Immunity and cross-immunity to bird flu

A new paper has just appeared in PLoS Medicine on an old topic: whether seasonal influenza vaccines might also cause enough cross-reactivity to protect against H5N1. The basic idea is simple. The immune system "sees" the surface proteins on the flu virus and makes protective antibodies against them. The major stimulant for this is the hemagglutinin protein (HA), the H part of H5N1. There are 16 different immunological flavors of HA that cross-react very little. Since the human population has never had widespread infection with a flu virus that has the H5 subtype (we have had H1, H2 and H3 pandemics), most people would have little immunologic protection from past infection or vaccination against a virulent H5 containing flu virus. But there is the other surface protein, the neuraminidase (NA) part, which has 9 different immunologic flavors. The major pandemic of the 20th century was an H1N1 virus. In 1957 it was replaced by viruses with N2 proteins, but in 1977 H1N1 made a comeback and now routinely co-circulates with the H3N2 that first appeared in 1968. The seasonal flu vaccine therefore has both H3N2 and H1N1 components (as well as an influenza B component). Might there be some immunologic protection conferred by the N1 component in the flu vaccine or the periodic infections with H1N1 that still occur? Indeed this flu season in North America seems to be primarily an H1N1 year (although Europe is reporting a lot of H3N2 as well).

The new paper reports that antibodies against seasonal influenza N1 partially protect mice against H5N1. The results are interesting and suggestive, but the animal model system is sufficiently far from the human situation that we shouldn't have a lot of confidence in its relevance to an H5N1 pandemic at this juncture. In any event, here are some of the details. Researchers at St. Jude in Memphis (one of the premier influenza research centers in the world) prepared an N1-containing DNA vaccine and immunized mice via an injection into their muscles. This kind of vaccine is unlike conventional vaccines. It contains a small piece of DNA that also codes for the N1 protein. Mouse cells use the DNA to produce the N1 protein and then the mouse's immune system reacts by producting anti-N1 antibodies. The researchers also produced two viruses using a common laboratory strain (PR8). Each contained 7 of the 8 segments of PR8 and one segment each of N1 from a human virus (huN1) and one from a bird virus (avN1). They also had a full H5N1 virus isolated from a patient in Vietnam in 2004. All three of these viruses were lethal to unvaccinated mice, but the vaccinated mice were fully protected against challenge with the huN1 virus and partially protected against lower doses of the avN1 and H5N1 viruses. In the avN1 and H5N1 mice half themice died at doses that were ten times the amount that would ordinarily kill half the mice. If the dose was increased to 100 times that dose, all the H5N1 mice died and most of the avN1 mice. In each case, the vaccine protected the mice inoculated with the human N1 virus. In other words, a vaccine prepared to produce antibodies against seasonal flu N1, provided partial protection against H5N1 and H1N1 containing bird N1.

There was another interesting set of results in this study. The function of NA for the virus is to act as an enzyme. If this function is interfered with, the virus is crippled. A study of sera taken from 38 people showed 31 had antibody activity sufficient to inhibit this function in the usual seasonal H1N1 virus. This showed that there was anti-N1 activity in these 31 people, which they may have acquired from previous natural infection or vaccination. But 8 of them had low N1 inhibiting activity against H5N1 virus as well, seven of them to two different H5N1 viruses (one isolated in Hong Kong in 2003, the other the Vietnam virus from 2004).

The authors note that there was a marked difference between detectable levels of antibody in the blood of the mice (12.5%) and the level of protection (50%). This suggests antibody detection methods might not be sensitive enough to predict protection from low levels of antibody, or that they are looking for the wrong antibody. This might explain the largely negative seroprevalence studies, although the data are very scant and the data in this paper are based on very small numbers.

It is known that anti-NA antibodies can modify the severity of illness and viral replication, although they are not completely protective. Moreover vaccines that work in mice too frequently don't work in humans. Even if they did, we know little about the relation of NA immunity to population effects and the level of NA in current vaccines is not standardized, unlike the HA antigen contents. Thus the vaccines from various makers or even lots from the same maker might differ in NA content.

This is an interesting study, opening up new lines of investigation. Unfortunately we have more lines of investigation than we have scientists and time to do the studies. Too bad we didn't start this earlier. I guess Big Pharma was too busy working on erectile dysfunction drugs. Priorities.

