Swine flu vaccines, adjuvants, equity, safety

When it comes to US swine flu vaccine policy, I'm not calling the shots, but if I were I'd do it differently than the current plan, which calls for a vaccine containing only viral antigen and no immunity boosting adjuvant. I opt for a vaccine with an adjuvant, probably the one that has been used for years in Europe, MF59. If I were to make a decision like that, I could well be making a mistake, because no one really can know at this point what is going to happen or not happen. We can only go on the best data we have coupled with some principles of what's right. On that basis and using my own fallible judgment I'd move as fast as I could to develop, distribute and deliver a swine flu vaccine that contained an immununity-boosting adjuvant.

Europe's adjuvanted flu vaccines don't appear to be any less safe than non-adjuvanted ones and are far more effective and efficient in the use of the scarce active ingredient, the viral antigen. It is availability of viral antigen that is limiting vaccine production. Unadjuvanted vaccines require much more viral antigen than those with adjuvants. We have written about adjuvants many time here (e.g., here), and recently Vincent Racaniello over at Virology Blog had a great post on the likely requirement for an adjuvant in any swine flu vaccine that could be given with only one dose. Obviously anything that will make more protection available to more people is a good thing, but like everything in public health, there is a balance to be struck and no sure way in knowing how to strike it.

One balance is between the potential added risk of a vaccine with an adjuvant versus one without it. The risks are on both sides. Any vaccine carries a risk but a call to slow down approval until the safety of the vaccine and/or adjuvant is assured misunderstands the problem and carries the risk of killing people who might have gotten the vaccine earlier or in a more effective form. Let's briefly discuss the safety issue (we've done it before, so this isn't new). The problem with any vaccine, adjuvanted or not, is that it will be given to hundreds of millions of people. Any clinical trial would involve at most a few thousand. If some very rare adverse event occurred in one in every 100,000 people from the vaccine, then there would be 500 such events if 50 million people were vaccinated (roughly the number vaccinated in 1976 against swine flu). No clinical trial could pick up an event that rare. It would be invisible.

The difference is that in 1976 the virus never infected anyone outside of the soldiers at Fort Dix (see our post here). But the current virus has gone pandemic. If it infects (conservatively) 30% of the population of the US and the vaccine is 70% effective, we would prevent 10.5 million people from being infected (that's the 1/6 we reach with vaccine -- 50 million out of 300 million -- 15 million [30%] of whom will be infected, of which 70%, or 10.5 million will be protected). If this is like seasonal flu, where the estimated CFR is 0.1%, we have 500 rare adverse events (some, but not all of which might be fatal) versus an estimated 10,500 flu fatalities and many more severely ill in the ICU. If the CFR is anywhere higher than 0.1%, the imbalance gets much worse. If we vaccinate many more than 50 million things tip in favor of the vaccine even more. But of course we don't know the attack rate, the vaccine efficacy, the CFR or the rate of rare adverse events (1 in 100,000 is actually pretty high). But almost any way I figure it, vaccination comes out ahead and there is no way to estimate the rate of a rare adverse event prior to using the vaccine. That's true for every drug or over the counter consumer product. It's why we need good post market surveillance. But saying we're going to wait to find out isn't an option. It's not feasible and it means no vaccine if we require it.

Another balancing problem. The regulatory approval process for an adjuvanted vaccine will take somewhat longer. The delay will mean that people who might have gotten vaccinated with an unadjuvanted earlier approved vaccine will be saved. This may or may not be true (Canadian authorities deny it). But the more important question has to do with global supply. If the rich countries like the US won't use adjuvanted vaccine, they will use up twice as much or more of the scarce viral antigen, meaning that much less for the rest of the world, including the world's poorest countries. Helen Branswell has a typically thorough article on the debate:

Individuals and organizations concerned about global equity are urging countries with vaccine contracts to stretch supplies by using boosting compounds called adjuvants so developing countries can also get some serum.


The WHO had asked countries with first access to pandemic shots to employ vaccine sparing approaches, such as the use of adjuvants, so that there will be more to go around. Without frugal use in wealthy countries, the vast majority of nations will have limited access, at best, to vaccine against the novel H1N1 virus.


