trh3n2

 This is a two-year-old girl, in Duoc, Long An and is now cured. For years, our country has recorded cases of infection with influenza virus A (H3N2) in humans, also known as regular seasonal flu, while flu patients is derived from pigs.

Recombinomics Commentary 13:15
February 15, 2012

The national flu monitoring system detected this case in April 2011. A two-year-old female baby in Long An province contracted the disease and was treated successfully at the Children’s Hospital No 1. in HCM City. The A/H3N2 flu virus she had originated from pigs.

The test results of the HCMC Pasteur Institute were confirmed on January 10, 2012, by the WHO laboratory at the US Centres for Disease Control and Prevention (CDC).

The above comments provide additional clarity on the dates surrounding the confirmed H3N2v case in Vietnam, but still leave many questions unanswered.  It is likely that this case was initially classified as seasonal H3N2 in 2011.  The H3N2v cluster in Iowa in November led to an alert issued by WHO, largely because the three confirmed cases had no swine exposure.  That alert was followed by a media report in Vietnam that described the US cases and increased surveillance in Vietnam.  Those reports incorrectly described the US H3N2v cases as H3N1.
Last week media reports in Vietnam again issued a warning about H3N2v cases, but only provided detail on the cases in the United States and again described the cases as H3N1, and a follow-up report claimed no H3N2v cases in Vietnam in 2012 (carefully parsed to avoid acknowledgement of the 2011 case).

Today, reports from Vietnam described the above case (age, gender, and location) and the English language reports clearly indicated this was a 2011 case that was confirmed over a month ago by the US CDC.

This raises several important questions, which have not been answered. None of the reports have cited a swine exposure by the confirmed case.  Similarly, the CDC has not released the sequences at GISAID, as was done for the 2011 variant cases in the United States (H3N2v, H1N2v, H1N1v).  Moreover, WHO has not announced the confirmed case, in spite of lab confirmation by a WHO regional center, although it is unclear if the WHO has announced this case at its password protected site.
Thus, a month after confirmation, all of the above questions remain unanswered by public data, although the sequence would clearly distinguish between a linkage to Asian or North American swine lineages.

The lack of transparency by WHO and the CDC continues to increase pandemic concerns.

Recombinomics Commentary 09:15
February 15, 2012

As reported by the National Influenza Center - Pasteur Institute of Ho. Ho Chi Minh, influenza surveillance system key southern countries found cases of A/H3N2 flu originated from pigs.

This is a new 2-year-old female patients in Duoc, Long An influenza have been treated at Children's Hospital 1 and then cured. Samples of these patients have been tested in a laboratory at the CDC standard WHO official - the United States and has been confirmed.

Yang said, this is the first case reported in Vietnam A/H3N2 flu originated from pigs. This slight movement of cases and no evidence of transmission from person to person.

The above translation describe the first case (2F) of H3N2v in Vietnam (Duoc, Long An).  In contrast to earlier reports, which described similar cases in the United States, this report describes a PCR confirmed case in the Mekong Delta region in southern Vietnam.

As noted earlier, there are 6 sets of public sequences from H3N2v in swine, isolated in 2010 (A/swine/Binh Duong/03_06/2010, A/swine/Binh Duong/03_08/2010, A/swine/Binh Duong/03_09/2010, A/swine/Binh Duong/03_10/2010, A/swine/Binh Duong/03_13/2010, A/swine/Binh Duong/03_14/2010). All six isolates are closely related and have human H3 and N2 genes, with swine internal genes that are generally more closely related to H3N2v swine sequences in Asia (South Korea and Hong Kong).

However, Hong Kong has released 3 sets of sequences from Guangxi and Hong Kong (A/swine/Guangxi/NS2783/2010, A/swine/Hong Kong/2503/2011, A/swine/Hong Kong/NS2439/2011) , which have similar H3 and N2 human genes surrounding six internal genes from H1N1pdm09. In the United States, all 12 of the H3N2v sequences in humans in 2011 have an H1N1pdm09 M gene. Prior H3N2v cases in the United States have PB1 E618D, which is not in the swine isolates from Vietnam, but is in the new sequences from Hong Kong and China, since E618D is in virtually all H1N1pdm09 PB1 sequences.

The above report does not cite swine contact, so the origin of the infection is far from clear.  H3N2v in Vietnam is readily distinguished from H3N2v in the United States.

Information on the constellation of genes in the case in Vietnam would be useful.

Recombinomics Commentary 16:00
January 6, 2012 HHS has contracted with pharmaceutical companies Novartis and Sanofi Pasteur to develop investigational lots of the vaccine. Novartis will produce its supply using cell-culture technology at its plant in Holly Springs, North Carolina, and Sanofi Pasteur will grow the vaccine in chicken eggs (a slower method of production) at its plant in Swiftwater, Pennsylvania.

The influenza virus being targeted is a variant of the A(H3N2) virus found in pigs.

The above comments describe preparations for spring clinical trials for an H3N2v pandemic vaccine.  These developments are not a surprise.  In August the CDC released sequences of vaccine constructs of A/Minnesota/11/2010, which was followed by a WHO September 29, 2011 report on vaccines, showing that the sera against the above target was effective against the first H3N2pdm11 isolate, A/Indiana/08/2011.
 
Although December media reports cited the creation of a seed vaccine, the real drivers for the clinical trials were the H3N2pdm11 cluster at the daycare center in Iowa, followed by the trH3N2 sustained cluster in the daycare center in Mineral County, West Virginia (which has a novel N2 which has acquired seasonal polymorphisms via recombination.

The West Virginia cluster was alarming, with 23/70 contacts of the index case exhibiting ILI (influenza-like illness), which led to a CDC request to all states to increase surveillance, especially in children.  Multiple states issued advisories or alerts, including Marin County, California, which also cited a new H3N2v case in a Napa county resident in its week 50 report.

Today the CDC published the December 23 early release MMWR, which described the West Virginia cluster, which made it clear that transmission was sustained for a month at the daycare center, but failed to note that 23 contacts had ILI.  In December the CDC also held a 50 state conference call.

An explosion of H3N2v cases and clusters is expected this month.

Recombinomics Commentary 05:00
January 5, 2012 More recently, investigation of a case in West Virginia has identified a possible outbreak, with 23 out of 70 contacts of the case reporting ILI; all have recovered.

The above comments are in the California Department of Public Health December 15 H3N2v advisory.  The West Virginia cluster was described in the CDC early release MMWR, but the 23 ILI cases were not mentioned.  Instead the report said there were several contacts of the index case, A/West Virginia/06/2011, which initially tested as negative.  trH3N2 was isolated from a contact, A/West Virginia/07/2011, which initially tested as inconclusive and was reported as an influenza A case.  The partial sequence of HA and NA were virtually identical to the index case, and both had a novel N2 that was easily distinguished from the first 10 cases in 2011 (H3N2pdm11).

Thus, the vast majority of cases at the day care center were not reported, and the two confirmed cases had serious testing issues.  The numbers cited in the California advisory indicate the attack rate was high, and the transmission was sustained for almost a month, but the CDC maintains that there is no sustained or community transmission of H3N2v.  None of the cluster members have reported contact with swine.

A pediatric case in Napa County, California has also tested positive for trH3N2 and is under investigation.  Anecdotal reports indicate ILI is widespread in pediatric cases in northern California, but most are mild and not tested.  As seen in the West Virginia cluster, testing is a serious issue, allowing the trH3n2 to silently spread.

An explosion of cases and clusters is expected this month.

January 4, 2012 — Taking no chances, the US Centers for Disease Control and Prevention (CDC) is laying the groundwork for a possible vaccine against a novel strain of a swine influenza virus that has surfaced in 5 states and sickened 12 individuals, mostly children, since July 2011, an agency official told Medscape Medical News Tuesday.

