Why blood of bird flu survivors is a lifesaver [Discussion]

[JJackson]

Why blood of bird flu survivors is a lifesaver [Discussion]
http://www.flutrackers.com/forum/showthread.php?t=9775
http://www.timesonline.co.uk/article/0,,25149-2333845,00.html

Those of you who have read my posts before are probably aware I am not expecting there to be useful quantities of vaccine during the first wave or waves of a pandemic and that I expect any pandemic form of the virus to develop Tamiflu resistance in short order – I will not reiterate my reasoning here.
Anything that looks like it has the potential to mitigate the effects of a sever pandemic and be scaleable, at reasonable cost, tends to catch my attention – does this meet those criteria?

• Immunoglobulins are antibodies produced by the immune system to fight germs
• When patients recover from a disease their blood contains antibodies against it, giving them an immunity
• These antibodies can be recovered by drawing blood from a patient and “fractionating” it to isolate immunoglobulins
• Immunoglobulins can be injected into another patient to boost his or her immune system’s response
• Immunoglobulin treatments are used against diseases including hepatitis A, chicken pox and measles
• In the event of a flu pandemic, it would be necessary to wait until a first wave of patients had recovered from infection with the dangerous strain before isolating the relevant antibodies
• It should take only a few weeks to make immunoglobulin treatments
• Immunoglobulins would not replace the need for vaccines and antiviral drugs like Tamiflu. It would be valuable as an alternative treatment, however, if the virus developed a resistance to Tamiflu

How specific are the Anti bodies? Does it work like vaccine and to the same extent? i.e. if the flu which caused the creation of the anti bodies was 97% homologous with the pandemic strain would the fall off in protection be akin to the fall off from a 97% homologous vaccine? Is it more – or less - strain specific?
“In the event of a flu pandemic, it would be necessary to wait until a first wave of patients had recovered” – If Jones Gitting donated a litre of his blood how could this be scaled up? What production facilities are required? Do we need humans or can we use cattle (BSE tested) or cell culture?

From my meagre (and quite possibly erroneous) understanding of the immune system, undifferentiated B Cells on contact with an antigenic site on the HA or NA of the flu’s surface convert to Plasma Cells producing antibodies specific to that antigenic site. Post infection, the number of these specific Plasma Cells are reduced but a few remain for quick response in the case of re-infection by a virus with the same surface antigen. If this is basically correct (if it is not please edit or post a correction so I am not misleading anyone) then how does the immune system react to the introduction of an antibody not an antigen (i.e. the key not the lock)? Is there an adjuvant analogue?

What is the difference in the level of protection offered by this form of immunisation compared to traditional vaccines?
If immune overreaction (cytokine storm) turns out to be a major cause of clinical severity & death does this form of immune system prepping differ form that of traditional vaccines?

The article talks about this system being used for hepatitis A, chicken pox and measles but not flu "The approach has not yet been used against flu in humans, largely because existing vaccines and antivirals are more effective and less risky." Why?

As you can see I am quite good at generating questions, just not so good on the answers. Help please.

 

[Mingus]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

There is many good reason to have so much question about that treatment option and you point it out somes.

For those who want, the original complete article that exposed that idea is available here at FT in that thread :
Convalescent Plasma Might Lessen H5N1 Mortality-empirical therapy against Spanish flu

I'll take time to read it completely before I do more comment but I'll say that this kind of "serotherapy" is used in veterinary medecine as a "lowtech" therapy when vaccine is not available and when the disease is already widespread.

We should understand that the principle is to directly inject the antibody from the survivor in the blood of the sick ones.

Many of the problems that is linked with blood transfusion will also be there.
Using it massively can lead to spreading "others blood-born diseases" like AIDS...

Here in Québec, we used the "serotherapy" method to reduce morbidity of the PMWS syndrome caused by the circovirus in the swine industry.
It showed some efficacity until the vaccine get ou this spring.

My job at the time was to check and double check by PCR the serum "lots" to be sure others swine blood-born diseases where not unclude in the serum intended to be use in the therapy.

I would like to hear comments from human medically skilled members on this...

Now I'll go read that article...

