This year the WHO officially announced the worldwide eradication of smallpox. This disease, caused by the variola virus, had claimed the lives of billions of people in its five millennia-long heyday. And how did we beat it? Through vaccination.

As early as 1,500 B.C. Hindu doctors started combating smallpox by practicing inoculation. In this procedure infectious material from a smallpox pustule was taken from someone infected with a relatively mild form of the disease and scratched into the skin of a healthy person. The newly inoculated patient would then suffer a small bout of the pox, and would more often than not recover with an immunity that would last a lifetime.

Smallpox epidemics have decimated human populations throughout our history. The virus was endemic to Egypt by 3,000 B.C., and from there it spread to India, through Asia, and into Europe. In the early 18th century, an influential lady named Mary Wortley Montagu, who was impressed by the practice whilst in Istanbul, introduced inoculation to the west. She had lost her brother to smallpox, and upon her return to England she made sure that all members of her family received an inoculation.

In 1796 Edward Jenner made the observation that milkmaids had beautifully smooth complexions that lacked the poc-marks associated with having had childhood smallpox. He subsequently showed that the reason for this was that they had been exposed to cowpox, a virus related to smallpox that didn’t cause disease. The virus was called vaccinia, after the Latin vacca for “cow”, hence the term “vaccination”.

Throughout the 19th century vaccination proved far safer than inoculation, and in 1967 the WHO began a massive worldwide distribution program with the lofty goal of eradicating smallpox. 44 years later we’re free of this killer disease (well, besides those lab stocks various governments refuse to destroy), a feet that would have been inconceivable without such an effective means of prophylactic control.

However, when it comes to beating human diseases, smallpox is our only success story. (The only other disease we have successfully eradicated through vaccination is rinderpest, a virus that infects cattle.) There are a variety of reasons for this, and perhaps the most pertinent to today’s rhetoric is the lack of public confidence in the effectiveness and/or safety of vaccines and vaccination schedules.

The Human Element

Anti-vaccine ideologies are not a new thing. When inoculation practices were first introduced in Europe the Christian church spoke out against them quite vehemently. It was believed that disease was a punishment sent by God to teach sinners a lesson, and by intervening doctors were defying God’s will.

In the late 19th century, Stockholm was the site of a massive smallpox outbreak. A combination of religious and personal rights-based objections resulted in a drop in vaccination rates to less than half of that of the rest of Sweden. Similarly, in the 1970s there was a safety scare related to the whooping cough (pertussis) vaccine in the U.K. Vaccination rates dropped from 80% to 31%, and epidemics broke out across the country, in some cases killing the affected children. Importantly, in both of these cases public confidence was quickly restored by the medical profession, and vaccination rates climbed back to above 80%. The infectious cycle was broken and the diseases all but disappeared again.

Most recently the public has been focused on the idea that vaccines can cause autism, a spectrum of mental and social problems that generally manifest in children at around two years of age. In the mid 1990s Dr. Andrew Wakefield published a paper in The Lancet, a medical journal based in England, that purported to show a causative link between the MMR (measles/mumps/rubella) vaccination and autism spectrum disorders. The media picked up this idea and ran blindly and destructively with it, the result of which was a fairly large international panic regarding the safety of the MMR vaccination. After multiple reports failed to recapitulate his data and a conflict of interest involving tens of thousands of pounds was uncovered, the study came under intense scrutiny. The data were found to be falsified, and last year Wakefield was convicted of fraud, subsequently losing his medical license.

Since it has been demonstrated repeatedly that the risks of complications from vaccination are much, much, MUCH lower than the risks associated with disease, not to mention the discovery that Wakefield’s autism/MMR study was fraudulent, it is perhaps surprising that the vaccination debate continues today. What’s different this time than after previous scares when the public was reassured by good science and medical expertise? With prominent celebrity endorsement influencing the actions of new parents and a few high profile court cases that have sided against vaccination, anti-vaccination campaigners have the perfect marketing combination of well-known faces and a rampant and sensationalist media. It is also clear that part of the problem is our culture of blame. Parents of autistic children, for example, looked to Wakefield’s studies as a reason for their child’s condition. And on the flip side, it also seems as though those parents who now refuse to vaccinate their children don’t want to be blamed in the extremely unlikely situation in which complications arise. It should be the other way around; they should be far more worried about the consequences of letting their kids get sick.

