The live virus H5N1 vaccine paper

Whenever I hear about the latest H5N1 vaccine fix I have the same reaction. If only we'd started doing this several years ago when the threat of an avian influenza pandemic was plausible, we'd be so much farther ahead, if not "there" by now. But we didn't. CDC chased the bioterrorism phantom, to please King George, and Big Pharma was mainly interested in their obscenely profitable (and sometimes fatal) big items for aches and pains and impotence (oh, excuse, me; I mean erectile dysfunction). Oh, well. We'll take what we can get, now.

The latest is a live virus H5N1 vaccine from MedImmune, the company that makes the live virus FluMist vaccine for seasonal influenza. The new H5N1 experimental version has only been tested in mice and ferrets, but it shows promise, although there is much still to do before it can be used in humans and still some lingering questions about whether it could reassort or revert to a more virulent form. The MedImmune scienstists and their collaborators report this week in Public Library of Science Medicine on their preparation of a live but weakened H5N1 vaccine that is administered by a spray in the nose. The crippled virus contains proteins that provoke an immune response to H5N1 that seems to work across all existing strain subgroups (clades 1, 2 and 3) obtained from human isolates in 1997, 2004 and 2005.

The weakened virus is produced by combining the internal proteins of a cold adapted mutant of an H2N2 virus (A/Ann Arbor/6/60). This was isolated from a sick child in 1960 during the century's second pandemic, which started in 1957. The mutant virus was made by growing it in primary chick kidney cells and successively lowering the temperature of the cell culture until a virus was produced that grew as well at 25 degrees. C. as it did at 33 degrees C. (body temperature is 37 degrees centigrade). This virus is not only cold adapted ca, it is temperature sensitive, replicating at only one hundredth the level at 39 degrees C. as it does at 33 degrees C. In addition, the serial passages through chick cells and then chicken eggs produces a virus that is adapted to chickens rather than humans, that is, it is a host range (hr mutant as well as a cold adapted one. hr mutants are weakened, too, but we know this weakening (or attenuation, as it is termed) is unstable. It appears from experience, however, that the combination of ca and hr mutations produce a stably weakened but still live virus, i.e., one that still replicates but at a very low level at body temperature, doesn't transmit, and doesn't revert to a fully replicating wild type virus.

The mutations responsible for the weakening (both ca and hr) are on the six internal genes of A/Ann Arbor/6/60. Thus the strategy is to combine the genetic segments that make the surface proteins of H5N1 (the H5 and the N1 proteins) with the 6 internal genes of A/Ann Arbor/6/60 to produce a cold adapted and host range mutant virus that looks to the immune system like H5N1. Large droplet sprays of the virus are introduced into the nose of the person or animal, where the virus grows at a low level but enough to provoke a reaction from the immune system. One advantage of a live virus vaccine like this is that you need to grow much less virus because enough additional virus is made in the nose by viral replication; and the other parts of the immune system, mediated by various immune cells, can also come into play, adding to the protection produced by antibodies. This type of vaccine is not new. MedImmune's FluMist uses the same principle to combine A/Ann Arbor/6/60 with the H1N1 and H3N2 of seasonal influenza A and proteins from the prevalent influenza B type. These live virus vaccines are a minority of flu vaccines given each year but have a good record for safety and effectiveness.

In the study reported in PLoS Medicine, three different ca viruses were prepared by taking the H5 and N1 genetic segments of human H5N1 isolates from 1997, 2004 and 2005 (clades 3, 1 and 2, respectively) and combining them with the other 6 genetic segments coding for the internal proteins of A/Ann Arbor/60. The H5 segment was modified to eliminate the extreme virulence of the virus for chicken cells by clipping out the extra basic amino acids at the cleavage site of H5. The N1 segment was unmodified from the wild type H5N1s.

After one dose, mice were protected from being killed by wild type H5N1 viruses of any of the clades. Thus this vaccine afforded cross protection for the various H5N1 sublineages (clades). This is important as there is doubt that the current killed virus vaccines made against a non-pandemic strain of H5N1 would also protect against one that has mutated to pandemic form. Since we still don't have a pandemic virus to test this vaccine against (fortunately) we don't know if this kind of live virus vaccine would have a better chance to work also against a pandemic strain. but these data suggests it has this potential. One reason for the cross protection might be additional participation of the cell mediated immune system directed against the internal genes, which show much less genetic variation than the HA and NA surface protein genes that are under intense selective pressure. After two doses of the new vaccine, mice and ferrets are not only protected against the lethal effects of H5N1, but the virus no longer replicated in the respiratory tracts of the vaccinated animals.

