Top Experts Discuss Vaccine Safety Issues

The National Partnership for Immunization (NPI) hosted a media conference call on December 10, 2003, in which leading experts discussed new science on the safety and benefits of vaccines. The call was led by David Neumann, PhD, Executive Director of NPI. Dr. Neumann was joined by both Paul Offit, MD, Chief of Infectious Diseases at the Children's Hospital of Philadelphia and Professor of Pediatrics at the University of Pennsylvania School of Medicine, and by Polly Sager, PhD, Assistant Director for Research in Infectious Diseases, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases.

Following is a transcript of the conference call.

Influenza and Vaccine Supply | Thimerosal and Vaccine Safety | Media Questions and Answers

David Neumann:

Good morning, this is David Neumann of the National Partnership for Immunization. Thank you for joining us this morning to talk about vaccines and vaccine safety. As you well know, two issues that are of keen interest to the people in the U.S. these days are the issues of the influenza epidemic this year and the more general issue of vaccine safety.

With us today are Doctors Paul Offit and Polly Sager, recognized experts in a number of fields related to vaccines and vaccine safety. Dr. Paul Offit is Chief of Infectious Diseases at the Children's Hospital of Philadelphia and Professor of Pediatrics at University of Pennsylvania School of Medicine. Dr. Polly Sager is Assistant Director for Research and Infectious Diseases with the National Institute of Allergy and Infectious Diseases. We will begin with some commentary from each of them before opening the floor to your questions. And so with that, I'd like to ask Paul to share with you the audience some of his comments and thoughts.

Influenza and Vaccine Supply

Paul Offit:

Thanks, David. What I thought I would do for five minutes or less is to just kind of briefly go through some thoughts that I have about influenza and the current outbreak. Although it has been so well covered by the media I am not sure I can tell you anything you don't know.

But briefly, it's clear that the influenza outbreak this year is occurring earlier than it typically does. It's clear that it involves a strain, the A/Fujian strain, which has genetically drifted from the strain that is currently in the vaccine, so the vaccine will be somewhat less effective than it would have been had it been a perfect match for that particular strain. And third, that this outbreak, this A/Fujian outbreak, appears to be more severe than typically.

But one can say that when one does see epidemics of an influenza which do occur every year there's about 115,000 hospitalizations, and there's about 35,000 to 40,000 deaths every year. When you look at the hospitalizations, they occur primarily in those less than four years old and those greater than 65 years old. And when you look at those less than four years old, it's primarily in those less than one year old. And so it's actually very common for children to come into our hospital and all hospitals in this country with severe and occasionally fatal influenza infection. The deaths, obviously, occur primarily in the greater than 36 year old -- I am sorry, the greater than 65 year old.

The influenza vaccine is about 80 to 85 percent effective at protecting against moderate to severe disease, and probably to a somewhat greater extent than that at protecting against death from influenza. But it's been an underutilized vaccine, and it's always been an underutilized vaccine. I mean you could make the argument that everyone in this country benefits from that vaccine, and certainly the extremes of age both benefit from that vaccine. But, we traditionally have not recommended its use for all age groups.

What you see this year with an epidemic that's earlier and more severe, and with tremendous media coverage, and there's a tremendous desire to get that vaccine. And the result is that there's what appears to be a functional shortage. I mean I think in part it's the distribution problem. But for the physicians in the Philadelphia area from whom I have gotten a lot of calls over the last few days, they simply don't have vaccine.

I think one of the reasons that they don't have vaccine is if you look at the number of vaccine makers who make vaccine for all recommended age groups there's one, it's Aventis Pasteur, that's it. And that's not unusual. I mean if you look at, for example, the measles-mumps-rubella vaccine, there's one vaccine maker. Varicella vaccine, one vaccine maker. Pneumococcal conjugate vaccine, one vaccine maker.

And the result is that we don't have a very nimble system. When outbreaks like this occur or when shortages occur, we generally don't have stockpiles that we can quickly go to to meet those unmet needs. And I think it's frankly, to make it a broader issue, because we don't value prevention in this country. I mean we're not willing to pay for prevention.

I heard that there's one Philadelphia Inquirer media person on this conference call, and I think if you want to understand why there's vaccine shortages you need look no further than the Philadelphia Inquirer today. There's an article in the Business Section that says 'Merck expects to submit one drug for vaccines by 2006.' The article goes on to talk about how Merck is going to be submitting -- I think it was a diabetes drug for 2007, and that they have essentially two major vaccines that will be coming out in 2006. One is a rotavirus vaccine, which will prevent 50,000 hospitalizations and about 20 to 40 deaths a year in the U.S., and certainly prevent a disease that is a big killer worldwide. And the other is a papilloma virus vaccine, which is a vaccine that prevents probably 90 percent of cervical cancer in this country. Those are big deals.

