Friday, July 22, 2016

A Vaccine Side Note This Week: Intranasal Flu Vaccine ("FluMist") Ineffective

One of the concerns I've had about vaccines is that we humans have evolved to mount an immune response to bacterial and viral invaders as they come to us. For example, tetanus is "injected" by deep injuries into soft tissue. Polio is ingested in the mouth and invades via the gastrointestinal tract. The flu is either inhaled into the nose, or gets sort of rubbed in there when our hands touch a contaminated person or surface, then we touch our own faces. (This is why hand-washing is such a big preventive of infections!)

So, I've always thought that it would make the most sense to deliver vaccines to people the way the germs are "delivered" to us in nature. Thus, FluMist, sprayed into the nose should be safer and more effective than injecting it into the arm with a needle; and polio vaccine dropped onto a sugar cube and eaten (anyone remember that? I do.) should be safer and more effective than another shot. Right?

However, in both instances this hasn't been the case.

Oral polio vaccine is no longer used in the country because it led to a detectable increase in cases of "post-polio syndrome": a condition in which polio-like paralysis occurs late in life. This has been seen in both types of polio vaccination, but the oral form seemed actually worse and more frequent. Now this week we find that the effectiveness of intranasal flu vaccine is only 3% in children aged 2-17. (Adults were not discussed in this article.)

Then there's the case of hepatitis B vaccine. The manufacturer states that it must be injected into the arm muscle (the deltoid) in young people and adults, rather than one of the other common sites (the rear end, the thigh, etc.) we could use. This is because immunity doesn't "take" as well when injected into these other sites.

So now what?

Well, it's likely that multiple factors affect this equation: composition of the vaccine (protein "parts" vs. killed virus, for example), how much blood circulation a vaccine site gets, and perhaps some special aspects of the genetic coding of our immune cells and how that plays out in the overall system.

For a long time, I felt that we should try to give vaccines to people just like Nature gives people the germ in a natural setting. I felt that made intuitive sense. These days, I no longer believe the analysis is that simple. Not everything we intuit about medicine and biology works out the way we believe it ought to--and this, of course, is the purpose of science! For the reader contemplating a flu shot next season, the less painful path may not turn out to be very effective, which is too bad, especially for the kids who don't like shots (and that's all of them, right?)

  1. ACIP votes down use of LAIV for 2016-2017 flu season [news release]. Atlanta, GA: Centers for Disease Control and Prevention. Published June 22, 2016. Accessed June 30, 2016. (Image from Clinical Advisor online.)

Tuesday, July 12, 2016

The History & Science of Vaccination

Previously, I talked about the vaccination debate in the context of two opposite views: the good of the public and the good for individuals. Immunization advocates typically argue that the science supports the safety and effectiveness of immunization as an absolute good. Immunization opponents argue that the science is incomplete, and that this incompleteness is actually a deliberate act; they argue that drug companies and doctors actually overlook science that doesn't support their view that immunization should be universal and complete.

Vaccination is actually a very old practice. There's evidence that in the 1100s, the Chinese, Turks, and Africans used materials contaminated with smallpox to immunize against that disease. We often think of smallpox as being very lethal. It's true that one series found a case-fatality rate of 62%. On the other hand, smallpox epidemics existed during times that were less technologically advanced. Moreover, some subtypes of smallpox are more lethal than others, so overall the fatality rate is about 30%--still pretty scary! Mild cases exhibit a fatality rate of less than 1% (CDC, 2007), and inducing "mild" cases was the basis of the crude immunization techniques in the ancient world.

The story we are most familiar with is the work of Edward Jenner, who in 1796 used material from the lesions of cowpox, found on the hands of milk maids, to immunize against the similar virus, smallpox. Later, Louis Pasteur and Emile Roux used the blood of a rabies-infected mouse to immunize a boy who had been bitten by a rabid dog. Allowing the blood to dry out for nearly 2 weeks "devitalized" the virus, which must live in blood. This process preserved the viral proteins, however, and the boy's immune system could recognize these proteins, and act on them, reprogramming itself to fight the virus.

Rabies has a case-fatality rate of about 99%. Most victims die because their immune systems can't act fast enough to fight the virus before it kills them. The cause of death is general neural failure. Basically, nerve functions, including the drive to breathe, fail. Introducing a germ--or parts (proteins) of a germ--allows the body to see and begin to recognize it. There are two main branches of immunity, innate and acquired. Innate immunity is prompt and readily attacks germs, but it does a sloppy job and often misses a lot of them. Those germs that get past the innate immune cells go on to cause disease.

