The first of the putative "universal" vaccines against influenza A is entering Phase I (small scale safety and efficacy) testing. Manufactured by UK vaccine company Acambis, the vaccine is designed to protect against a wide range of influenza A viruses of many subtypes and many strains. Here's the idea. The immune system mainly "sees" viral proteins on the outside of the virus. The most visible of these is the hamagglutinin (HA) protein which gives its initial letter to the H-subtypes like H5N1 and H3N2, etc. The other visible protein is the neuraminidase (NA) protein, the initial letter of which is the second part of the binomial subtype designations (i.e., the N1 part of H5N1). The immune system also makes antibodies to NA, although it is thought that more protection is afforded by the anti-HA antibodies and it is against HA that all the current vaccines are directed, although those that use whole virus will elicit antibodies to various other viral proteins as well. The problem is that the virus is continually mutating, in effect changing how it looks to the immune system. Just when your immune system has been trained to find one HA, the virus puts on a new HA-look and immunity falls off. That's why we need a new flu vaccine every year or two. So how is the Acambis vaccine supposed to get around this problem?
The Acambis vaccine is one of a new crop of flu vaccines which targets yet another viral product, the M2 protein, an ion-channel protein also the target of the older antiviral drugs Amantadine and Rimantadine. M2 regulates the acidity of the viral core and is essential to the "uncoating" of the virus once it has entered a host cell. When the acidity of the core changes it allows the genetic material to be released into the host cell where it can hijack the protein synthesis and genetic replication machinery to make new copies of virus instead of proteins needed by the infected cell. The antivirals work by preventing this uncoating. But it turns out that bundles of M2 protein also get incorporated into the membrane of host cells and a portion, called the M2e domain, appears on the membrane surface and becomes part of the viral envelope when the virus buds from the infected cell surface. Antibodies to M2e have been shown to reduce but not eliminate illness in mice and ferrets. The most effective (but not the only) way to prepare M2e antigen is by fusing it with hepatitis B protein (just a fragment of the hepatitis virus, not the virus itself) and administer it with an antibody production boosting additive called an adjuvant. This is what the Acambis preparation does, using bacteria (E. coli) to produce the fused HepB-M2e antigen and adding one of two different adjuvants to boost antibody production. This all seems very promising, but there is a great deal we don't know about how the immune system works, as evidenced by this:
The best protection was reported for mice vaccinated by the intranasal route with an M2e-hepatitis B core fusion protein construct and detoxified heat-labile Escherichia coli enterotoxin adjuvant; almost none of these mice died after a virus challenge that killed 90% of control mice. However, in contrast to the significant protection seen in most mouse models, pigs vaccinated with recombinant M2e-hepatitis B core protein or plasmid DNA encoding an M2e-nucleoprotein fusion protein showed no protection or even had higher death rates, respectively, after virus challenge. This finding needs to be confirmed, and the explanation for it remains unknown. At this time, it serves as a reminder that immune phenomena are complex and that observations made in 1 species may not apply to another. By the same token, good protection in an animal model does not guarantee protection in humans. (Gerhard et al. Emerging Infectious Diseases; cites omitted)
Given this, it will be interesting to see how this Phase I trial turns out. There won't be a challenge with flu virus but presumably some monitoring will take place during the next flu season, an antibody response will be determined and the safety profile crudely examined. The trials will take place in the US, although I don't know where. M2e is a conserved protein fragment, meaning it exists in only a few variations. Thus escape by mutation is less likely. Use of recombinant DNA engineering to make this antigen in E. coli is a rapidly scalable technology, so the ability to ramp up production quickly exists once the technique is mastered on an industrial scale.
The noteworthy thing about this announcement is that it is a human trial. Challenge trials in animals are some evidence but not the best evidence, as the contradictory results from mice and ferrets versus pigs suggest. It's likely we will be seeing more Phase I trials as a host of new vaccine technologies matures. Interesting times. In terms of public health, is it in enough time?
