cases.

The linkage to H1N1 is also suggested by the concentration of fatalities in Pennsylvania in general (with 8) and eastern Pennsylvania in particular (with 5) since the entire United States only has 19 confirmed influenza deaths, as reported by the CDC.

The two clusters in eastern Pennsylvania (Lehigh and Montgomery counties) raise concerns that the H1N1 that has been circulating in the UK and is associated with a significant spike in severe and fatal cases, is now also transmitting in Pennsylvania and could become more dominant. Currently in Pennsylvania and the United States in general, H3N2 is the dominant strain, but H3N2 levels worldwide are declining, raising concerns that H1N1 could be dominant, as seen in the UK and Europe, leading to a third pandemic wave involving a more virulent sub-clade.

Details on the sub-type of the three fatal cases, the large number of unsubtypable cases, as well as sequence data on the five fatalities in eastern Pennsylvania and the severe H1N1 cases in Lehigh County would be useful.

[dothedd]

H1N1 Immunological Escape Signals Wave 3
Recombinomics Commentary 17:50
January 5, 2011


The Irish Nurses and Midwives Organisation has said there were 569 patients on trolleys in hospital emergency departments this morning - the highest number ever recorded.

Critical care beds across Greater Manchester are near breaking point as hospitals battle to cope with a surge in swine flu victims.
The region has around 119 intensive care beds – but at one point yesterday all but three were full.


Dozens of patients have ops postponed at Leicester's hospitals as beds are full. The beds are being used for swine flu patients needing specialist Ecmo (extra corporeal membrane oxygenation) treatment.

ALMOST half of Britain’s 3,000 intensive care beds are occupied by swine flu victims.


That is the warning from experts who last night said the pandemic – the worst in two decades – shows no sign of easing. If new cases continue to rise as people return to work and school, hospitals may turn operating theatres into intensive care units.

The above comments are from various media reports describing the pressure on intensive care units at hospitals throughout the UK. The vast majority of these cases are due to H1N1 infections, indicating that the H1N1 circulating in the UK has largely escaped the immunological reponse generated by infection or vaccination with the H1N1 circulating in the UK last season.


The vaccine breakthrough was initially cited in Australia over the summer, and related sequences have become dominant in the UK and other northern hemisphere countries where vaccine breakthroughs and dramatic increases in severe H1N1 cases is becoming increasingly common.


These new infections are creating additional problems because vaccine uptake was low, and preparedness was relaxed because of the WHO declaration of the end of the H1N1 pandemic phase. This declaration was based on widespread immunity due to infections in 2009 as well as a re-emergence of H3N2.
However, in many European countries, including the UK, H1N1 dominates and continues to target those under 65. Moreover the frequency of severe cases in patients without underlying conditions is higher, leading to more hospital admissions and an associated increase in admissions requiring ICU beds and ECMO machines.

Recent reports from other northern hemisphere countries, including the United States, have raised concerns that these spikes in H1N1 cases represents the start of a third wave of H1N1 that will sweep through the region and produce greater numbers of severe and fatal cases, leading to a serious strain on health care delivery.

[dothedd]

S188T On 22/41 Recent H1N1 Sequences In England
Recombinomics Commentary 23:55
January 6, 2011


The Health Protection Agency has recently published a paper in Eurosuveillance entitled “Virological analysis of fatal influenza cases in the United Kingdom during the early wave of influenza in winter 2010/11.” The paper includes a HA phylogenetic tree which includes 41 sequences from the recent outbreak, including the four sequences that were released at GISAID. One of the released sequences, A/England/4880374/2010, contained S188T, which was seen in early 2010 in a swine from Thailand and was subsequently found in human isolates from Thailand, India, Australia, New Zealand, Ghana, Japan, and Iran, raising concerns that the location adjacent to the receptor binding domain at position 190 would lead to immunological escape, similar to changes seen in seasonal H1N1 associated with the fixing of H274Y.

Vaccine escape had been reported in Australia and the rapid spread of H1N1 in England suggested that the sequences there were also allowing such sequences to spread widely and rapidly.