This is good news, at least on the surface, but vaccines that work in mice but not in humans are common. The ferret, however, is thought to be a relatively good model for human infection, so the ferret data in this paper provides some reason for optimism. Still, the safety and efficacy of a live, attenuated H5N1 vaccine in humans has yet to be demonstrated, nor do we know important parameters such as how long it takes for protection to develop. There is also the lingering doubt that the live vaccine strain could reassort with a co-infecting wild type human virus to produce a reverted pathogenic strain. In the setting of a pandemic, however, this might not be much of an added risk. The population would already be getting infected with wild type H5N1.

The current version is still produced in eggs, which has two practical consequences. Productive capacity would still be limited by the availability of eggs, although the fact that less virus is needed than for killed virus vaccines helps. And the final spray product also contains egg allantoic fluid, so it cannot be used in people with egg allergies.

So the news is modestly good. Too bad we didn't do this years ago.

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This researh is good news, but it will probably take 5 years for a human vaccine to be ready, and even if the vaccine existed today, no country has the facilities to produce an adequate amount. So if the pandemic hits soon, what good does this research do us, except to give us a false hope of salvation as we observe friends and relatives dying, by drowning on their own body fluids, or becoming permanently disabled by the disease?
Below is a news report:
The woman who walked away

Via Reuters, a story from South Africa that echoes stories from Indonesia: Officials under pressure to contain deadly TB. Excerpt:

Health officials in South Africa are fighting to contain the spread of a deadly, drug-resistant strain of tuberculosis (TB) after an HIV-positive woman with the disease refused treatment and walked out of a Johannesburg hospital.
And a quarantined woman Extreme Drug Resistant-TB (XDT-TB) walked out of a clinic in Africa.

"Doctors have since located and quarantined the woman, but fear she might have infected several others with extremely drug resistant tuberculosis (XDR TB), a virulent disease that has already killed 52 people in the east-coast province of KwaZulu-Natal."
The doctors fear she may have infected others while she was out of the clinic. So now we have XDR-TB going worldwide. Does anyone have a vaccine for this deadly TB bacteria? The anwer is no.
And H2H H5N1 may already exist, if you observe what is happening in Indonesia. Sick birds are probably not the vector that is infecting H5N1 patients in Indonesia. The only blood match they have is from a cat. And so the mammalian vector is unknown, and killing sick chickens is not going to stop the transmission of H5N1 in Indonesia. And since the vector is unknown, there is no way to protect the public from infection.
So the situation is exactly the same as it was in 1918 with the Spanish Flu Pandemic. The only difference is we can identify the organism and they could not. But we have no way of stopping the spread, since we do not know what the vector is. To insist sick chickens are spreading the disease just does not conform with the scientific evidence. So the killing of sick chickens has the same impact as those in 1918 that carried a rabbits foot for good luck, hoping it would stop the spread of Spanish Flu.
Do you remember when Bush stated it may be necessary to use the military if there is a pandemic? If XDR-TB becomes a pandemic along with H2H H5N1, who is going to tell the president it is wrong to quarantine the cities in the US?
Of course it will not help, but do you want to let XDR-TB patients loose on the public, if they refuse quarantine?
Do you want these people fleeing into small towns to escape detection?
Does the public have a right to detain these people?

willilam: I think my point was that it would conceivably have done us some good if it had been started 5 years ago (which a rational public health policy would have done) but instead we were occupied with "other things," which have turned out to have endangered us by distracting us from more important issues (like a flu vaccine, which everyone who thought about this knew was needed).

Still, we follow the science on this blog, at least to the extent it interests us (which is a selected portion of the many developments on the flu front in science). Most of us will still be around in five years so it could conceivably benefit the ones who are. And maybe we will be lucky and something can get done to protect some people, although the way resources are distributed it isn't going to be the poor and the meek in this world who get it.