More like this

Good reading! Thanks Revere.

One thing though, I cringe at cynicism. You end your comments with a jab at Big Pharma. But St. Jude isn't "Big Pharma". It's almost as if the Big Pharma comment was an afterthought. St. Jude isn't Big Pharma but could have been researching earlier as well (maybe they were). While Big Pharma was guilty of frying "other fish" and could have been working on research earlier, so could many other researchers/entities.

In fact, our indifference to, and in fact in some cases, outright distrust of vaccines is what has driven Big Pharma's decisions regarding vaccine research. Throw the threat of litigation into the mix and it's no wonder they put it on the backburner.

Nobody wins the blame game. Just my 2 cents.

Patch: Inartful writing on my part. I didn't mean to imply St. Jude was Big Pharma. I meant to imply that we could have done many of these things much earlier if Big Pharma had been interested and we hadn't decided to let them lead policy by whatever it was they wanted to do. We could have supported this kind of research much more vigorously by not assuming the private sector would always optimize what was needed. In this case (and many others) they didn't. We should not rely on "the market" for vaccine technology or production, IMO, which was what I was trying to say (although not saying it well, as you point out).

Precisely. Well said!

Big Pharma is business. It stands to reason, that their decisions are based on business models. Making and researching vaccines nobody wants (or trusts) was not a wise business decision. At least in the past.

It is unfortunate. I hope researchers, like St. Jude can help us play catchup.

Patch. Yes. Big Pharma is business, and a highly successful one at that...

...I for one, certainly wouldn't want them to have to give something back for all they have taken.

How quickly we forget about the model provided by Connaught Laboratories at the University of Toronto...I guess those were the good old days...Eh!!

I'm glad to see that St. Jude's looked into this. When the new wiki forum opened I did a post there (or was it at CE?) about redefining vaccine success in the environment of a highly lethal virus, from 'prevents illness' to 'prevents death'. For ordinary flu, 'death' is a rare enough outcome that this would be a useless measure, but for H5N1 in its current mortality, such protection would be a significant advantage.

If our existing vaccinations work in the 'prevents death' category, the economy will still be tanked by the rate of illness, but recovering from that dip should be much easier, as people will be slightly less afraid to return to normal activity and the demand for heathcare intervention may be less.

If these results hold true for humans, it would not change the individual household's need to 'prep' for economic disruption, but it might make the burden on governmental and healthcare structures a little more manageable.

By Lisa the GP (not verified) on 14 Feb 2007 #permalink

Given these results, and given that existing vaccines are currently approved and considered safe for human use, would there be any utility to immediately starting a study of H1N1-containing vaccination in high-risk groups in Indonesia to see if there is any detectable reduction in H5N1 fatalities in those who acquire the virus among the vaccinated group? I fear you would have to cover a very large population to get even one 'case' occurring in your study population, yet I think you could ethically justify exposing such a large number to your 'study drug' given that it is approved and you're investigating an 'off label' usage--plus benefit to the study participants of having immunity to the seasonal flu could be your 'payment' for study participation, maybe?

How could such a project be rapidly financed? Who would have the seasonal flu vaccine containing N moieties in quantity sufficient to attempt such a project?

What would be the politics of such a study, given the Indonesian's recent idiotic IP move with Baxter?

By Lisa the GP (not verified) on 14 Feb 2007 #permalink

Lisa: I think you have put your finger on the main problem: very low incidence makes detecting an effect very difficult. It's a reasonable idea, though, just as a public health measure.

Lisa/Revere, just as with the poultry though couldnt taking the flu shot help to mutate an already rapidly mutating bird bug.

This year I opted for the pnemovax and havent been sick at all. The rest of the family was dropping like flies and they took both. Flu shots in the military made me sick as a dog. Finally I got a waiver and havent had the flu in about 10 years. Dunno, got any science on that?

By M. Randolph Kruger (not verified) on 14 Feb 2007 #permalink

Vaccination won't change the mutation rate, it will just select for a different variant out of the currently existing swarm.

In theory if you could vaccinate enough potential hosts in an environment, that should drive the virus toward a less lethal form, as the host would have to survive longer in order to be certain of encountering a vulnerable individual to act as the virus's next host.

This doesn't work so well in chickens only because there's an entirely new population of chickens to infect every 4 months.