U.S. authorities have made it clear they will only use adjuvanted vaccine if their supplies won't meet American needs. They will not use the boosting compounds to stretch supplies for the developing world.

That position has also drawn fire, including by the head of the Gates Foundation's global health program.

In a commentary published in the New England Journal of Medicine, Dr. Tachi Yamada said it would be inexcusable for people in poorer countries to die because richer countries use up most of the limited vaccine supplies. And he specifically pointed to the reluctance to use adjuvanted vaccines, currently licensed in parts of Europe but not in North America.

"Under a global health crisis where millions could die we have to really think hard whether we play by the rules we establish for normal times, or we think much more aggressively and take greater risks," he said in an interview last month. (Helen Branswell, Canadian Press)

There are a lot of other balance issues here, including one raised by WHO's vaccine chief Dr. Marie-Paule Kieny. If the swine flu virus drifts genetically, those getting an adjuvanted vaccine may be at an advantage.

The bottom lines for me as a public health professional and as an advisor to friends and family is this. For reasons of global equity and plausible public health advantage, the US should move expeditiously to an adjuvanted vaccine, probably with something like the MF59 adjuvant that has been used for a dozen years in Europe without apparent mishap. I will myself get both seasonal flu vaccine, and when my turn in the queue comes, the swine flu vaccine (containing an adjuvant, I hope, which would be especially helpful to people my age). I will urge every member of my family from my youngest grandchildren to my aged mother-in-law to do the same, and to add pneumococcal vaccine to the mix if they haven't already done so. I will urge this on anyone and everyone who asks or is within hearing to do the same. But . . .

I am not in favor of forcing people to be vaccinated. If too many people decline this could result in a public health tragedy, the loss of life or productivity that could have been saved. If enough people are vaccinated to produce sufficient herd immunity to dampen an epidemic, those who aren't vaccinated will have been free-riders, but that's the way it is sometimes. Some will decline out of fear, some will decline out of selfishness, some will decline out of ignorance, too many will be denied by lack of access. And some will, like me, make a decision based on their own informed and considered judgment and come up with a different answer.

Good luck to all of us.

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You make the probably incorrect assumption that those who will die under your scenarios are the same "groups". 20000 additional deaths from the high risk categories may not be a good trade off for 2000 additional deaths from the young , healthy and future productive. It is rather other-worldly to treat all cases as "equal"

Graeme: Maybe I don't understand you. If you value the H1N1 deaths more (because they are young) then the value of the vaccine becomes that much greater so my argument is stronger. Or maybe I misunderstood? In other words, I took a very conservative view and still came out in favor of the vaccine.

I also plan on receiving the vaccine and getting kids vaccinated. I am approached everyday by doctors and nurses asking me whether I think the vaccine is safe and what am I going to do in regards to my own children (ages 14 and 10). I am absolutely amazed at how many very smart, medically trained individuals are dead set against having their kids or themselves receive a influenza A pandemic (H1N1) 2009 vaccine. Apparently this mistrust by health care workers isnt only in my neck of the woods but is international: with a recent BMJ survey study in Hong Kong showing a large percentage of health care workers planning on saying no thanks to a vaccine. http://www.bmj.com/cgi/content/abstract/339/aug25_2/b3391

This will be a public health tragedy and if my colleagues refuse vaccination, then I am going to be really really busy since they are going to spread the flu without themselves knowing to their children and patients. This is a public relations problem that needs to be addressed and fast. Revere any suggestions?

By BostonERDoc (not verified) on 07 Sep 2009 #permalink

I would get the shot with or without adjuvant, but it may be that one shot is enough... data still out on that.

And while PH is good with the science, it's terrible with the reality of dealing with the public sometimes. Putting out an adjuvant-related vaccine in the absence of increased virulence or even widespred disease would make people less likely to get needed vaccine. If it's the risk groups we are talking about, only 500K pregnant women get vaccinated annually out of 6 million pregnancies, for example (flu is a risk every year for pregnant women) as one example. Only 50% of HCW get the annual jab, as another example of not doing such a great job with vaccinations. The reality is (Keystone feedback to CDC) the public wants a fairly encouraging but not all out effort to vaccinate. That's reality.

