Wednesday, March 13, 2013

Vaccine Safety: A Conversation With Dr. Paul Offit

We occasionally feature posts about vaccines on this site and our Facebook page, to debunk declining but Internet-fanned beliefs about vaccines being linked to autism. Though our 2011 interview with vaccine and infectious disease expert Dr. Paul Offit addresses most questions people have about autism and vaccines, we sometimes get queries outside that interview's scope. So I was grateful for the opportunity to have another conversation with Dr. Offit when he spoke at the Children's Hospital and Research Center of Oakland earlier this month, and ask him some of your questions. Matt Carey from Left Brain/Right Brain joined the conversation as well. -SR

TPGA: Autism rates have not declined since 2001 event though thimerosal was eliminated from most vaccines in the US by then. In some cases, those who believe in an autism-vaccine link have just shifted the goalposts to injection of foreign substances into the body and other theories. What are your thoughts?

Dr. Offit: When the hypothesis was raised about whether or not the MMR vaccine caused autism, that was a pretty easy series of studies to do. You could look at children who did or did not receive that vaccine in retrospect, and do a pretty good job of controlling for medical background, socioeconomic background, health care-seeking behavior.

Same thing is true for thimerosal, because there were Canadian provinces that used thimerosal-containing vaccines, others used the same vaccines without thimerosal, Western Europe had taken thimerosal out of vaccines by 1991, we used the full complement of thimerosal-containing vaccines until 2000, so those were easy studies.

Then you get to the harder studies, the questions about aluminum, or fetal bovine serum. You're not going to be able to have a study where you look at vaccines that contain aluminum and vaccines that don't, because those studies don't exist.

The best you can do is look at the studies by Charles Woods and Michael Smith, where you look retrospectively at large numbers of children who either got vaccinated in accordance with the AAP (American Academy of Pediatrics) / CDC (Centers for Disease Control) schedule, or got very few vaccines -- 1 or 2 or 3 in those first couple years of life. You can do that study. This handles many of the things you said, because it handles the aluminum as adjuvants idea, it handles the issue of other excipient materials: things like fetal bovine serum, or porcine gelatin, etc. That obviously shows no difference because it wouldn't make any sense that you would see a difference.

We're exposed to small quantities of heavy metals all the time, living on the planet earth. We're all exposed all the time: Mercury and thallium and beryllium and cadmium. If you really want to scare yourself, there's a guy at UCSF, Eric Delwart, who has a kind of high throughput, deep sequencing technology where he can detect very few copy numbers by the polymerase chain reaction of the genes, from very few fragments of genes. I think if he took that technology to the grocery store, and just surveyed the surfaces of the fruits that we buy, I think you would find genetic fragments of DNA from all sorts of things, and I'm including humans -- I mean, we die, we get absorbed into the planet earth, we get into the aquifer.

Understood. We sometimes hear from people complaining about things like formaldehyde in vaccines, when our bodies make formaldehyde naturally.

That's true, formaldehyde is part of single carbon metabolism, and your body makes it al the time. And you make more when you drink! So if you really want to avoid formaldehyde, no beer, no wine, no alcohol. While you might not give your baby wine, your baby does have single-carbon metabolism.

We hear a lot from people complaining about "too many vaccines, too soon" even thought the actual antigen load is less than it used to be. How would you address this issue?

The way the smallpox vaccine was made 100 years ago is the way that it would be made today -- we still have stocks of so-called dry vaccine in the freezers at Wyeth -- and if we were to need it again, here is how it's made:

You take a calf, you shave it. Then you take a rake, this excoriating device, and you scrape it along the sides of the calf, causing these four lines of blood to form. Then take this virus, vaccinia virus  which is not quite cowpox virus -- it's actually a combination of cowpox and swinepox and horsepox, and you put it dropwise on these bloody streaks. You wait a week for the pustules to form, then you harvest the pus, you spin out the white cells and the hair, you dry it -- and that's your smallpox vaccine.

