Stories about experimental vaccines that "work in animals" are a dime a dozen these days. That's not bad. It means there is a lot of activity on the innovative technologies front. But there is a huge distance between "works in mice" and "works in humans." So news that one of these technologies is entering human trials, even small scale Phase I trials, is rarer. Recently we posted on the proposed start of Phase I clinical trials for a "universal flu vaccine" that works across subtypes (H5N1, H1N1, H3N2, etc.) as well as across drift variations within subtypes (the genetic differences seen from year to year in seasonal influenza, for example). Now a DNA vaccine, specifically for H5N1, is starting clinical trials at NIH:
The first human trial of a DNA vaccine designed to prevent H5N1 avian influenza infection began recently, when the vaccine was administered to the first volunteer at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD. Scientists from the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID), one of the NIH Institutes, designed the vaccine.The vaccine does not contain any infectious material from the influenza virus. Unlike conventional flu vaccines, which are developed by growing the influenza virus in hens' eggs and then administered as a weakened or killed form of the virus, DNA-based vaccines contain only portions of the influenza virus' genetic material. Once inside the body, the DNA instructs human cells to make proteins that act as a vaccine against the virus. (NewsRX)
The advantage of DNA vaccines is that they can be made much faster and in large quantities and thus can respond quickly to changes in the genetic make-up of the virus. Moreover the viral antigen doesn't have to be grown in tissue culture (e.g., eggs or dog kidney cells) because the method uses the vaccinee's own cells to manufacture the antigen, and only the antigen. There are no infectious virus particles involved.
But there is a lot to be learned about this technique clinically, epidemiologically and in terms of how to scale it up for industrial production. First and foremost are: Is it safe? Will it work? Phase I trials are an initial stab at these latter questions. Because these trials are very small -- 45 volunteers ages 18 to 60, 15 receiving placebo and 30 active vaccine -- only the most common adverse events would be detectable and efficacy can only be measured by antibody response. A challenge study with live virus would not be ethical.
But it's a start and success here is a much bigger step than the "works in animals" kinds of results we see often. Even big steps have to be measured in terms of how far we have to go before we have a vaccine capable of protecting us from a pandemic influenza strain, however. Right now, that's a very, very big distance.
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I wonder, whether these unethical studies are maybe
been done elsewhere. China,Myanmar,North Korea,
former Soviet Union,Afghanistan,Guantanamo,... ?
I'd like the opinions of some unrelated experts.
Fauci is biased here. How promising is it ?
What do you estimate is the probability that more
than a million doses will be produced until 2017 ?
I'm not sure about the likelihood that it will work. I know that initial results with DNA vaccines in general have not matched the hype. But I haven't followed this field closely enough in recent years to know what advances have been made.
I do know that making a million doses @ 1 mg plasmid/dose is quite feasible. A single 10,000L fermenter run could probably do it. I know people who do this at 500L scale already.
qetzal: Making enough quickly isn't the problem. The scale problem would be having it sufficiently pure and then packaged into individual doses. We'll see.
Actually, purifying and packaging it would not be significant problems either. There are multiple scalable ways to recover and purify plasmids from E. coli. And once it's pure, it can be vialed using standard pharmaceutical procedures.
Like I said, I know people who do this at 500L scale already. If you gave them this plasmid tomorrow, they could probably give you ~ 50,000 single dose vials before the end of this year. And it would be >= 99.5% pure, manufactured and tested under cGMP. (I don't know what the cost per dose would be, though. That could be an issue for a vaccine.)
The techniques for doing this are not fundamentally different than producing therapeutic proteins (e.g. recombinant human insulin) from E. coli. Obviously, they have to be adapted, since the target is DNA, not protein. But those adaptations are already pretty well worked out.
I think it's pretty safe to say that making it at scale should not be a problem (barring idiosyncratic problems with this particular plasmid, which do sometimes occur).
Proving that it's efficacious is the key issue.
Well, consider having to make 100 million individually packaged doses from a bulk supply in a month: that's 3.33 million doses a day or 140 thousand an hour or 2300 a minute or 40 individual dose packages a second. Uncontaminated.
...and all that for a vaccine that has never been proven to be efficacious!!
/:0)
I'm not sure why you're focusing on the packaging aspect of all this. If there's any part of the whole process that's off-the-shelf, it's the vialing and packaging. Pharma has been doing that for decades. Plus, any challenges would apply equally to any H5N1 vaccine. They aren't specific to a DNA vaccine.
According to a CDC press release, vaccine companies produced more than 100 million doses of conventional flu vaccine last year, so obviously it's possible to vial than many doses in a relatively short time. I think conventional vaccines are often packaged in multi-dose vials, but I don't see why an H5N1 vaccine couldn't be done the same way. So, I don't think packaging would be a show-stopper.