 

[wetDirt]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

Well, if you don't mind serum sickness, there is always this approach:

http://www.sciencedaily.com/releases/2006/03/060330084126.htm

A horse has lots more blood to give than a human, and can't give you those nasty diseases, although I'm sure they could have _something_ humans would not like much. How low-tech is this method? Do you just centrifuge the blood, separate serum, and go?

 

[kent nickell]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

In an associated editorial Dr. Treanor dealt with some of these issues and caveats...

http://www.annals.org/cgi/content/full/0000605-200610170-00140v1

Avian Influenza: Exploring All the Avenues
John J. Treanor, MD

17 October 2006 | Volume 145 Issue 8

An excerpt:

Passive immunotherapy to treat infection with influenza viruses, including H5N1, has been effective in a mouse model. Other viral diseases offer ample precedent: Passive antibody prevents many human viral diseases, including varicella, rabies, hepatitis A and B, and respiratory syncytial virus (RSV). However, the distinction between prevention of disease and treatment of active disease is important. Few recent data support the use of passive antibody therapeutically after disease manifestations have already begun. For example, although passive antibody is highly effective at prevention of RSV infection in high-risk infants, systemic administration of antibody with high levels of RSV neutralizing activity is not useful therapeutically in infants with RSV disease ( 7).

Nevertheless, the concept is important and it should be explored further, especially given our lack of proven interventions to prevent or treat illness due to H5N1 influenza. The use of serum from recovered patients as the source of antibody for passive immunotherapy has the advantage of being technically simple, and ample numbers of convalescing patients should be available for plasmapheresis. The resulting antibody would be polyclonal, which would decrease the chance of an escape mutant developing in treated patients. The serum also might have antibody to other bacterial pathogens, which might decrease the severity of coexisting bacterial superinfections (a mechanism that may account for some of the efficacy of serotherapy in 1918). Balanced against these optimistic considerations are several major concerns. Formidable logistical hurdles would complicate the ability to obtain, characterize, and prepare these materials for use in the midst of an outbreak. As yet, we don't know if patients who recover from H5N1 influenza develop particularly high levels of antibody (8).

 

[Mingus]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

Well, if you don't mind serum sickness, there is always this approach:

http://www.sciencedaily.com/releases/2006/03/060330084126.htm

From that link

Horse Antibodies Against The Bird Flu Virus H5N1 Are Effective As Treatment In Mice

Antibodies against the bird flu virus H5N1, derived from horses, prevent mice infected with H5N1 from dying from the virus. A study published in the open access journal Respiratory Research (http://respiratory-research.com) reveals that a dose of 100 µg of horse anti-serum effectively protects infected mice. These results suggest that anti-H5N1 antibodies developed in horses could potentially be used to prevent death from H5N1 influenza, or as early treatment for the disease, in humans.

I don't know if there is a higher risk of allergy associated with the use of Horse serum instead of human one...

 

[Mingus]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

How low-tech is this method? Do you just centrifuge the blood, separate serum, and go?

Something like that!

When I say low-tech I mean low tech...

The veterinary here haved heard of how It was done in some place in France and successfully reduce morbidity and mortality.

They where only harvested survivors blood in drums, let it decant in a garage for some night and then directly inject this to the youngs pigs before the critical age where they usually fall sick.
( You have to know that this circovirus disease has a long developping period a little bit like AIDS and almost every hoards are positives so the trick is to reduce the viral load to prolonge the healthy phase. )

The group that want to do this here haved the project of centrifugate the blood in olds washing machine...

So when they tell this to the lab administration here, they offer them a real professionnal service of centrifugating filtrating and quality control .( test for others diseases in the serum by PCR ) to ensure the best quality with all the modern scientific standards.

The project lasted for almost a year until the vaccine commercialisation.

So like vaccine, depending of how you like it safe you have the choice of get it very very low-teck.

 

[wetDirt]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

Something like that!

When I say low-tech I mean low tech...

The veterinary here haved heard of how It was done in some place in France and successfully reduce morbidity and mortality.

They where only harvested survivors blood in drums, let it decant in a garage for some night and then directly inject this to the youngs pigs before the critical age where they usually fall sick.
...
The group that want to do this here haved the project of centrifugate the blood in olds washing machine...