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The first of the putative "universal" vaccines against influenza A
Hi, please excuse me but I'm not too familiar with the medical principles here and I'm trying to understand this bit: So this is a universal or mostly-universal vaccine, but only against influenza of some "type A"? Is there an influenza B that this vaccine would not work against?
Coin: Influenza B also has an M2e protein but it is different than the influenza A M2e. So presumably if this works, there would also be a flu B version, perhaps a bivalent vaccine to cover them both at once. Currently the trivalent flu vaccine has two A antigens and one B antigen, but they change each year as the circulating strains change. For a "universal" vaccine the yearly changes would not be necessary. It would work for all flu A strains and not require yearly vaccinations, although boosters might be required. But we are a long way from that, unfortuantely.
Apparently, on reading the paper which looked at pig responses that is cited in this paper, it seems they found that the M2e antibodies aren't virus neutralising but instead mediate infected cell targeting responses. Additionally, the chellneged the vaccinated pigs with H1N1.
Thus, the pigs lung epithelium were still getting infected and then were being targeted by NK, CTL's and complement when they presented viral antigen on their surface. Thus, the presence of antibodies to M2e was likely contributing to the 'cytokine storm' effect that has been noted with H1N1
I'm not sure what the difference in cell-mediated immune strength is between swine and mice, but it could go some way to explaining the different responses.
Like you said revere, there is still so much to learn about the immune system...
I am very hopeful that targeting M2e will be an effective way to provide some immunity to influenza. What Revere pointed out about this particular universal influenza vaccine approach though it key; the vaccine does not protect people in the same way or as well as specific seasonal influenza vaccine does. This means that if this approach proves out, there will still be the need to administer a specific trivalent seasonal vaccine too in order to get the best results.
We have no idea what this 'best result' will be. There could be an additive effect, a synergistic effect, or even a negative effect (anti-body blocking?). For this reason, it will be very important to do these trials carefully and not in a great number of people before we release the M2e vaccine into large scale phase III testing. If there were negative synergy, this would mean those participating in vaccine trials of M2e would not be able to benefit from use of seasonal flu vaccine in the future, a very severe adverse event.
I don't think there will be negative synergy but just wanted to raise the point so folks don't get so excited about one approach over another until we really have a safe and effective answer for this. In my opinion though, this is a very critical safety issue and means that if this approach is going to be properly and quickly studied, the only way I can see of doing this would require clinical trials of subjects in 3 groups. These would be a control group with shame vaccination, the second would be an M2e only vaccinated group, and the third would be an M2e plus seasonal flu vaccinated group. Then, all three groups would need to be purposely exposed to seasonal flu virus and the results recorded. No other study design will answer. Interesting, this design might violate current EU guidelines for human investigations but would probably not violate current US FDA good clinical practice regulations for human trials.
The live attenuated virus developed by MedImmune for season flu is a very interesting approach that in some populations appears to be more efficacious that the conventional vaccine. The same is true for live attenuated polio vs. killed virus vaccines. Of course the Small Pox vaccine was a live attenuated strain and it was so effective that its worldwide use has now eliminated this plague. Use of a live attenuated vaccine is slightly riskier since some people can become pretty sick from the 'attenuated' virus or it can mutate into a more virulent form during passage person-to-person. Nevertheless, there is a lot to recommend this approach overall and its ability to provide herd immunity is likely to be faster because of the transmission of the live attenuated strain to a few others the vaccinated person comes into close contract with. It is also a more physiological approach to vaccination. What's more, there is no need to combine a live attenuated viral vaccine with an adjuvant since the infection caused by this approach is more than adequate to stimulate an excellent immune response.
A variation on this theme is the use of a well-adapted human viral strain that have been both attenuated and genetically engineered to carry influenza coat antigens on their surfaces. This promising technology has application in therapy for cancer too (cervical, melnoma, prostate, breast etc). The nice thing about this approach to producing a pandemic vaccine is that once outbreak occurs there is no need to attenuate the wild influenza strain. All you need to do is identify the influenza virus genetic sequences responsible for the target surface antigen and insert it into the live attenuated carrier virus genome. I am not claiming that this will be easy to do but simply that it can be done with a great deal of work and resources. Once accomplished, the new vaccine could be produced in very large quantities and rapidly. Vaccines like this are grown in tissue culture rather than in eggs, which is why it can be scaled up so quickly.