A bigger question, though, is being prepared for all this in advance. Suppose an avian epidemic really takes off. We'd want H5N1 vaccines produced ASAP. If the fermentation, purification, vialing, and packing operations weren't already in place, there could be a major lag while they came up to speed. Even if we had complete freedom to appropriate any vaccine or pharma company's facilities, it would take some time.
Maybe that's what your really getting at? (Although even then, I'd guess the vialing and packaging would be the easiest part to convert.)
Tom: Not true. This is a vaccine that has never been tested. Unless it is your view that no vaccine against influenza is possible, but I don't know what argument you would have for that.
qetzal: I bring it up because that's what someone from MedImmune mentioned when I was on a panel with him. He specifically said this was a major issue. Remember the 100 million doses of flu vaccine weren't all in individual lots and were dispensed and distributed over an entire flu season, not all in a short period of time under emergency conditions.
"Unless it is your view that no vaccine against influenza is possible, but I don't know what argument you would have for that."
Revere What I meant to say that no study has proven seasonal influenza to be efficacious. Half the anecdotal studies say it works...and half say it doesn't work.
What I am saying is that we are spending scarce resources on an unproven technology...
...and it looks like all the money was spent and is spent and will be spent on Tamiflu and vaccine...both of which it appears will be useless.
Once they have the infrastructure insulated and healthcare insulated and basic supplies of antibioitics and oral electrolytes and antifever drugs avaliable for about twenty-five percent of the population...and food supplies arranged with farmers to feed everyone...
...then and only then should they waste the publics resources on their two 'magic pills' that don't and won't work.
If you have any evidence to the contrary, I would like to see it.
Thanks
revere: I agree. If things aren't in place before an epidemic gets going, there's no way to make and distribute the needed number of doses in a timely manner.
Of course, that's true no matter what sort of vaccine is contemplated.
Tom: They are spending the money to prove it, so criticizing them for not spending it on a proven technology seems a bit, well, unfair. Vaccines are a great method if they work. They aren't the only way, of course.
I was born into a polio outbreak...and live in what was the highest rabies incidence area in the world...there is no greater believer in vaccines than me.
However, unfortunately, seasonal influenza is to unstable, genetically shifting away from any vaccine in the production lag periods.
They spend money to prove it in lab animals and it works in lab animals only because they freeze-frame the virus preventing any natural shift to occur...so if the virus is blocked artificially from genetically drifting, the vaccine works...but in nature that doesn't happen.
In humans, they say a titre is protective when they know damn well that a titre often is not protective at all if the portion of the virus that they produce the titre against does not prevent infection.
I have used protective vaccines proven with lab animals and released with great fanfare and glossy advertising... that when used made a whole lot of animals sick with the disease that the vaccine was supposed to be protective against...
...and in the case of H5N1, I believe a vaccine strain caused it in the first place in China and I believe that the used of vaccines in commercial flocks has driven the virus underground and allowed directed evolution towards mammals and humans.
We would have been better to ignore the vaccine and slaughter if we really wanted to attempt eradication.
For all of these reasons...I believe current vaccine technology for humans is a waste of time...so practically is Tamiflu as well...
...I am waiting and hoping to be proven wrong with irrefutable data independently verified by third parties.
Is that too much to ask?
Tom: If you believe we can eradicate this disease, I have a 1995 Volvo for you.
I don't see how you can say you hope to be proven wrong when you complain about any attempt at testing, as in a Phase I clinical trial as we have here. Irrefuatble data is extremely rare in medicine, veterinary medicine or public health. It seems to me you are asking for an unattainable standard of proof for things you don't like but don't mind handwaving for favored hypotheses.
As for the current outbreak being a vaccine strain, why would they be making a vaccine against a strain that was circulating? What is your evidence for this? This seems pretty far out when the most plausibe explanation is that influenza is a naturally occurring disease of birds.
You can't eradicate anything when China is the source...just ask Vietnam and the other border countries...there is a long and growing list.
In my opinion, H5N1 is too good to be natural. It was 'cooked' probably unintentionally...a vaccine that reassorted in the field of an experiment that got out of a lab.
Why is it that we have not seen the sequences from the soldier in 2003 even though a scientific paper was published and I believe release is a requirement?
I didn't say a vaccine caused it...I said a vaccine allowed the virus to go underground. Vaccinating when you are attempting to eradicate doesn't work. I guess they thought it was endemic in Asia ten years ago?
Why is it that a series of high pathogenic avian influenza's have suddenly decided to break out...all within a few years?
...and generally speaking, in my profession, we do like to have proof before we put all our eggs in two baskets at the expense of proven technologies that will save lives.
The fact is that vaccines and Tamiflu don't work and won't work...
...is there a Plan B?
Jeez, Tom. They are planning to test it. What more do you want?
I believe in Australia this winter, the quote was that 70% of those who died were vaccinated.
So first of all, I believe an epidemiological study should be set up that will conclusively, once and for all, answer the question...does seasonal vaccine work?