...

So like vaccine, depending of how you like it safe you have the choice of get it very very low-teck.

*trembles* *runs* *hides*

 

[wetDirt]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

I don't know if there is a higher risk of allergy associated with the use of Horse serum instead of human one...

Yes, very much. That's why they try not to use it anymore. I think there are still a few uses, tetanus antitoxin is one still. Something like 15% of the population will have a bad, but not life-threatening reaction, and an unlucky few who have had horse serum before will get anaphylactic shock. It appears to be a pretty desperate option, knowing that a large number of people will have severe side effects, and that this trick might only work once per person, because the side effects are likely to get worse the second time around. But in the face of a 75% CFR, the benefit to risk ratio could make sense for some.

 

[Mingus]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

But in the face of a 75% CFR, the benefit to risk ratio could make sense for some.

Denefinitively yes, the ethics questions are always around when talking of high CFR.

I had just took time to read the complete article.

Frankly, this is a great work that come right in time.
The most amazing thing is that is is a study realysed without many budget an made with old historical study from the 1918 era.

The "new" that is to conclude from that is that "seroterapy" can be apply to influenza even if the disease is a respiratory one.
They bring generals statisticals evidence from that historic documentation analysis.

The benefit from that kind of therapy seem statistically relevant, the side effects seem high from todays standard but the main goal to reduce mortality and morbidity is greatly helped.

The autors are couscious of the controversial matter of that "archa?c" medecine revisited.

They advocate the need to realise modern study to probe potency for the H5N1 treat.

Given the vast availability, and the low cost of the the "idea", his potency enven with his limits , it is a information we just can`t ignore.

This is a stong statistical study that must be followed by modern clinical data.

The idea of giving blood after recovered from the disease to help the later recover better is ... something like...

 

[gsgs]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

hmm...

So, in a pandemic will there be a (black-)market for blood from
recovered victims ?

Will there be lots of blood from recovered Chinese reaching USA
for low price before even panflu reaches America in full strength ?

Will recovered patients be at risk from illegal blood-hunters ?

 

[Mingus]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

hmm...
So, in a pandemic will there be a (black-)market for blood from
recovered victims ?
Will there be lots of blood from recovered Chinese reaching USA
for low price before even panflu reaches America in full strength ?
Will recovered patients be at risk from illegal blood-hunters ?

There is no way to get the "blood-giving" outside of the current non-profit organisation like the Red-Cross or others NGO highly regulated.

Non ethical blood-giving will lead to non-ethical serum transfusion wich will spread blood-born diseases like AIDS all around.

Blood and serum should only be transit on a local scale to prevent all kind of disease spread

 

[Mingus]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

A collection of relevant quotes from the original statistical study...

(...) relevant studies involving 1703 patients<SUP> </SUP>were found. Treated patients, who were often selected because<SUP> </SUP>of more severe illness, were compared with untreated controls<SUP> (...)</SUP>
The overall<SUP> </SUP>crude case-fatality rate was 16% (54 of 336) among treated patients<SUP> </SUP>and 37% (452 of 1219) among controls.
(...)
The range of absolute<SUP> </SUP>risk differences in mortality between the treatment and control<SUP> </SUP>groups was 8% to 26% (pooled risk difference, 21% [95% CI, 15%<SUP> </SUP>to 27%]).
(...)
The overall crude case-fatality rate was 19% (28 of<SUP> </SUP>148) among patients who received early treatment (after <4<SUP> </SUP>days of pneumonia complications) and 59% (49 of 83) among patients<SUP> </SUP>who received late treatment (after