Incorporating the RNA responsible for expression of the M2e antigen into a live attenuated human carrier virus could also make a very effective universal influenza vaccine. There is a good chance that this approach would be much more efficacious than the one currently under study. As stated, it would not require the use of an adjuvant since use of this technique results in much higher levels of the M2e antigen being presented to the human immune system. It has the virtue of stimulating a much more vigorous and physiologic host immune response since the carrier virus is actually infecting cells rather than just being presented extracelluarly either within the upper respiratory tract of interacutaniously.
Grattan Woodson, MD
Gratt: You make some very important points and I don't have a lot to add. The question of antibody competition would seem to be an important one, although it isn't clear to me how important it would be as both vaccines would present fairly high antigen levels. The problem now, as I understand it, is that the competition between HA, NA and M2 relates more to the relative amounts of antigen the immune system sees, but I may be wrong. Or we may not know exactly. We know a great deal about the immune system at a primary level but the secondary levels involving the interactions of the various arms and components within each arm is still pretty much a black box as far as I can see.
Probably the best example of spreading immunity from live virus vaccine is Sabin polio vaccine. It also illustrates the pitfalls. In the developed world about half the cases of paralytic polio are vaccine associated, although these cases are very, very rare and the vaccine has prevented many orders of magnitude more polio than it has caused. On the other hand, it is one reason we are moving back to the Salk vaccine (not live virus). Smallpox vaccine isn't, strictly speaking, an attenuated vaccine since it's a different virus, but that's a minor point.
Revere, Okay so lets say it works and we go for four or five years. What will the flu virus do IYO? Will it mutate? Will we see it given to poultry as we have as of late along with Tamiflu? If thats the case then wouldnt it go bumping around the vaccine/Tamiflu and come back to get us in a very, very ugly way some time later.
This is one smart cookie virus. Unique and the more I read about reassortment/recombination and evolution of flu I am almost ready to call it and say that it was an engineered virus.Very likely a bug from a VEKTOR lab and sold to the Chinese. Isnt it odd that just about the time that the place was closing up we saw SARS and AI just suddenly appear? Very strange, very unprovable. But this stuff looks like it has a mission. Was or is it possibly a sexed up H1N1 virus?
I am no conspiracy theorist but this one has me wondering. Did the bug get out of a cooler somewhere? Or did literally a chicken fly the coop?
Randy: So far the M2e domain, which shares a sequence with M1, doesn't have much leeway to mutate, even under selection pressure. There are only two other mutations that have been observed and it is plausible they are the only possible ones. There are some things viruses can't do, as we've seen with smallpox and polio. But the vaccine might not work at all, so . . .
Howdy Randy,
Hope you are well... Oh, I know you are wondering -- yes, the bigoted Australian people who abused me during the 90s are still acting as if I don't exist (kinda like the Aussie version of Gitmo).
As an unpaid freelance Australian transgenic pathogen
research analyst, I completely agree with your sentence but from a different angle: "[The] more I read about reassortment/recombination and evolution of flu I am almost ready to call it and say that it was an engineered virus."
Yes, the hyper-evolution seen in transgenic (cross species)
pathogens such as H5N1 appears artifical -- a human created frack up, possibly arrising from dodgy tech in genetically modified crops interacting with the natural environment...
Cheers:*) and Aloha pumehana -- Jon
C21*S*E*Research -- The Politics of Horizontal Gene
Transfer (how the H2H H-this N-that virus evolved and
painfully destroyed half the human species)
I suspected genetic engineering was dangerous back in
the late 90s when first seeing a tv news item on H5N1
contamination in Hong Kong -- six people (adults and
kids) "cytokine storm" died of this transgenic flu
during a late 1997 outbreak in Hong Kong's Special
Administrative Region.