The strain, designated A(H3N2)v, is a variant of the A(H3N2) virus that circulates among humans on a seasonal basis. What makes it a variant is a gene from the pandemic 2009 influenza A(H1N1) virus that codes for matrix proteins found in the viral shell.

In Indiana, Pennsylvania, and Maine, the virus appeared to have spread from pigs to humans, according to the CDC. In Iowa and West Virginia, however, the evidence suggests limited human-to-human transmission. In general, the novel virus is no more severe than ordinary seasonal influenza, and all the people infected with it have recovered.
The CDC is encouraging public health agencies and clinicians to collect more nasopharyngeal swabs from patients presenting influenza-like illness for testing to determine whether the novel virus may be spreading on a sustained basis.
CDC spokesperson Thomas Skinner told Medscape Medical News that the agency already has prepared a "seed virus" obtained from A(H3N2)v specimens that drug manufacturers can use to develop a vaccine if needed. Preparing a seed virus involves genetically manipulating specimens to incorporate preferred features.
Because the new virus is different enough from the seasonal viruses now in circulation, the seasonal influenza vaccine for 2011-2012 "is not expected to provide significant protection" against the newcomer, according to a Morbidity and Mortality Weekly Report that the CDC published on December 23. The trivalent seasonal vaccine is formulated to protect against the 2009 pandemic virus, the regular A(H3N2) virus, and an influenza B strain.
CDC Could Be Preparing for 2012-2013 Influenza Season
So far, the evidence does not suggest that the A(H3N2)v strain is spreading freely through communities, which would create the need for a vaccine. The bug could fizzle out, according to Christine Layton, PhD, MPH, a public health researcher and influenza pandemic expert at RTI International in Research Triangle Park, North Carolina.
"There have been past instances where a novel virus comes up and then goes back down," Dr. Layton told Medscape Medical News. "There may be something about the virus that [prevents] sustained human-to-human transmission."
If the A(H3N2)v virus ever takes off, she said, drug manufacturers would have a tough time turning out a corresponding monovalent vaccine "at the drop of a hat." Influenza vaccines are still mass-produced, for the most part, by being grown in chicken eggs. Together with testing and licensing a vaccine, this process easily can last 3 to 4 months.
A more likely scenario, said Dr. Layton, would be incorporating an A(H3N2)v strain in the trivalent seasonal vaccine for 2012-2013, assuming the novel virus becomes that much of a threat. Each February or so, an advisory panel of the US Food and Drug Administration (FDA) recommends 3 strains of influenza that should make up the seasonal vaccine for the coming fall on the basis of what it expects to see circulating then. The CDC then develops the seed viruses for these 3 strains, which the FDA distributes to vaccine makers. 

http://www.medscape.com/viewarticle/756348

CDC confirms two human infections with novel influenza viruses

December 9, 2011 -- CDC has confirmed two cases of human infection with two different novel influenza A viruses in different states. Both patients have fully recovered. While the viruses infecting both patients have been found in U.S. swine and some of the prior human infections with these viruses have been associated with direct or close swine contact, there are no reports of direct or close contact with swine prior to illness onset in either of these cases. Laboratory testing at CDC has confirmed that both novel viruses are susceptible to the antiviral medications oseltamivir (Tamiflu®) and zanamivir (Relenza®).

West Virginia
One case of human infection with a novel influenza virus was reported by West Virginia and involves infection of a child with the novel influenza A (H3N2) virus with genes from swine, human, and avian lineages with the M gene from the 2009 H1N1 virus that was first identified in August 2011. Ten prior human infections with this virus in four other states have been confirmed. These occurred in Indiana (2), Pennsylvania (3), Maine (2), and Iowa (3).

These novel influenza A (H3N2) viruses are substantially different from currently circulating seasonal (human) influenza A (H3N2) viruses, but are distantly related to human influenza viruses that circulated among people in the 1990s. For that reason, some adults may have some residual immunity against this virus. This might help explain why 10 of the 11 cases that have been detected have occurred in children.

Most human infections with viruses that circulate in swine (but not humans) have been associated with swine exposure, but limited human-to-human transmission associated with these viruses is thought to have occurred as well, most recently in Iowa. While an investigation is ongoing in West Virginia, no direct or indirect contact with swine has been reported, implying that limited human-to-human transmission of this virus may have occurred again.

No ongoing community transmission of this virus has been detected in the United States. However, CDC is taking this situation very seriously. Surveillance surrounding reported cases is being further enhanced and, as a precaution, a vaccine virus has been developed and provided to manufacturers for them to begin vaccine production should that become necessary.

Minnesota
The other case of novel influenza A virus infection was reported by Minnesota, and is associated with a different influenza virus; an influenza A (H1N2) virus that circulates in swine  in the United States, but does not normally infect or cause illness in humans. This case also was in a child. This is only the second case of human infection with this novel influenza A (H1N2) virus reported to CDC since novel influenza virus infections became nationally notifiable in 2007. The first such case was identified in Michigan in 2007. By some characteristics, this H1N2 virus is close to human influenza A (H1N1) viruses called “A/New Caledonia /20/99-like,” which circulated and caused illness among people as recently as 2007. As a result, people who were exposed to A/New Caledonia/20/99-like viruses may have some existing immune protection against the virus detected in Minnesota. Again, no direct or indirect contact with swine has been reported with this case, implying that limited human-to-human transmission may have occurred in this instance as well.

Detection of Swine Influenza Infections in Humans
Human infections with novel influenza A viruses normally found in swine are rare events. Recently, however, the frequency of such detections has increased. This could be occurring for a number of reasons, including one or more of the following factors: First, laboratory methods for testing for these viruses in the United States were improved following the 2009 H1N1 pandemic. These improvements may be resulting in viruses being identified now that would have gone undetected previously. Second, this could be due to increased surveillance in the United States for influenza at this time of year. CDC has requested that states analyze, and then send, their first influenza virus specimens of the season for seasonal influenza surveillance purposes. This practice, coupled with very low levels of seasonal flu activity at this time, could mean that sporadic novel influenza infections are more likely to be tested. Third, it is possible that the increased frequency of detection of novel influenza viruses with swine origins identified by CDC represents a true increase in the number of such cases, possibly occurring from exposure to infected swine  or through subsequent, limited human-to-human transmission.

The novel influenza A (H1N2) virus identified in Minnesota is known to circulate in U.S. swine herds. While the prevalence of the novel influenza A H3N2 virus with the 2009 H1N1 M gene in swine is unknown, the virus has been detected in U.S. swine through the United States Department of Agriculture’s swine influenza surveillance program.

In response to recent human infections with novel influenza viruses, CDC would like to convey the following information:

1. 1. CDC recommends an annual seasonal flu vaccine to protect against seasonal influenza viruses; however, a seasonal flu vaccine is unlikely to protect against flu viruses that normally circulate in swine.
2. There are two FDA–cleared drugs that are expected to be effective in treating illness associated with these viruses. The antiviral drugs oseltamivir and zanamivir – which are used to treat infection with human seasonal influenza viruses – also have shown activity against influenza viruses from swine. (For more information about influenza antiviral medications, please see www.cdc.gov/flu/antivirals/whatyoushould.htm )
3. Influenza has not been shown to be transmissible to people through eating properly handled and prepared pork (pig meat) or other products derived from pigs. For more information about the proper handling and preparation of pork, visit the USDA website fact sheet “Fresh Pork From Farm to Table.”