I was at the Wistar Institute as their chief medical officer a number of years ago, and they were doing a study of the Vaccinia virus vaccine recombinant -- it's the smallpox vaccine, except they inserted into it a gene that coded for one protein, a sort of a rabies protein. So they were going to take this vaccine, and distribute it; they were going to soak the heads of chickens with this Vaccinia virus recombinant, and distribute them out on Parramore Island off the coast of Virginia to try to decrease rabies in raccoons.

I had to vaccinate about 30 veterinarians -- big, lumbering guys with plaid shirts and beards -- with the smallpox vaccine before they could to go to Parramore Island to distribute these chicken heads. One guy came to me a few days later, and he had fever and a tremendous swelling of the lymph gland under his arm which I thought was infected with the bacteria. So I took him to my boss, Stanley Plotkin (the developer and inventor of the rubella vaccine, and the rotavirus vaccine) and thought he was going to say that this guy had an infection of the lymph node under his arm, for which he would need to be admitted to the hospital and receive intravenous antibiotics. But Stanley looked at it and said, "Good take" meaning that's what you'd expect to see when you have a "good take" from the smallpox vaccine.

That smallpox vaccine is from 100 years ago, and it contained more immunological components than all the vaccines we use today. So when people say things like, "As we give children more and more vaccines and challenge their immune systems more and more, and worrisomely perturb or overwhelm or weaken their immune system," that is nothing. We live in an era where we have advances in protein purification, chemistry, and recombinant DNA technology where we can make very pure, very safe vaccines -- much safer than the smallpox vaccine we gave 100 years ago. We encounter far fewer immunological components in today's fourteen vaccines that we give to young children than we gave in one smallpox vaccine. And we make them a lot better. We don't take calves and shave them anymore.

Matt Carey: But what we do do is throw in adjuvants, so we are doing something to amplify the immune response. So is the math actually solid to say, "Take just that one comparison -- number of antigens then and now -- for what our immune response is going to be"?

Fair enough. We do things to allow us to give fewer doses of a vaccine and lesser quantities of antigens. For example, if you were infected with diphtheria, that bacteria produces a toxin in large quantities which gets distributed throughout your body and induces a vigorous immune response to the bacteria as well as to its toxin. When you give a diphtheria vaccine, you take that toxin, you kill it so that it can't cause harm. That makes it much less immunogenic, much less capable of inducing an immune response. So you have to find a way to get your immune response without causing the harm from the diphtheria toxin -- and that's where the adjuvant comes in.

The adjuvant does increase the immune response, it's true, but it certainly doesn't do it at a level that would be greater than natural infection -- it's less, and that's why you have to give many doses. If you're infected with diphtheria once, you're probably protected against diphtheria for the rest of your life. But you have to give many doses of diphtheria vaccine, even with an adjuvant, because you've so significantly weakened that diphtheria protein by inactivating it.

So when you see fever with vaccines, frankly, mostly it's because of the adjuvant. And fever is a good thing! I know most parents don't feel this way, but the question is, "Why do we have fever?" And it's clearly an adaptive response. All mammals on the face of this earth that are endotherms, meaning having the capacity to make their own fever, have it for a reason, and the reason is that it makes your immune system work better.

Your immune system works better at a higher temperature. And there are many proofs of that -- one is that if you take people who have chickenpox, for example, and you give them antipyretics (fever reducing agents) like Tylenol, and compare them to people who don't get Tylenol -- those who don't get the fever reducing agent and are allowed to have a fever, their blisters will "crust" much more quickly. Therefore, having a fever benefited them, in terms of getting better.

If you take adult volunteers and infect them with rhinovirus, the common cold viruses, and give only some fever reducing agents, those you give the fever reducing agent to shed the virus longer.

A fever is a good thing. A fever is a sign of a health immune response -- it just feels bad, it's uncomfortable to have a fever. You pay a metabolic price for fever. But the degree to which we go crazy trying to lower our children's body temperatures is unnecessary.

