Is H7N9 Spreading from Human to Human in China?

[jflorida]

Re: Is H7N9 Spreading from Human to Human in China?

U.S. to provide Taiwan with virus strain for H7N9 vaccine [ http://focustaiwan.tw/news/aall/201304100022.aspx ]

Taiwanese officials in the U.S. have informed the government that once the U.S. develops a seed vaccine for the disease, the U.S. will provide it to Taiwan so that Taiwan can make its own vaccine, Ma said during a visit to the Central Epidemic Command Center.

The president also instructed relevant agencies to be on high alert for a possible spread of the disease in Taiwan, saying that the serious acute respiratory syndrome (SARS) that created panic a decade ago was spread to Taiwan from China at a time when there were no direct flights across the Taiwan Strait.

With today's closer cross-strait interactions and more than 600 direct flights each week, Ma said Taiwan cannot afford to lower its guard.

 

[Nika]

Re: Is H7N9 Spreading from Human to Human in China?

Isn't chicken feet (maybe bird feet in general) um a 'delicacy' there? If these birds are walking around through infected feces then they may themselves not be infected, but be able to carry the infection to other locations. For that matter you may not have to eat the feet at all, they'd just need to perch on something you touch then touch your eyes or mouth with.

I raise chickens for eggs and meat. I do my own butchering too. The feet are amazing for making broth.

One must clean the feet before using. The feet are washed extensively. Then you scald them and then you peel off a tough outer layer of skin/keratin scales. Whats left is as clean as any other part of a clean chicken carcass.

Re plucking ... U dip the dead chicken up and down in hot water (gets filthy very fast) and soak down to the pin feathers but only until u can pull feathers out and before the chicken gets cooked. There is nothing clean about this process. Once plucked u rinse very very well and then put it into ice water as it waits for u to butcher it as soon as possible (minutes).

 

[NS1]

Re: Is H7N9 Spreading from Human to Human in China?

With the current H7N9 Hemagglutinin polymorphism constellation, neither major PB2 mammalian revision is required to be dominant prior to transmission from avian to mammal.

Several of these emergent H7N9 HA polymorphisms are found across mammal infections in multiple Influenza A serotypes.

Felicity finds function from experiential proximity.

And the proof is in the proximity.

 

[Laidback Al]

Re: Is H7N9 Spreading from Human to Human in China?

The case report on the first two H7N9 cases has just been published.

H7N9 avian influenza virus - search and re-search
Citation: Emerging Microbes & Infections (2013) 2, e18; doi:10.1038/emi.2013.18
Published online 10 April 2013

Link to full article: http://www.nature.com/emi/journal/v2/n4/full/emi201318a.html

This report identifies the date of death for 87-year-old Li (Lee) as February 27, 2013 and the date of death for the 27-year-old Wu as March 4, 2013. A look through the posts here at FluTrackers shows that Mr. Li was reported to have died on March 4 and Mr. Wu on March 10. Even the Ministry of Health reported these dates. link

When dates of death have such a large margin of reporting error in China, it makes you wonder how accurate the other official reports are.

 

[Laidback Al]

Re: Is H7N9 Spreading from Human to Human in China?

NEJM - Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus

And now a case review in NEJM continues to identify the date of death for Case 1 and Case 2 as March 4, 2013 and March 10, 2013, respectively. Clearly one of the studies must be wrong.

link to full text of NEJM article: http://www.nejm.org/doi/full/10.1056/NEJMoa1304459#t=articleTop

hat tip to Catbird

 

[Laidback Al]

Re: Is H7N9 Spreading from Human to Human in China?

Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

The first indication of human-to-human transmission (H2H) of a novel disease is the identification of a localized geographic cluster of several individuals with similar symptoms within a short time span. Such clusters can result from infections from a common nonhuman host, so collecting detailed case data is the first step in determining whether humans are infecting each other. Of course, sequence analysis, when available can differentiate infection sources.

So H2H spread will be first recognized in a localized cluster of cases that have a high probability of transmitting the virus between individuals.

So far there have only been three possible localized cluster reported by China for H7N9.