At this time, CDC recommends the following:

1. People who experience flu symptoms following direct or close contact with swine and who require medical attention (see below) should mention this exposure to their doctor or health care provider. (A list of flu symptoms is available at www.cdc.gov/flu/about/disease/symptoms.htm.)
2. For people who have NOT had exposure to swine and develop ILI, CDC’s recommendations for seeking treatment are the same as they are for seasonal influenza.
   1. If you have symptoms of flu and are very sick or worried about your illness contact your health care provider.
   2. Certain people are at greater risk of serious flu-related complications (including young children, elderly persons, pregnant women and people with certain long-term medical conditions) and this is true both for seasonal flu and novel  flu virus infections. (For a full list of people at higher risk of flu related complications, see www.cdc.gov/flu/about/disease/high_risk.htm.) 
   3. If these people develop ILI, it’s best for them to contact their doctor. (The majority of recent novel influenza A (H3N2) cases have been in children.)
   4. Your doctor may prescribe antiviral drugs that can treat the flu. These drugs work better for treatment the sooner they are started.

More information about swine influenza and links to all previous reports related cases of novel influenza A (H3N2) viruses infections are available on the CDC swine influenza website at www.cdc.gov/flu/swineflu/index.htm.

Source: http://www.cdc.gov/media/haveyouheard/stories/novel_influenza.html

by Agencies

04:45 AM Nov 28, 2011

//

WASHINGTON - Flu experts are gearing up their response planning, after an odd new flu virus has been detected, a senior official of the World Health Organization (WHO) said.

The virus is currently jumping from pigs to people in parts of the United States, and experts are "figuring out what needs to be done if the virus continues to spread and a global response is required", Dr Keiji Fukuda, assistant director-general for Health Security and Environment, was quoted as saying by The Toronto Star.

The virus is influenza A of the H3N2 subtype, a distant cousin of H3N2 viruses that circulate in humans.

Since the virus was first spotted in July, 10 cases have been confirmed in Maine, Indiana, Pennsylvania and Iowa.

All the victims were children under 10, with an exception - a 58-year-old adult.

Flu expert Malik Peiris, chairman of the Department of Microbiology at the University of Hong Kong, said exposure to contemporary H3N2 viruses might provide some protection against these swine viruses.

"It is important to see the serological data to see how much vulnerability or susceptibility there is in the human population," he was quoted by the paper.

The WHO's desire to be ready without causing alarm comes after its failure to communicate uncertainties about the H1N1 swine flu pandemic in 2009.

Critics said the WHO had created panic about the swine flu virus, which turned out to be moderate in its effect, and caused governments to stockpile vaccines that went unused.

http://www.todayonline.com/World/EDC111128-0000016/New-flu-virus-has-WHO-gearing-up-to-respond

Some of the media reports above reference the current flu vaccine as a good preventative measure for trH3N2. This is not true. That strain is not included in this year's trivalent flu shot.

Recombinomics Commentary 17:30
November 26, 2011
 "We have received disturbing information on the WHO alert system that the U.S. two people the virus H3N2: a seven-month child in Illinois and 46-year-old man in Pennsylvania, "- told Interfax Rospotrebnadzor head Gennady Onishchenko.
 
The WHO wants to be ready to make recommendations and issue guidance to countries if the need arises — though Fukuda stressed at this point it is far from certain there will be that need.

"We're very aware that we don't want to over-play or under-play. We're trying to get that right," says Fukuda, a leading influenza expert.

"(We're) trying to make sure that we're ready to move quickly, if we have to move quickly, but also trying not to raise alarm bells."

The desire to be prepared without raising alarm is a legacy of the 2009 H1N1 pandemic. The WHO was heavily criticized in Europe for declaring that event a pandemic when the outbreak turned out to be far milder than originally feared.

But what exactly the agency — and the world — might need to prepare for now is very unclear. With the public relations problems of the 2009 outbreak fresh in the minds of health officials, no one is using the "p" word these days.

Yet in some respects the parallels to 2009 are striking.

The above comments are from the response to the WHO pager alert (in blue), issued almost exactly one year ago, and the latest media report (in red) of current WHO pandemic plans.

The alert issued in November, 2010 cited two trH3N2 isolates (A/Wisconsin/12/2010 and A/Pennsylvania/14/2010), but WHO and the CDC were probably aware of a third case (A/Pennsylvania/40/2010) who developed symptoms less than a week prior to the Wisconsin case (cited as an Illinois cases in the alert).

If the WHO and CDC didn’t know about the second Pennsylvania case when the alert was issued, within days they knew of that case, as well as a case from Minnesota (A/Minnesota/11/2010) and symptomatic contacts.  When the CDC released the sequences from these cases, there was clear cause for concern, as seen in slide 7 from the CDC (Nancy Cox) presentation in February, 2011 (at the FDA vaccine advisory committee meeting). 

The H3 sequences from cases in Wisconsin, Pennsylvania, and Minnesota were clustering, indicating the H3 for all three cases were remarkably similar and distinct from trH3N2 swine isolates.  Moreover, the sequences from the Wisconsin case and the Pennsylvania case that was not mentioned in the alert, were virtually identical, creating striking parallels between the trH3N2 data and the initial cases in southern California at the start of the H1N1 pandemic in 2009.

However, the absence of the sequences from the second case allowed the CDC to offer assurances that there was no human transmission because of sequence differences between the two cases in the alert, which were isolated 6 weeks apart.  The announcement of the second case in Pennsylvania was delayed until February 5, because the case was initially classified as seasonal H3N2, but sequence data showed that the case was clearly trH3N2.  That sequence was used in slides 7 and 8 in the CDC February 25, 2011 presentation, but the sequence was not released until Sunday, April 17, 2011 at GISAID without comment.
As seen in slides 7 and 8, the PA/40/2010 sequence was virtually identical to WI/12/2010 and this identity extended to all 8 gene segments.  Moreover the two cases developed symptoms within a week of each other, even though they were not epidemiologically linked.  Thus, the only significant difference between the trH3N2 matches in 2010 and the trH1N1 matches in 2009 was the claim of “swine exposure” for the trH3N2 cases.

However, this “exposure” was listed in the CDC slide as a “visit to a local animal fair”.  Since the Wisconsin case was only seven months old at the time, the extent of “contact” was likely limited, and no trH3N2 was reported at any of the swine at the fair.  Similarly, the Pennsylvania case (3F) was only 3 years of age, and swine contact at the fair was also likely limited, and no trH3N2 matching the human cases has been reported from either state.  Similarly, the other case from Pennsylvania (PA/14/2010) had no reported exposure to swine, although he lived in a rural area (and closely related sequences to this case were subsequently identified in Pennsylvania swine).

Thus, the red flag raised over a year ago in the WHO pager alert signaled the start of a series of events which left little doubt that the trH3N2 had begun in 2010, and gained significant speed in 2011.  In week 21 of 2011 trH3N2 was lab confirmed (serologically) in the daughter of the Minnesota case and her lack of swine exposure led to the CDC concession that the case represented limited human to human transmission.

This concession was made again for the first 2011 trH3N2 case (A/Indiana/08/2011), who also had no swine contact.  However, the caretaker of the patient had swine exposure, so the case was said to have “indirect swine exposure” even though the caretaker and swine were asymptomatic and not trH3N2 was identified in either case.

Similarly, the first 2011 case from Pennsylvania (A/Pennsylvania/09/2010) also visited an agricultural fair (Washington county) but no symptomatic swine was identified at the fair, which included the market hogs exhibited by the second Pennsylvania case.  The third case also visited the fair and a friend who exhibited swine, but there was no evidence that any of the three cases were infected by trH3N2 in swine at the fair, and the sequences from the 2nd and 3rd Pennsylvania case (A/Pennsylvania/10/2011 and A/Pennsylvania/11/2011) were virtually identical to the Indiana case.

Thus, the matches between cases that were not epidemiologically linked as seen in late 2010, was repeated in the initial cases in 2011, although this sequence had evolved from the 2010 sequences by acquiring an NA gene matching the other Pennsylvania case (PA/14/2010) and an M gene segment from 2011.

This constellation and lineage has now been found in all 2011 human cases, including the Iowa cluster, which had no swine contact and involved three confirmed cases and two symptomatic family members of the index case.