Yet if you look at what it says in this article, it says 'if you look at the research and development pipeline nothing comes out until 2007' which is talking about the drug. It said 'Hemant Shah, an independent pharmaceutical analyst in Warren, New Jersey, said that, 'Some vaccines may come out earlier but those have a very limited market. They're not for chronic diseases.' Meaning they're not something one can take every day like lipid lowering agents or cardiac agents. Todd Lebor, a pharmaceutical analyst formerly of Morningstar Incorporated in Chicago agreed, 'It's a freak of nature for vaccines to be blockbuster products.'

You know, a couple of things, one is that do these people think that most of us know that, or that GlaxoSmithKline, or Aventis Pasteur, or Chiron, or Wyeth don't know that their drugs make more money for them than vaccines? I mean the reason that they make vaccines, and I think a large reason they make vaccines is because they think they're meeting unmet medical needs and they at some point realize it's the right thing to do. Certainly these companies are composed in large part of scientists and doctors who went into it because they like to do the right thing. And I just find it a little galling that nowhere in this article is there a statement by a public health official that thanks Merck or companies like Merck, for at least trying to get these products out there.

I mean it's just not a very good business, or not a big business. And for that reason I think we all suffer. I think it's not going to be until we really value prevention by putting more money in the Vaccines For Children program, thereby in some way trying to create incentives that make it worthwhile to make vaccines, that we're going to get away from these kinds of shortages and fears that we have.

And if you recall, and this is the last point I'll make, since 2000 this is the seventh shortage. There was a big shortage for tetanus vaccine, for diphtheria-tetanus-acellular pertussis (DTaP) vaccine, for measles-mumps-rubella (MMR) vaccine, for Varicella vaccine, for Haemophilus influenzae type b (Hib) vaccine, for pneumococcal conjugate vaccine, and now for flu vaccine. And I just think that this represents at some level a slight crumbling of an infrastructure that is at risk.

And so I'll stop there, David. I'll get off my soapbox and turn it over to Polly.

Thimerosal and Vaccine Safety

Polly Sager:

Hi, this is Polly Sager, and I was asked to provide you with a little bit of background information and an update on the research that the National Institute of Allergy and Infectious Diseases is sponsoring in terms of vaccine safety. Our purview includes actually looking at questions related to thimerosal in vaccines.

Part of the debate on thimerosal has focused on the assumption that methyl mercury was a good model for thimerosal, which is actually an ethyl mercury product. And so we have taken on two scientific questions. One is whether or not using methyl mercury guidelines and data were appropriate for assessing the safety of thimerosal, and how the distribution, metabolism and excretion of thimerosal and methyl mercury may be related. Specifically, we were looking at whether they were equivalent, whether they were similar, and whether the methyl mercury guidelines would really offer an appropriate margin of safety, or whether the two forms of mercury were significantly different.

Just to remind you a little bit about the methyl mercury guidelines, methyl mercury exposure occurs primarily through food, and it's an oral intake. The guidelines are really based on almost continuous exposure through food sources. There's exposure both to the mother and the fetus, and the data we have for methyl mercury in humans is primarily from poisonings and poisoning outbreaks that have happened in various parts of the world. And from those data we know that the developing fetus really is the most sensitive to damage from methyl mercury. Infants who were exposed to methyl mercury in breast milk or through food after birth were really much less sensitive to the damage.

Thimerosal exposure for the most part occurs in the postnatal period, such as infants receiving vaccinations, as with newborns and with young children. Although there may be some exposure prenatally if pregnant women are using products or drugs that contain thimerosal or are receiving vaccinations.

We have two studies that we've done in children. One is the study that was published in November 2002 in The Lancet. In that study, we looked at 20 two-month-old children, 20 six-month-old children, and 20 control children. The control children received vaccines that did not contain thimerosal. The other children were children who received thimerosal-containing vaccines as part of their routine vaccination. The study was done prior to the recommendation that thimerosal be removed from infant vaccines. The children received their vaccinations, and samples of blood, urine, and stool were obtained from the children at various times between a few hours up to 30 days after their vaccination.

The conclusion from that study is that there were in some children measurable levels of mercury in blood. There was almost no mercury that could be measured in the urine of most of the children. Using the data and various modeling techniques the investigators determined that the half time for clearance of mercury from the thimerosal-containing vaccines in the children was much shorter, six to eight days, in the children as opposed to 30 to 40 days for methyl mercury.