The phylogenetic confirmed this concern since S188T (labeled S185T in the tree here) was in 22 of the 41 sequences. The tree also had several examples of recombination. D100N (labeled D97N) was not in the released sequence with S188T, but it was in A/England/4780352/2010. However, D100N was appended onto many of the S188T sequences in the phylogenetic tree. Moreover, two sequences with S188T and D100N also had D225G (labeled 222G) which were from two severe cases, A/England/4880378/2010 and A/England/4940476/2010, and the two sequences were identical, signaling transmission.

Information on the relationship between the two severe cases with D225G, as well as release of the 37 sets of H1N1 sequences used in the tree in the paper would be useful.

[dothedd]

H1N1 D225G Recombination and Transmission In The UK
Recombinomics Commentary 02:25
January 7, 2011


The Health Protection Agency published a paper on recent sequences from the current H1N1 outbreak, which included phylogenetic analysis of 41 HA sequences. S188T was present in 21 of the 41 sequences, extending its worldwide expansion and domination in England.

However, the sequences with S188T had additional evidence of recombination. One subset had acquired D100N, which was present on an earlier sequence and was also found on different genetic backgrounds outside of England.

Of great concern was two sequences, A/England/4880378/2010 and A/England/4940476/2010, which had D225G appended onto the background with S188T and D100N. D225G had previously been associated with severe and fatal cases in Ukraine and Russia, and to a lesser extent in many countries with sequences representing multiple genetic backgrounds, demonstrating expansion by recombination. In England both cases with D225G were severe. However, both sequences also were identical, signifying clonal expansion.

The paper did not explain the relationship between the two patients with D225G, but a clonal expansion is a concern. This concern is increased because both sequences contained S188T, which is dominant in England and is likely associated with immunological escape, as well as D100N, which is on multiple genetic backgrounds and also becoming increasingly common.

D225G hitchhiking on a dominant genetic background could lead to a significant increase in the polymorphism leading to more severe and fatal cases. Two of the five HA sequences from 1918 had D225G demonstrating the transmissibility of D225G under the appropriate circumstances.

In the upper branch of the tree with S188T and D100N, 5 of the 7 sequences are from severe or fatal cases, including the two with D225G. Detection of D225G is somewhat dependent on when and where the sample is collected. Thus, the level of D225G on this branch may be higher than the two cases noted.

This branch has two changes in or near the receptor binding domain, D225G and S188T, recombined with D100N, which is on at least two different genetic backgrounds in England, signaling more recombination.

The new combination raises serious concerns about an increased frequency in severe and fatal cases, as seen in England. More information on the two cases with D225G, as well as a release of all sequences used to create the published phylogenic trees would be useful.

Most publications require the deposit of such sequences in a public database so statements and conclusions in the paper can be independently evaluated and confirmed by the scientific community.

[dothedd]

S186P On 14/41 Recent H1N1 Sequences In England
Recombinomics Commentary 05:35
January 7, 2011


The Health Protection Agency released four sets of H1N1 sequences at GISAID, which was followed by a paper with phylogenetic analysis of 41 HA sequences from the current 2010/2011 outbreak. The rapid spread of H1N1 suggests the new sequences had escaped from the immunological response generated against last season’s H1N1.

One such change was S188T, which was adjacent to receptor binding domain position 190. When H274Y was fixed in seasonal flu, A193T was in all sequences, and it was flanked by changes at positions 186, 189, and 196. Thus, S188T was expected to aid in immunological escape and was present in 22 of the 41 sequences.

However, S186P was also present in one of the four sequences released by the HPA, A/England/118/2010, raising concerns that this change would also generate immunological escape.

The phylogenetic analysis presented in the above paper indicated S186P was in 14 of the 41 sequences.

Thus, 36 of the 41 sequences in the United Kingdom had S186P or S188T, providing a mechanism for immunological escape, and the rapid spread of H1N1 in the UK.

This parallel with the spread of seasonal H1N1 in 2008/2009 increase concerns that the addition of D225G to these drivers of pandemic H1N1 will have a catastrophic effect, which is increased by the presence of D225G on two identical recombinant sequences with S188T.

More information on these two patients, as well as release of the 37 sequences published in the phylogenetic tree would be useful.

