THE COMING WAVE (An Interview With Mother Abigail)

Page #17

This vaccine will be in addition to the regular seasonal influenza vaccine.

Again, people over 65 years of age, young children, pregnant women, and people with diseases of the heart or lungs should all receive these vaccines assuming they are not allergic to some component of the vaccine.

Q: If that is true, then why are you so worried about this new virus?

MA: Just as it is often not the seminal event that results in huge problems but the ensuing poor decisions (think Watergate)- thus it might be with this outbreak.

What we can safely assume is that (baring some very profound discovery) when fall arrives in the Northern Hemisphere and school resumes there will be a second wave of novel H1N1 cases flooding the world.

We can also reasonably infer that by then there will be a huge storehouse of neuraminidase inhibitors stockpiled and ready for distribution to millions of patients.

Individuals are buying these products online and with prescriptions just to have them ready for the first small symptom of the flu.

So what you will most certainly see in the next few months is a massive introduction into the human species of a mixture of novel H1N1 virus, a rapidly developed flu vaccine and million and millions of doses of neuraminidase inhibitors - many self-administered and many given long after the brief window where they might have helped.

We as scientists owe everyone a calm and reasoned examination of the effects of such a cocktail.

Have we evaluated the repercussions of these actions?

Are there any potential contraindications of which we should be aware?

I would like to discuss these issues with you.

Q. Please go ahead.

MA. Influenza viruses multiply by gaining entry into a host cell and upon entering these cells they commandeer the host machinery to produce new viral progeny. And they do this very well. So, if we may, let us spend a bit of time visualizing exactly how this event occurs.

The virion is generally a circular entity enveloped in a lipid membrane with two different types of spikes emerging from this surface. These spikes are proteins – actually glycoproteins - because they consist of protein linked to sugars – and are known as HA (hemagglutinin) and NA (neuraminidase).

One of the spikes, a triangular rod-shaped molecule, has haemagglutinin activity, while the other spike, a mushroom-shaped molecule, with a square box-like head sitting on top of long thin stalk, is the enzyme, neuraminidase.

Hemagglutinin is the method by which the flu virus takes hold on the infected cell whereas the neuraminidase is the enzyme that clips off the newly formed virus, so that the ‘free’ virus will infect another cell. But we can discuss that later. For it is neuraminidase and it's association with virulence that will be the focus of our discussion after we review the basics.

Q: (I did not know, at the time, that the review would take all winter)

Page #19

JUNE 2009

We sat under that big old tree by the Lake in the late evening. I was enjoying the questioning from MA. She seemed pleased that, at long last, I was able to understand and converse about Influenza Virology (in some small way) with her.

There had been no articles to read and no materials to study on this trip up and so far it had been more like a final exam than anything else.

For the best part of the afternoon MA had explored my understanding of the subject matter and my ability to answer fairly difficult questions concerning the replication process.

I felt I must have passed, because she smiled and asked if I would like to walk back to the house and have a cocktail.

Now there are few times in my life when anything sounds better than a tall Gin and Tonic. So I jumped up from the old wooden chase chairs and said "very much so".

As MA was getting up from her chair it seemed she was a having a little trouble rising. I immediately reached over and offered her my hand and she gladly used my hand to smoothly rise and start back the path.

It may seem a small thing but it made an impression at the time. Other than the original handshake upon meeting MA - I had never touched her.

She carries herself with such a dignified and professional aura that the normal hug or cheek peck seems totally out of the question.

From the lake, the path leading back to the main house is little more than two worn tracks where people have driven down to the beach. It is like a walk in the country. She has two small cabins between the lake and her house that are rarely used but are what she calls "guest houses".

They stand in stark contrast to the magnificent lakefront house that her neighbor has built on the adjacent property. Simple wooden cabins with wooden porches. They are both beautiful and entirely fitting.

As we were about halfway back to her house she did something entirely unexpected - she placed her small hand on my arm and smiled at me. I can not explain what joy it gave me.

Then she said "when you come up next weekend please bring your tape recorder, we need to look forward a bit". And so I did.....

Page #20
LATE JUNE 2009

MA: What is the most efficient and economical way of fighting viral disease?