Is a live virus vaccine different from a whole virus vaccine? A killed virus vs an altered, live, virus?
About 1 week ago there were media reports (The Lancet) of Chinese human test results (Sinovac Biotech) on a whole virus vaccine. Initial results seemed good, high antibody titers at relatively low (10 microgram ) doses. However there was no mention of cross strain effectiveness and it was administered by injection.
The nasal mist administration technique would be a hugh advantage in underdeveloped countries.
William, *if* the live virus vaccine works in humans and does provide long lasting, cross strain, protection, this is a major advance. It won't help much if a pandemic starts tomorrow, but given enough time, it would be possible to either stockpile large quantities or just gradually vaccinate the population, though as Revere says, those most at risk will probably be the last to get it.

Kevin: Yes, they are different. You can make a non-live vaccine from the whole virus (whose have worked better; the Sinovac and the GSK are whole virus products with adjuvants) or just the supposed immunogenic protein (e.g. H5). Those split vaccines have required a lot of antigen and probably aren't practical now.

The live virus vaccines are just that: live virus. The virus grows in your nose and that produces the immune response. You hope the virus doesn't produce disease or side effects, since it is infecting you. We use live virus vaccines for polio (Sabin oral version) and smallpox (which we use the non virulent cowpox for which gives cross immunity). There is also the live virus flu vaccine FluMist, made by the same company as the one reported in this paper.

Another silly question. Why the apparent difference in cross protection between the live virus technique and the killed whole virus technique?

There are two good news items here, if you look closely.

1 - This is good news about a possible vaccine that may give protection from variations of a virus.

2 - 5 years from now, we won't be saying, "We should have started 5 years ago". We have started!

Strides are being made. For those of you reading this looking for rays of hope, small slivers are beginning to break through. Let's hope the clouds break and we can all start worrying about asteroids and such.

patch: I am with you. The development of these H5N1 vaccines had begun some years ago, and we were just starting to see the results published now. Be positive, revere and the likes. At least it works in mice and ferrets......

Bob Webster is sitting on a vaccine here in Memphis that produces huge titer response. Only problem is that it would likely kill you in its own right. Got to remember one thing though about the bioterrorism thing Revere as I move this stuff for the government and its a real threat. Variola specifically is one of the big time mentioned bug beasts. We have to be so multifaceted in this that I wonder if what we do will ever be enough. I also wonder if perhaps the Chinese looking at their growing Muslim population might have launched this thing as an engineered virus to tamp down its population and that of possible enemies. William would love the conspiriacy thought of that.

Lots of interesting uglies out there and we have to take resources and deploy where we think the enemy might attack. Its not like the 1500's where wars were fought at specific times and using specific tactics, we gotta be prepared. I agree fully with you that if and when the bird bug comes that someone is going to come up short even if a viable vaccine is out there. It will likely mutate before they can vaccinate everyone anyways and the big shit countries will protect their own first and then donate whatever is left to the underdeveloped ones. That means dead people with H5. Nothing ever changes except the players in the game, the results are always the same. Someone gets screwed in the deal.

By M. Randolph Kruger (not verified) on 14 Sep 2006 #permalink

I've been a lurker on this blog for quite a while. Learned a lot. I have a primary immune deficiency of a kind that renders me hugely vulernable to respiratory infections. The doc says I can use killed virus vaccines, and may get some immune boost from them, but live viruses like Flumist are a no-no.

Anybody have any thoughts about whether it would be better to use a potential bird flu Flumist vaccine and take my chances?

Given that a simple cold decimates me by progression to sinus infection or bronchial pneumonia, I figure I'm a goner right off the bat with any pandemic flu. Unless it is an overactive immune response that follows from the bird flu -- there I might have an advantage.

Also would Tamiflu work for me? I'm not exactly sure how it works or would work for someone who doesn't produce enough antibodies to attack respiratory viruses.

Appreciate any thoughts.

Sarah: If Tamiflu works againts the pandemic strain and you get it in time or ue it prophylactically (when it is probably most effective and that's what I'd recommend) then it will work for you. It doesn't use any component of the immune system. As for taking a chance on a live virus vaccine in a pandemic situation, I'd say yes. Better to be infected with a less virulent bug and hope you get some protection than the real thing that can kill you with or without a good immune system.