By Lisa the GP (not verified) on 14 Feb 2007 #permalink

is it B-cell immunity or T-cell immunity ?

anon: It was B-cell immunity as evidenced by passive transfer of protection via antibodies from one mouse to another.

From my recollection of all the vaccination papers I've read in the last 12 months, it seems that most vaccines will confer limited immunity to H5N1. They won't stop you from getting infected but they will reduce the severity of the disease, which seems to me the most important point.

Thanks Marissa.

We are spending or are going to spend billions of dollars on a vaccine that might be avaliable 6 months after the pandemic starts, in very limited quantities and now it is admitted, providing only 'partial immunity'.

Partial immunity, in my opinion, is the worst of all worlds...

...take front-line healthcare workers and make them asymptomatic shedders or extend the period they will continue to work while spreading pandemic influenza among the unvaccinated public...

...tell me again that we are better off then they were in 1918?

How many essential workers in China or the army have been vaccinated with a 'partially effective' H5N1 which in addition to the above, assists the adaption and evolution of H5N1.

By the way, it was reported last night that there have been 21 cases of influenza in my local community with 30% of citizens vaccinated...

...It was also reported that 3 of the 21 infected persons were vaccinated.

Tom DVM: I really respect you and your continued commitment to the issue of pandemic flu.

I must say, though, even if 3 of 21 were vaccinated, does that necessarily mean the vaccine was useless? Do you know when those people were vaccinated? I just got my shot last week. I was sick for about a month over the holidays, so I kept putting off going in for the vaccine. I won't have real protection for another week or so.

Also, wasn't there a study about vaccine and use of anti-inflammatories? What if those three happened to pop a few Tylenol to reduce pain & swelling from the shot? Couldn't that reduce the effectiveness of the vaccine?

I know there are plenty of reasons to doubt that some H5N1 vaccine will save us all. And it's likely that news-tellers will latch on to any reason to believe that all disaster can be diverted with a magic bullet. Still, the numbers you cite from your town don't seem to prove that the current vaccine is not helpful for garden-variety flu prevention.

Just an observation.

By wenchacha (not verified) on 15 Feb 2007 #permalink

Hi wenchacha. Thanks.

There are two independent issues here: seasonal influenza vaccine and pandemic influenza vaccine.

This topic is highly complex and normally, I would take a week to mull it over in my mind, before giving a hopefully complete response but I will do my best here.

The seasonal influenza is a matter of faith and choice and I am not suggesting that someone should not get it...I am asking that those who recieve it to be fully informed of its limitations.

The first precept of medicine is do no harm. This is particularly significant with influenza vaccines because there is no evidence that they are what are the adverse effects of influenza vaccines and how frequent are serious side effects occurring.

Influenza is the most successful virus in history because it has harnessed its own instability to its advantage...and it is precisely this evolutionary adaption that makes vaccines less effective then for many other diseases.

The vaccine works in the laboratory because the exact same strain that is used to produce the vaccine is used to test the response in laboratory animals to the vaccine...

...however, in the real make the vaccine to a strain but the instability of the influenza virus results in its genetic drift away from the genome you are making the vaccine out of...therefore, in the lag period before the vaccine is produced, the virus has drifted away sufficiently so that the vaccine can no longer recognize the virus...and the vaccine fails.

Okay, you will see many studies that will indicate that seasonal influenza why would I as a veterinarian say that they don't other than a very small porportion of the population, less than ten percent.

Influenza is actually a very sporadic disease that is misdiagnosed very frequently. I have done quite a bit of work on food poisoning and it is reported that 95% of food poisoning cases are misdiagnosed as influenza... can see that in the data from my local area. Of all the infections this winter, and there has been some serious respiratory infections going around, only 21 cases have been identified as influenza...this presents serious problems for studies to measure effectiveness and has serious implications as to immunity to pandemic strains.

Given the above information, you will read many reports that state that vaccines are effective. First, laboratory animal studies don't count because they freeze the evolution of the virus which is a completely artificial construct invented only to get artificially positive results...

...secondly, the other studies are using completely subjective criteria...for instance asking hospitals or doctors to tell them which persons have influenza without any blood tests and specifically without paired blood test the first day and another in 2-3 weeks that identifies an immune response to the infective agent.

Subjective criteria have been used by epidemiologists in the past twenty years to produce some highly questionable results...and the data on the effectiveness of seasonal influenza vaccine, in my opinion, is similarily tainted.