Q: Vaccination?

MA: Yes of course. Vaccines are the most efficient means for preventing human and animal disease.

Smallpox and measles are excellent examples of successful vaccines, however some enveloped viruses still are without vaccines – think HIV as the most prominent example.

MA: So here is my question for you. How can the measles virus vaccine still function after over 40 years, whereas the influenza virus vaccine needs to be replaced almost every year, and it has proven impossible to produce an HIV vaccine?

Q: I don't believe I can answer that.

MA: It is all about mutations child - all about mutations. The replicating enzymes of RNA viruses, such as measles, influenza, and HIV, make approximately one mistake per every 10,000 nucleotides.

But the answer to the differences in affectivity lie in the peculiar structure of the measles H glycoprotein, against which neutralizing antibodies are produced.

The influenza virus hemagglutinin glycoprotein, which binds to the viral receptor sialic acid, is richly covered with sugar chains. The receptor binding site at the top of the molecule is a shallow hollow.

Most of the amino acids around this hollow and others on the surface of HA can mutate without significantly affecting receptor binding. However, HA has a rather rigid structure, and many mutations are not allowed because they would destabilize the molecule or lead to a nonfunctional molecule.

MA: You see why that could not be allowed?

Q: Sure, you get some mutations in non-essential areas, but none in the binding site or in a "mission critical" area.

MA: Yes. The accumulation of mutations, selected and directed by the immune pressure in the host population, is such that the vaccine strains have to be frequently replaced - in order to be effective. H1N1 is such a strain. The vaccine needs to be adjusted to be effective.

However, the HIV surface glycoprotein, against which neutralizing antibodies should be made, is GP120.

This molecule is much more flexible than influenza virus HA. GP120 has a number of highly variable surface loops that do not seem to have a specific three-dimensional structure.

These structural changes are very large and are possible because the molecule is plastic. The combination of the sugar chains on the surface of GP120 together with its plastic structure and the variable loops that have no sequence constraint results in a molecule that is too flexible and variable for the production of neutralizing antibodies.

Because of the flexibility in its design the glycoprotein for HIV (GP120) prevents the production of neutralizing antibodies - making an effective vacine targeted at the binding site an almost impossible task.

This is an important factor to consider when explaining how HIV could be so hard to defeat.

Page #21

MA: So we have seen that some viral infections are fought rather succesfully using vaccines and some are not.

Do you know of any other problems with vaccines?

Q: I remember the dust-up about there being mercury in some vaccines.

MA: Yes some vaccines do contain Thimerasol, a mercury-containing preservative. However, there is no hard evidence that this product causes autism - and that is what has been claimed. But I do believe that children under 5 or 6 are often given Thimerasol free vaccines if possible, but my information might be a bit dated.

It is another aspect of vaccines that I would like to make you aware of and especially with the coming flu season.

Q: And what is that?

MA: It is a phenomena called antibody-dependent enhancement.

As we discussed this winter the majority of viral infections of animals and man are not fatal, but are followed by recovery and the development of a state of relative or absolute resistance against re-infection with the same virus.

Much of this resistance can be attributed to specific antiviral antibodies, although cellular immune mechanisms also contribute to the protection of the host.

However not all antiviral antibodies are necessarily virus neutralizing antibodies - in addition to these virus neutralizing antibodies or non-neutralizing antibodies a further group of antibodies exist: antibodies which enhance the infectivity of the virus.

This phenomenon is known as antibody-dependent-enhancement (ADE) of viral infectivity and has been observed with various macrophage-infecting viruses.

The common features of viruses exhibiting ADE are:

1. preferential replication in macrophages
2. ability to establish persistence
3. and antigenic diversity

Q: That's odd. How does it work?

MA: ADE occurs when the host is more efficiently infected by a combination of virus plus antibody than by the virus alone.

Can you see that?

Q: Yea, I guess. But it seems strange that an antibody would aid the virus in infection.

MA: Child, nothing in the world of Virology is strange. Let's go back to our favorite subject the HIV virus for a moment.

Page #22

MA: A recent article explains that a vaccine trial for HIV was stopped prematurely in September 2007 due to evidence that vaccinees may have been more susceptible to HIV infection than the placebo given control group.