If seasonal vaccine works then that makes the potential for a vaccine against 'the monster-H5N1' better but not proven...unfortunately we will only prove that it is efficacous after everyone has already died in the pandemic...
...because they will not be able to keep the chickens and eggs alive long enough to produce vaccine under real H5N1 pandemic conditions...as humans will be reverse vectors and plant workers and their families will become ill as in the general population.
If DNA vaccines can produce say...one billion doses in a month from the pandemic onset...then maybe they will make a difference. The chickens and eggs won't die but the workers and their famillies will be.
Tamiflu is a joke...hardly worth even discussing other than the side effects that will play havoc with the bravest of all...the healthcare workers who stay on the frontlines.
What do I want? It's quite simple really.
I do not want one child or one young parent or one pregnant women to die from secondary bacterial infections that are entirely preventable because authorities did not see fit to stockpile enough treatments to dispense (healthcare systems will collapse in the first two weeks) so that parents and grandparents will at least have half a chance to save them.
Is that too much to ask? It seems to be at the moment.
Sorry, Tom, but those are not facts.
Vaccines do work. The problem is they often don't work well enough.
You may be right that our resources would be better spent on more conventional measures. OTOH, I trust you'd agree that preventing infection is preferable to treating it. If an efficacious H5N1 vaccine is possible, surely it's worth pursing.
The difficulty comes in deciding if it's possible. And I suggest neither you nor I know enough in this area to make an accurate judgment.
As an aside, you have an interesting double standard about evidence. Regarding conventional vaccines, you expect irrefutable proof. But your opinion is enough to support your claim that H5N1 is "unnatural"? Any chance you'll acknowledge the illogic there?
Tom: The only kind of study that would answer the question to your satisfaction cannot be done. It is a randomized clinical trial and placebo vaccines wouldn't be ethical. It would also be horrendously expensive, but that's a side issue. So we will have to make do with the observational studies we have and continue to use. As I have said to you before, you are entitled to your own opinions but not to your own facts. qetzal is correct. Those are not facts.
"In my opinion, H5N1 is too good to be natural."
Hi qetzal. I believe I stated a personal opinion...and did not make a statement whether my opinion was the truth or not...I don't believe there is anything wrong with and I don't believe it is a double-standard...but you are entitled to your opinion as well.
Yes "Vaccines do work"...just in my opinion, seasonal influenza vaccines don't work other than in the lab for the reasons I have given.
There is no irrefutable proof that they work even a little bit...it seems maybe that is not needed in human medicine to spend billions of scarce resources on what may be a 'faint hope'.
They need enough antibiotics, oral electrolytes, anti-fever medications etc. for one quarter of the American population. If the pandemic starts tommorrow morning at 9:15, how many treatments do they have?
They know healthcare will collapse...what is their plan B?
There is enough food in Toronto Ontario grocery stores for four days food supply for its citizens...just in time warehousing is in trucks going down the highway...what is their plan B?
I have a friend who is much more knowledgable then me on these things and I am quite sure that given a little time, he/she will design a study.
Will you be willing to publish and then debate the epidemiological study that will prove it without any risk to experimental subjects, once and for all, whether seasonal vaccine works or not?
tom: "Will you be willing to publish and then debate the epidemiological study that will prove it without any risk to experimental subjects, once and for all, whether seasonal vaccine works or not?"
Of course (I assume you are talking about a study with data). If it is a legit study I might even be able to get it published in a peer reviewed journal (I am a journal editor but my journal is in a different technical area; however I know people).
Revere.
What I meant was will you debate the concept.
I don't have the power or the financial resources or the time or for that matter the credibility in Canada to undertake such a study.
I burned my bridges on preservatives and other intentional adulterants in imported Chinese food products and BSE and a few other Public Health issues several years ago.
The fact that I may have been right doesn't change the end result.
/:0)
Thanks!!
Tom: Yes, I'll debate or comment on the design (or endorse it).
Thanks!!!!!!!!!!!!!!!
It is the summertime but I will make contact with my colleagues and see what we can do...
...I will get back to you as soon as possible.
Tom:
Fair enough. But that's still a pretty serious claim. It would be nice if you offered more evidence than just, "In my opinion, H5N1 is too good to be natural."
The available data shows pretty clearly that they do work in real world settings. A few minutes reviewing abstracts at PubMed will confirm this. (The data is not irrefutable, but that's an unreachable standard for any scientific question.)
HOWEVER, whether and how well they work is definitely variable. It depends on what is measured - serologically confirmed influenza infection, influenza-like illness, hospitalizations, mortality, etc. It also depends on the study population - healthy adults, immunocompromised people, elderly (in or out of nursing homes), kids, infants, etc.
There's plenty of room to argue whether they work well enough in the real world, and what that says about the potential value of an H5N1 vaccine. However, I don't see a reasonable basis to claim they only work in the lab.