Thus, the “swine exposure’ link, which generated the more advanced testing at the CDC required to confirm trH3N2, was absent from the Iowa cluster, leaving little doubt that the novel trH3N2 was spreading in humans and was orders of magnitude higher than the ten confirmed cases from four states (Indiana, Pennsylvania, Maine, Iowa) as well as one novel trH3N2 swine isolate from New York, A/swine/NY/A01104005/2011.

Consequently, WHO is planning for the trH3N2 pandemic, without using the “P” word.

Currently, the CDC is watching the development of a novel strain of influenza A H3N2 identified as S-OtrH3N2 [Swine-Origin, triple reassortant (H3N2)]. Triple reassortant H3N2 was first identified in pigs in 1998 (link) and a few years later found to be endemic in pigs and turkey populations in the USA with evidence of interspecies transmission (link). The first reported possible human case of trH3N2 was a farm worker from Ontario Canada in 2005 (link).

Since 2009 there have been sporadic scattered human cases in the USA, most from apparent interspecies transmission.

2009-2010 Influenza Season

http://www.cdc.gov/mmwr/preview/mmwr...cid=mm5929a2_w

2010-2011 Influenza Season

http://www.cdc.gov/mmwr/preview/mmwr...cid=mm6021a5_w

2011-2012 Influenza Season

Since July 2011, 10 additional human trH3N2 cases have been reported in the USA, all carrying the M gene from the pH1N1 virus. The virus is now officially referred to as S-OtrH3N2. The first seven of these 10 cases appear to have resulted from interspecies jump from swine to humans on different occasions.

http://www.cdc.gov/mmwr/preview/mmwr...m60d1123a1.htm

Of these seven cases 2 are from Indiana, 2 from Maine, and 3 from Pennsylvania.

Indiana (2):
1. http://www.cdc.gov/mmwr/preview/mmwr...cid=mm6035a6_w
2. http://www.in.gov/isdh/files/Week43-2011.pdf

Maine (2) : http://www.maine.gov/tools/whatsnew/...id=318365&an=2

Pennsylvania (3)
1. http://www.cdc.gov/mmwr/preview/mmwr...cid=mm6035a6_w
2. http://www.cdc.gov/media/haveyouhear...b_testing.html
3. http://www.cdc.gov/media/haveyouhear...b_testing.html

Human to Human Transmission – Iowa

Yesterday, The CDC published an MMWR report on three new S-OtrH3N2 human infections from Iowa (link). These three reported cases are all children who attended the same day care center. The staggered onset dates suggests that one of the children infected the others. And none of the children were reported to have contact with swine. In addition, another sibling and parent of the children also exhibited ILI symptoms but were not tested. These 5 individuals perhaps represent the first reported human cluster of S-OtrH3N2 infection resulting from human-to-human (H2H) transmission. These cases represent intraspecies transmission of S-OtrH3N2; the threat of this novel virus as a pandemic virus has increased.

Discussion and Implications

So far, human infections with S-OtrH3N2 have not resulted in any deaths, but several of the cases have been hospitalized. Children under 10 years are the most commonly infected individuals, suggesting that previous exposure to earlier strains of H3N2 may provide some cross-protective immunity. The ultimate virulence of this novel strain as it continues to infect human is unknown. The CDC has already developed and submitted a sample strain of this virus for potential inclusion into future influenza vaccines (link).

http://www.flutrackers.com/forum/showthread.php?t=177008

Recombinomics Commentary 22:45
November 23, 2011
 Prior to the three cases in Iowa, most human infections with this virus were associated with exposure to swine. In Iowa, however, no swine exposure has been identified. At this time, it appears that unsustained human-to-human transmission may have occurred.

The above comments are from the November 22 “Have You Heard?”, a CDC backgrounder for the media.  The latest Iowa cluster leaves little doubt that the novel trH3N2 with the H1N1pdm09 M gene is transmitting in a sustained manner.  The CDC maintains its “unsustained” claim by limiting testing.

Since the trH3N2 virus has a human H3 and N2, it frequently tests positive for seasonal H3N2.  This mis-classification can be corrected in the newly approved CDC PCR test, which has two swine genes from H1N1pdm09, but low abundant RNA samples can test negative for these markers to produce a false positive for seasonal H3N2, as was reported for a case from 2010 (A/Pennsylvanai/40/2010), as well as the second case from Maine (A/Maine/07/2011).  Therefore sequencing is required to conclusively classify the H3N2 positive case as seasonal H3N2 or trH3N2.

The CDC has released 14 sequences collected from adolescent samples that were influenza A positive since July 20, 2011.  9 of the 10 confirmed trH3N2 cases in 2011 were from patients aged 1-9.  Thus, only 5 seasonal H3N2 sequences have been identified in public sequences which include the patients age and gender, as updated below.  trH3N2 cases are in bold.

As seen below, 64.2% of the US cases were trH3N2, and the percentage for those under 10 years-of-age is 75%.  Moreover, for cases in the four states where trH3N2 has been detected, 90% of the cases have been trH3N2 confirmed (all have the H1N1pdm09 M gene and all eight gene segments are from the same lineages). 

Other than the 9 cases from children, one novel trH3N2 case was from an adult, A/Indiana/10/2011, and one case was identified in swine, A/swine/NY/A01104005/2011 .

Thus, trH3N2 is common and transmitting, and cases will explode if the CDC begins serious testing, including sequencing of influenza A positive samples from children under 10 years of age.

A/Iowa/09/2011                11/14 2M
A/Iowa/08/2011                11/14 1M
A/Iowa/07/2011                11/14 3F
A/Maine/07/2011              10/24 8M
A/Maine/06/2011              10/10 8M
A/Indiana/09/2011             10/03 1M
A/Washington/17/2011      09/14 10F
A/Pennsylvania/10/2011 08/26 9F
A/Florida/24/2011               08/25 1M
A/Pennsylvania/11/2011 08/25 9F
A/Pennsylvania/09/2011 08/20 2F
A/Louisiana/06/2011          08/16 13F
A/Florida/20/2011               08/05 8M
A/Indiana/08/2011              07/27 2M

Three children in Iowa have come down with a new type of flu virus previously linked to pigs, but this time the bug appears to have been spread by people.

The children, who live in rural Webster and Hamilton counties, did not become seriously ill, said Dr. Patricia Quinlisk, medical director for the Iowa Department of Public Health. But the detection of the virus known as swine-origin A/H3N2 in patients who hadn't had contact with animals raises concerns about potentially greater spread of a new type of flu.

"We have pretty good evidence of person-to-person spread," Quinlisk said. "None of the children or anyone around them had exposure to swine, turkeys or other sources."

Officials with the Centers for Disease Control and Prevention had previously detected seven cases of people with the new H3N2 virus that appears to have acquired a gene that may make it more transmissible from H1N1, the flu that sparked the so-called swine flu pandemic in 2009. Flu viruses often swap genetic parts. Officials say the new virus was probably formed when a pig became infected with the H3N2 virus and the H1N1 virus at the same time.

The new bug has components of human, avian, H1N1 and swine flu viruses, all mixed together in what scientists call a recombinant virus.

The first new H3N2 case was identified in a child in Indiana in July, and has been followed by cases in Pennsylvania, Maine and, now, Iowa.

In the previous cases, however, the patients either had direct exposure with pigs, or exposure to a person who'd been around pigs. In the new cases, it appears that one of the children transmitted the flu to the other two, and none of them had any animal exposure, Quinlisk said. She declined to identify the children or their ages, saying only they were younger than 18. No further cases have been identified in the past week, she said.

The Iowa cases are nothing to panic about, health officials emphasized. The H3N2 flu causes symptoms similar to the regular seasonal flu, including fever, cough, fatigue, body aches and loss of appetite. 

"People need to be most concerned about the regular, everyday seasonal flu," Quinlisk said.