Cluster 1: Lee family, Shanghai (probable)

The first H7N9 case officialy reported from Shanghai, an 87-year-old-man surnamed Lee, was one of three family members admitted to a hospital in mid to late February. Mr Lee died on either February 27 or March 4 (see discussion above). One other relative also died during this period. Of the three hospitalized cases only the 87-year-old family member was confirmed with H7N9.

link: http://www.flutrackers.com/forum/sho...d.php?t=201633


Cluster 2: Gu Family Cluster, Shanghai (confirmed)

The second cluster, this one confirmed, represents a family cluster of a husband and wife from Shanghai. The wife had symptoms starting on March 27, was hospitalized, and died on April 3rd. The husband experienced symptoms on April 1st, was hospitalized on April 4th, and apparently is still being treated.

This cluster could be H2H or infection from a common nonhuman host.

link: http://www.flutrackers.com/forum/sho...d.php?t=203779

Cluster 3: Beijing Neighborhood Cluster (confirmed)

Two children who are neighbors in Houshayu in Shunyi district have been confirmed with H7N9. A 7-year-old girl surnamed Yao, started experiencing symptoms around April 11 and is still being hospitalized (FT link). Today, a neighbor child, a 4-year-old boy surnamed Chuk (?), is reported to be asymptomatic but tested positive for H7N9. Media reports indicate that the parents of the girl were engaged in the poultry business and the parents of boy may have purchased some poultry from the girl's parents (FT link).

There are conflicting reports that one or both parents of the girl, who were keeping her company in the hospital, are exhibiting ILI symptoms.

As of today, the two children, both confirmed cases, could have resulted from infection from a common source. If the parents of the girl are sick and confirmed with H7N9, or if this cluster grows, H2H transmission need to be carefully evaluated.

Conclusion

Sustained H2H transmission is not demonstrated by any of these clusters -- yet. <object style="position:absolute;z-index:1000" type="application/x-dgnria" id="plugin0" height="0" width="0">

</object>

 

[gsgs]

Re: Is H7N9 Spreading from Human to Human in China?

some say the girl's family got the chickens from the boy's family
which seems to make h2h less likely.

Can our newshounds figure that out, please ?

the boy4 got it from the girl7 or vice versa or from either parents
and their poultry ? Who went through the stories

p(girl7)sell chicken and fish in another district
p(boy4)sell chicken across the street of p(girl7)
girl7 bought chicken from boy4

-------------------------------------------------------------------
p(boy4) are poultry and fish sellers, and their neighbors across the street
had bought chicken sold by p(girl7)
boy4 was one of 24 people tested in connection with girl7's infection.
p(girl7) live and sell poultry in Shunyi,NE-Beijing
--------------------
The bamboo surname boys parents engaged in poultry fish to the sale of the work,
its across the street neighbor bought Beijing first case of human infection of H7N9
avian influenza confirmed cases have trafficked chicken.
------------------------
monitoring the father of cases of trafficking poultry crowd, found a 4-year-old bamboo
surname boys H7N9 avian influenza virus nucleic acid positive.
The boys' parents engaged in the sale of poultry fish, its across the street neighbor
bought the family of the first confirmed cases of trafficking chicken.
found a father first case of human infection of H7N9 avian influenza confirmed cases
of trafficking poultry populations Active screening monitoring 4-year-old bamboo surname boys
---------------------------------------
http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/apr1413china.html
http://www.flutrackers.com/forum/showthread.php?t=203835

 

[gsgs]

Re: Is H7N9 Spreading from Human to Human in China?

E627K may have evolved in each human separately after
catching a H7N9 from chicken.
Maybe H7N9 only infects humans, when it has a special NP


H5N1,Qinghai-strain,K627E,LD50 in mice increased by 3 orders of magnitude,
lethality in chicken remained at 100%
reverted to PB2-627K after only one passage in mice but did not revert in chickens
Reversion to PB2-627K in mammalian cells required the presence of the
[Qinghai] nucleoprotein (NP). This finding corresponds to results of others that during
replication of avian strains in mammalian cells, PB2-627K restores an impaired PB2-NP
association.
http://jvi.asm.org/content/85/20/10691.full


also: http://jvi.asm.org/content/86/17/9211.full

 

[JJackson]

Re: Is H7N9 Spreading from Human to Human in China?