4 days of pneumonia complications).<SUP> </SUP>
<SUP>(...)</SUP>
Only 2 trials (17, 19, 20) reported sufficient data to compare<SUP> </SUP>both early and late treatment groups with a control group. The<SUP> </SUP>mortality rates among patients treated within 4 days compared<SUP> </SUP>with controls were 32% (10 of 31) versus 53% (201 of 379) (17)<SUP> </SUP>and 14% (3 of 22) versus 43% (9 of 21) (19, 20).
(...)
The most commonly<SUP> </SUP>reported mild adverse event was a brief "chill" reaction with<SUP> </SUP>a transient elevation in body temperature by 1 to 2 °F<SUP> </SUP>30 to 120 minutes after the transfusion. The rates of the chill<SUP> </SUP>reaction were reported as 16% (17), 75% (18), or 10% (25) of<SUP> </SUP>patients, or that the occurrence of this event was "frequent"<SUP> </SUP>(19, 20) or "infrequent" (23, 24), or seen in "some" patients<SUP> </SUP>(26).
(...)
One study reported<SUP> </SUP>a case of "anticipated anaphylaxis" after transfusion with non–ABO-matched<SUP> </SUP>blood, which was administered because no matched donor was available<SUP> </SUP>and the patient's condition was critical (the patient survived)<SUP> </SUP>(19, 20).
(...)
The overall rate of moderate to serious transfusion-related<SUP> </SUP>adverse events from studies (17, 19, 20, 23, 24) that provided<SUP> </SUP>quantifiable data was 4% (9 of 235 patients).
(...)
One study (19, 20) reported<SUP> </SUP>that 28 patients in the treatment group had more rapid resolution<SUP> </SUP>of fever (average duration, 9.5 days) and an increase in leukocyte<SUP> </SUP>count (average increase 3 days after transfusion, 7000 cells/mL)<SUP> </SUP>compared with 21 controls (average duration of fever, 15 days;<SUP> </SUP>no change in leukocyte count)
(...)
Data from Excluded Studies
Most excluded studies (Appendix Table) reported that use of<SUP> </SUP>influenza-convalescent blood products was beneficial (27–29,<SUP> </SUP>32–43). One large study at a U.S. Army recruit training<SUP> </SUP>hospital investigated the use of influenza-convalescent serum<SUP> </SUP>in patients with Spanish influenza but not pneumonia (27). The<SUP> </SUP>treatment group consisted of 26 patients with influenza who<SUP> </SUP>were selected on the basis of highest fever and clinical severity<SUP> </SUP>of illness and were compared with a control group of 219 concurrent<SUP> </SUP>patients with uncomplicated influenza. Compared with controls,<SUP> </SUP>treated patients had faster resolution of fever (average, 3.6<SUP> </SUP>days vs. 5.8 days), fewer cases of pneumonia (1 of 26 treated<SUP> </SUP>patients [4%] vs. 30 of 219 controls [13.7%]), and fewer deaths<SUP> </SUP>(0 of 26 patients vs. 6 of 219 patients [3%]).
(...)
Discussion
Our analysis suggests that patients with Spanish influenza pneumonia<SUP> </SUP>who received transfusion with influenza-convalescent human blood<SUP> </SUP>products may have experienced a clinically important reduction<SUP> </SUP>in the risk for death and improvements in clinical signs and<SUP> </SUP>symptoms. Adverse effects included chill reactions and possible<SUP> </SUP>exacerbations of symptoms in a few seriously ill patients.
(...)
Our<SUP> </SUP>subanalysis indicates that early treatment (after <4 days<SUP> </SUP>of pneumonia complications) was superior to late treatment (after<SUP> </SUP>

4 days of pneumonia complications). The mortality rate among<SUP> </SUP>controls and late-treated patients appeared similar and is consistent<SUP> </SUP>with the modern recognition that early definitive therapy for<SUP> </SUP>pneumonia and hypoxia is clinically important.
(...)
Our biological hypothesis for why mortality and morbidity may<SUP> </SUP>have been reduced is that the virus was neutralized by anti-influenza<SUP> </SUP>antibodies in the blood product. Rapid viral clearance would<SUP> </SUP>halt further replication and the stimulus for the cytokine cascade<SUP> </SUP>that is responsible for the acute respiratory distress syndrome
(...)
Reductions in the mortality rate may have also resulted from<SUP> </SUP>fewer secondary cases of bacterial pneumonia, empyema, and septicemia.
(...)