BostonERDoc, Peter Sandman had a good post on this:


Telling the public whoâs at the front of the vaccination line â and why â is certainly a messaging task. But thatâs not the big messaging question. The big messaging question is how aggressively to urge people to roll up their sleeves. Should the CDC and officials in other countries with vaccine supplies be offering pandemic vaccination or pushing pandemic vaccination? (There is little if any support for requiring pandemic vaccination, except for healthcare workers in some jurisdictions.)

I vote for offering.

Revere: Two questions. First, how much of the European experience with adjuvant, specifically MF59, has been with pediatric immunizations? Second, why get a seasonal flu shot this year? Novel H1 has significantly overtaken seasonal flu Type A viruses in circulation, especially seasonal H1. H3N2 may be a bit more in circulation, but about 5% of it is mismatched to the vaccine. 89% of circulating B is mismatched with the current vaccine. Thus, it would seem to me (were I to play the role of a contrarian for a moment) that this year's seasonal vaccine may not be of sufficient benefit to justify its cost and, more importantly, the complexity it adds to setting up and implementing the novel H1 vaccination program.

Technically, I agree (to the limits of my understanding!) with everything you said about adjuvanted vs unadjuvanted flu vaccine.

However, I think the U.S. has an unfortunate but valid reason for not moving forward at this time with an adjuvanted flu vaccine.

There is a great deal of undue -- but thoroughly unmitigated -- anti-vaccine feeling and fear in the U.S. The anti-vaccine activists and the vaccine-causes-autism activists are ready to roll with every flu vaccine Teachable Moment that comes along.

The more traction they can get by encouraging doubt and skepticism about flu vaccine among parents, the more children will end up unvaccinated against the "usual" childhood diseases.

So in the U.S., this is a really bad time to change the flu vaccine any more than necessary (a strain change is necessary, of course).

It is also a bad time to do any kind of high-pressure flu vaccination campaign. People who feel pressured to get vaccinated, rather than feeling informed and then making their own decision, are more likely to blame any subsequent bad reactions on the vaccine, and they will have less confidence in official determinations about whether the adverse events were "associated" or "causal".

For years, I've been attending meetings where vaccine researchers such as John Treanor expressed enormous frustration that the U.S. wasn't moving faster to approve cell-culture and adjuvanted vaccines. Clearly, the time to have done this -- and to start routinely using cell culture-based flu vaccine -- was in peace time: before there was an urgent need combined with understandable public skepticism and doubt due to history (1976) and the evil shadow of Andrew Wakefield.

I am okay with the U.S. optimizing for not hurting the childhood vaccine program any more than it already is.

My greatest fear is that CDC will do a good "We strongly recommend (re: high risk groups), but you decide" campaign -- but then the states will go martial or at least high-pressure ( Md. Gov calls seasonal flu shots a âpatriotic dutyâ).

(I fear this because of what happened in 2004, after half the U.S. flu supply became unavailable. The CDC suggested that low-risk people "voluntarily" abstain from getting their usual flu shots, and then most states almost instantly turned "voluntary" into "mandatory." Any flu vaccine campaign that even approaches such high-pressure tactics is very likely to backfire, both in terms of vaccine uptake and in terms of perceived (as opposed to actual) serious adverse events.

reveres- This is so timely! I am in the process of being screened for an NIH vaccine trial for the swine flu vaccine with and without adjuvant (ASO3 is the adjuvant in question). I would very much like to take part in the trial - I believe dose-sparing techniques are worth serious consideration right now - but have become concerned by all the talk of adjuvants triggering autoimmune disorders.

There seem to be some animal studies showing a connection between adjuvants and autoimmune conditions (for example, here: http://cat.inist.fr/?aModele=afficheN&cpsidt=15892345 ). Could you shed any light on this? Is this something to be concerned about?