E627K may have evolved in each human separately after
catching a H7N9 from chicken.
Maybe H7N9 only infects humans, when it has a special NP


H5N1,Qinghai-strain,K627E,LD50 in mice increased by 3 orders of magnitude,
lethality in chicken remained at 100%
reverted to PB2-627K after only one passage in mice but did not revert in chickens
Reversion to PB2-627K in mammalian cells required the presence of the
[Qinghai] nucleoprotein (NP). This finding corresponds to results of others that during
replication of avian strains in mammalian cells, PB2-627K restores an impaired PB2-NP
association.
http://jvi.asm.org/content/85/20/10691.full


also: http://jvi.asm.org/content/86/17/9211.full

I have tried to address this, from a mechanistic point of view, in post #50 & #67 on this thread.
As the Chinese are not releasing their sequence data at present we have little to go on but my working hypothesis is that most human infections are still from an avian source (only limited H2H so far) and that the avian hosts have predominately E627. As flu operates as a quasi species (the virus in a given host are not all the same genetically) the human host may get some K627 in the initial infection and then select for it or may be creating the E627K change as it generates its own constellation of variants.(When a sample is sequenced the most common amino acid (AA) at each point on the RNA is listed but there will usually be some % of other AAs e.g. 80% K627 & 20% E627 would be a K627 in the PB2 sequence data)
As can be seen from Gs's post

reverted to PB2-627K after only one passage in mice but did not revert in chickens

a single passage is enough time to change the protein at position 627 given enough selection pressure.
Re.

Maybe H7N9 only infects humans, when it has a special NP

If readers review #50 at the earlier link they will see that PB1, PB2, PA & NP form a functional set involved in kick starting the replication process in the new host. Although I did not mention it the infecting virus carries within it a starter set of these proteins from its old host. If the host was avian this set will probably be the E627 form but once replication is under-way as K627 mutations occur a mammalian host will favour them and they will become the norm. From this it should be clear that the RNP set that starts the infection is what ever the old host had and is not involved in cell entry and only needs to be 'good enough' in the new host to work in the first cell infected. Once the old RNP is producing mRNA in its new host sloppy replication can do the rest. The above also, hopefully, accounts for this finding.

Reversion to PB2-627K in mammalian cells required the presence of the [Qinghai] nucleoprotein (NP). This finding corresponds to results of others that during replication of avian strains in mammalian cells, PB2-627K restores an impaired PB2-NP association.

It may also be helpful to think through what happens across the infection cycle.
One or, possibly more, virions from the old host seed an infection.
The imported RNP and genetic package get replication under-way.
The sloppy RNP creates a range of mutations (including those genes that code for the RNP).
Those best adapted to the new host are most successful in infecting new cells.
Up to this point the interaction is largely on a virus to cell basis.
Once the infection really gets under-way the host immune system gets aggressive and the patient gets symptomatic to some degree.
The immune system either wins or the patient dies.
At some point in the process the host may, or may not, seed a new infection. If they do it is most likely to be with the most dominant strain(s) in their system at the time and will include a starter kit of that RNP.
Return to step one and repeat.

If this keeps repeating - as it seems to be at present in China - some of the hosts will produce viral forms which are better able to infect a human. Initially they may not be very good at it and clusters will be limited to very close personal contacts but these are seeded with a better human optimised starting kit. This new host can tinker with the mix and improve its H2H ability so a 'reasonably close' rather than 'very close' contact will suffice. Again return to step one and repeat until you have a human not bird flu.
If the avian form, with ability to infect mammals, is well established and fit there does not seem to be any way out of this loop unless you can stop bird to human contact. As we do not know how most cases got infected it could be by the fomite route (bird droppings probably) which could be almost impossible to prevent, assuming it is well established in wild birds as well as domestic poultry.

 

[Laidback Al]

Re: Is H7N9 Spreading from Human to Human in China?