Acquired immunity engages a series of very specialized cells that go through a complex dance which results in the generation of very specific, highly targeted antibodies and cells that are highly lethal to those germs. Let's say you get a cut on your finger. Immediately, special cells in the skin and blood go after whatever germs got into that cut. But at the same time, a few cells "read" the proteins on those germs and send signals to other cells that start to rearrange their own DNA in order to develop a profile of those germs. They then grow and divide, these new-reprogrammed cells, to create highly specific cells ("killer cells") and chemicals ("antibodies") to eliminate those germs.

If there are any immunologists out there reading this, I know I'm simplifying this quite a bit. The thing is this is a well-understood mechanism for how we fight off disease, which we are exposed to every day.

It's possible to take advantage of this feature of our biology to prevent disease. Exposing people to germs or parts of germs, whether viruses or bacteria, can engage this system of acquired immunity. Once the acquired system has been activated, a lineage of these specialized cells will persist in the body, one line for each unique germ. These are called memory cells. Because of these memory cells, whenever the body is re-exposed to a given germ, instead of it taking 7-14 days to develop a targeted response, it takes only hours to days.

One of the important features that we have to know about is the stability of whatever germs we're trying to protect ourselves against. Smallpox is very genetically stable. Cowpox is also very stable, and presents a very similar protein "picture" to smallpox. Again, I'm simplifying here to make a point, and that is that genetically unstable germs are more difficult to vaccinate against. For example, the common cold still defies attempts to develop a vaccine. That's because the viruses that cause the common cold (mainly rhinoviruses or "nose viruses" literally! There are few less common viruses that cause colds) are prone to mutate. 

This is also why we get multiple colds. Cold viruses mutate.

But if the infecting agent is genetically stable in the wild, and you either had the infection before, or you got a vaccine against it, your memory cells ramp right up to fight the infection if you run into it again. 

This is also the case with HIV, for example. HIV mutates a lot! Those mutations often cause viruses to become inactive, but it also often gives them a "stealth" characteristic that makes it hard to the acquired immune lineage to recognize that this was seen before, say in a vaccine shot. It's also why some people can have multiple strains of HIV at one time.

Unfortunately, this system isn't perfect, and we don't fully know why. Hepatitis B vaccine typically provides protection to 96% of healthy adults (Merck & Co., 2014). Looked at another way, about 1 in 24 vaccinated adults will not develop immunity to hepatitis B when vaccinated properly. I am one of those people. I was vaccinated four times when I was ER nurse, and I never developed antibodies to give me immunity to an infection that at the time had an incidence rate among ER personnel of 35%!

Infanrix, a product that immunizes against diphtheria, tetanus provides, and whooping cough reportedly provides 100% immunity for the first two conditions, and 84% of children achieve immunity for whooping cough (GlaxoSmithKline, 2016). 

Last year, the flu vaccine--which mutates a lot--had a protection rate of 47% (CDC, 2016). Not all that great.

One study that looked at duration of immunity over time found that this was disease-dependent, and that actually having the disease tended to confer more durable immunity than having been vaccinated for it (Amanna, Carlson, & Slifka, 2007).

In short, vaccination works most of the time for its stated purpose. In cases like the flu, most years you could flip a coin to predict who it will work in (until we figure out why, at least). And while a lot of people get protected, that protection can wane over time, necessitating booster shots.

The U.S. now immunizes for 18 diseases in 35 doses plus approximately another 15 doses if one includes annual flu vaccines. Many of these are given in combinations (e.g., measles, mumps, rubella), or several in one child health visit, and on several occasions, since in many cases a single shot isn't enough. 

Amanna, I.J. Carlson, E. & Slifka, M.K. (2007). Duration of humoral immunity to common viral and vaccine antigens. New England Journal of Medicine, 357: 1903-1915.

Sunday, July 3, 2016

Public vs. Private Health

As we close in on the Summer Olympics in Rio de Jeneiro, the persistence of the Zika virus problem has led to various recommendations, not all of them official. Some say attendance poses a hazard to certain people, like pregnant women, so those people should not attend. Others worry about the possibility of male to female sexual transmission (which is a thing) and so, what? Maybe no one should attend? All of this angst overlays concerns about the displacement of native Brazilians from their homes during the construction of Olympic venues, the shifting of public money into that construction, money that many Brazilians have said could have been used for education, health care, and improving the lives of the poor--all things that would materially improve the public health. Meanwhile, pharmaceutical companies, funded in part by public dollars, are trying to develop a vaccine. More public money is going toward mosquito abatement, although there are those who warn that some approaches (like genetically engineered mosquitoes, GEM) could have untoward environmental consequences, themselves a threat to public health.