The real surprise from this study was that the infants excreted a significant amount of mercury in their stool. This had not been looked at in any of the children from the previous studies, at least that we could find any data on. But certainly in animal models of mercury metabolism using methyl mercury there's very little excretion until after the animals are weaned. So this excretion in the feces, together with the shorter half-life led us to believe that we really need to look at this in greater detail. And we're doing that in two ways.

The first is a follow-up clinical study that's being conducted in Argentina where we're enrolling a larger number of children, around 72, at birth and at two and six months of age, each. These are all children that are receiving routine immunizations that contain thimerosal, and we are collecting samples prior to immunization and after immunization beginning with 24 hours and up to 30 days, to really solidify our data on how thimerosal is handled in these children, and to really look in more detail at excretion in the stool samples.

The second study that we're doing to really nail down this comparison between methyl mercury and ethyl mercury is a study being done at the University of Washington. It compares methyl mercury and thimerosal in infant macaque monkeys and is being done by Danny Shen at the University of Washington, and Tom Clarkson at the University of Rochester. In this particular study we've tried to mimic the immunization schedule that children receive in the macaques, and so the animals are given either oral methyl mercury which is modeled but has the most data in primates, or thimerosal. And in addition to thimerosal, they also receive various vaccinations. The thimerosal or methyl mercury is given in such a way that the animals receive the same amount of mercury per dose, and they're exposed to mercury in vaccines at birth and at one, two, and three weeks of age.

The data from this study have not yet been published, but they have completed the analysis of the data, and I can tell you a little bit about the conclusions from this. The maximum concentration of mercury in the blood of the methyl mercury animals was approximately 40 nanograms per mil for methyl mercury, and about 12 nanograms per mil for thimerosal. This is measuring mercury in the blood. The half-life for washout from the blood for the methyl mercury animals was on the order of about 20 days. It was just under four days for thimerosal. And the washout from brain for methyl mercury is about 60 days and just under 20 days for the thimerosal treated animals. If we look at the highest concentrations in brain, we find that the mercury, the methyl mercury was approximately three times higher in the brain. The mercury levels in the methyl mercury group was about three times higher than in the thimerosal group and it was cleared much faster by the thimerosal group.

So our conclusions from this study so far are that the initial absorption and distribution of all methyl mercury and mercury derived from thimerosal are similar, that the blood mercury derived from thimerosal has a much shorter half-life, that there is minimal accumulation between exposures to thimerosal, and so for thimerosal you get a peak and then it's cleared from the blood and you get another peak and it's cleared, whereas with methyl mercury, because it is cleared so much more slowly, it never goes back to baseline and you get continued accumulation after each exposure.

Media Questions and Answers

David Neumann:

OK, thank you, Polly, and thank you, also, Paul. We'd like to spend some time addressing questions and issues related to thimerosal. As many of you know, the Institute of Medicine convened an expert committee to look at the safety of vaccines. And one of the issues that they did explore in 2001 was the question of the relationship between exposure to thimerosal and vaccines, and its possible relationship to neurodevelopmental disorders. And as you may recall, the committee concluded that the evidence was inadequate to accept or reject a causal relationship between that exposure in vaccines and the occurrence of developmental disorders.

Since that time there have been a number of studies including the two that Polly described, that really lead us to rejecting a causal association. Science moves forward slowly in a step-wise process. It's rare that a single experiment or single study will provide the definitive answer that allows one to accept or reject certain hypotheses, but over time as additional studies are conducted there is a weight of evidence which begins to accumulate that leads one to draw, with confidence, conclusions of causality. And at this point the studies produced or published over the last four to six months including the study published last year that Dr. Sager described really are helping to provide the scientific basis for disassociating a causal relationship between thimerosal exposure in vaccines and the development of neurodevelopment disorders.

Cheryl Wetzstein (Washington Times):

Yes, Dr. Sager, the first study you told us about, could you tell me what your hypotheses is? In other words, what would be the impact if, indeed, the thimerosal is excreted greatly or it has a half time clearance?

Polly Sager:

Well, the study did not have a particular hypotheses other than the question was to simply see what happened to the mercury from thimerosal. There had been a lot of discussion about whether the amount of mercury children were receiving, infants were receiving in their vaccines would exceed some of the guidelines established by the FDA or EPA, or various other organizations for exposure to methyl mercury. And since there was no data on thimerosal, people were sort of using the methyl mercury data to make assumptions about safety levels for thimerosal. So the study was really designed to see what data we could gather on thimerosal and how infants handled it.