But Iowa health officials are now testing samples of people with flu-like illness to detect further spread of the new bug. And CDC officials have asked states across the country to be vigilant in looking for it, said Dr. Joe Bresee, the agency's influenza and epidemiology branch chief.

The current seasonal flu vaccine being offered by doctors and clinics was not developed to protect against the H3N2 virus. It contains some antigens similar to a flu virus that circulated in the 1990s, so some people who had the flu then or were vaccinated could have some immunity, but it's not clear how much, Quinlisk said. The Iowa children apparently had not been vaccinated, she added.

With the new cases, CDC officials have confirmed 31 cases in the U.S. of the new swine-origin virus since 2005, including 10 with the H3N2 virus that carries the M gene from the 2009 H1N1 virus.

The best prevention for the new flu, as with any flu, is to wash hands frequently, cover coughs and sneezes and limit spread of germs by staying home when you're sick, health officials said.

http://vitals.msnbc.msn.com/_news/2011/11/23/8977636-new-flu-virus-in-three-iowa-kids-raises-concern-about-wider-spread

Recombinomics Commentary 14:00
November 23, 2011
Iowa has increased flu surveillance state-wide. And Cox said the CDC has asked bordering states to enhance their surveillance efforts as well.

The three children attended a small day-care together. They live in adjacent counties, Webster and Hamilton, in the centre of the state.
One became sick first and appears to have infected the other two. Quinlisk said it's not clear how the first child got infected.

Another child who is a contact of the first child was ill with what may have been influenza prior to the first child's infection, she said. But by the time laboratories had confirmed the cases, that other child had recovered.

The above comments on the trH3N2 cluster in Iowa leaves little doubt that the novel virus has spread across the United States, yet the CDC continues to deny the extent of the spread and is increasing surveillance in “bordering states”.

The trH3N2 has already been confirmed in children in Indiana, Pennsylvania, Maine, and now Iowa, in addition to a pig in New York.  Surveillance remains abysmal in spite of rates of 100% in confirmed cases in children in Maine and Pennsylvania, and 50% in Indiana.  All seven of the prior isolates match in all 8 gene segments, which also match the swine isolate in New York, signaling a jump from human back to swine.

The CDC has maintained a “swine exposure” narrative, leading to a request for samples with “swine exposure” when the first two cases were announced in the early release MMWR.  The denial of human transmission was maintained in the Maine CDC advisory claiming that all prior 2011 cases had a swine exposure, which was not true for the case in Indiana, and the cases in Pennsylvania had limited exposure to asymptomatic swine at a state fair (and only one had direct contact).  Moreover, the Maine state epidemiologist claim “no thought” of human transmission, and these agency claims were propagated by media and ProMED reports, and remarkably, this narrative on swine exposure is still be propagated by CIDRAP in its report in the Iowa cluster.
The upcoming MMWR on the cluster in Iowa should demand an increased surveillance throughout the country to get a true estimate of the extent of spread and the number of hospitalized cases.

The silent spread of a trH3N2 pandemic two years after the trH1N1 pandemic raises serious concerns about influenza surveillance in the United States and worldwide.

Recombinomics Commentary 12:30
November 23, 2011
"It appears the seasonal influenza vaccine currently available may offer some protection against this novel strain,” said IDPH Medical Director, Dr. Patricia Quinlisk.

The above comment on the cross reactivity between the current seasonal H3N2 vaccine, which targets A/Perth/16/2009, and the novel trH3N2 spreading across the country ignores the recent WHO data in its recent update on pandemic vaccines.

The report noted that production of a vaccine against A/Minnesota/11/2010 had started, and various activities were released in table 7, Antigenic properties of a recent A(H3N2 SOIV).  The A/Perth/ 16/2009 (Perth/09) anti-sera had a titer of 640 against A/Perth/16/2009, but the level dropped to 10 for A/Indiana/08/2011, the first novel trH3N2 isolated.

All seven 2011 trH3N2 sequences are closely related to each other (and the sequences from the three Iowa cases are expected to be similar), and titer will be similar.

A titer of 10 is not protective and the current seasonal H3N2 vaccine will be of little value.  Moreover, the cases in Indiana and Pennsylvania (as noted in MMWR early release on first two trH3N2 cases in 2011) had been vaccinated previously with the current tri-valent vaccine.

The H3 and N2 in trH3N2 is linked to seasonal H3N2 infection of swine in the early 1990’s, but the trH3N2 has evolved significantly from the H3N2 circulating in the 1990’s (as seen in phylogenetic trees in CDC report to FDA vaccine advisory committee), and as seen by the WHO data, the current seasonal vaccine will have little utility for the trH3N2 spreading throughout the United States.

Recombinomics Commentary 14:00
November 10, 2011
International Travel epidemic

The United States - H3N2 swine flu

Source: WHO Event Information Site for IHR National Focal Point, 2011/11/2

U.S. 11 / 1 reported two cases of swine-derived H3N2 influenza cases, prior to the onset had a history of contact with pigs. 1 case of 8-year-old boy, the incidence of 10/22, 10/24 medical treatment; the other 1 case of 58-year-old male veterinarian, the incidence of 10/20, 10/21-10/24 hospital. The United States this year, total 7 cases swine-derived H3N2 influenza cases so far in 2005 total of 15 cases.

Relevant countries and regions:

The above translation is from the Taiwan CDC website which warns of travel to all 50 US states and District of Columbia due to the two most recent trH3N2 cases described at the WHO password protected site (IHR National Focal Point) for the reporting of diseases covered by International Health Regulations.

As seen above, like the WHO update on pandemic vaccine target, the 15 trH3N2 confirmed cases are reports as beginning in 2005, although the first US case was reported in August. 2009.  Thus, the concentration of cases is far higher than indicated on the WHO website designed for submission and reporting of a variety of cases including those infected by a novel influenza, such as trH3N2.

Although media and ProMED are reporting these cases as “sporadic” jumps from pigs to people, all 7 cases from the US, including the two cases cited above, have the identical constellation of flu genes which has never been reported in swine.

The finding of the 3 or more identical constellation of genes in triple reassortant cases, other than those infected with H1N1pdm09, is without precedent and clearly signals human transmission. Thus far reported 2011 trH3N2 cases have been limited to Indiana, Pennsylvania, and Maine, the 7 cases represent 70% of influenza cases reported by these states since July, 2011.

There has been limited and biased testing in the US, due in part to the CDC request for samples in the early release MMWR describing the first two 2011 cases, which limited samples to cases with a swine exposure.

The CDC should announce a modified request for pediatric samples from cases with flu-like symptoms and/or those that are influenza A positive.  These cases cannot be tested for trH3N2 by state agencies and samples must be tested by the CDC at this time, but an expanded testing of samples without swine exposure, such as the atypical pneumonia cases in Shelby County Indiana, is long overdue.

Asymptomatic Swine Linked To Indiana Veterinarian With trH3N2
Recombinomics Commentary 12:30
November 10, 2011

1 case of 58-year-old male veterinarian, the incidence of 10/20, 10/21-10/24 hospital.

The above translation is from the travel warning issued by the Taiwan CDC regarding trH3N2 in the United States.  The warning sourced the above information to the WHO Event Information Site for IHR National Focal Point dated 11/2.

The above dates and description of the trH3N2 case matched the characterization sheet associated with the sequences released by the US CDC for A/Indiana/10/2011 and subsequently reported by the Indiana State DoH and the US CDC.

Therefore, Recombinomics contacted Dr Bret Marsh, State Veterinarian at the Indiana State Board of Animal Health, who investigated the case.  He noted that all of the swine contacted by the veterinarian prior to symptoms had been asymptomatic for at least a month prior to contact, reducing the likelihood that these swine were the source A/Indiana/10/2011.

Similar results had been reported for the caretaker for the first 2011 trH3N2 case (2M) from Indiana.  The case had no swine contact and the caretaker ,as well as the swine linked to the caretaker, were asymptomatic.

