Genetic engineering meets vaccinology: or how to get the attention of all kinds of protesters

ERV wrote yesterday about a cool, new genetically-modified food that has the potential to act as a vaccine against cholera. The basic idea is that they are expressing a gene from cholera in rice. When you eat the rice, you are exposed to the fragment of a protein from cholera and will make antibodies to it. That way when you are exposed to cholera in the future, you will be immune to it. What are the advantages of this approach? From ERV:

So really this rice is going to be ground up and put into pill form, which is fantastic on so many levels!

1. Dont need a needle. Ive said over and over and OVER (are you listening, HIV-Circumcision 'researchers'??) its really damn hard to make sure your needles/equipment is appropriately sterilized in the third world. I dont care how many seminars youve had on how to sterilize needles. It doesnt always get done. Plus, I dont think youll hear any kids complaining about a lack of needles ;)

2. Can be kept at room temperature. No refrigeration. Aint gonna always have that in the third world either. Sure you might have a fridge, but it might not have power. And they tested batches that were left at room temp for 1.5 years-- Still worked. AWESOME!

3. Introducing the antigen through the intestinal mucosa. These folks found that introducing the cholera antigen orally works great because cholera normally infects through your digestive tract! Convinces lots of sentinel immune cells to hang out in your intestine and wait for another cholera bug to float by!

I thought I would write about another super cool approach to vaccines of the 21st century, and this one is a little closer to home as my wife and I both work on things that are indirectly related to this. (Though I confess, I'm a little worried that this post will attract the anti-vaccination mob along with the anti-genetic-engineering crowd).

Live-vector vaccines are what a lot of folks are hoping will be the vaccines of the future. How do they work? Over the last 30 years, we've learned an awful lot about how several different bacterial pathogens work. Pathogens like Salmonella and Listeria actually enter your cells and express their genes inside you (these are not viruses, mind you, but bacteria that go intracellular). We also know an awful lot about how to stop pathogenesis at certain steps. There are all kinds of mutants that are able to go intracellular, but are blocked at later stages of pathogenesis, so are unable to spread, or unable to express certain toxins, or otherwise unable to complete the disease process.

How does this help us build vaccines? These mutants that are blocked at later stages of pathogenesis actually elicit an immune response from the host. That is, when your body sees foreign bacteria in their cells, you are able to mount a potent immune response to it, so the second time you see Salmonella or Listeria, you are able to fight it off (though given that Salmonella has so many different varieties, it is quite difficult to vaccinate against all of them). It also allows you to mount both an antibody response and a cell-mediated response (these are two different immune responses that I will write about later). The long and the short of it is that most vaccines only elicit an antibody response, which doesn't protect well against pathogens that climb inside your cells to evade the antibodies.

Well, these days it is rather trivial to genetically engineer Salmonella. And Listeria is also able to be genetically engineered. So it's easy to put genes from another pathogen into them. (And before you cry, "What?! You're building a superbug?!! - it takes hundreds of genes working in concert to create a pathogen. One or two genes does not a pathogen make). One example of a live vector vaccine is here. Folks at the Center for Vaccine Development put part of the tetanus toxin into Salmonella. They then gave the Salmonella to mice, and found that the mice made antibodies to tetanus that have been previously shown to be able to protect them from infection.

So, big fat hairy deal. They've built a vaccine for an infection that there is already a potent vaccine available. Well, this is a potent demonstration that this technology is viable. There are a bunch of labs working to build vaccines against disease in a similar manner (including for diseases that don't currently have available vaccines).

What are the advantages of this approach? It's similar to the rice vaccine above:

1. You can get both cell-mediated and antibody immune responses, whereas most subunit vaccines that are available only give an antibody response. In non-science language: your immune system responds in a way that's more likely to prevent disease.

2. No needles! (You can just drink this).

3. Easier shipment and administering of the vaccine. And shipping to remote locations (think parts of Africa & Asia) is much simpler. That, and you don't need to have anyone who is highly trained giving the vaccine. Merely an eyedropper and a bottle to drop it into a glass of water will do.

4. Cheap. Growing Salmonella is easy. And building genetically modified Salmonella is infinitely easier than genetically modified plants or animals.

5. Generalizable. It is easy to imagine building multiple different vaccines in this manner, and then administering them simultaneously (either as a single organism, or a cocktail of several different bugs).

