Skip to comments.US puts flu vaccines on trial - NIAID director Anthony Fauci explains testing strategy.
Posted on 07/28/2009 10:29:04 PM PDT by neverdem
The US National Institute of Allergy and Infectious Diseases (NIAID) announced last week that it will begin five clinical trials for two pandemic H1N1 influenza vaccines in early August. These trials will help inform a likely US mass-vaccination campaign beginning in September. NIAID director Anthony Fauci talks about what vaccines were chosen, and why.
To increase the amount of flu vaccine available, the World Health Organization recommends using adjuvants, which boost the body's immune response to the drug. But the five trials you announced last week are for non-adjuvanted vaccines. Why?
We have planned seven priority trials. The five I announced on 22 July are for non-adjuvanted vaccines, but we also plan two more: testing GlaxoSmithKline's AS03 adjuvant with vaccine from Sanofi Pasteur and from CSL Biotherapies. We prioritized non-adjuvanted vaccines as the US government seems likely to recommend using these for vaccinating the first tier of priority groups expected to include children and groups at higher risk of severe disease, such as those with certain underlying illnesses and pregnant women. We fully intend to proceed with trials of adjuvanted vaccines.
Will you test adjuvanted vaccines in children?
The Europeans have lots of data on the use of adjuvanted flu vaccine in the elderly, but I don't think anybody has really good data on adjuvants in children. The Department of Health and Human Services (DHHS) has therefore decided that we are not going to take the chance, and has made a policy decision that we are not going to give adjuvanted flu vaccines to kids. We don't have the time to collect substantial data.
Might not trials including at-risk groups help inform how vaccines are used?
Yes. But, as in other countries, there are many ethical constraints. We are working with both principal investigators and institutional review boards to draw up protocols for such groups. Even if the Food and Drug Administration (FDA) is considering the initial non-adjuvanted vaccines as simply a strain substitution of seasonal vaccine, it's still a new vaccine, so we want to get data from healthy adults before launching into risk groups.
What information will the NIAID get that vaccine makers won't from their own trials?
We are asking questions that will inform policy decisions likely to affect how we use vaccines, whereas the focus of vaccine makers is generally directed towards studies needed to get a licence for their vaccine. The sort of information that the FDA, DHHS and the vaccine makers told us they needed most included what levels of antigen per dose are essential to getting an adequate immune response, and whether one or two shots of vaccine will be needed.
So two trials will test both single and double shots of both 15-microgram [the amount in seasonal H1N1 vaccine] or 30-microgram doses of antigen, using antigen from Sanofi Pasteur and from CSL Biotherapies. We will give the first doses in the first week or so of August, and the second dose 21 days later. We will learn very quickly after 21 days, when we draw blood, if one dose of 15-microgram is enough. And if it isn't, if 30-microgram is any better. And if 15-microgram is enough, does 30-microgram give an even better response? Shortly after 42 days, we will have data on the second doses.
Why are you testing vaccine only from Sanofi Pasteur and CSL Biotherapies, when Novartis accounts for the bulk of vaccine ordered by the United States?
Novartis has quite a sophisticated clinical-trials apparatus. The United States will purchase 45% from Novartis, 26% from Sanofi Pasteur and a little bit less than 19% from CSL Biotherapies. Novartis is able to carry the ball itself, so we made a reasonably well-based decision to fill in the gaps and get information on CSL and Sanofi Pasteur.
You also plan to test co-administration of pandemic 2009 vaccines and seasonal H1N1 vaccines. How will the immune system react to these together?
We don't know. Testing two vaccines against different H1N1s at the same time has never been done. We'll look at three test regimes: giving the pandemic 2009 vaccine before, at the same time as, or after seasonal H1N1 vaccine.
If you give the pandemic H1N1 vaccine first, will subsequently giving the seasonal H1N1 enhance the response to the original dose, or will there be antigenic competition or interference? If you give both at same time, is the body going to have a response that is enhanced against seasonal flu and not do a very good job against the pandemic vaccine, or will it actually amplify the response? And if you give pandemic vaccine after [seasonal vaccine], is that going to have an enhancing or suppressing effect? Immunologically, you can't predict the outcome.
What if we have a vaccine and then the genetics of the virus changes?
You never can predict that, but things look encouraging to me from a molecular-virological standpoint. If you look at the molecular and genetic make-up of the virus from the very first isolates in early April compared to what we are seeing now in late July, it's virtually an identical virus everywhere. So it doesn't look like it is under pressure to mutate to a significant degree. We hope it stays that way for the autumn and winter season.
Interview by Declan Butler. For more H1N1 coverage, see www.nature.com/swineflu
micro ping - Speaking of the devil, but naturally, my questions were ignored.
FReepmail me if you want on or off my health and science ping list.
I look at this through an utterly cold, ruthless prism, which is how I suspect it is being done by its proponents. Here are the axioms:
1) H1N1 is not a serious threat, it is just a convenient “dress rehearsal” for an extremely severe threat, H5N1 Avian flu. H5N1 is as serious a threat as nuclear war, which explains the utterly ruthless attitude being taken against it.
2) There is no possible way to stop H5N1 from killing as many as a billion people worldwide. However, millions of American lives might be saved if we can respond hard enough and fast enough, with the equivalent of “total war” against the disease.
3) This H1N1 “dress rehearsal” is the one and only opportunity for a complete and integrated national response. Every experimental anti-flu drug we have will be tested on a huge scale, which may tell us the best way to attack the H5N1 pandemic.
4) Again, to possibly save millions of American lives, there is a willingness to sacrifice a few hundred, or few thousand people, who will fall victim to side effects of this treatment. There is no intention to harm, but an acceptance that some amount of harm will happen.