The fact that it's cleared so much more quickly and the half-life is so much shorter means that the mercury going in, as thimerosal, is eliminated from the body much more quickly than methyl mercury. So that means that the guidelines, which are based on safety factors, probably provide a great additional margin of safety for thimerosal than for methyl mercury. The fact that it's excreted in stool really is pretty exciting. I mean it's a very simple concept. The defecation or pooping out of the mercury, means it's not in their bodies, it's not getting to their brains, and it can't do damage. So that's a really valuable piece of information.

Right now we're really trying with the second study to get many more samples, to look at a wider range of time points, and to really confirm that the mercury from thimerosal leaves the body of infants much more quickly than if it were methyl mercury. And therefore, these safety guidelines really are providing probably a significant additional margin of safety. So, if you say 'X amount of mercury goes in,' it's potentially much more dangerous if it's methyl mercury than if it's thimerosal.

Maggie Fox (Reuters):

Today the FDA is presenting some guidelines on how much mercury can be in fish. I hear from a lot of mothers who are concerned about mercury exposure to their infants, and I'd like to be able to answer the questions in my story, such as what's the equivalent if you eat fish? You know, they say 'I want to minimize my kids, but I'm worried about their exposure to mercury, and so I want the thimerosal free vaccines.' Is the flu vaccine free of thimerosal? I'd like to be able to say something to the effect of 'well, if you eat, you know, salmon twice a week you're getting more mercury.' Is there any way to address that question? And then I have a second question if I can ask it, afterwards.

Polly Sager:

I know that there are studies that have looked at the amount of mercury in fish. A lot of State Health Departments have guidelines for how many times a week a pregnant woman should eat fish, and not all fish is equivalent in terms of its mercury content. Cold water fish are ...

Dr. Polly Sager accidentally disconnected from the conference call.

David Neumann:

Let me respond while we're waiting for her to reconnect. I know that where she was going at least over the short term was to make the case that not all fishes contain the same amounts of mercury, that cold water fishes from the ocean are probably somewhat lower in mercury content than what we see in certain freshwater species. There's been any number of reports about the mercury content of fishes in the Great Lakes, and they typically tend to be higher, particularly in urban or industrial areas than elsewhere.

I would speculate that she was going to say that because of differences in the route of exposure, that of ingestion for mercury containing fish versus injection for thimerosal, it's hard to draw those relationships. I don't know that we have hard numbers, but I certainly think that's something our community will try to pay attention to.

Maggie Fox:

And can I ask a second question? Representative Dan Burton is really fond of showing that little film of mercury instantly killing brain cells. What do studies tell us about how long the mercury is in the body, and about how potentially damaging it could be? And isn't there some evidence that the way thimerosal is formulated the mercury is less likely to damage cells?

Paul Offit:

You can look at the study by Mike Pichichero (The Lancet 2002) that was alluded to earlier, which looked at the half-life of ethyl mercury as it appeared to be in infants that were inoculated with ethyl mercury in the form of thimerosal-containing vaccines. The half-life appeared to be in the range of about seven days as compared to methyl mercury, which appears to have a half-life that is at least seven times longer, more like 49 days.

The other point is how can you equate, for example, the amount of salmon that one eats that would contain methyl mercury to the quantity of ethyl mercury that's contained in vaccines. I think it's very hard to make that analogy because those two molecules are just very different. It's like trying to make an analogy between ethyl alcohol, which is the alcohol contained in wine or beer and methyl alcohol, which is wood alcohol and causes blindness. One, methyl mercury, is taken up actively into the central nervous system, and the other isn't. They're just biologically very different agents. Much as ethyl mercury and methyl mercury are very different agents.

I think the problem is that the word 'mercury' is at the end of both of them, and there's just no way that mercury ever sounds good. Although, you know, we live on the earth, and the earth crust contains mercury and aluminum, and lead and iron. And to some extent, we all have trace quantities of these heavy metals in our bodies, trace quantities that are below levels that would ever be considered dangerous. I just think that we have trouble understanding the quantity issue.

Polly has done, I think, a wonderful series of studies, but when you talk to parents you're trying to get them to understand the trace quantities involved such as picogram quantities or nanogram quantities that are so much less than the milligram quantities or high microgram quantities that one could be exposed to in fish. But you just lose them, because to them mercury is bad; it doesn't matter how much it is. And, you know, it's difficult to communicate that.

Maggie Fox:

I just want to also ask does it matter how long it takes to excrete. If mercury is instantly toxic to cells does it matter whether it's in your body for seven days or 49 days?