[dothedd]

Receptor Binding Domain Changes Drive H1N1 Spread In UK
Recombinomics Commentary 12:45
January 7, 2011


The 2009 H1N1 pandemic is entering its third wave, which is following an evolutionary course that requires genetic changes that will target the human population that was infected or vaccinated last season. The appearance of S188T, a change adjacent to receptor binding position 190, raised concerns that pandemic H1N1 would follow an evolutionary path similar to changes seen in 2008/2009 for seasonal H1N1.

The fixing of H274Y was facilitated by that change hitchhiking on an H1N1 genetic backbone that had acquired A193T and at least one additional change at positions 186, 189, and 196. These three positions where each changed at least two times in the seasonal H1N1 sequences that emerged in the 2008/2009 season. Virtually all H1N1 sequences had this combination of changes, demonstrating how dominant and critical the changes were for the seasonal H1N1 emergence in 2008/2009. These combinations allowed frequencies of H274Y to increase from 0% to 100% in one season in many countries.

Thus, the appearance of S188T and its rapid spread led to concerns that it was driving immunological escape, and the release of four HA sequences from recent fatal cases in the United Kingdom increased those concerns. S188T was present on one of the sequences, A/England/4880374/2010, from a fatal case. The publication of a phylogenetic analysis of 41 recent sequences from the UK included 22 sequences with S188T, demonstrating its role in establishing pandemic H1N1 in the UK.

However, another sequence, A/England/118/2010, from another fatal case, had an adjacent change, S186P, and the phylogenetic analysis demonstrated this receptor binding change on 14 additional sequences .

Thus, as was seen in seasonal H1N1, two changes in this key region could be found in the vast majority (36 of the 41 sequences) of cases, demonstrating the role of these changes in the spread of pandemic H1N1 in a population that had been exposed to pandemic H1N1 in the previous season.

Of additional concern was the presence of D225G on sequences, A/England/4880378/2010 and A/England/4940476/2010, from two severe cases because both sequences were identical, signaling clonal transmission. These two sequences were on a branch that had S188T as well as D100N. D100N is on multiple genetic backgrounds. In the phylogenetic analysis it was on three backgrounds, including two that are currently co-circulating in the UK. Moreover, the branch with D100N, S188T, and D225G had seven sequences and five of the seven were from severe or fatal cases. This clustering raises concern that D225G was in additional patients, but not detected in the sample collected or virus isolated.

The transmission of D225G via a dominant gentic background could be catastrophic. Two of the five sequences from fatal cases who died in 1918 or 1919 had D225G, demonstrating its transmissibility under certain circumstances. Last season the frequency of D225G was relatively low in the overall population, but almost all sequences with D225G were from severe or fatal cases, as reported for samples from multiple countries and on multiple genetic backgrounds.

The detection of two identical sequences with D225G on a genetic background with drivers such as S188T and D100N raise concerns that the frequency of D225G could increase markedly and generate a much higher frequency of severe and fatal cases.

Currently, the level of severe and fatal cases in the UK has clearly taxed the health care delivery system, filling up ICU beds and raising use of available EMCO machines to 100%. A jump in the levels of D225G could seriously impact health care delivery and significantly increase the H1N1 case fatality rate.

More details on the two severe cases with identical sequences carrying D225G with powerful drivers like S188T and D100N would be useful.

[dothedd]

Health Protection Agency Releases UK H1N1 Sequences
Recombinomics Commentary 13:45
January 7, 2011

The Health Protection Agency has released the remaining HA sequences (at GISAID) from recent cases in the UK. Included are the sequences with the two key receptor binding changes, S188T (see list here) and S186P (see list here).

The HPA is to be commended for making these key sequences available to the scientific community in a timely manner.

[dothedd]

Liverpool H1N1 Death Cluster Increases to Nine
Recombinomics Commentary 13:15
January 10, 2011


His wife of 30 years, Carol, said it was first thought he had a bad cold which developed into a chest infection until the morning of December 23 when he became “delirious”.

Mr Hanson, a Liverpool FC fan, was taken to Arrowe Park Hospital by ambulance where he was found to be in a critical condition.

He died, surrounded by his family, on New Year’s Eve, after his organs failed.

At least nine people in the region are already known to have died from the swine flu virus this winter.

Mr Hanson was not considered to be part of the “at- risk” groups, so had not had the flu jab.