And then... on the cautiousness we must not forget

(...)
Our findings are provocative, but our review has important limitations.<SUP> </SUP>Studies were few, and the size of most was small. The medical<SUP> </SUP>and research practices of the 1920s are archaic by current standards.<SUP> </SUP>None of the studies was a blinded, randomized, or placebo-controlled<SUP> </SUP>trial.
(...)
Moreover, we could not acquire and analyze every study.<SUP> </SUP>World War I coincided with the most intense waves of the Spanish<SUP> </SUP>influenza pandemic, and wartime censorship, death, or illness<SUP> </SUP>of investigators and rapid demobilization of drafted physicians<SUP> </SUP>may have prevented the publication of negative (or positive)<SUP> </SUP>studies.
(...)
Current human H5N1 outbreaks are small, sporadic, and geographically<SUP> </SUP>distant. The comprehensive study of this treatment will probably<SUP> </SUP>require a global approach because a series of underpowered,<SUP> </SUP>nonstandardized, and nonrandomized case studies will not conclusively<SUP> </SUP>demonstrate or disprove efficacy. A central body of experts<SUP> </SUP>should be convened to consider H5N1 plasma therapy and to make<SUP> </SUP>recommendations regarding a research strategy and possibly treatment<SUP> </SUP>guidelines in the event that therapy is required before the<SUP> </SUP>research is completed. A standardized protocol could be created<SUP> </SUP>and then submitted by a consortium of international investigators<SUP> </SUP>to local or national investigational review boards.

And about technical details ...

In the event of a severe pandemic, antiviral agents, antibiotics,<SUP> </SUP>and intensive care medicine may be rationed or not available<SUP> </SUP>to most severely ill patients. Modern plasmatherapy may be an<SUP> </SUP>effective and practical health care delivery alternative. Large<SUP> </SUP>volumes of plasma are currently produced by existing hospital-based<SUP> </SUP>plasmapheresis and blood collection centers (60, 61), and U.S.<SUP> </SUP>Food and Drug Administration regulations (62) allow individuals<SUP> </SUP>to donate 1000 to 1200 mL of plasma per week. A single H5N1<SUP> </SUP>convalescent donor could provide a weekly volume of plasma sufficient<SUP> </SUP>to treat multiple patients with H5N1 influenza. Donation is<SUP> </SUP>safe and entails few adverse events because the cellular components<SUP> </SUP>of the blood are returned to the donor under sterile conditions,<SUP> </SUP>and risks should not increase for convalescent donors. Locally<SUP> </SUP>produced plasma from convalescent donors or early vaccine recipients<SUP> </SUP>could be immediately effective in the event of a virulent influenza<SUP> </SUP>epidemic or other disease for which no good treatment exists.
(...)
As a point of discussion, existing<SUP> </SUP>transfusion practices could be used to administer acute convalescent<SUP> </SUP>plasma to patients with H5N1 infection, in quantities of at<SUP> </SUP>least 1 to 2 mL/kg of body weight (9, 62).

 

[Mingus]

Ethical dilema

Ethical dilema

Frankly, I am very surprised there is not much reaction,

This study may have point out the cheapest and mostly available treatment to effectively reduce morbidity and mortality in the course of a high CFR pandemic.

The method may be a archa?c medecice trick, it is not supposed to be harder to manage than blood transfusion and blood transfusion is used currently in modern medecine.

look...

relevant studies involving 1703 patients were found. (...) selected because of more severe illness (...)
The overall crude case-fatality rate was 16% among treated patients and 37% among controls.

Ok now,
imagine this hypothethical situation...

You haved been very sick but you recovered... some week later your childrens fell sick and the pneumonia turn bad very quick.

Would you, based on that study, feel the need to ask your doctor to collect some ml of you serum ( today, syringe filter exist that can collect only serum, it can be done in a ambulance almost costless) to inject it to your childs in the hope you help them to survive ???

I really would like to hear FT's member tought about that

 

[Snowy Owl]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

Thank you for the invitation Mingus,

As a parent of course I would do anything possible for my children. That being said, I will try to get as much information as possible concerning the virulence of the strain hanging around while I would try to get as much information on this process.

This is certainly a path worth consideration, but with actual datas.

 

[Shannon Bennett]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

I would like to preface my comments with the statement that I am not a health care professional.