Matt: But there's obviously a point at which the fever becomes problematic.

Sure, but that's not usually the story with vaccines. Vaccines are usually associated with low-grade fevers, not high spiking fevers.

TPGA: We also get questions about virus shedding, specifically with regards to the flu vaccine and whether or not vaccinated people can infect others with the flu virus.

Well the flu shot is not a live virus. So you can't possibly infect other people.

With the nasal spray flu vaccine, the early transmission studies show that the virus is not transmitted from once person to the next. I mean, there's only one vaccine that is not recommended to be given inside the household of someone who is immunocompromised, say, a child living with someone who is undergoing chemotherapy as a cancer treatment -- and that's the oral polio vaccine, which we don't give in the United States. All the others are so weakened that they don't cause a problem.

Can you talk a little bit about the nature of the FluMist vaccine? What does it mean that it is "cold-adapted?"

There are a lot of ways to weaken a virus: You can weaken it by growing it in non-human cells, which makes it less capable of growing in human cells. You can weaken it by growing it at a temperature lower than body temperature, which makes it less capable of growing in cells at body temperature. And that's what the FluMist vaccine is: a live attenuated influenza vaccine that can reproduce itself in the nose, which is a degree or two lower in temperature than the rest of the body -- and so, assuming someone has a normal body temperature, it cannot cause influenza in them. So even people who have a lesser capacity to fight infection, i.e., people who are immunocompromised -- those people aren't *colder* than other people, so it's not a problem.

This question is from Twitter: How do we know that vaccines are truly safe in combination?

Whenever a new vaccine comes onto the market, the FDA will not license it unless it is clearly shown to be safe when it is given concomitantly with all the other vaccines on the schedule -- for example, the rotavirus vaccine came onto the market, it was to be given by mouth at 2, 4, and 6 months of age. Even though that vaccine was given by mouth and all the other vaccines were given as shots, you had to prove that when you gave the rotavirus vaccine, you did not decrease the immune response or change the safety profile of the other vaccines -- and vice versa. Those are so-called concomitant use studies, of which there are hundreds, and you have to prove that.

We also get a lot of people saying that the pertussis [whooping cough] vaccine doesn't work, and so people shouldn't take it -- that the people who are coming down with pertussis were actually immunized. How would you respond?

The newer whooping cough vaccine is not as effective as the older whooping cough vaccine -- but it's still more effective than not getting a vaccine. That's been shown over and over again. During the 2010 pertussis outbreak in California, you were eightfold less likely to get whooping cough if you got the vaccine than if you didn't get the vaccine.

So is vaccine-induced immunity to pertussis less effective than that of other vaccines?

With diphtheria and tetanus vaccines, if you look at that data, the antibodies from those vaccines are pretty robust from the time you get the vaccine until five, seven, eight years. It starts to come down a little bit at ten years. With the whooping cough vaccine, on the other hand, immunity starts to fade at around three years -- it's less effective than the tetanus or diphtheria components of that combined vaccine [Tdap, etc.]. But again in all cases it's better to get a vaccine than not to get one.

Can you talk about your own experience in managing vaccine skepticism in medical support staff?

Children's Hospital of Philadelphia is a big hospital, we're a 650 bed hospital. There are a lot of patients who are severely immune-compromised, and others who are too young to get a vaccine -- with the flu, you're not recommended to get the vaccine before six months of age. And there are a lot of kids in our hospital who are vulnerable to influenza.

Yet people come into our hospital with influenza every year, and every year there are a number of children who get influenza in the hospital even though they didn't come in with it -- when they get it, they generally get it from us, when a caretaker transmits it from one patient to the next no matter how careful we are. You can decrease -- not eliminate -- the chance of that happening by getting an influenza vaccine.