The above comments describe the latest reported fatality in the Liverpool are, increasing the cluster to nine. As noted above, this patient did not have an underlying condition and died during the period covered by the latest HPA report, which added 10 more deaths, but all 10 had underlying conditions.

The case above increases the number of Liverpool deaths reported in the media to nine, which represent 20% of the total H1N1 deaths reported by the HPA. Media and anecdotal reports indicate the known death toll is many fold higher than the 45 cited in HPA reports to date, indicating the vast majority of H1N1 deaths are being withheld.

Moreover, the deaths described are almost exclusively those with underlying condition (21/22 of the most recent reported deaths, in contrast to earlier reports of 12/26). This dramatic change of less than half to almost all is not explained in the HPA reports, and clearly represents heavy bias in the release of data.

Concern over the biased release of data is increased by a gag order on information of future H1N1 deaths in England.

This withholding and selective release of data consistent with agency messaging targeting the at risk population, in part because of a significant vaccine shortage, continue to raise pandemic concerns.

[dothedd]

Withheld UK H1N1 Death Data Raises Pandemic Concerns
Recombinomics Commentary 12:00
January 10, 2011


Health bosses have been slammed for trying to keep secret details of swine flu deaths across the region.

MPs and patient groups have blasted the gag which stops local health trusts revealing the number of victims, and the area they are from.

It comes as the region bears the brunt of this winter’s outbreak, with at least 12 deaths in Greater Manchester and Macclesfield, out of 50 nationally.

The above comments increase concerns regarding the withholding of data on fatal H1N1 cases in the UK. Although the HPA reports have the disclaimer “These cases will not represent all influenza-related deaths.” associted with the latest update on fatalities: “ Up to 5 January 2011, 50 fatal cases have been verified by HPA as related to influenza infection. Of these cases, 45 have been associated with H1N1 (2009) infection and five with influenza B infection", the data is not only being withhelkd, but is being selectively released.

The total of 50 deaths is not a credible number. It is below numbers appearing in media reports, which represent a fraction of the total number of actual H1N1 deaths in the UK. The selective release of data is also seen in reports on underlying conditions. Initially most of the cases did not have an underlying condition (14/26 as reported in week 51 report). However, in the week 52 report, only 1 of 12 newly reported cases did not have an underlying condition, and in the latest week 1 report none of the 10 cases did not have an underlying conditions.

Thus, the death cases are being withheld, and the released numbers are almost exclusively from cases with underlying conditions.

The withholding of information also extends to the sequences released from GISAID, There is genetic clustering in recent severe and fatal H1N1 cases, yet all associated demographic information (age, gender, and location) is also being withheld with the disclaimer “HPA will not provide patient information that could lead to deductive disclosure or identity”.

Thus, the HPA is not only withholding the actual number of deaths and locations of clinical cases, but it is also withholding demographic data which would localize the cases with concerning genetic changes.

The withholding of death data continues to increase pandemic concerns.

[dothedd]

H1N1 D225G Transmission in the US and UK
Recombinomics Commentary 23:30
January 13, 2011


The CDC has released a small series of H1N1 sequences at GISAID. One isolate, A/Kentucky/09/2010 (KY/09), had G158E and D225G in addition the S188T. The isolate was collected November 1, 2011 and was closely related to A/Kentucky/08/2010, as well as a well defined sub-clade in the United Kingdom.

KY/09 was most closely related to the two sequences from the UK, (A/England/488-378/2010 and A/England/4940476/2010), which had D225G and were from severe cases. These two sequences were identical, but collected more than one month apart.

All of these sequences have S188T, which is in a rapidly expanding sub-clade and was present in the majority of the recent sequences from the UK (22/41). Similarly, S188T was in 3/5 recent H1N1 sequences from the US.

The presence of D225G in two identical sequences from the UK suggested that it was transmitting. The presence of D225G in the US on a closely related sequence similarly supports transmission.

Transmission of D225G could create serious problems due to its tight association with severe and fatal cases.

More information on the cases in Kentucky as well as the two cases in the UK would be useful.