. . .
Up to this point the interaction is largely on a virus to cell basis.
Once the infection really gets under-way the host immune system gets aggressive and the patient gets symptomatic to some degree.
The immune system either wins or the patient dies.
At some point in the process the host may, or may not, seed a new infection. If they do it is most likely to be with the most dominant strain in their system at the time and will include a starter kit of that RNP.
Return to step one and repeat.

If this keeps repeating - as it seems to be at present in China - some of the hosts will produce viral forms which are better able to infect a human. Initially they may not be very good at it and clusters will be limited to very close personal contacts but these are seeded with a better human optimised starting kit. This new host can tinker with the mix and improve its H2H ability so a 'reasonably close' rather than 'very close' contact will suffice. Again return to step one and repeat until you have a human not bird flu. . .

So in each infected individual the virus is experimenting and making "sloppy" copies. Some of these may be better for human transmission and some may not. External factors such as host vitality, treatment, additional available hosts, will affect whether or not the more fit, more adapted virus is transmitted to another human or animal host.

Is this correct?

Given this progression it would seem that eventually the virus will become sufficiently adapted to become easily transmissible among humans. But When would this happen?

Looking at human H5N1 infections as a parallel model, we know from lab experiments that "transmissibility" is possible. We also, know that ease of transmission has not yet occurred naturally in the population and we have been watching H5N1 for a decade.

On the other hand there have only been about 600 confirmed H5N1 cases since 2003. We have now had about 80 confirmed H7N9 cases in the past two months. It took from from 2003 to 2005 to accumulate that many confirmed H5N1 cases.

 

[JJackson]

Re: Is H7N9 Spreading from Human to Human in China?

So in each infected individual the virus is experimenting and making "sloppy" copies. Some of these may be better for human transmission and some may not. External factors such as host vitality, treatment, additional available hosts, will affect whether or not the more fit, more adapted virus is transmitted to another human or animal host.

Is this correct?

To the best of my knowledge - Yes. If you give them Tamiflu then any variant with one of the Oseltamivir resistance marker will be given a selective advantage. If the host has met a surface antigen before (not likely with H7N9) then that would be selected against. While the mutations are random which wins out is not.

Given this progression it would seem that eventually the virus will become sufficiently adapted to become easily transmissible among humans. But When would this happen?

Not a clue. The virus obviously has some barriers to overcome but what they are and how likely they are to first occur and second be fit is beyond me, and I suspect even for virologist who do this for their day job.

Looking at human H5N1 infections as a parallel model, we know from lab experiments that "transmissibility" is possible. We also, know that ease of transmission has not yet occurred naturally in the population and we have been watching H5N1 for a decade.

On the other hand there have only been about 600 confirmed H5N1 cases since 2003. We have now had about 80 confirmed H7N9 cases in the past two months. It took from from 2003 to 2005 to accumulate that many confirmed H5N1 cases.

I know there is an active debate about how many sub-clinical/undiagnosed human H5N1 cases there have been based on contradictory sero-prevalence studies but my gut feeling is it is a lot more severe in humans than H7N9. As a consequence I am expecting - if and when we have sero-prevalence data for H7N9 - to find far more human cases than H5N1 generated, even given this has probably only been causing infections for a year or so. As I posted, in another thread, I think this is much more likely to go pandemic but if I were to make a wild guess it would be more of a problem than H1N1(2009) but not in the same league as an HP H5N1 pandemic. As both are avian viruses, not human, it is wild guess work at this stage to say anything very much about the virulence of a human pandemic case zero, as this does not exist, and would be the genetic progenitor of all subsequent human infections.

 

[gsgs]

Re: Is H7N9 Spreading from Human to Human in China?

I calculate ~1000 replications per year, each 8hours.
With 35 mutations per year and 13000 nucleotides
and only considering A-G,C-T mutations we get
a probability of 2e-6 that one specified nucleotide mutates
in one replication. 2 days after infection with 627E and 6 replication cycles
you have maybe 0.1% of your 50T cells infected and 5e15 viruses
5e10 of which are 627K.
If 627K would have double as much progeny per following cycle
as 627E, that gives a balance of 627E and 627K after ~3 further days.