Talk about being stuck on the horns of a dilemma. I think the possibility of lessening the dire outlook of the virus means we should investigate every avenue. In this case we need to address some specific concerns.

My sister is now suffering from Hep C, which the doctors believe she got many years ago from a blood transfusion. We all have either known someone or have read of people who got AIDS from transfusions. I know these were in the past but this method has me somewhat concerned. If we could not be assured of a safe product, the only way many of us would go ahead with a human based serum is using a source from previously healthy nuns or children. We need therefore to fix the problem now with possibly contaminated blood or, use an alternate source of serum. Otherwise, many of us will worry ourselves sick if we have only put off dying from bird flu for dying from AIDS?

As for horse serum, I wonder if a prick test would alert the future recipient of the inoculation of a possible adverse reaction? If so, then how long before you got the horse serum would you have to have been scratched? Are their alternative sources, chimps, cats, pigs? Have any of these been tested? Are horses susceptible to H5N1?

 

[Sally Furniss]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

Prick test for allergy to horses is fast, measured in minutes.

 

[Shannon Bennett]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

Anne, you have relieved my mind considerably. If not then why not then?

 

[JJackson]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

I have to agree with Mingus that this approach has potential and needs further exploration. Our main defences, as things stand at present, are Tamiflu and …er …. well Tamiflu. Tamiflu has been administered to many of the infected but not always as early in the infection as required on the packet. Despite the mercifully small number of human cases to date there have already been resistant cases and resistance in H3N2 is well documented. In addition while my government stockpiles for 25% of its people regretfully that is not the case for most of the worlds population.

From the articles linked to in this thread it would seem that serotherapy, even when given to the sick, has a significant benefit but the more promising avenue is probably prophylaxis.


From the discussion section of the Meta-Analysis paper (link in post #2)

Our analysis suggests that patients with Spanish influenza pneumonia who received transfusion with influenza-convalescent human blood products may have experienced a clinically important reduction in the risk for death and improvements in clinical signs and symptoms. Adverse effects included chill reactions and possible exacerbations of symptoms in a few seriously ill patients. Our subanalysis indicates that early treatment (after <4 days of pneumonia complications) was superior to late treatment (after 4 days of pneumonia complications). The mortality rate among controls and late-treated patients appeared similar and is consistent with the modern recognition that early definitive therapy for pneumonia and hypoxia is clinically important. Although we calculated a pooled estimate of possible effect, we urge caution in the interpretation of the summary estimate and do not think that it should be generalized to other virulent influenza strains without further study.
Our biological hypothesis for why mortality and morbidity may have been reduced is that the virus was neutralized by anti-influenza antibodies in the blood product. Rapid viral clearance would halt further replication and the stimulus for the cytokine cascade that is responsible for the acute respiratory distress syndrome. Reductions in the mortality rate may have also resulted from fewer secondary cases of bacterial pneumonia, empyema, and septicemia. Several human and animal studies (44–58) have reported protection with use of passively acquired anti-influenza antibodies and provide support for this hypothesis. Successful treatment of a pulmonary influenza virus infection in severe combined immunodeficiency mice with hemagglutinin-specific antibodies with very low virus-neutralizing activity in vitro (51) and in H5N1-infected mice with equine-derived H5N1 F(ab) fragments (52) provides direct evidence that anti-influenza antibodies are therapeutic in a model of severe disease.

Going back to the immune system model.
Scenario 1- An immunologically naive host (i.e. a host with neither the right antibodies or the plasma cells to produce them) is infected then there is a good chance of some virons infecting a host cell (due to a weak challenge from an unprepared host). Once they release lots more virons the hosts immune system should kick in and produce the appropriate response but the virus has already established a head start and is difficult to eradicate.
Scenario 2 – A recovered – or vaccinated - patient is challenged by the virus. This time there are already suitable antibodies present and these bind to their matching antigenic sites and in so doing ‘paint the target’ for an aggressive attack by the hosts other immune cells. The plasma cells are already present and ready to produce more antibodies. In this case the virus fails to establish a bridgehead and is repulsed.
Scenario 3 – This is the case in this paper. The patient is infected as described in scenario 1 when antibodies are injected into the system, these will supplement those already being produced by the plasma cells and will bind to the virus and focus the immune response. The serum will not include live plasma cells this does not immediately increase the rate of production it a one off shot but should by some time.
Scenario 4 – The patient is given serum before being exposed to the virus. What happens here? In theory I would expect these antibodies to bind to the viron and reduce the chance of it binding successfully and subject it to a heightened attack – hopefully stopping or slowing infection.