I once asked my teacher at homeopathic medical school if he could discuss the "health issues of vaccines." He responded with, "Vaccines aren't a health issue, they're a public health issue." He went on to say that we are taught to view vaccination as an individual medical intervention. But the "benefits" of immunization programs are not necessarily individually oriented; they are oriented toward a manipulation of the environment in which germs must live, to make that environment inhospitable for those germs. They're an environmental intervention.

Take smallpox for example. It has only one possible host: man. If all humans are successfully immunized, the environment for smallpox disappears. It has no place to reside. This is exactly what has occurred with smallpox, and now the only known examples of this virus exist in laboratories in Russia and the U.S. The disease is gone.

Smallpox did kill a lot of people (ask the Indians of North America), so this killing off of wild smallpox seems like a real win. It's possible that the existence of smallpox had some sort of environmental upside, but to date I haven't seen anything like that reported. This shouldn't be dismissed casually. In working toward management of the Zika problem, some proposals have us killing most mosquitoes using either poisonous sprays or genetically engineered mosquito-attacking germs or even GEMs themselves, which would reduce or eliminate the bug's ability to breed.

Terrific! No mosquitoes!--except that mosquitoes are food for many birds and beneficial insects. We've seen successful mosquito-borne disease reductions in many parts of the world. Yellow fever, malaria, and other diseases have been reduced, mostly at this moment by using poisons. But then those poisons have ended up in the food chain and come with their own public health risks.

And the use of these approaches assumes that the majority of people in affected areas support the benefits of these programs and accept the risks.

What I have observed in practice is that the selection of acceptable risks by individuals is a lot more complex. The individual calculus of risk acceptance isn't the same as the calculus used by public agents (citizens, policy-makers, doctors and nurses) to decide what measures should be imposed on everyone in a jurisdiction or an environment.

In upcoming posts I'll tackle the vaccine issue with this in mind. To get us started, I circle back to my teacher's comment about the real issues in immunization: public versus private health. The former is a collective decision that makes a choice about what is valuable for all and what the acceptable risks are for society as a whole. The latter is an individual decision undertaken in private with one's clinician. Such benefits and risks are based on particular features of the person. Here's an example: A person accepts his nurse practitioner's offer of a tetanus booster shot because she knows the man has a high risk of suffering dirty wounds in the course of his work as farmer. Opposite this would be the person who declines the offer, because she has a history of tetanus allergy, even though she has suffered a dirty wound.

If that sounds far-fetched, it's not. I had a patient once who nearly died because the doctor insisted she try a tetanus shot for an injury she suffered from an electric fan blade. We resuscitated her, but it was a close call!

One might ask, What's the risk of getting tetanus from such a wound? In about a half hour of searching the scientific literature on this Sunday morning, I have been unable to find an "attack rate" for tetanus. That is, I couldn't find information that would predict the number of people who get the disease tetanus ("lock jaw") from any wound, or from specific types of wounds ("clean", "dirty", etc.). This makes some sense, because conventional wisdom says that the risk of a known adverse reaction from the tetanus vaccine is fairly low, and the risk of dying from tetanus is about 13%. Furthermore, almost all cases of tetanus occur in unvaccinated people, or in people who'd been vaccinated but then didn't get boosters for long periods. Their protection had waned.

The numbers are small enough that attack rates for certain kinds of wounds haven't been calculated. Tetanus itself is a disease that is caused by a specific event: a wound, usually dirty and deep (hence the rusty-nail-in-the-foot as a common cause, in the popular mind). Tetanus from other types of wounds (paper cuts, shallow wounds, scrapes, blunt trauma, cuts from kitchen knives, etc.) is rare.

But tetanus isn't a disease that spreads from person to person, like measles, whooping cough, or diptheria, among others. When that's the case, how does it reframe our discussion? The vaccine "debate" has two poles: those who believe it to be necessary and those who believe it is not. Each side demonizes the other. Advocates argue that immunization is a medical marvel that saves lives with little adverse consequence. Opponents argue that it's unecological, harmful, and even a plot by Big Pharma to make money.

In upcoming posts, I'll deconstruct this argument in a different way.