It could depend on how quickly immunity sets in and that could be
slower in the elderly, 627K would only develope in big numbers
late in the disease

 

[JJackson]

Re: Is H7N9 Spreading from Human to Human in China?

I calculate ~1000 replications per year, each 8hours.
With 35 mutations per year and 13000 nucleotides
and only considering A-G,C-T mutations we get
a probability of 2e-6 that one specified nucleotide mutates
in one replication. 2 days after infection with 627E and 6 replication cycles
you have maybe 0.1% of your 50T cells infected and 5e15 viruses
5e10 of which are 627K.
If 627K would have double as much progeny per following cycle
as 627E, that gives a balance of 627E and 627K after ~3 further days.

It could depend on how quickly immunity sets in and that could be
slower in the elderly, 627K would only develope in big numbers
late in the disease

In one of your earlier posts you noted that on certain genetic backgrounds the E627K change was found, experimentally, to create a ~1000 fold increase in virulence. If that is solely, or even largely, due to more efficient replication then your

If 627K would have double as much progeny per following cycle as 627E

could be a lot higher. But I would certainly agree that the longer the infection is given to run, before seeding a new host, the further it would have adapted to any applied selection pressure. I will trust the rest of your math which only effects the speed and not the principle anyway.

 

[JimO]

Re: Is H7N9 Spreading from Human to Human in China?

It appears that H2H transmission in the first cluster has been confirmed.

see: http://www.flutrackers.com/forum/showthread.php?p=493553#post493553

So, the mantra for the next few weeks will be no "sustained" H2H transmission.

 

[Giuseppe]

Re: Is H7N9 Spreading from Human to Human in China?

Bump this

 

[jeffrey]

Re: Is H7N9 Spreading from Human to Human in China?

Thank you Giuseppie for putting some calm on this whole "Pandemic" flu. Not saying it wont go that way, and I certainly have none of your expertise or anyones, but I do read alot and at this time I think we need to all wait and see when we get the proper information and we will. IMO, because of H1N1 and H5N1, people are just a little uneasy, I know I am, but it is this type of calm nature that helps people put things into perspective. Thank you! :tiphat:

 

[Giuseppe]

Re: Is H7N9 Spreading from Human to Human in China?

But, regarding the Shanghai familiar cluster, here the tweets of the day:

@HelenBranswell Good news MT @HaertlG: @WHO

''#H7N9 serosamples are apparently being collected and will be tested when serotest is available.''

‏@ironorehopper--> @HelenBranswell--> @HaertlG--> @newprof1--> @WHO

''It seems that among 5 patients identified retrospectively in Shanghai, some was discovered w/Serum''

@HaertlG--> @ironorehopper--> @HelenBranswell--> @newprof1--> @WHO-->

''The existing #H7N9 seratest is unreliable and has to be confirmed with further lab work.''

‏@ironorehopper--> @HaertlG--> @HelenBranswell--> @newprof1--> @WHO-->

''Really! It's strange, thus, to have almost a couple of conf. cases with this method...''

‏@HaertlG--> @ironorehopper--> @HelenBranswell--> @newprof1--> @WHO-->

''#H7N9 seratests followed up by other tests in order to confirm.''

----

 

[Laidback Al]

Re: Is H7N9 Spreading from Human to Human in China?

I am not ready to concede H2H transmission in this family cluster. The details are hazy and given how little we know about H7N9 these individual could have all been exposed to the same source, e.g. pet animals, a big chicken dinner, who knows.

What is significant is that clusters are not yet increasing in numbers. Counting this family as a confirmed cluster, we are only up to three clusters (link).

I don't think anyone here at FluTrackers is "crying wolf". We are all just trying to understand what is going on so we can make prudent decisions about the future.

 

[Emily]

Re: Is H7N9 Spreading from Human to Human in China?

So, the mantra for the next few weeks will be no "sustained" H2H transmission.

And it could be the mantra for years.

 

[Giuseppe]

Re: Is H7N9 Spreading from Human to Human in China?

But if the Hartl said that 'serodiagnostics' is unrealiable, then how did Chinese make the diagnosis after four-fold increase in Abs titer for the above mentioned case?