But what is the downside? The upfront costs will be high. New vaccines are expensive as the manpower to make them is highly skilled, and the number of tests that they have to undergo to demonstrate safety is high.

The other major downside is the PR side. The public at large is so woefully uneducated about basic science issues, and even conventional vaccines have been controversial in the public arena. I can only imagine the anti-vaccination folks now:

Genetically modified pathogens! *gasp* You're playing God!

Yep, every time you save a kid from a disease you're playing God. Some people think that's okay. I think that the time is right to start telling people about these vaccines so that when they do start to become commercially available that there isn't a visceral, knee-jerk reaction against them. When I tell people about what I do, they say, "You genetically engineer bacteria? Why would you want to do that?". If they're calm enough to sit down for a few minutes and talk to me about it, they often ultimately agree that it is a good idea.

Cost benefit analysis of a vaccine (Gardasil)

Kudos to the New York Times (again). They publish a simple, fantastic piece about the risks and benefits of the new Gardasil vaccine against HPV. The risks?

They may include pain, swelling, itching and redness at the injection site, as well as fever, nausea and dizziness.

Well, this sounds like what you might expect from any vaccine. The pain, swelling at the injection site are basically signs that your immune system is working. And the fever as well. Nausea and dizziness are pretty common side effects of any injection. And:

Another concern involves long-term safety. How do we know this vaccine will not eventually cause other problems like autoimmune or neurological disorders or lose its protective powers or foster the dominance of other HPV variants?

Actually, we don’t. But we do have at least five years of safety data that include no hints of long-term risks or waning effectiveness. But if the vaccine should begin to lose potency over time, that could easily be remedied by a booster shot.

Honest, informative. Some people may not feel comfortable with the idea that we don't know the effects of the vaccine in the long term. But any new vaccine, you won't know what the long term effects are for 20 years (until you've been using it for a long term). And so far, there are very few vaccines that have had any serious long term effects.

Hmmm... So should you have give your daughter the vaccine? What can she get from it? Well, it prevents infection with the subtypes of HPV that cause up to 70% of cervical cancer. And, in a 3 year followup, it prevents pre-cancerous lesions in nearly 100% of vaccinees who got the vaccine prior to exposure to HPV. It even provides some protection to women who have previously been exposed to the virus. Up to 17% protection from pre-cancerous lesions for women who had already been exposed.

This is why it's so important to give this vaccine to children, before they are exposed to HPV through sex. Once they're old enough to choose the vaccine for themselves, it's likely already too late to get much benefit from it.

Granted, we can't say whether or not it prevents cancer. It takes twenty to thirty years for cancer to show up in women who have been exposed to HPV, and this vaccine has only been in production for a few years. But it prevents HPV infection of the most prominent subtypes, it prevents precancerous lesions... it's not a stretch to suggest it will almost certainly prevent cancer. And that sounds pretty good to me.

There are no known risks of Gardasil (though to be fair, there is a small chance that longer term studies will find some). There are some very clear benefits to getting the vaccine. So when you're making up your mind for your child - make the calculation - prevent HPV vs. no known risks. It seems pretty clear to me.

HPV and oral sex

Now that I have your attention...

I have a sneaking suspicion that if protecting your daughter from cervical cancer isn't sufficient reason for getting the Gardasil vaccine, then protecting your daughter (or son) from throat cancer won't change your mind:

The same virus that causes cervical cancer is the principal cause of throat cancer, according to a new study.

The research also suggests that unprotected oral sex is a major reason people are contracting throat cancer - not just smoking and excessive alcohol consumption, as previously believed.

"It's the human papillomavirus that drives the cancer," said Maura Gillison, assistant professor of oncology and epidemiology at Johns Hopkins University in Baltimore, Md., and lead author of the study.

She said the more oral-sex partners a person has, the greater the risk of contracting oral cancers (located in the tonsils, back of the tongue and throat). The good news is that the risk remains low over all.

"People should be reassured that oropharyngeal cancer is relatively uncommon, and the overwhelming majority of people with an oral HPV infection probably will not get throat cancer," Dr. Gillison said.

A new vaccine protects against infection by several strains of HPV, including the one associated with oral cancer, HPV-16. However, Dr. Gillison said it has not been specifically tested for its effectiveness against oral cancer.