This poses the question what is the half-life of an antibody? If the serum includes no active plasma cells then the antibodies will not be replaced as they are broken down or excreted. In a patient fighting an infection there may be many disease specific plasma cells, and antibodies, but as they recover most are destroyed and only a small number remain to prime the system against a future infection. Presumably these plasma cells do not live that long so there needs to be a feed back mechanism to maintain a suitable antibody titre. How is this achieved? If antibodies are injected will this stimulate plasma cells to make more (as the antigen would) or will they just tend to zero. If we produce small quantities of vaccine can the vaccinated be used as serum donors? If serum antibodies produce plasma cells can those injected then produce more serum? (As stated in my first post, if my rudimentary immunology is wide of the mark please edit or post corrections)

The research implied that one convalescent patient could provide serum for several sick ones. Would it go further if used as in scenario 4? How much further? We do not want to wait for a devastating first wave to produce lots of donors. In the case of diseases where serum is used (either in human or veterinary medicine) does anyone know if & how volumes can be increased? We only have about 100 recovered H5N1 patients and there are 6.6 billion of us so some kind of amplification is going to be needed.

What was encouraging in the quote from the paper above was the absence of severe side effects despite what I assume to have been pretty crude separation techniques. Mingus’ washing machine based centrifuging system not withstanding, I suspect we should be able to produce a more sophisticated fractionation technique and hence less adverse reactions. Assuming we had a blood supply what do we need to produce acceptable medical grade serum? Is there enough hardware (including in the third world)? What is the storage life of antibody serum?

All thoughts gratefully received.

 

[wetDirt]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

I have no doubt that this method will be used by the military to keep functional. I think all you need is a good refrigerator to transport the stuff. I think a person's antibody response lasts a considerable time, because the notes about immunity are written down in stem cells in the thymus or bone marrow, which produce the copies circulating in the blood. So temporarily depleting the blood doesn't remove the record of immunity. It grows back. In a month. This is going to take a lot of donors. Maybe it's time to consider clean living a prep.

 

[JJackson]

Re: Why blood of bird flu survivors is a lifesaver [Discussion]

In the post that opened this thread I asked a lot of questions aimed at exploring whether fractionated blood products from convalescent H5N1 patients could be used to enhance the immune response of either of H5N1 patients or prophylactically.

Mingus has been busy reading and posting papers (in the Scientific Library) around the subject and I would like to draw your attention to one of these in particular which provides an extremely promising line of research and therapy using Monoclonal Antibodies (Mabs).Antibody-Based Therapies for Emerging Infectious Diseases http://www.flutrackers.com/forum/showthread.php?t=9864



To recap in 1918 serum was used on H1N1 patients and found to have a measurable beneficial effect however using blood products like this has several major drawbacks. Firstly quantity - With so few H5N1 survivors getting anything like enough serum is unlikely to be possible until a pandemic starts at which point we would be racing against the clock as the antibodies we are after are not produced until late in infection and pandemic waves are scarily fast. Secondly adverse reactions – One of the most attractive aspects of serum therapy is its low-tech nature, basic centrifuging as a means to extract the fraction with the antibodies but in this crude form there are a large numbers of other blood products which may cause adverse reactions. The more sophisticated the preparations the less side effects but the higher the cost and less people helped. Thirdly disease transfer – For a system like this to be practical on a large scale you would need to move to industrial scale production which means mixing blood products from many donors which in turn means careful screening for HIV, vCJD etc. which is already done by Blood transfusion services but is again moving us away from a cheap 3rd world solution. Where does all this leave us? There may still be a role for crude single donor to single patient treatment if a cheap disposable filter was available as envisaged by Mingus

today, syringe filter exist that can collect only serum, it can be done in a ambulance almost costless

here you are trusting the donor does not have any unpleasant blood born disease and may be useful between family members.