Last year I sent some questions to MedImmune about their inhalation vaccine, like FluMist and maybe a H5N1 in the future.
What about the inhalation technique: is it suitable for little children, and from what age on?
How do you transport and store those vaccins if they are so temperature sensitive? (What in case electricity and cooling capacity fall out in the beginning of a pandemic and you still need it?)
(didn't get an answer)

We can add questions about the management of body temperature when people are vaccinated using the live attenuated vaccine in winter. Some people have the risk of subnormal body temperature when they have e.g. a heart problem or burn out. Have they been doing experiments with those cases included?
People with a lowered functioning of immune system, like missing a spleen or having their immune system suppressed by some medical treatment better take as optimal and most diverse antiviral stuff as they can get.

Glad to see MedImmune obtained some H5N1 sample and started experimenting with it.

I think the problem with the idea that the Chinese might have engineered H5N1 to get rid of their burgeoning muslim population is that viruses don't really know a muslim from a christian from a jew from a.....chicken. Since we are genetically the same species despite race, color, creed, political affiliation etc, a religious preference is not really something one could genetically engineer.

By mary in hawaii (not verified) on 14 Sep 2006 #permalink

M in H. I agree, but from sheer numbers the Chinese might be the preeminent power after a bird bug pandemic. If they tamped down 30% of all of the EU/US/Russian/Japanese/Indonesian populations and had prepared prior to this with something that worked or didnt and just stocked up they would still have one heck of a lot of people. Something to consider. Their population at last count was 1/3rd Muslim and nearly all to the western side of the country. Isolate it and use a biobug on your own people? I dunno. Maybe.

Sarah, can you take the pneumovax as a preventative? I dont know whether thats weak live vaccine or killed virus.

By M. Randolph Kruger (not verified) on 14 Sep 2006 #permalink

On another note, this recent news from So Korea about turning up a number of aymptomatic cases of H5N1 from a couple of years back is odd (to say the least). They apparently have antibodies to the virus, but never got sick? Hope Dr. Niman gets the sequences of this So Korean variety to analyze and compare with the genetics of those varieties of H5N1 that are currently killing at such a high rate. By knowing what has changed or is different in the sequences, we might get a better idea of both what makes the current strains of the virus so lethal, and where the virus might be heading (mutation wise). Or, if the changes are insignificant, then we might take a look at what is different about the South Koreans that makes them less susceptible than, for example, the Indonesians and Thais. Is it genetics? diet? Environmental factors? Interesting...

By mary in hawaii (not verified) on 14 Sep 2006 #permalink


FluMist can be given to children aged 5 and above, and to adults up to age 49. It has to be stored in a non frost free freezer at or below 5F, but it maintains efficacy if given within 60 hours after defrosting if kept at normal refigeration temperature (36 - 46F).

By Gaudeamus (not verified) on 15 Sep 2006 #permalink

Thank you, Gaudeamus.
My point is that I am not so optimistic about the opportunities to produce and store these kind of vaccines if a pandemic sets off.
The job'd better be completed before it does.

Serious topics such as H5N1 do not warrant childish comments such as "King George". Those comments are neither constructive nor valuable to the discussion. If anything they show the bias of the poster and will immediately turn some eyes away from the rest of the article. The author presumes that five years ago, in 2001, the year of the twin tower attacks, a different President would have taken H5N1 more seriously than "King George". How about focusing on constructive thoughts on how to address the potential pandemic than sinking into childish behavior?

By LowRecoil (not verified) on 16 Sep 2006 #permalink

LowRecoil: This is a blog, my friend. Moreover it is a political blog about public health. We have spent in inordinate amount of time explaining to the likes of comments like this why we think religion, war and politics are part of public health. Feel free to peruse the more than 1300 posts here and the old site, many of which are on that topic. Moreover, every Sunday we do a Freethinker Sermonette about atheism.

Regarding King George, King George was the target of Shelley's poem. If you choose to consider George Bush an analog (I invite it, surely), it shows you get it, somewhere in your heart of hearts. Good for you.

This is not a bird flu blog. It is a public health blog. Consider it like TV. Use your eyes like a remote control. If you don't want to read something, don't. If something interests you, read it. Or you can just tune in Fox News.