As an interesting aside, I wonder why this has been picked up by 2 major Canadian news media outlets, and no major American news outlets (as of May 10 at 4:30, ET).

How does a scientist determine causation?

After talking it over with Mrs. Factician (who is also a molecular biologist), I realized that yesterday's post might not have made sense to everyone in the way it does to me. I would like conspiracy factory to be more than a place where scientists whine to each other that no one understands us. I'd like it to be educational to folks who don't do science every day. I'd like people like my Mom to come here and read it and find something useful for their day.

That said, I'm going to spell out the comic a little better. For those of you who are skeptics/scientists, this may seem a little like explaining a joke (if you have to explain it, it's not funny). But it should be educational, too. So go over, look at the comic, and come back if you have to. What does it have to do with autism? The joke is that scientists don't immediately assume causation if two events occur close together. The fact that the scientist gets zapped by lightning immediately after pulling the lever doesn't necessarily mean that the lever caused the lightning. (Granted, it may have caused the lightning, but until you've seen it multiple times under controlled conditions, you can't say for sure). Of course, doing an experiment that involves being shocked by lightning certainly wouldn't be performed by a scientist. It would be performed by her graduate student. ;)

What does this comic to do with autism? As it happens, the folks who claim that vaccines cause autism mostly rely on the fact that autism begins to show its ugly head around 2 years of age, right after children get a series of booster shots for their vaccines. Does this mean that vaccines cause autism? No. Especially once you realize that autistic children present with autism around 2 years of age whether they've had vaccines or not. It just happens that these things coincide in time with each other.

An experimentalist who wants to ask the question: "Do vaccines cause autism?" would examine a large group of children who get the vaccine and a large group of children who don't (who otherwise are living in similar circumstances) and see if a similar frequency of children get autism in both groups. As it happens, several groups have done this (National Academy of Sciences summarizes the studies here). And they do see similar frequencies. This pretty much kills the argument. (To further extend the analogy to the comic, this would mean that the scientist who pulls the lever a thousand more times would never get shocked again).

A Gardasil limerick

A limerick posted at the Limerick Festival by the folks at Broadsheet:

Why block a vaccine? Here's our answer.
Gardasil is no values-enhancer.
To prevent HPV
Causes sex, don't you see?
And quite frankly, we prefer cancer.

Anti-vaccine lunatics

I've posted earlier on anti-vaccine nuttery. The latest news on anti-vaccine lunacy was posted in Orac's blog, Respectful Insolence, today. He's got a great summary on this story of nuttery.

First off, a little background. Since the late 1990s, there have been parents groups that have been arguing that the mercury preservative thimerosal causes autism. The news media has been all too happy to promote their bunk, with articles that say things like: "Epidemiologists say there is no link between vaccines and autism, but parents disagree." It's sad that this is news, because if you substituted it with a sentence like: "Physicists say that there is no link between gravity and forest sprites, but parents disagree" there would be little discussion in the public media.

What are the data that suggest that mercury in vaccines causes autism? Well, autism usually starts to present itself around age 2. And this is an age when children get several different vaccinations. This is also an age when parents start taking toothbrushing seriously for their children. Yet no one is asserting that toothbrushes cause autism (yet). What is the evidence against mercury in vaccines causing autism? There are a number of large trials that show that children who don't receive vaccines, and children who receive vaccines that don't use the mercury preservative thimerosal, get autism at the same frequency as children who do receive mercury-containing vaccines. Case closed. That clearly demonstrates that thimerosal doesn't cause autism. Sadly, there are true believers out there, and it's hard to convince a true believer with data.

The latest in this sad story, is that there are people claiming that the symptoms of Shaken Baby Syndrome are caused by vaccines. What??? Yep, now if you want to hurt your baby and get away with it, you can just claim that those bruises and broken bones are the result of vaccines. This is made possible by the grotesque ignorance of the public at large on how science is done, and how much we know about vaccines. In some other post, I will talk about the real side-effects of vaccines (there are side-effects to most vaccines, but they are less severe than the disease that they vaccinate against). But we can clearly say, you won't break bones or get bruising on your brain from vaccines. Babies get that from abusers. Check out this example of someone who used this excuse to get away with murdering a baby.