This will be a public health tragedy and if my colleagues refuse vaccination, then I am going to be really really busy since they are going to spread the flu without themselves knowing to their children and patients. This is a public relations problem that needs to be addressed and fast. Revere any suggestions?

Make sure that they're on record so that the lesson is likely to stick.

By D. C. Sessions (not verified) on 07 Sep 2009 #permalink

I am an average guy with no science background. I have two children about to head back to school tomorrow, one 7 and one 11. I am in Portland, OR. I want to know with today's information how many kids in America are expected to die from H1N1- the best estimate.

Jeff, I'd like to point out that the popular perception of Y2K is that it was much ado about nothing. If you ask the Pat in the street about Y2K you'll find out that the anticlimax proves that experts don't know a damn thing.

From this it follows that predictions of climate change, resource depletion, pandemics, etc. are all worthless. Ignore them.

By D. C. Sessions (not verified) on 07 Sep 2009 #permalink

Jeff: No one can say but every year it is somewhere between 30 and 150, ballpark. Will this be different. Could be. But maybe not. The number is quite small and many are developmentally impaired, but if it's your kid the number isn't small at all. But with kids there are a lot of things to worry about, not just flu. My theory about why kids think they are immortal is that they dont have kids. Because once you do, you start thinking about things that can happen to them.

"estimated CFR is 0.1%, we have 500 rare adverse events"

Is not there an error here. 0.1% of 50 million is 50000. It is OK with the 1:100 000 adverse effect rate however.

I am not professional in this topic. Is CFR = 0.1% means 1: 100000?

Ahh, CFR = 0.1% is for the 10.5 million infected. This gives the 10500 death. It is clear. Sorry!

Yes, thank God for Keystone and the CDC's PR department. "Three (or four!) for you and me", indeed! Maybe if we can get Elmo to sing a song about it, nobody will notice that we're asking pregnant women, babies and children to get up to 100mcg (25mcg/dose) of mercury injected into them in a three week time span. "Three (or four!) for you and me!" It's got a good beat, but will they dance to it? Gee, hope so because as we all know any "unforeseen" consequences will all just be "coincidental". After all, who could predict that injecting that much mercury into a gestating woman or small baby could cause irreparable harm? So lucky for us all that this obviously-well-thought-out epidemic-busting plan couldn't possibly have any negative effect whatsoever on the public's overall trust in the CDC and the vaccine program. Bravo! Truly! Stunning work!

By Garbosmed (not verified) on 08 Sep 2009 #permalink

I am not in favor of forcing people to be vaccinated. If too many people decline this could result in a public health tragedy, the loss of life or productivity that could have been saved. If enough people are vaccinated to produce sufficient herd immunity to dampen an epidemic, those who aren't vaccinated will have been free-riders, but that's the way it is sometimes. Some will decline out of fear, some will decline out of selfishness, some will decline out of ignorance, too many will be denied by lack of access. And some will, like me, make a decision based on their own informed and considered judgment and come up with a different answer.

But what if you take the vaccine, but because the vaccine isn't 100% effective, it doesn't protect you? Then with all those people not taking the vaccine meaning we don't reach herd immunity, they put you at risk, through no fault of your own.

Note: I'm not saying we should force people to take it, but I was just wondering what people's responses are to the above point.

Alex: No guarantees in life. You just try to do your best. In this case, getting vaccinated is my idea of doing my best for myself, my family, my friends and my community. Sometimes it doesn't work. That's life.

Vincent: A quick preliminary read looks good. There are the usual complexities. We don't really know the level of real protection afforded by these assay levels, but the 15 mcg dose is surprisingly effective by the usual measures. Use of an adjuvant might stretch it by a factor of four, based on data with seasonal virus, but the difficulties there have been discussed plenty already. I still come down on the adjuvant side because of the global equity issue but I think good arguments have been made on the other side, too. Life is messy. Besides the dose sparing of one dose versus two there is the time saved, cutting it in half, which could be extremely important because we could deploy protection faster. We live in interesting times.