This is very important - do you understand what I just said?

Q: Yes, they were trying to find a vaccine for AIDS and when the tried the experimental vaccine they had to stop the trials because the vaccinated subjects were acquiring AIDS faster than the control group. That not only seems Greek to me but a bit out of the way, as related to our discussion of the novel H1N1 virus.

MA: But it is central to our conversation. Some cells do not have the usual receptors on their surfaces that viruses use to gain entry. The antibodies bind to antibody Fc receptors that some of these cells have in their plasma membrane. The viruses then bind to the antigen binding site at the other end of the antibody - thus enhancing the infection.

So it is possible for antibodies to a virus to acctually enhance the ability of the virus to infect the host. That is why when you challange any host with either a virus or vaccine, you must be certain that the results are overwhelmingly positive. We must always look at the pitfalls that might appear in the very near future. It is kinda what they pay us for.

Q: OK, it's just that I don’t really get the problem yet. I understand that there is an inherent danger in giving new vaccines to large numbers of people. As you point out - sometimes these things can backfire. But do you really anticipate a problem with the flu vaccine - whatever that may be?

MA: No I don't, but as we started this conversation last summer - it is often the results that you do not plan for that are the most damaging.

Q: I don't understand?

MA: I did not expect you to - yet. We have discussed how influenza is spread, how it replicates, how it can be inhibited, , how vaccines are effective in preventing diseases in humans and animals and how some vaccines can have unintended consequences. We have spent some extra time on Neuraminidase, Glycosylation and SIAS. Now, we need to return our conversation to where we started on that hot summer day when I first met you. Is that OK with you?

Q: Good to go...

MA: When we first met last summer, we had a long conversation about the state of human evolution. How we as a species are doing in the big picture sort of thing. Because I am a bug doctor, my overall perspective is always going to be a bit skewed, and there is no denying that. However, let me ask you this. In the year since our conversation is there any development that alters your very steadfast opinion that, on balance, there are no real "game altering" factors on the horizon?

Q: MA, an asteroid could hit tomorrow, Russia might get pissed at the Chinese or the sun might send a toasty little flare our way. No one can know what might be.

MA: Well that is certainly true to a degree, but we make intelligent predictions every day on the future. When you buy a home, or sell some stock you are looking at future events and making an informed decision on the outlook for tomorrow. Wouldn't you agree?

Q: Well sure, to some degree. But, I know that you are speaking of a much larger evaluation with much greater consequences. And I am still not convinced that we can predict events on that scale.

Page #23
MA: Very well.

Let's discuss what we do know for a bit, and see if we have any common ground in our worldview.

Q: Rock on....

MA: There is a collogue of mine who long ago wrote this famous phrase:

MOST SPECIES ARE SUBJECT TO CYCLES OF SUSTAINED GROWTH AND SUDDEN CALAMITY.
IT IS A RHYTHM AS OLD AS LIFE ITSELF.
Do you think that is accurate?

Q: I am not sure, I know that wild animals (when they loose their predators) multiply until starvation or hunters or something weeds them back down. Is that what you mean?

MA: Pretty much. Few, if any natural populations are constantly at equilibrium densities. Variation in the weather, predation, health and other environmental parameters results in great variability in populations.

In our discussion of rhythms or Chaos, I explained that Chaos is a set of rhythms that lie outside our normal perception. A nonlinear system will be chugging along with easily understood parameters, but often it will move to a "period doubling" phase and on to chaotic dynamics (which can be read as "all hell breaking loose" or "I can't tell what is going on).

MA: Which brings us to human population, which is following an exponential growth pattern. With the advent of modern medicine, better sanitation, and increased food supplies, the biggest constraints on population growth were removed.

Many people feel uncomfortable discussing this issue, but because I am very old and have spent a large part of my life in close contact with issues of disease and death - I do not have that reservation. Can you and I have that conversation?

Q: Yes of course.

MA: Would you like a drink first?

Q: Very much so....

MA: When we look at the potential outcomes for any event we are required as scientists to look at a broad spectrum of possible results.

That does not make us negative, nor does it leave us without recourse. It simply makes us prudent in our approach and honest in our work.