Starting around 2002, we really tried to get people working in our hospital to get vaccinated -- we had educational programs, we had town hall meetings, we had raffles and games, we gave away Eagles tickets -- and we got immunization rates up to 60 - 70% percent. Then we had a declination form, which read like it should have a skull and crossbones on it -- it basically said, "I know influenza comes into our hospital. I know that I can catch influenza, I know that as a health care worker, I can transmit it to someone in the hospital, I know my patient can suffer and die from influenza, and I'm still choosing not to get a vaccine." And a solid fifteen to twenty percent of people signed that form, sadly.

And so, we took the next step -- we figured that if you were choosing to work among a vulnerable population of hospitalized children, that there was a responsibility that came along with that. There were 10,000 people who we defined as health care workers -- not just doctors, nurses, and nurse practitioners, but anyone who could walk on the floor -- environmental services, dietary services, etc. And we insisted they be vaccinated for influenza. And virtually everyone bought into the program, but there were nine who didn't, and we asked them not to work in the hospital anymore, not to work around those children. And since then we really haven't had a problem.

You mentioned during your talk that not all doctors understand the biology of vaccines, and that there is vaccine misinformation in the medical community. How do you think it takes root and spreads?

So on the planet you're talking about, people go to college and then go to medical school and learn about the biology and physiology and microbiology of vaccines, and then are influenced by those data, and then make the right choices.

That's not our planet. On our planet, there are still a lot of myths and misinformation at all levels. There are doctors in our hospital who don't understand vaccines very well. Maybe it's a failure on our part to adequately educate at the medical school and during the residency.

Understood. Last year, after the CDC's 1 in 88 autism prevalence numbers came out, I was asked to be on a local radio show with a doctor whose approach to autism was rooted in pseudoscience. But he was their "autism expert," because they didn't know any better. And it was extremely frustrating, because he was the medical doctor, and I'm just a parent -- yet I was the one defending evidence-based information about autism.

Anyhow. How do you recommend doctors and people in general reach those who are skeptical about vaccines?

I think it's OK to be skeptical about anything you put in your body -- you should ask questions about it. But it's not OK to be cynical, to believe that vaccines are all a conspiracy to sell product. That's when you cross the line into being much less able to be convinced by evidence.

And the evidence is clear: vaccines work and they're safe. A choice not to get one is a choice not to take an unnecessary risk that can cause permanent harm. In this country, the odds are that if you choose not to get a vaccine, you're going to be fine. But you're still playing a game of Russian Roulette, and it's a dangerous and unnecessary game to play.

If you want to be convinced, spend some time with the advocates from organizations like Families Fighting Flu or the National Meningitis Association, because they all tell the same story: "I can't believe this happened to me." And then they become vigorous activists, and try to educate others that this could happen to them too.

We have town hall meetings at the hospital, with groups of 50 to 100 parents who come in to talk about vaccines, who are hesitant about vaccines. The first meeting we had was in a Jesuit church, you know, with a big cross behind me. And it was a tense meeting. I was on the ACIP (CDC Advisory Committee on Immunization Practices) at the time, and people were asking questions, and there was a sort of "me versus you" feeling going on -- I felt like I was on stage, even though I was at the same level as everyone else. And then a toddler sort of toddled up to me, maybe a 3 or four year old, and absently I just sort of took him and put him on my lap because I had young children at home and it was an easy thing to do and I love children. And the whole tone of the room changed -- suddenly I was one of them, because I was seen as a human, seen as a father -- which is what I am.

The whole dichotomy that we have, of parent versus doctor -- we give these vaccines to our own children. I don't distinguish the two. It's not a matter of training or expertise. I put that child on my lap and suddenly I was them. That stuck with me.

Matt: Why are you still in academia? You could do anything you want right now.

I'm doing exactly what I want. I love the academic freedom. Were I to go into industry, I'd lose that freedom. I love that I can write what I want and say what I want.

When I was in research, my task was always to write things that are new, to advance the field. That's sort of true now too, in a sense -- in the books that I write, the educational materials that we do, to try to think of a way of saying things that's compelling -- it's really fun. I love the freedom of academia. It's the world's best job. You get paid to do what you love. I could never imagine going into any job in which your voice was restricted.