Iâm quite new to this and I donât have any medical background besides dealing with my own multiple chronic conditions, so please forgive my ignorance. I am curious about the affects of an immunity boosting adjuvant on those with autoimmune diseases â couldnât boosting the immune system have disastrous results for those who immune systems are already overly strong?

I personally have four autoimmune diseases, and catching a cold or flu can send one or more of them into serious flares for four to six months. Because of this I have never had even the seasonal flu vaccine, as my doctors donât know how my immune system will react to it. My husband is always vaccinated, I work from home, and I practice rigid cold and flu safety whenever I am out of the house (antibacterial gel, not touching my face, etc).

From what I have read about the Spanish Influenza pandemic in 1918, the reason many young and healthy people died is because that influenza strain was resistant to attacks from the human immune system. The body would respond by making more white blood cells to try to kill the virus, and eventually the white blood cells pile up and start attacking the bodyâs own tissues, leading to destruction of the throat and lungs. So most victims of the 1918 pandemic died from a cytokine storm â a massive autoimmune attack â or from a pneumonia infection into the areas ravaged by the bodyâs own immune system.

This scenario is especially dangerous for someone like me, whose immune system has âmalfunctionedâ and attacked healthy tissue multiple times in the past and is exceptionally strong (I get over colds and fluâs in about half the time it takes others to recover, and then hold my breath to see if itâs set off any of my autoimmune diseases). My understanding of why H1N1 is such a big deal is that it bears a lot of the same markers as the 1918 influenza, and could behave similarly, if it mutates in a similar pattern.

If H1N1 does mutate the same way that the Spanish Influenza did, the vaccine could realistically be the difference between life and death for me personally. But an immunity boosting adjuvant I believe could potentially be extremely detrimental for my system, even landing me in the hospital if it set off a large enough flare of my existing autoimmune diseases â to say nothing of setting of a new autoimmune disease, or the sort of autoimmune response seen in the Spanish Influenza.

At this point I am leaning towards getting whatever H1N1 vaccine becomes available in the US, adjuvant or not â I would rather be hospitalized early in the season with autoimmune flares that will eventually subside than risk exposure to pandemic H1N1 later in the season. But I would be very interested in the opinions of those here as well.

Hey Paul:

Those you didn't defeat are coming, those you didn't defeat are coming. Yup. the Canadians.

On October 8th, NIAD announced a small scale trial comparing unadjuvanted vaccines and adjuvanted vaccines. Judging by what's in use elsewhere the viral material dosage is high.

"Participants will be divided into five groups based on the amount of vaccine they receive and whether or not it is paired with the AS03 adjuvant. The five groups are 3.75, 7.5, or 15 micrograms of vaccine plus adjuvant; and 7.5 or 15 micrograms of vaccine without adjuvant. Each volunteer will receive two doses of the vaccine with or without the adjuvant approximately 21 days apart. Neither the volunteers nor the study researchers will know who receives which vaccine preparation."

NIAD rejected MF59 as the adjuvant. Instead they those AS03 from GSK. In a surprising coincidence, 98% of Canadian 2009 H1N1 vaccine will consist of 3.75 mcg of viral material and an adjuvant, AS03 from GSK.

By Shel zz66eeaa99ww123 (not verified) on 19 Oct 2009 #permalink

Shel: Let 'em come. These trials have been in the works for a long time, as a back-up in case of a big time pandemic and shortage of vaccine. No adjuvanted vaccines are licensed n the US, although I am on record as saying I wish we had decided to use it. I don't see a lot of difference between MF59 and AS03. Both are squalene-based. So if you don't like one you won't like that other and if one is OK, so probably is the other. But the question is moot because the US vaccine is not adjuvanted.

Now anytime Canada wants to swap health care systems with ours, I'll take that deal any day.