[dothedd]

Pennsylvania H1N1 S186P Death Cluster Matches UK Clade
Recombinomics Commentary 11:00
January 14, 2011


The US CDC has released a series of recent sequences (at GISAID) from the US and other locations in Asia and South America. Many of the US sequences were similar to sequences in the UK and had S186P or S188T. The sequences with S186P fell into two major branches, with sequences from the UK on both branches. The two major branches had G451A, T598C, and C1464T. One branch also had T933C, T1020C, G1206A, and T1374G (see matches here).

This branch had two identical sequences from Pennsylvania (A/Pennsylvania/16/2010 and A/Pennsylvania/17/2010), which were from the two previously described Lehigh Valley fatal cases (45M and 22M). Other sequences from this branch were from Wisconsin, as well as Iran, Bhutan, Bangladesh, and England (Whitechapel, Manchester, Newcastle-upon-tyne, County Durham).

The two cases from Lehigh Valley were previously healthy young adults who were moved to the ICU and placed on ventilators and died within days of each other. The Pennsylvania Department of Health had issued an advisory, which was followed by a press release from Montgomery County, citing three more deaths in two young adults and a child.

The matches between the Lehigh death cluster and those in the UK suggest this sub-clade is associated with deaths, which is likely linked to the receptor binding domain changes, which are associated with immunological escape, and provide additional information on the spread of these S186P sub-clades.

[dothedd]

Flu mutation: UK and Iran Transmit Hyper-Zoonotic Genetics in Late 2010

The Tehran University of Medical Sciences has made available 3 sets of sequences at GenBank recently that were sampled on 2010_10_02 with 2 additional divergent samples taken on 2010-12-06. These sequences directly parallel the developments from the UK Severe Wave and additionally feature hyper-zoonotic, sub-segment HA genetic acquisition.

Though considerable divergency is currently being demonstrated within the recent UK severe wave, two different sets of combinations have been coalescing throughout the world since late 2009 and have begun forming sub-clades in the past 4 months that are demonstrated well in these 3 Iranian sequences.

Do these Iranian sequences signal the type of zoonotic genetic behaviour that is driving some areas of the UK today to report an 800% rise in the number ill from Pandemic H1N1?

Though the origins of the primary branching polymorphisms begin much earlier, the later stages of transmission during late Summer and early Fall 2010 (Northern Hemisphere designations) more clearly distinguish the coalescence. Florida13 and Florida14 during August 2010 are recorded as having progenitor co-circulation of these two divergent sub-clades that transmitted and continued into the UK and Iran. Florida13_2010_08_02 has 4 of the same SNPs as IranBandarAbbas5096_2010_10_02. 100% of those matches [4 of 4 (137T, 186P, 377G, syn474C)] between Florida and Iran are also found in animal reservoirs.

Recall that small incursions of genetics from animal reservoirs are known to imbalance viral behaviour in the new human host. The HA 377G found on Florida13 and BandarAbbas5096 exists on the fatal UKEngland4500186_2010_11_f sequence and four other UK sequences from October and November of 2010, but was not notated on the HPA Ellis Figure3 1 phylogenetic tree.



◦UKEngland83_2010_10
◦UKEngland87_2010_10
◦UKEngland5500192_2010_10
◦UKEngland119_2010_11
◦UKEngland4500186_2010_11_f
GeneWurx has annotated the Ellis Figure3 1 phylogenetic tree with green boxes next to the four fatal GISAID 2010-12-20 deposited sequences and has proposed polymorphism notations including the zoonotic HA 377G on various unmarked branches in an attempt to provide clarity. Version 5 of the Emerging Genetics spreadsheet is available with the Iranian sequences, the 4 representative UK 377G sequences (UKEngland5500192_2010_10 is identical to UKEngland87_2010_10) and the majority of the released UK fatalities.

◦UK_2010_Phylo_ELLIS_Fig3new_4_GISAID_Notated_2011_ 01_13.JPG
◦GeneWurx_UK_December_Emerging_Genetics_v5.xls
The IranShahriar5336_2010_12_06 evaluation details a remarkable hyper-zoonosis. At least 78% of the polymorphisms (7 of 9) are clearly demonstrated as amino acid variation or single nucleotide polymorphisms in animal reservoirs, primarily H3N8, H5N1 and H7N7. Wisconsin08_2010_08_10 shares homology at 7 of the IranShahriar5336_2010_12_06 SNPs. 86% of those matches [6 of 7 (137T, 186P, syn297N, 388K, 444K, syn474C)] between Wisconsin and Iran are found in animals (5 in H3N8).