Would you agree?

Q: Yes

MA: Very well, lets you and I consider the novel H1N1 flu pandemic of 2009 in a larger context and see if there are any issues that are being overlooked.

Would you consider influenza to be the most threatening virus to us as a species?

Page #24

Q: No, I would think Ebola or Marburg would be far more likely to do real damage.

MA: I believe I disagree. While Ebola and Marburg are very deadly bugs, they are rare and geographically contained.

Q: What about Reston?

MA: Yes, there was a huge potential for an outbreak in that situation, but even if Ebola Reston proved lethal to humans - the old tried and true measures of isolation, barrier nursing and containment would have prevailed. It is a matter of how easily the virus spreads.

Ebola is extremely deadly but difficult to catch. If you spend a lot of time butchering primates, then you have some serious infectious issues, but even then it is just not that easy to transmit.

The most common vector is actually preparing the dead.

MA: That is not to say that strange things couldn't happen and mutation or biological warfare or some nut job could really cause problems but it is largely just a very rare and distant medical oddity - no, Influenza is far more threatening than that.

Q: O.K. the flu is much more dangerous because of how easily it spreads.

MA: That and the introduction of new strains to a naive population can have devastating effects.

Do you see any other pathogens as being very dangerous to the species as a whole?

Q: Well...... how about SARS?

MA: SARS gave us quite a startle; I must admit that for a brief few weeks there was a very dark cloud hanging over health care workers of all stripes.

But, in the end the application of the most basic nursing techniques - Barrier Nursing - was enough to crush the outbreak. I might mention that contact tracing was, and will always be, a necessity in these types of outbreaks.

But on balance SARS is now just another notch on our collective gun belts.

Q: To me those are the major players, I don't know of anything else that raises red flags or is in any way "scary".

MA: What about AIDS?

Q: AIDS? My thoughts are that unless you live in Africa or participate in very risky sexual activity then it is a moot point.

MA: I don't believe that is quite accurate; however I will grant you that it is the normal mindset.

What do you know about the pathogen that causes AIDS?

Page #25

Q: Not much. It is a virus and from our lessons this winter I know that it has some similar mechanisms as the Influenza A virus.

MA: Yes it is a virus, it is called HIV. It stands for the Human Immunodeficiency Virus and is a Retrovirus.

The target cells for HIV are immune cells, called CD4+T cells, these cells help the body fight infection and disease. But they are HIV's primary target.

HIV is spherical in shape. The outer coat of the virus, known as the viral envelope, is composed of two layers of fatty molecules called lipids, taken from the membrane of a human cell when a newly formed virus particle buds from the cell.

MA: Does that sound familiar?

Q: Very much so - that sounds just like the Influenza A virus.

MA: Yes indeed it does.

Also similar is that embedded in the viral envelope are proteins from the host cell, as well as copies of a complex HIV protein (frequently called “spikes”) that protrudes through the surface of the virus particle.

This protein, known as Env, consists of a cap made of three molecules called glycoprotein (gp) 120, and a stem consisting of three gp41 molecules that anchor the structure in the viral envelope.

When you think back to the functions of HA and NA in the Influenza A virus, GP 120 is very similar.

The HIV glycoproteins aid in its attachment to the target cells - CD4, the primary HIV-1 receptor.

This binding exposes a site on gp120 that enables interactions with secondary coreceptors and further conformational changes. Remember how the HA in H1N1 unfolds and attaches.

Q: Yes, that is a very dramatic little trick it does.

MA: But the point is that the viral structure in both these pathogens, while differing in many key ways, is fundamentally a variation of the same form.

Q: OK I understand that, but why is it important?

MA: I believe it to be very important. But before we get back to how patterns of glycosylation of a virus can be an important factor in its virulence, would you indulge me in a bit of a sidebar?

Q: Why of course.

MA: When we had our original discussion last summer and I explained to you that I had very serious concerns about our vulnerability, as a species, to emerging pathogens you thought that H1N1 was my major worry - did you not?

Q: Yes - I assumed it was the flu - what with your log in name and such.

MA: Well, the answer is both yes and no. As with much of science - when you hear hoof beats it is normally a horse - but occasionally it is a zebra.