So the question becomes...are they only using subjective criteria because there actually is no way to measure the effectiveness of an influenza vaccine in the field.

The only way to measure the effectiveness of a vaccine is through double-blind studies...studies where the examiner-observer does not know whether the person was vaccinated or not.

One way to do this is to vaccinate one group and leave a second group unvaccinated and then challenge both groups with influenza vaccine up the nose...the problem with this method is that a certain percentage of those infected with seasonal influenza can become quite sick and even die from seasonal influenza...that makes this procedure unethical.

The second way to do it is to follow persons natural choices. In other words, you choose from the population, one segment that chooses not to be vaccinated and a group that does choose or is willing to recieve a free vaccine...

...then you monitor their infections for a period of time and diagnose every infection with paired serology (as has occurred in my locality to identify influenza cases)...

...There are many benefits to such a study...

1) the question is answered whether influenza vaccine works and more importantly, in what porportion of the population.

2) What is the actual rate of food poisoning in the population and what is the cost of food poisoning to the economy of a nation. In my Province of Ontario in Canada, food poisoning was estimated to cost the provincial economy more then 500 million dollars each year.

3) As a screening tool to measure the other infections that are often misdiagnosed as influenza. From my treatment of animals, a lot of these infections look like RSV or respiratory synctial virus infections.

It should remember that a precept of the scientific method is repeatability and therefore, similar screening should occur in different localities by different researchers.

Pandemic vaccine is a whole different animal from seasonal influenza vaccine for a number of reasons.

First, it is going to be produced during a pandemic...where it is possible that a significant percentage of the workforce at a vaccine plant might be sick themselves or desert to protect their families...

...secondly, workers may introduce H5N1 or H7 or any of the other pandemic potential viruses into the plant and contaminate the samples.

Also, this is an egg based vaccine and poultry and eggs are susceptible to the virus...which I fully expect will result in the total breakdown of vaccine production in multiple plants at the same time.

Also, H5N1 does not replicate well in eggs

Also, our immune systems have responded very poorly to pandemic vaccines so far produced.

Also, the total production of vaccine at some indeterminate point after six months will presently protect only 300 million people.

Also, there is unlikely to be healthcare workers to administer a vaccine even if it could be produced...congregating people to get it could end up with worse consequences then in the unvaccinated population.

Also, the vaccine may be immunosuppressive which could cause problems in the time period between vaccination and protection 2-3 weeks later.

In my opinion, and it is only my opinion, there are too many weak links in the chain for this to be a successful strategy... why spend billions when you know it won't work...

...instead of helping people with packages of treatments and supports that they can give at home

...and fixing infrastructure (washroom doors that open without handles and disenfection on escalator railings etc.) that will assist in preventing community transmission.

Hope that helps.

Okay, that fleshed it out quite a bit. Thanks.

The greatest problem I see right out of the gate is the limited amount of any vaccine that will be produced. That alone seems reason enough to have a very robust Plan B for dealing with a pandemic flu. Can you ballpark the cost of Plan Vaccine vs Plan Fix Infrastructure? I have no idea, I'm just curious.

If there were a clear way to show the benefits of your Plan B, it could offer some encouragement to each business, each school system, each hospital to at least do what they can to improve chances for survival of those stricken.

I'm not suggesting abandoning a Plan Vaccine entirely. I think there must be some decent brainpower behind the problem of how to formulate a working vaccine for flu. But I also understand your frustration if all the dollars back that one horse instead of betting on a few others as well.

By wenchacha (not verified) on 15 Feb 2007 #permalink

wenchacha. Excellent points!!

As a person who looks at this issue from the chicken's and the dog's and the cat's and the muskrat's perspective rather than the human perspective...I see no possible way for humanity to avoid a pandemic at this late date...and given the emergence of High pathogenic influenza's as zoonoses (H5,H7, H9 etc) the next pandemic is going to be one of significant impacts...the only question left is timing?

It should be kept in mind that the longest interpandemic period in history is 43 years...and we are currently 39 years out from the last pandemic.

There have been ten pandemics in the past three hundred years...three of the last six have been high impact pandemics...1830, 1890 and 1918.

A former Prime Minister of Canada, named Joe Clark, I believe once said that a country is a 'community of communities'.