Polly Sager:

Yes, it does, because mercury is distributed fairly quickly into the blood. And then from the blood it moves into the brain. And how much gets into the brain depends on how much is in blood. And so if you have a lot of mercury sitting around in the blood for three weeks that's three, four, five weeks that mercury can be -- can move from the blood into the brain. And the more you get into the brain the more likely there is for damage.

If it's excreted from the blood or cleared from the blood then it can't get into the brain. And so although we talk about the levels in blood because that's what we can measure in children, certainly there's a direct correlation with what gets into brains where the damage is done. And I don't know that there's evidence that says mercury is immediately damaging to the nervous system. I think at least for methyl mercury, studies in Iraq showed there was a threshold, and once you got to a certain level of mercury in the brain then you began to see damage, but below that level they didn't see damage that they could measure in those children. That was methyl mercury. But I think the issue remains that the faster it is cleared the less gets to brain and the less potential there is for damage.

Paul Offit:

You know, if I could follow-up on Polly's comment. The statement about Dan Burton's claim that brain cells which when exposed to high concentrations of mercury in vitro, meaning in a dish, are instantly killed draws the analogy to formaldehyde. I mean if, for example, formaldehyde which is a single carbon molecule that is a natural product of the synthesis that is required to make proteins and also the synthesis that is required to make DNA. So we all have trace quantities of formaldehyde in our bodies. If you took formaldehyde and you -- and this has been done -- and you expose it to cells at high concentrations in the laboratory, you can cause cancerous changes in those cells. There's no doubt about it. But that doesn't mean that formaldehyde at the levels that we have in our bloodstream, and we all have it, is causing cancer.

There's been probably 70 epidemiologic studies that have tried to address the question, if you work with high concentrations of formaldehyde, like you're a mortician or a medical student, are you at increased risk of cancer? And the answers to those questions have always been 'no.' So, I mean, again, it's always an issue of quantity.

Tom Walker (Dispatch Broadcast Group):

Hi. This is a question for basically anybody who cares to answer it. I had to bail out for a minute, and so I may have missed an answer to this question already. I hope not, but what is your advice to parents, and what do you think their level of concern should be about thimerosal content in flue vaccine being given out now?

David Neumann:

Yes, I mean the theoretical concern that was raised about ethyl mercury in vaccines was that it was theoretically possible for children less than six months of age to receive a series of vaccines that would have caused them to have exceeded slightly the Environmental Protection Agency's recommendation for what was considered to be a safe level for methyl mercury. And I think Polly has made this point redundantly already, that these are two very different things, methyl mercury and ethyl mercury.

Now you're talking about a vaccine which isn't given to the less than six months old. And it's the only vaccine that is routinely recommended now that contains, you know, what I consider to be trace quantities of ethyl mercury. And so it, to me, is not even a theoretical concern anymore.

But again, trying to explain this is like, you know, trying to close the door after the horse is already out. It's, I think, that the word thimerosal has now become a scarlet letter. And so any thimerosal content -- even if it's in a vaccine given to a child who is over six months of age, even if there's no concern about exceeding the guideline levels for methyl mercury, which is obviously a far more dangerous toxicant, is suspect. It is really a non-issue. But it's become an issue for some, and I just think all you can do is to try to be reasonable, and explain to parents what the science is and how they are far more likely to be hurt by influenza than they are to be hurt by the thimerosal in vaccine. Frankly, they are far more likely to be hurt on their drive to the office to get the vaccine.

I just think we have, a very skewed vision of what is real risk. I think we take risks, like the risk of not getting the influenza vaccine because we just don't understand the risks we're taking.

Tom Walker:

Would all of you agree with that?

Paul Offit:

I would.

Polly Sager:

And I would, too. I would also point out that thimerosal free flu vaccines are available. And so if parents still have concerns it's far more important to be vaccinated than it is to not be vaccinated.

Paul Offit:

The fact is, there are about 83 million doses of flu vaccine in this country; 73 million are made by Aventis Pasteur. And they do make a thimerosal free vaccine, however, which is much more expensive. It costs about one-and-a-half to almost two times what the thimerosal-containing vaccine costs. The thimerosal free vaccine is not dangerous, but again, the word thimerosal is like a scarlet letter. By analogy, it's like free range chicken. You can buy it, it's more expensive, but is it really any better than regular chicken? No! And that's true with this vaccine also.

David Neumann:

OK, it appears there are no further questions or comments at this time. Thank you very much for calling in and talking with us, and for asking questions. I think all of us are willing to be available should you have follow-up questions on these issues, or others related to vaccine safety. I bid you all a good day, and thank the speakers, Dr. Paul Offit and Dr. Polly Sager for their time and interest today. Thank you all.