Page #26

Why don't we go back up to the house and I will tell you a very interesting story.

Q: Let me go to my car and get the tape recorder and I will be right there.

MA:Thank you.

The reason that I so enjoy the new math of Chaos is that I find life so full of beautiful rhythms. Most are obvious - when the bees start hanging around the garbage cans in the late summer then I know it is time to start thinking about winterizing the cabin.

Some are not.

In the 1980's I was still working in the wonderful world of nasty bugs and everyone I knew was all gaga about monoclonal antibody technology. We could literally see the magic bullet on the horizon - where a specific drug, bound to a monoclonal antibody zeroes in on its target and delivers the drug or toxin there where it is needed. ABC stuff, we were about to cure it all.

Didn't happen. But during that exchange of information I became aware of a new and strange development in the world of microbiology. In the summer of 1981 after a huge increase in requests for the drug pentaminere, a smart young lady in Atlanta reported to the CDC that there was an outbreak of pneumocystis carinii pneumonia in Los Angeles. Now this was off the chart for a rare disease cluster so it sparked my attention.

In the winter of that year PCP was being found in IV drug users. I might note that this outbreak was not considered to be caused by an infectious agent at that time.

By the summer of 1982 homosexuals, Haitians and hemophiliacs were all getting sick and contact tracing was beginning to point at an infectious agent.

However in December of 82 there was a case of a 20-month old child (who had received multiple transfusions) dying of what was now being called Acquired Immune Deficiency Syndrome - and all doubt was removed.

We had a bug.

While my research at that time was centered on DHF (dengue hemorrhagic fever) and especially the outbreaks in Puerto Rico - the new bug caught my attention and I followed the developments very closely.

During the next few years the homosexual connection became apparent and we discovered that it was not airborne.

As the disease gained a foothold in America there developed a battle about one of the most important tools in epidemiology - contact tracing.

I won't go into all the arguments but in the mid to late 80's there was stiff opposition to the medical community doing normal contact tracing (as we would with any sexually transmitted disease) in AIDS cases.

The disease had become political.

And so it was - the virus, even though it is a poorly transmitted bug, had obtained it's beachhead in the human species.

Page #27

MA: And so it went. The decades have past and we have made great strides in many medical fields but this deadly HIV virus has thrived in our midst.

But that is not surprising considering that it lives to destroy our immune system and kill human beings.

I understand that bugs have no drive and no destiny, but this deadly bit of RNA frightens me.

What we have learned is not good. It hides out for years in long term memory cells multiplying and waiting for an opportunity to re-emerge and ravage the carrier.

It has actually developed numerous strategies for eluding the body's defenses and our best medications. We also know that HIV modifies the cell structure system of the host cells enabling them to enter the cells more easily.

HIV especially attacks immune cells of the T-helper type. These cells support not only direct defense against the bugs, but are also necessary for building sufficient antibodies against the invader. For this, they must rely on their mobility.

The cell structure element actin, which also gives muscles their mobility, aids in the motility of immune cells. This is necessary for immune cells to be able to establish contact with each other and combat the virus.

And now we discover that cell mobility is inhibited by the HIV Nef protein.

Nef causes an enzyme that normally has nothing to do with cell mobility to deactivate a regulator for actin regeneration. Nef therefore causes a short-circuit of two cellular mechanisms, thus inhibiting the reorganization of the cell structure element actin and the cell's ability to move. Thus, the affected immune cells can no longer fulfill their function.

MA: Do you understand how important that is?

Q: I guess that by short-circuiting the method that the immune cell uses to have good mobility the HIV virus prevents the body from mounting a good defense.

MA: Well yes, but the negative effect of Nef on the mobility of T-helper cells also has far reaching consequences for the efficient formation of antibodies by B-lymphocytes in the patient.

We often see a malfunction of B-lymphocytes in AIDS patients and now we understand why.

It is not this one extraordinary thing about HIV but the multitude of functions and abilities that gives me great pause and eventually intrigued me enough to study the mechanism of HIV virulence.

Q: I see – and that is going to bring us around to your theory on Neuraminidase isn’t it?

MA : Yes it is.

Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.