I think we need two things...first, we need a political leader to lead rather then follow...meaning to state unequivocally that we are going to have a pandemic and it is going to be serious...

...and two, we need to put the emphasis and the control and significant funding at the local level where the responsibilty will come to rest anyway, after the first few weeks of a pandemic.

I believe that twenty dollars per person could go a long way to provide essential medications...telephone and other supports could be planned at a local well as training for famillies in how to avoid infection, proper fitting of masks, dispensing of waterless disenfectants and serious refitting public infrastructure.

I think this would be far cheaper than there antiviral and vaccine strategies that are both doomed to failure.

Thanks again.

Tom I saw where the CDC was letting out contracts in the CBD for a new series of commercials on Avian Influenza preparedness. I hope they dont suck as much as their previous ones. Talk about retarded, it reminds me of one of those dumb 1960's nuke attack preparedness flicks.

Your points above might be better than the approaches taken so far. I havent seen anything to date work that could be atrributable to some drug or vaccine. That flu shot stuff from the last few days might save a few (maybe) but it hasnt fixed the antigen yet that comes after us either. I wont be placing any stock in it. On the other hand I sure as hell wouldnt be sending one red cent to the Indonesians though. They went Chinese on us. Next thing you know they'll be calling it just pneumonia.

I said it months ago, this is a chase for a vaccine. He who gets a working vaccine gets a Nobel, he who makes a working vaccine gets a half trillion before it mutates out of effectiveness.

Better math. Buy stock in the body bag companies.. Theres a sure bet and likely as profitable. They charge 18 bucks per bag-10 wholesale. Deliveries in quantities of 10, 100, 1000, 50000. Made in China of course. I have a link for anyone who wants it.

By M. Randolph Kruger (not verified) on 15 Feb 2007 #permalink

MRK - Your remarks are always interesting, screamingly funny, controversial, fun, thought provoking and you really stick it too the masses. Love your comments.

When we were all becoming aware of AIDS - The Australian government had a terrific commercial. The Grim-Reaper (smoke machine working over time and a foreboding voice over) would roll his bowling ball towards a bunch of people (lined up like ten pins), mowing them down in the process. It was a simple and very effective way of describing how the disease was indiscriminate. The simple ideas work.

Re: Tom DVM - 15 Feb "By the way, it was reported last night that there have been 21 cases of influenza in my local community with 30% of citizens vaccinated...

...It was also reported that 3 of the 21 infected persons were vaccinated."

Not too surprising actually. With an R0 reported as between 2 and 4, it might take as much as 50%-75% of the population being immune to suppress transmission. Most efficacy calculations put the vaccine at about 70%. So 3 out of 21 might not be that bad.

drd Thanks.

" Most efficacy calculations put the vaccine at about 70%. So 3 out of 21 might not be that bad."

They do not the efficacy of influenza vaccine in the field because they had not done the study required to determine if it is effective...all estimates are based on anecdotal studies... seems to me that while they are spending billions on an H5N1 vaccine, they might be able to spare a few millions for a proper study. Hormone replacement also worked until it was actually examined.

As far as the three vaccine failures out of 21 confirmed cases...I think if any other vaccine worked this poorly, they would go back to the drawing board...but it will take someone better than me with statistics to prove it.

Influenza shifts genetically faster than the lag period for vaccine although it works in the lab with laboratory animals when genetic shift is freeze-framed, I am not sure existing technology will ever work.

But the bottom line is let's do the study and prove this one way or another.

I'd love to see someone update that PSA!

a map of various countries on the floor, one nation for each PSA, so they see different ones through the day, and the black Panflu ball knock down however many of the pins for each country's 2006-2007 cfr is... (can someone make some YouTube videos?)

Too many of the public bought the "it's just in Asia, hasn't gone h-h, and you have to play with sick chickens" spin; if they do hear

the timeline, countries and mammal species, and human age groups and numbers, some listen, and go stock up.

(It's getting them to stop running away with their hands over their ears that's the hard part.)

By crfullmoon (not verified) on 17 Feb 2007 #permalink

(ok - not enough caffeine for me yet this morning-
it's not panflu yet -perish the thought-
tag the bowling ball H5N1,
even though "no one can be 100% sure that will be the next panflu")

By crfullmoon (not verified) on 17 Feb 2007 #permalink