Similarly, the swine presented at the Washington County fair in Pennsylvania were asymptomatic and the disease onset dates for the two Maine cases reduces the likelihood of a swine origin for these case.  The first case (8M) was from Cumberland county and he developed symptoms on October 7 (sample collected October 10).  He attended a agricultural fair in the week prior to symptoms, which was almost certainly the Cumberland County fair, which ended October 2.  The five day gap between the end of the fair and the disease onset dates reduces the likelihood that the swine were at source of A/Indiana/06/2011.  The second case was also exposed to swine at an agricultural fair and since the second case lived in the vicinity of the first, he (also 8M) his “exposure” was also associated with the Cumberland County fair, but he developed symptoms two weeks later (sample collected October 22) significantly reducing the likelihood that the swine at the fair were a source of his infections.  Moreover, there have been no reports of symptomatic swine at the fair in Maine.

The absence of linkage to any symptomatic swine by any of the 7 confirmed cases is consistent with the sequence analysis of the isolates from the human cases, which share the same constellation of genes with each other, including an M gene from H1N1pdm09, which has never been reported in swine anywhere in the world in spite of increased swine surveillance, including SOIV sequences from swine in Indiana and Pennsylvania collected in 2010 and/or 2011.

Moreover, the trH3N2 cases dominate the confirmed cases in the above states.  The two trH3N2 cases in Maine represent the only two reported cases since July 2011.  Similarly, the Indiana cases represent 2 of the 3 influenza cases in Indiana, while the Pennsylvania cases represent 3 of the 5 confirmed influenza cases in Pennsylvania.

Thus, the swine “exposure” is more closely linked to sample collection and testing than transmission from swine, which highlights the need for aggressive testing of cases without swine exposure, such as the atypical pneumonia cases in Shelby County, Indiana.

Recombinomics Commentary 14:00
November 9, 2011
Swine-Origin Influenza A(H3N2)
Swine influenza A(H3N2) viruses are enzootic in swine herds of North America and other parts of the world. Characterisation of recent A(H3N2) viruses from swine in North America indicates that their HA genes have evolved from the human virus precursors that circulated in the mid-1990s. Isolation of swine-origin influenza viruses (SOIV) A(H3N2) from humans has been reported infrequently. The United States of America reported eight infections due to A(H3N2) SOIV between January 2005 and 15 February 2011.

A(H3N2) SOIV infections from 16 February 2011 to 19 September 2011
There have been four human infections with A(H3N2) SOIV in the states of Indiana (1) and Pennsylvania (3), United States of America, in this period. The HA and neuraminidase genes of these four viruses were similar to those of swine viruses that circulate in the United States of America. Sequencing data indicated that the matrix genes of these viruses were acquired from an A(H1N1)pdm09 virus, unlike SOIV isolates from previous human cases.

The above comments are from the WHO update on pandemic influenza vaccine targets.  The update appears to have taken some of the information from the CDC website on SOIV in humans since 2005.  That website presented very fuzzy data on the history of US cases (which has been recently clarified), which then was extended and misrepresented in the above WHO comments. Although the first triple reassortant case in the US was in 2005, all 13 H1 cases (twelve H1N1 and one H1N2) were prior to the 2009 swine flu pandemic.  The first US (SOIV)H3N2 case was in 2009 (A/Kansas/13/2009), which was followed by a second case in 2009 (A/Iowa/16/2009) and 6 cases in 2010 (A/Minnesota/09/2010, A/Pennsylvania/40/2010, A/Wisconsin/12/20110, A/Pennsylvania/14/2010, A/Minnesota/11/2010, daughter of A/Minnesota/11/2010).  Thus, the 8 cases were in a period of just more than one year, and not the 6 years cited above.  Reporting of the first Pennsylvania case was delayed 5 months and the reporting of the sequence was delayed 6 months.  The reporting of daughter of the Index case for the Minnesota cluster was delayed 6 months, and was after The February 15, 2011 cited above.

Similarly, the first reported case with an M gene from H1N1 was from an infection in late July, so the 2011 cases were reported over a 2 month time period prior to the report, and there were 3 more October cases, bring the total number of reported cases to seven over a three month period. Moreover, the first 2011 case had no swine exposure.  The CDC speculated that the case was infected by his caretaker, who had swine exposure, but neither the caretaker nor associated swine had symptoms, and no SOIV has been reported in either.

Thus, the first three cases reported in 2011 supported human to human transmission.  The Pennsylvania sequence matched the Wisconsin sequence in all 8 gene segments.  The Minnesota case lab confirmed human to human transmission in the cluster, and suggested the symptomatic contacts who tested “inconclusive” were also trH3N2 infected.  The first trH3N2 case in 2011 had no swine exposure and was acknowledged to be due to human to human transmission.  Moreover, the constellation of flu genes had never been reported in swine, and was matched by the next six trH3N2 cases in 2011.  Thus, all seven 2011 cases have the same constellation of genes which has never been reported in swine.

In spite of the overwhelming evidence for human to human transmission, the CDC early release MMWR requested samples from cases with a swine exposure, further biasing the testing for trH3N2.  This bias was extended by the Maine CDC who claimed that all 2011 trH3N2 cases had a swine exposure (which was in the advisory associated with the first October case in Maine).  Similarly, the Indiana DoH claimed that there was no novel influenza circulating in Indiana, even though the only PCR confirmed cases in week 43 was trH3N2, and this isolate was only the second confirmed flu cases in the first month of the 2011/2012 flu season (weeks 40-43).  Thus, the trH3N2 case represented 100% of the PCR confirmed cases in Indiana week 43, and 50% of confirmed cases in the 2011/2012 season.

The WHO summary also does not note the relationship of the 2011 isolates to the 2010 sequences.  However, Table 7 lists the ability of the four trH3N2 antisera (A/Kansas/13/2009, A/Wisconsin/12/2010, A/Pennsylvania/12/20110, and A/Minnesota/11/2010) to recognize the first trH3N2 from 2011, A/Indiana/06/2011.  The recognition is high because the H3 is closely related to the targets from Wisconsin and Minnesota, while the N2 is closely related to the isolate from Pennsylvania.
 
The September publication confirmed that Minnesota/11/2010 was the pandemic H3N2 vaccine target, as suggested by the release of sequences in August, and the September report was e-mailed to WER subscribers on October 21 (but was not updated to reflect the three confirmed October cases.

The two most recent October cases were the subject of reports in the media and ProMED, which noted the development of seed stocks, which were largely ignored, due in part to the representations in the CDC and WHO reports, which focused on swine exposure minimized the significance of the sequence matches, the Minnesota cluster, the lack of swine exposure in the first reported 2011 trH3N2 case, and the absence of the human contagion constellation in swine.

An outbreak of an usually mild form of pneumonia has been reported among school-age children in Shelby County, southeast of Indianapolis.

Several of the children, primarily in elementary and middle schools, have been hospitalized, the Shelby County Health Department reports.

"At least 20 students have shown a similar chest x-ray pattern, and several have required hospital admission and treatment with intravenous antibiotics," said a news release from Shelby County health officials. "The affected students are distributed throughout Shelby County, and thus the disease is not associated with any one school or other specific location or activity."

The exact cause is unknown, but it is believed to be a type of "walking pneumonia," which comes from specific bacteria that does not respond to drug treatments including penicillin and cephalexin. The bacteria can be fought with drugs including erythromycin (also known as Z-Pak), fluoroquinolones (also known as Cipro, Levaquin), and tetracyclines.

Typical symptoms include fever, cough, bronchitis, sore throat, headache and tiredness, according to the Indiana State Department of Health's epidemiology resource center, which said walking pneumonia usually is mild and rarely requires hospitalization. Infections of the middle ear

also can result.