Should pregnant women get the vaccine and are there safe alternatives? The Tainted Blood Scandal occurred because federal doctors were more worried about profit than the public health and safety or trust.The last bad batch of flu vaccine was shipped causing serious harm because scientists were threatened with lawsuits and blacklisting under confidentiality clauses. I know all about black listing (see www.cancerfraudbadbiotech.com)because I reported fraud and not only did the federal government cover it up but also helped plagiarize my research, and I had support from an M.D Anderson scientist and a US Surgeon General.So I know that the federal government has no regards for TRUTHFUL Signed Assurances, they are profit motivated, not safety, nor honesty.So pregnant women must DEMAND to know if there are any studies on birth defects caused by adjuvants etc.,and if there are any secret reports, because the government has given the drug companies immunity from any liability. So if harm or life long defects occur to your unborn child its is YOUR fault, not the government's! Are there safe alternatives? An Israeli med school studied elderberry extracts with good results, Sambucol, and a Big Pharma company is now marketing it. So ask the government is this a good alternative? Remember the government's track record: eHealth, the Breast cancer mix ups etc etc. So demand answers, not pats on the head.

Dear Sir, as I have no understanding of your credentials or particular insight knowledge on the subject, I have to presume that your opinion is, well, just that.... opinion. As such the above can be given no more or less weight than average bar stool parlor. The fact is that an overwhelming majority of Europeans have declined the vaccine BECAUSE its adjuvated. Ironically, this means that much more vaccine has been wasted on so-called "world minded" countries than say belligerently wealthy countries such as the US. Thus, your second point on the benefits of adjuvated vaccine was short sighted. As to your first point, whether you decide to inject yourself with a turbo version of the vaccine or not is an independent decision bearing neither for nor against adjuvated vaccine. Nor is the argument that people are being "selfish" or "ignorant" by declining the vaccine bears little weight. Statistically, the H1N1 novel virus is not any more dangerous in terms of severity or death rates than seasonal flu. Hence, extra-ordinary counter measures to vaccinate the world population is not any more imperative than at any other time. I conclude, thank you for your opinion, noted, and o-filed. Enjoy your day.

Follow up.

I am back here in Europe. It turns out that the Governments and Military had vaccinated themselves with the pure vaccine (no adjuvant). Then out of the same hippocritical lying mouths, they preach to the masses to take that Rat Poison. You are fooling yourself if you think it is any different here than in the US. It IS every man, woman and child for themselves.

As soon as I get back stateside I am heading straight over to my Physician and get dosed with the pure stuff. I have lived both sides of the pond. People here show up to work sick and don't bother to cover their mouths when they cough and sneeze. The world is back asswords my friend and it extends well outside the bounds of the US. Thank GOD for America.

So there.

Not sure if these vaccines are safe or not. I am not a biochemist. It is rather strange though that we the population are being inundated with the this latest vaccine. I mean, how many vaccines are we, the people, going to be required to take in our lifetime?

It's incredible the number of vaccines a kid receives by the time he or she reaches the age of 2. Hare to believe in this day and age that so much chemicals are required in the body to stay healthy. How much chemicals can the human body withstand before something adverse takes affect? Whatever happened to proper eating habits and taking our vitamins and mineral?

I wonder how much of a pandemic it would be worldwide if big pharma were told they were not allowed to make one cent profit from the sale of this H1N1 vaccine? Afterall, if these pandemic is bad as it is portrayed to be, one would think human decency would come into play by these pharmaceutical companies, and do everything possible to help fellow world citizens to stay healthy, or become healthy again. And do it out of love for fellow man, not the bottom line.

I wouldn't have a clue if these vaccines are safe or not, but this just seems a little suspicious to me how this is being pushed on the general population. We the people are like sheep. We follow the one infront of us, even if we don't have a clue as to what is being given us.

Folks, whatever happened to good old fashion responsibility of our own health and care? It's a shame to see our population being poisoned with the foods we are now supplied on a daily basis. We have become mere chemicals of society it seems.

I'd like to conclude in saying that if we are going to fast track a vaccine in this world, I can think of a number of other dis-eases that kill far greater numbers of our population that the swine flu, and I am sure you can as well. Why aren't we bringing a vaccine forward for those? I wonder if that bottom line factor comes into play here? Uhmmmm. What is more profitable, prevention or treatment??????

Good health to all.