The homology between Iran and the UK is more striking than either of these vivid US examples and may be well visualised by scrolling through the GeneWurx v5 spreadsheet detailing these specific changes with combinational development over the course of this pandemic.

. . . . IranShahriar5336_2010_12_06 (
. . . . . . . . 137T (aCA) [H3N8 donor aAT, aGT, aGC],
. . . . . . . . 186P [Avian H12 2008, 2009], [Avian H1N1],
. . . . . . . . syn297N [H3N8 gadwallRussiaAltai1325_2007_09],
. . . . . . . . . . . . . . . [H5N1],
. . . . . . . . . . . . . . . [Wisconsin08_2010_08_10
. . . . . . . . . . . . . . . . . . . . . . with 39R, syn78S, 137T, 186P, syn297N,
. . . . . . . . . . . . . . . . . . . . . . . . . . syn326S, syn346G, syn388K,
. . . . . . . . . . . . . . . . . . . . . . . . . . syn413K, 444K, syn474C,
. . . . . . . . . . . . . . . CalifVRDL2_2010_01_11
. . . . . . . . . . . . . . . . . . . . . . with syn121P & 502K,
. . . . . . . . . . . . . . . YaroslavlIIV196_2009_12_04_f
. . . . . . . . . . . . . . . . . . . . . . with syn159N, 225G,
. . . . . . . . . . . . . . . WiscD0128_2009_11_15
. . . . . . . . . . . . . . . . . . . . . . with syn343G, 377G, 471H,
. . . . . . . . . . . . . . . Brussels243_2009_11_09
. . . . . . . . . . . . . . . . . . . . . . with syn44L, syn159N & syn323N,
. . . . . . . . . . . . . . . Australia6_2009_07_18
. . . . . . . . . . . . . . . . . . . . . . with syn159N, 233H]
. . . . . . . . syn326S [Wisconsin08_2010_08_10
. . . . . . . . . . . . . . . . . . . . . . with 39R, syn78S, 137T, 186P, syn297N,
. . . . . . . . . . . . . . . . . . . . . . . . . . syn326S, syn346G, syn388K,
. . . . . . . . . . . . . . . . . . . . . . . . . . syn413K, 444K, syn474C,
. . . . . . . . . . . . . . . Zhongyuan1643_2009_11_16
. . . . . . . . . . . . . . . . . . . . . . with 208G],
. . . . . . . . syn383N [H3N8],
. . . . . . . . syn388K [H3N8, H5N1, S7],
. . . . . . . . . . . . . . . [OzVictoria508_2010_07_24
. . . . . . . . . . . . . . . . . . . . . . . with 238D,
. . . . . . . . . . . . . . . swIowa44837_1_2009_11_08_xL
. . . . . . . . . . . . . . . . . . . . . . . with 188R, 225N & 230I,
. . . . . . . . . . . . . . . Utah20_C2_2_2009_07_25_VxX
. . . . . . . . . . . . . . . . . . . . . . . with 159D & 227G, et al],
. . . . . . . . syn411N (AAc) [H7N3 & H7N7 donor ATc],
. . . . . . . . 444K (AAg) [H3N8 gAg],
. . . . . . . . syn474C [H3N8, Avian H1N1 2010],
. . . . . . . . . . . . . . . [Michigan10_2009_06_03 with 137T, 225N, et al])

[dothedd]

RBD Driven H1N1 Immunological Escape In UK
Recombinomics Commentary 12:20
January 18, 2011


The US CDC has released a series of recent H1N1 sequences at GISAID and declared three of the isolates as “low reactors” signaling a titer reduction of four fold or higher when tested against anti-sera directed against the current pandemic H1N1 target, A/California/7/2009.

Two of the low reactors were from Costa Rica and had changes among positions 156-159 (one, A/Costa Rica/5458/2010, had a K156E mixture, while the other, A/Costa Rica/5529/2010, had G158E). All prior pH1N1 low reactors identified the CDC had a least one change in this region.