Symptoms may persist for a few days to more than a month, according to the state center. Symptoms begin 15 to 25 days after exposure and generally develop slowly, over a period of two to four days.

The State Department of Health provided local physicians with testing kits for the bacteria mycoplasma to help determine if it is the cause of the ailment, Shelby County authorities said. The bacteria are transmitted via droplets from coughs or other contact with saliva.

There are no vaccines to prevent mycoplasma pneumonia, the state reports.

Children with the ailment should stay home from school, the health department said.

"If your children have a cough and any of the symptoms above, please keep them home from school and seek evaluation from your primary care physician," the release said. "As always, cough into your sleeve, wash your hands frequently or use antibiotic hand gel, and dispose of tissues properly."

http://www.indystar.com/article/20111108/LIVING01/111080396/Pneumonia-breaks-out-among-Shelby-County-children?odyssey=mod|newswell|text|IndyStar.com|s

Atypical Pneumonia in Indiana Children Raise trH3N2 Concerns
Recombinomics Commentary 19:45
November 8, 2011
"Every time it went away it would always come back, and it was 102," said parent Kim Dickmann.

Her son Luke, 6, has pneumonia.

"When you start seeing chest X-rays with infiltrates, fluid in the lungs, you know this is more than just your typical illness," said Dr. Paula Gustafson, a Shelby county pediatrician.

Gustafson said she saw 15 possible cases of pneumonia last week and upward of five possible cases on Monday.

"We've had some of them complain about intense cough, tightness in their chest, they've been on a couple rounds of antibiotics, and they aren't getting better," she said.

The above comments describe an atypical pneumonia in elementary and middle school students spreading throughout Shelby County, Indiana.  The Shelby County health department is treating the outbreak as Mycoplasma, but as seen above, cases have a high temperature and are not responding to antibiotics and there has been no lab confirmations reported.  Moreover, at least five of the more than 25 symptomatic students have been hospitalized.

The age demographic matches that of most confirmed trH3N2 cases this year (six of the seven were 9 years of age or younger), of which two were in Indiana.  Media reports do not suggest these patients have been tested for influenza.

More information on testing would be useful.

Recombinomics Commentary 17:45
November 2, 2011

Maine confirmed a second case of swine origin novel influenza A virus. The first case was confirmed on October 17th, and the second case was confirmed October 31st. Both cases had multiple exposures to pigs.

The above comments are from the Maine week 43 influenza surveillance report, and extends the number of 2011 trH3N2 cases with swine “exposure” to six, and it is likely that the seventh case (59M) will also have some sort of “exposure” raising concerns that the absence of cases without an exposure represents a charade which withholds such cases pending results of ongping epidemiological investigations.  All seven of the 2011 cases reported to date have the same constellation of flu genes, which has never been reported in swine in spite of increased swine surveillance and public sequences from swine isolates as recent as July, 2011.

The emergence of a trH3N2 human contagion was predicted by sequences from 2010 isolates, which were released after WHO issued a pager alert on two cases (in Illinois and Pennsylvania).  The pager alert created some concern, especially in eastern Europe, but the CDC noted that although both cases were H3N2 triple reassortants, sequence differences indicated the trH3N2 was not transmitting in humans.
However, the release of the sequences (at GISAID) revealed clustering of sequences and linkage to sequence isolate from a trH1N1 outbreak in Huron County, Ohio in 2007.  This outbreak yielded isolates from a presenter and her father (A/Ohio/01/2007 and A/Ohio/02.2007), which included internal genes which were precursors to the genes in the trH3N2 isolates.  Moreover, two dozen Huron fair attendees had flu-like symptoms, which are uncommon in August in Ohio, suggesting the trH1N1 spread well beyond the two confirmed cases.

The first trH3N2 case in the United States was from an infection two years after the Huron County outbreak.  The Kansas case, A/Kansas/13/2009, was followed by a case in Iowa, A/Iowa/16/2009, and one in Minnesota in early 2010, A/Minnesota/09/2010.  The isolates from the two cases in the pager report were A/Wisconsin/12/2010 and A/Pennsylvania/14/2010.  Just after the pager alert, a second case in Minnesota, A/Minnesota/11/2010 was reported, and additional cases in Minnesota were under investigation. The H3 sequence in the Minnesota isolate was closely related to the Wisconsin sequence, as were most of the other genes, which extended the clustering.

This trend was accelerated by the first two cases confirmed in 2011, which were cases that experienced significant reporting delays.  The first case (also from Pennsylvania) had developed symptoms less than a week prior to the Wisconsin case, but had been initially characterized as seasonal H3N2 and confirmation of trH3N2 was delayed due to technical issues linked to virus isolation.  Consequently, the case was reported 5 months after infection, and the sequence, A/Pennsylvania/40/2010, was closely related to the Wisconsin sequence, voiding the CDC assurances that followed the WHO pager alert.

The assurances were also voided by the second case reported in 2011, which was the daughter of the Minnesota case.  trH3N2 infection was lab confirmed by serological studies, which led to a six month delay in reporting.  The daughter had no swine contact, and represented the first lab confirmed examples of human transmission of trH3N2.  Like the Huron outbreak, the number of infections was likely markedly higher than the lab confirmed cases, because additional Minnesota family members had symptoms, but lab results were “inconclusive”.

Thus, the first two cases reported in 2011 strongly suggested that trH3N2 was transmitting based on sequence similarities between the cases in Pennsylvania, Wisconsin, and Minnesota, as well as lab confirmation of the Minnesota cluster.

However, the sequence data supporting human transmission was increased dramatically by the 2011 infections.  The first case reported was in Indiana and that case, A/Indiana/08.2011 also had no swine contact.  However, his caretaker had swine contact, but neither the caretaker nor the associated swine were symptomatic, and no evidence of SOIV infection has been reported.  The sequences from this case were novel.  Five of the gene segments, including H3, were closely related to the dominant sequence from 2010 (A/Pennsylvania/40/2010, A/Wisconsin/12/2010, A/Minnesota/11/2010, and the daughter of the Minnesota index case).  The NA gene however was closely related to the N2 of the other human case from late 2010, A/Pennsylvania/14/2010, while the PB1 gene was closely related to the sequence from the two confirmed 2007 cases in Ohio.

Of most interest however, was the M gene segment, which was acquired from H1N1pdm09, and this acquisition was of significant concern because a recent study indicated that the M gene was critical for the jump of H1N1pdm09 from swine to humans.  Moreover, this constellation of genes had not been reported in swine.

Concerns increased when the CDC issued an early release MMWR, which included the Indiana case as well as a case from Pennsylvania, A/Pennsylvania/09/2011, which had the same constellation of genes.  It was a drift variant, so the CDC noted that the same source for the Indiana and Pennsylvania was unlikely because of minor sequence differences.  However, these assurances were voided by two more cases from Pennsylvania, who like the first case had attended the Washington County fair.  These sequences matched each other, as well as the Indiana case, supporting human transmission.  Moreover, although swine were exhibited at the fair, there were no reports of symptomatic swine or identification of SOIV infection.

The emergence of a new human contagion was supported further by the first case in Maine (8M), which had a matching constellation of genes a seen in A/Maine/06/2011.  Swine exposure at an agricultural fair (likely the Cumberland County fair) was again cited, but no symptomatic swine were reported.  That case was followed by another case from Maine, A/Maine/07/2011, and Indiana, A/Indiana/11/2011 which were also from patients infected in October by trH3N2 related to each other and the first Maine case.

Thus, all seven 2011 cases have the same constellation of genes which has not been reported in any swine.  In spite of this strong evidence of human transmission, all reported cases have a loose “swine exposure” component, suggesting cases without a swine exposure are being withheld pending epidemiological investigations.
trH3N2 cases without some sort of swine exposure, would confirm widespread human transmission and the start of a new pandemic, and this announcement has been delayed by the charade that releases sequences from cases with a swine exposure, and delays confirmation of cases without an exposure.