5) Nothing of this sort has ever been tried before, and it is being approached with proper fear and trepidation. It is also no guarantee that any of this will work against H5N1. But it will test, on a national scale, what may be our one and only hope.
Now so long as H1N1 doesn't mutate a la 1918 . . . .
(I have a personal connection to that one. My maternal grandmother was a bacteriologist at the Medical College of Georgia during the '18 pandemic. She needless to say was permanently affected by that adventure. We used to wash the skin off our hands when we went to her house . . . )
It is still a matter of scale. There is considerable “partial resistance” to H1N1 strains, because of 1918, which severely limits mortality. In the US, even with a worst case H1N1, we could have about 1.5M die.
But compared to H5N1, for which there is no immunity, we could experience 30M dead. Even the Spanish flu does not come close, and the only comparable epidemic, even deadlier than Avian flu, was the intentional myxomatosis plague that wiped out 98% of Australia’s rabbits in 1950.
The key factor is Acute Respiratory Distress, or ARD. When a brand new pathogen is introduced to the immune system, at first the immune system does not recognize it, but after a few days, it may overreact, in what is called the “cytokine storm”, overproducing about 150 histamines and other chemicals. This is essentially a profound allergic reaction centered in the lungs, which damages them.
(Importantly, just in the last few months it was discovered that the semi-metal arsenic “confuses” the immune system’s pathogen recognition system, and makes ARD much more likely to take place.)
The Spanish flu, H1N1, had a mortality of between 10-20% of those who were infected, because of this cytokine storm. But since then, different strains of H1N1, if not the original strain, still exist and regularly infect people with mild flu. But for most people, it is close enough to more dangerous H1N1 strains, that their immune system doesn’t overreact.
Most, but not all. This is why H1N1 could still kill many Americans.
But with H5N1, no one has a recognition of that flu type at all, so the cytokine storm would be very common among people with a strong immune system.
For this reason, there is a lot of ongoing research to find a way to prevent the immune overreaction from taking place, by inhibiting enough selected major histamines to short circuit the cytokine storm. Hopefully with an OTC formula.
This would not be a prophylaxis against catching Avian flu, but when a person did, they would take enough of these medicines to fend off the cytokine storm, which happens about day 5 of symptoms.
So far, a tentative formula includes a Histamine-1 blocker, like Benedryl; a Histamine-2 blocker, like Tagamet, normally used against acid reflux; 12,000 IU of Vitamin D, which is a hormone that blocks some pathways used in the histamine response; and Ibuprofen, or Advil, which blocks prostaglandin.
Other possibilities include Cromolyn, found in the OTC nasal spray NasalCrom, which is a MAST cell inhibitor, and a number of prescription drugs that inhibit other histamines.
And luckily I have all that stuff in my medicine cabinet!
There is no practical way of doing so. Let me explain why.
The chief epidemiologist of Vietnam discovered a herd of pigs, each of which had no fewer than five different H5N1 strains, in competition with each other to become the dominant strain. Then, when a dominant strain would emerge in one pig, it competed with the dominant strains devised by each other pig, to become the dominant strain of the entire herd. This happened because influenza has a very high number of what are called “flexible”, or easy to mutate genes in its RNA.
This is happening around the world right now not just in herd animals, but in wild bird flocks. As such, it acts like a natural selection supercomputer trying to devise the best possible strain of that type of influenza.
Once each strain varies far enough from other strains, it becomes alien enough to immune system recognition that the current vaccine used no longer works for the new variant.
If it is still “second cousins” to the vaccinated strain, the immune system might develop partial immunity for most cases. While you still get sick, the immune system doesn’t overreact and hurt you.
But right now, there are hundreds of thousands, or likely millions of different varieties of H5N1 in the world, most of which are only distant relatives to each other. And the human and most animal immune systems have zero familiarity with, or resistance to, this virus.
Only after the “winning” virus jumps to humans can we make a vaccine close enough to it to even give partial, much less full immunity. When that jump happens, our scientists will put a sample on the fastest aircraft in the area to take it to the CDC in Atlanta, to be grown and distributed to the drug companies, with around the clock haste and an unlimited budget.
Up until now, once we had the actual virus, it would have taken the US six months to make just 30 million vaccinations. That would not help in an H5N1 Avian flu plague, so the government has ordered those drug manufacturers who possibly can, to go into massive, full scale production and distribution as soon as they receive the actual virus.
And this is what is being tested with H1N1 right now. To say that the government and medical community are quietly terrified would be an understatement. This truly is the dress rehearsal for the worst plague in human history.
I guess we just hope the rehearsal goes well.
There is going to be a lot of bitter argument about “needless vaccinations”, with as I said, hundreds or even thousands of people who are injured or die in this test. A lot of people will refuse for them and their children to be vaccinated, and they are going to be part of the statistics as well.
And the government knows that it is going to be hammered when the actual disease strikes. Desperate and angry people will demand “Why wasn’t more done sooner?”
The truth of the matter is that we really aren’t much better off than we were in 1918, with a few exceptions. So we need to take these exceptions to heart, and try to protect ourselves before we have to defend ourselves, because by then it will be too late.
The first of these exceptions is public hygiene awareness. There was a great campaign to teach the public hygiene during and after World War II, and it will save many lives.
The other big exception is our communications system. Information can get out quickly, and knowledge is half the battle. The Internet allows for the near instant transfer of complex knowledge quickly, around the world. The value of this cannot be overestimated.
The vaccination conspiracy theorists (vaccination, adjuvants, mercury cause autism, etc.) have already started on the flu vaccine.
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