However, the third “low reactor”, A/India/5103/2010,was wild type at positions 156-159, but it had S186P and S188T. These two changes dominate recent sequences from the UK, with 36/41 HA sequences having at least one of these two receptor binding domain changes, signaling immunological escape.

Changes in these regions mimic escape for seasonal H1N1 in 2007-2009. In the summer of 2008 H274Y became fixed by hitchhiking with receptor binding domain changes flaking position 190. In South Africa H274Y levels rose to 100% and the dominant sub-clade had A193T. Sequences also had additional changes in this region, with at least one change at positions 186, 188, or 196. Moreover, seasonal H1N1 sequences targeted these positions, which led to a database with multiple versions of each position (N187S, N187D, G189A, G189N, G189S, G189V, H196R, H196N).

The sequences from the UK mimic this strategy, with 36/41 sequences having either S186P or S188T. However, a small subset of sequences has additional changes in this region. A/England/4640543/2010 has S188T and D190G, while A/England/4500186/2010 has S186P and D190Y. Similarly, A/England/119/2010 has S186P and D188N. Thus, multiple changes at the same position (S188T, S188N, D190G, D190Y) co-circulating in the UK suggest more combinations will appear via recombination, signaling additional immunological escape.

This escape is supported by the high frequency of these changes in UK isolates, as well as an antigenic characterization assays with a checkered past. Although these assays have been in place for decades, the sensitivity and reproducibility issues has plagued analysis, especially for H1N1 isolates. For pH1N1, G158E has implicated in the generation of “low reactors” by multiple labs, including the US CDC. An early pH1N1 sequences from Germany had G158E and was designated as a low reactor. Similarly, another isolate from Germany with G158E was also designated as a low reactor by Mill Hill. This change was also cited by MedImmune when characterizing California/7 clones. One clone with G158E grew well in eggs but was not selected because of low reactivity with California/7 anti-sera. In addition analysis of escape mutants identified G158E.

However, when sequences with G158E began to appear in US pH1N1 isolates, they were not designated as low reactors by the CDC, even though the earlier sequence from Germany was, which is alos true for the recent 2010 isolate from Costa Rica, signaling intra-lab variation. This type of sensitivity, reproducibility issues also arose for a sequence from Ukraine. A/Lviv/N6/2009, which had D225G, was designated a s low reactor by Mill Hill. However, all CDC low reactors were limited to changes between positions 156-159, and all low reactors from the US had changes at position 159. Moreover, when the CDC published a sequence from the above sample from Ukraine, their sequence had G158E and D225G, but was not designated a s low reactor. The WHO regional center in Australia published ferret anti-sera data and A/Lviv/N6/2009 had a striking reduction in titer against a variety of antisera, demonstrating inter-lab variation.

This type of variation in WHO regional centers was also seen in the 2007/2008 season, which had A/Solomon Islands/3/2006 (clade 2A) as the seasonal H1N1 vaccine target, which represented a change from New Caledonia/20/1999, and New Caledonia (clade 1) was clearly declining. However, Solomon Islands/3 was also declining and was being replaced by clade 2B (A/Brisbane/59/2007) and clade 2C (A/Hong Kong/2562/2006). The CDC used anti-sera which could distinguish clade 1 from clade 2, but not the three clade 2 sub-types from each other. Consequently the clade 2B and clade 2C where designated as Solomon Island-like and a “match” for the vaccine. However, the WHO regional center in Australia developed anti-sera against Brisbane/59 grown in mammalian cells and that anti-sera could clearly distinguish between the three clade 2 sub-clades, and the target for the 2008/2009 was changed to A/Brisbane/59/2007.

However, the mismatch with Solomon Island/3 aided immunological escape, and when Brisbane/59 was introduced, Brisbane/59 was dominant, but had the receptor binding domain changes flanking position 190, leading to many reports of vaccine breakthroughs in the 2008/2009 and the fixing of H274Y worldwide.

This season, the same paradigm is being employed against the outdated pH1N1 vaccine target, A/California/7/2009. Vaccine breakthrough was reported in Australia, and now the designation of India/5103 with S186P and S188T supports escape by isolates with one or more of these changes and subsequent dominance as seen in the recent sequences from the UK.