Details on suspect trH3N2 cases under investigation are long overdue.

Recombinomics Commentary 12:45
November 1, 2011
 The CDC has released sequences (at GISAID) for new trH3N2 cases in Indiana, A/Indiana/11/2011, and Maine, A/Maine/07/2011.  Full sequences from the Indiana case (59M collected September 22) indicate all 8 gene segments are closely related to the five prior 2011 trH3N2 cases.  Partial sequences (HA, NP, MP) from the Maine case (8M collected September 24) indicate it is also closely related to the prior human isolates from 2011.  The CDC is again commended for the rapid release of these important sequences.

These sequences leave little doubt that the novel trH3N2 human contagion is transmitting in humans.  More detail on swine contacts would be useful.  However, it is clear that trH3N2 in humans is far more common than indicated by the seven trH3N2 cases. 

A recent CDC paper describes fatal unsubtyables in the 2009/2010 season, which may represent additional trH3N2 cases which have not yet been confirmed.

Three October trH3N2 Maine and Indiana Cases Match
Recombinomics Commentary 16:45
November 1, 2011

The CDC has released two more sets of trH3N2 sequences from recent cases and once again the CDC is commended for the rapid release of sequences from these October cases.  The two cases (A/Indiana/11/2011 and A/Maine/07/2011) were collected two days apart (October 22 and October 24), but are closely related to each other, as well as the Maine case, A/Maine/06/2011, also collected in October (October 10, 2011).  The close relationship between all three October cases strongly supports human transmission, which is further supported by the close relationship between all seven of the 2011 cases, which are distinct from all swine isolates.

Thus, the human cases form two branches, those collected in July and August (A/Indiana/08/2011, A/Pennsylvania/09/2011, A/Pennsylvania/10/2011, A/Pennsylvania/11/2011) forming one branch, and those collected in October (A/Maine/06/2011, A/Indiana/11/2011, A/Maine/07/2011) forming another. 

The close relationship between isolates from different states also supports human transmission.

Similarly, the first Maine case was from Cumberland County and he had attended an agricultural fair prior to disease onset on October 7.  This fair was likely the Cumberland County fair, which ended October 2 and therefore was an unlikely source for the more recent Maine case, whose trH3N2 came from a sample collected two weeks after the first Maine case.  Moreover, the Indiana case is not likely to have been linked to the two cases in Maine.

The bizarre reporting of early unsubtypables suggested additional cases without swine “exposure” would be reported. 

Detail on swine exposure for the two latest cases would be useful.

Recombinomics Commentary 12:25
October 31, 2011
CDC has confirmed the fifth case of human infection with a swine–origin influenza A (H3N2) virus that carries the M gene from the 2009 H1N1 virus. This virus was first detected in a child in Indiana in July.  Subsequently three additional cases of human infection with swine–origin influenza A (H3N2) viruses carrying the same genetic change were detected in Pennsylvania. Though rare, human infections with swine–origin influenza viruses can occur, usually after close contact with infected swine.

The acquisition of the M gene likely occurred as a result of swine being co–infected with the swine influenza A (H3N2) virus and the human 2009 H1N1 virus. While we know the M gene plays a role in influenza virus infection, assembly and replication, the significance of this change in these swine–origin influenza A (H3N2) viruses is unknown at this time. CDC continues to investigate the implications of this genetic change.

The above comments from the latest CDC “Have You Heard?” acknowledges the fifth trH3N2 human isolate with the M gene from H1N1pdm09 (pandemic H1N1), as well as an interest in this acquisition, but still maintains the CDC narrative that these infections are rare and linked to close contact in swine, which is not supported by the sequences.  The Maine case provided compelling evidence for an emerging trH3N2 human contagion based on sequence data supporting evolution in humans.

This sub-clade has been reported in all five 2010 human isolates A/Indiana/08/2011, A/Pennsylvania/09/2011, A/Pennsylvania/10/2011, A/Pennsylvania/11/2011, A/Maine/06/2011), in contrast to the human trH3N2 sequences in late 2010, where most of isolates shared most of the gene segments.  In 2011 all human isolates share all gene segments which create a novel sub-clade which has never been reported in swine, in spite of increased surveillance for SOIV (swine origin influenza virus) in swine.

Recent reports have highlighted the importance of the M gene.  One report looked at gene segments in H1N1pdm09 to determine how the virus jumped from swine to humans, and concluded that the M gene segment was critical.  Another report noted the increased reassortment in swine from the US and noted that the M gene from H1N1pdm09 was central to the reassortants, which had various H and N swine triple reassortant combinations surrounding  internal genes from H1N1 pnd09, including the M gene segments.

Sequences from the increased swine surveillance describe two July isolates (July 16), A/Texas/A01104003/2011 and A/Texas/A01104004/2011, which have all eight gene segments from H1N1pdm09, which contain S188T, which represents the dominant H1N1 circulating in humans in 2011.  The recent collection date signals an active surveillance campaign, which has identified additional constellations with an M gene from H1N1pdm09.

Another July isolate (July 8), A/swine/Illinois/A00907647/2011, has an H1N1pdm09 M gene, as well as an NA gene that is closely related to the human trH3N2 isolates.  However, this swine isolate has an H1 and is likely to be similar to other H1N2 isolates collected in 2010 (A/swine/Minnesota/A01047604/2010 and A/swine/South Dakota/4/2010)) and 2011 (A/swine/Minnesota/A01049956/2011, A/swine/Iowa/A01049723/2011, A/swine/Iowa/A01049728/2011, A/swine/Indiana/A01049964/2011, A/swine/Illinois/A01049871/2011, A/swine/Illinois/A01049872/2011, A/swine/Iowa/A01049887/2011, A/swine/Iowa/A01049722/2011), which have multiple internal genes from H1N1pdm09.

In addition to H1N2 isolates with an H1N1pdm09 M gene, enhanced surveillance has also found H3N2 swine isolates (A/swine/Texas/A01049555/2011, A/swine/Texas/A01049556/2011, A/swine/Indiana/A01049750/2011, A/swine/Texas/A01049914/2011, A/swine/Texas/A01049915/2011) which likely have a similar set of internal genes (only the M gene sequence has been released in addition to the H3 and N2 sequences).  However, this swine H3 gene is easily distinguished from the H3 sequence found in all human 2011 trH3N2 isolates, which is closely related to the dominant sequence found in the human 2010 trH3N2.

This sequence has also been found in 2010 and 2011 swine isolates (A/swine/Indiana/A0109091/2010, A/swine/Indiana/A01049744/2011, A/swine/Indiana/A01049745/2011, A/swine/North Carolina/A01049436/2011, A/swine/Indiana/A01049653/2011),  but these swine isolates have a swine M gene. 

Thus, none of the swine isolates, including those from July, 2011,, match the human 2011 isolates, which match each other in all 8 gene segments.

This human sub-clade has evolved from the 2010 human trH3N2 isolates, which match in 5 of the 8 gene segments (PB2, PA, HA, NP, NS).  The PB1 represents the same lineage, but is more closely related to the sequences from 2007 H1N1 isolates, A/Ohio/01/2007 and A/Ohio/02/2007, which did not have E618D, which emerged in human trH3N2 (and is present in virtually all H1N1 pdm09 isolates).  The NA is in the above swine H1N2 isolates, but is also in the second 2010 human trH3n2 isolate, A/.Pennsylvania/14/2010, from Pennsylvania.  Thus, all eight gene segments in all five human 2011 isolates have been found in prior human isolates, once again signaling human adaptation.

Thus, the presence of these eight gene segments in all five human isolates, and the absence in all reported swine isolates, strongly supports human transmission, and the absence of human isolates without swine contact raises concerns that such isolates have been withheld because the absence of a swine epidemiological link is still under investigation.

Details on such cases should be released immediately.