How can we scale up?

The short answer is it does not seem to be possible by this method but a Mab cocktail is a distinct possibility.
Each Mab is specific to its matched antigen which makes it extremely effective as long as you have correctly predicted the antigenic site. With flu this is a problem due to the reasonably rapidly changing nature of the antigenic sites on its surface proteins hence the need to produce a cocktail including more than one Mab. H5N1 has seven antigenic sites 5 on the HA protein and the other 2 on NA. If two or three sites can be picked which are common to the strains thought most likely to be pandemic candidates these would form the basis of the cocktail.

Advantages of Mabs.

Production - MAbs are produced by tissue culture techniques. Industrial production of MAbs may utilize immunoglobulin synthesis in yeast, bacteria, or plants. i.e. They are scaleable. (Production on our scale would use Air Lift Fermentation)

Toxicity - Toxicity of serum was due to allergic reactions to animals protein. Human immunoglobulin preparations are well tolerated. Antiidiotypic responses remain a problem for humanized MAb therapy.

Relatively quick to get through regulatory procedures.

Administration is easy and due to large scale batch production product should be consistent.

Disadvantages.

Cost. This seems to be at least in part due to the small scales of production for the diseases which it is currently being used to treat.
Quote from http://www.flutrackers.com/forum/showthread.php?t=9869

The high expense of Ig preparations is related to the fact that these reagents are more fragile than small molecular weight compounds and that they originate from immune donors or cell culture production and hence are costly to obtain, produce, and maintain. In addition, many of the indications for which immunoglobulins are used represent relatively small markets, and the cost efficiency associated with mass production may not apply.
One difficulty that has plagued the development of antibody-based therapies in infectious diseases is that the market size for an antibody reagent is proportional to the prevalence of disease.[3] Since antibody reagents are almost always pathogen specific, the market for antibody-based therapies is often much smaller than that for drugs with broad antimicrobial activity. Small market size combined with high price and the availability of many antimicrobial drugs has not encouraged development of antibody-based therapies for many infectious diseases. However, in considering antibodies for biological defense, the market size equals the potentially vulnerable population. This consideration, combined with the fact that stockpiles would have to be replenished periodically as a result of lot expirations, could make the economic outlook more attractive to industry. Production of sufficient antibody protein for universal protection of the U.S. population against a specific biological agent would involve large-scale production and could result in cheaper unit prices.

For the future there are several other interesting possibilities. If you believe that a large part of the problem with H5N1 and the 1918 pandemic was not so much due to the flu itself as to the immune system’s overreaction then Mabs could be engineered to bind to and inactivate specific cytokines, this potentially allows for a variable dose to dampen the overreaction without interfering with the bodies other immune responses to the disease.

The versatility of antibody-based therapies is illustrated by the ability of digoxin-binding antibodies to reverse digoxin toxicity (36) and recent attempts to treat septic shock by employing MAbs that bind cytokines (37).

The next quote also contains a host of interesting possibilities.

Microbial targets for therapeutic antibody development are not necessarily limited to extracellular pathogens. Although intracellular pathogens are commonly believed to be outside the reach of antibody immunity, several reports have suggested that some MAbs are active against some intracellular microorganisms. Some IgA MAbs can neutralize intracellular viruses (31), and an MAb to Toxoplasma gondii has been reported to interfere with intracellular replication of the parasite (32). It has been proposed that intracellular virus neutralization by IgA occurs by antibodies binding to viral proteins and interfering with viral assembly (31). Additional evidence for intracellular antibody activity comes from the observation that IgG anti-DNA autoantibodies can enter the cytoplasm and nucleus of living cells (33).

The M2 protien would not normally be regarded as having antigenic sites as it is not a surface protein that is likely to come into contact with B cells and so provoke plasma cell generated antibodies but these can be produced synthetically and be introduced into to the cytoplasm they may well act as an ion channel blocker without the same dangers of resistance emergence. This is one potential example there are obviously many other points of attack.

This may also have use in drug resistant diseases like MRSA.