[dothedd]

CDC Issues H1N1 Alert In United States
Recombinomics Commentary 14:10
January 18, 2011


consideration of antiviral treatment for any previously healthy, non high-risk symptomatic outpatient with confirmed or suspected influenza, based upon clinical judgment, if treatment can be initiated within 48 hours of illness onset.

The above comment is included in the recent CDC health alert on influenza antiviral treatment and diagnostic tests. This January 14, 2011 alert follows a significant outbreak of H1N1 in the UK and reports of increased H1N1 activity in the northern hemisphere.

Initial reports from the UK indicated most fatal cases were young adults without underlying conditions. Subsequent reports have focused on patients with underlying conditions, but the high frequency of fatal cases without underlying conditions raised concern.

A similar death cluster was reported in Lehigh, Pennsylvania and recently released sequences by the CDC demonstrated the presence of S186P in the identical HA sequences from the two Pennsylvania cases, which were closely related to UK sequences.

Moreover, one of the sequences, A/India/5103/2010, without changes at positions 156-159 was declared a low reactor, and this sequence had S186P and S188T. These two changes are widespread in the UK, with 22/41 cases having S188T and another 14/41 cases having S186P. In addition to the case in India, a sequence from Japan, A/KANAGAWA/74/2010, also had both changes, and the most recent sequence from Japan, A/NIIGATA/1581/2010 also had S188T.

Other combinations were seen in the UK and Bhutan. In the UK there were sequences with S188T combined with D190G (A/England/4640543/2010) and S186P combined with D190Y (A/England/4500186/2010). Similarly, A/Bhutan/72/2010 had S186P combined with A189T. These combinations are similar to the immunological escape of seasonal H1N1 associated with the fixing of H275Y in 2008/2009 which involved A193T combined with at least one change at positions 187, 189, or 196.

These genetic changes indicate the current vaccine, direct against A/California/7/2009 will have less than optimal efficacy as sequences with the above receptor binding domain changes emerge and dominate. As noted, 36/41 recent sequences from the UK had S188T or S186P, and these changes are rapidly spreading throughout the northern hemisphere.

The CDC alert does not mention these changes, but includes antiviral recommendations, which includes use in previously health young adults.

The current H1N1 vaccine target, A/California/2009, has remained unchanged since it was selected in the spring of 2009. It is currently recommended for the 2010/2011 season in the northern hemisphere, and is the target for the 2011 season in the southern hemisphere.

Recommendations for the 2011/2012 northern hemishere flu season will be made next month. A target change is long overdue.

[dothedd]

All December H1N1 Iran Sequences Have S186P or S188T
Recombinomics Commentary 18:20
January 18, 2011


The National Influenza Centre in Tehran has released four more sets of pH1N1 sequences from patients infected in mid-December, 2010. Like the three sets of sequences from patients infected in early December, all had S186P or S188T.

The sequence with S186P, A/Karaj/5660/2010, had a large number of HA changes and mapped to the same branch as A/Shahriar/5336/2010. Like a series of UK sequences and the two sequences (A/Pennsylvania/16/2010 and A/Pennsylvania/17/2010) from fatal cases in Lehigh, Pennsylvania, all had G541A, T598C, T933C, T1020C, G1206A, T1374G, and C1464T, signaling clonal expansion. These sequences were distinct from A/Bandar Abbas/5096/2010, which also had S186P as well as A1172G which was found in 5 of the sequences from the UK.

The three sequences with S188T (A/Karaj/5685/2010, A/Karaj/5718/2010, A/Tehran/5675/2010), were similar to the earlier sequences with S188T, A/Karaj/5327/2010, which was related to sequences from Russia (A/Moscow/IIV-33/2010), Thailand (A/Thailand/594/2010 and A/Thailand/742/2010), and Brunei (A/BRUNEI/218/2010). All had a series of markers define this sub-clade and they all also had G605C, T0156C, G1171A, and G1403A, which was present in all of the UK sequences with S188T.

Thus, although the 7 sequences from Iran fall on three separate branches, and are from multiple locations in Iran, all sequences have S186P or S188T.

The National Influenza Centre in Tehran is to be commended for the timely release of these important sequences to the scientific community.

These sequences provide additional support for the fixing of S186P or S188T in pandemic H1N1 in 2011, and strongly support immunological escape.