Even a major pharma company, Roche, was worried back
in 1997 'bout the global implications -- in its Media
News 16 (May 2006) Roche says:
"Roche has been in discussions with governments as
early as 1997 regarding pandemic preparedness..."
www.roche.com/med-cor-2006-05-16
So how did H5N1 get here?
H5N1 is a transgenic polymorphic pathogen, a fast and
fiesty fracker of a virus. This highly mutable cross
species multi-strained virus probably originated from
genetic engineering.
Since the mid 1990s, consumption of GM (genetically
modified) crops by wild and domestic birds, animals
and humans (who eat crops, birds and animals) have
increased dramatically. It is very probable GM crops
containing CaMV 35S transcription promoter are the
horizontal gene transfer (HGT) causation vector thru
which transgenic viral pathogens (eg. H5N1) are
recombining (homologously) into existence with such
ease, speed and spread.
The "homologous recombination" process has, according
to Recombinomics.com, always been the explanation for
viral evolution and not "random mutation". But, the
thang bout the flawed technology of remix tweaking GM
organisms (eg. crops) sees Las Vegas-styled
"hyper-acceleration" and "unpredictability" entering
natural DNA evolution -- thangs move a darned sight
faster in dangerous directions...
Recombinomics -- Random Mutation Explanation of Flu
Genetics Is Fatally Flawed (March 30, 2006) @
www.recombinomics.com/News/03300602/Random_Mutation_Flawed.html
The defence against evolving polymorphic viruses is
rather simple and has been repeated many times by
numerous scientists worldwide -- cease the corporate
controlled release of genetically modified organisms
within the global environment.
Before the end of 2005, official gov-based efforts in
sequence tracking the genesis of H5N1 were criminally
lackluster -- we now know cross species strains are
present in birds and mammalian populations across the
entire planet...
But still, the question remains unanswered, how did a
transgenic virus with far reaching destructive power
appear out of nowhere?
The probable (but unproven) cross species vector is
GM/GE crops eaten by wild birds, etc, from the mid
1990s to present, HGT recombining H5N1 (via CaMV 35S
promoter) into a transgenic polymorphic pathogen, now
infecting and killing humans with an ever increasing
efficiency...
So, basically I'm saying gene flow has occurred as a
consequence of transgenic crops doing a CaMV 35S
promoter recombination hotspot remix in the bellies
(and bodies) of all organisms consuming such crops.
Prof. Joe Cummins was the first to warn against using
the CaMV 35S promoter or any viral genes in plants
because it had been shown that such viral transgenes
in plants could gene flow recombine with naturally
occurring viruses to generate, in some cases,
super-infectious viruses.
Subsequently, the CaMV 35S promoter has been found to
substitute for the promoter of many plant and animal
viruses to produce infectious viruses.
* Remixed excerpt ISIS Press Release 29/11/04 -- Fluid
Genome & Beyond @
www.i-sis.org.uk/Fluidgenomeandbeyond.php
Hiya Jonny. Something is definitely UP with this bug. I was reading back against some of the viruses that have mutated into human infectious capability and this onereally has gotten its act together.
1958 flu, another A type was rumbling apparently for about three years. Lots of flu but not "bad" flu and then it jumped and whammed us. Kind of like the herald waves of most pandemics. H1N1 from what I surmise was rumbling for almost 20 and there were very likely epidemics of it in China before it rolled west. E.g. Le Grippe in France was prevalent and especially in the S. for visibly 5 years. Was it mild BF. Uh-uh, cant get me out on that limb. But there was a lot of flu and pneumonia, hard type in the trenches of WWI. It was marked off as just that and not panflu. Yesterday I sent a graph that was superimposed over the top of slide 4 from the latest June 29 graphic from the WHO to Revere. It matches almost identically. Not in numbers, but almost exactly in the CFR's by ages. We just dont have the numbers yet, the spread though across the age groups is scarily close.
GM food? Might be a reach. I still want talk to someone about that third testicle that I grew and why the honey bees have gone missing. GM spread into clover.