One unfortunate side effect of living in a world where most serious diseases are no longer a public health problem due to the success of vaccination is complacency. We haven’t seen what pertussis or rubella can do to a child, or bumped into someone with a disfiguring case of smallpox. Some anti-vaccination campaigners even argue that certain diseases just “disappeared on their own” and that vaccination programs had nothing to do with it. But recent events on the west coast of America, where whooping cough has been making a rather large comeback, should (but as far as I can tell, haven’t) help people see the importance of maintaining vaccination until a disease is completely eradicated.

What makes a good vaccine?

Despite the controversy, I think it is quite clear that vaccination is an extremely useful tool in the prevention of a number of otherwise debilitating and highly infections diseases. Currently in the U.S.A. children are vaccinated against 15 diseases before the age of six; hepatitis A and B, rotavirus, diphtheria, tetanus, pertussis, haemophilus influenzae type b, pneumococcal and meningococcal meningitis, polio, influenza, measles, mumps, rubella, and varicella. This vaccination program has likely saved thousands of lives and prevented millions of potential complications.

The goal of a good vaccine is to promote an immune response that is strong enough to invoke a “memory” of the disease in our immune system without actually making us ill. Usually a vaccine contains an “immunogenic” component of a specific infectious particle. This stimulates the immune system by giving it a little taste of the full-blown infection. Thus, when confronted with an infection we are primed to fight it off quickly: Vaccination gives the immune system a tactical advantage over invading pathogens.

Currently there are five standard ways of making a vaccine. Killed vaccines are, rather obviously, inactivated versions of the disease-causing organism. Attenuated vaccines are similar to killed vaccines in that they utilize the entire organism, but in this case the viruses or bacteria are alive. Importantly, attenuated strains have been manipulated in a laboratory, for example by deletion of specific genetic elements, so that they can no longer cause disease. Subunit vaccines make use of the fact that microbes display specific proteins on their surface. By injecting just these proteins the immune system can be primed without introducing the whole organism. Similarly, toxoid vaccines use inactivated versions of the toxins excreted by bacteria such as diphtheria or tetanus. Some pathogens have come up with a way of subverting our immune response to exposed surface proteins, and so cover up these potential Achilles heel’s with layers of polysaccharides. Conjugate vaccines make use of a piggy-back mechanism whereby polysaccharides are linked to immunogenic proteins in order to invoke an immune response to the sugar.

Commonly an adjuvant is used in a vaccine preparation to boost its effectiveness. The mercury-based adjuvant themerosol (thiomersol in Europe) has been removed from vaccine production since 2000 due to a public outcry that (you guessed it) it caused autism. A direct causative link has yet to be shown. Now small amounts of aluminum adjuvants are used, and are an effective and safe means of improving vaccine efficacy.

All of these vaccine preparations vary in their effectiveness. Attenuated vaccines generally provide the best long-term protection from disease, a fact long attributed to the fact that they are able to replicate in our bodies and maintain a protective immune response. But a recent paper in the journal Nature showed that while the observation was correct, the proposed explanation was not.

The Life of the Party

Leif Sandler of Mount Sinai Medical School and colleagues set about testing the hypothesis that the immune system could recognize the simple fact that invading bacteria are alive. Their initial experiments showed that bacteria could only illicit an immune response in mouse bone marrow tissue if they were alive. Performing similar experiments with killed bacteria (that lacked any known virulence factors) did not provoke the same response.

By a process of elimination the team ruled out a number of potential factors that could be causing this effect, and finally found the molecular culprit; bacterial messenger RNA (mRNA). All cells produce mRNA as a means of converting the molecular information stored in DNA into proteins, but bacteria do it slightly differently from us. Our mRNAs are much longer lived within our cells, a feature that requires them to be protected from degradation. Bacterial mRNAs, on the other hand, don’t stick around that long and therefore lack these protective additions. It is this difference that the immune system can detect.

In a final set of experiments, laboratory mice were vaccinated with dead bacteria along with bacterial mRNA. Infection rates in these mice were almost identical to those vaccinated with a highly effective attenuated vaccine. In a way, the mRNA was acting as an extremely powerful adjuvant.

This is a very exciting prospect for vaccine manufacturers, as it means the efficacy of live viruses can be combined with the safety of dead ones. This discovery also paves the way for developing effective vaccines against previously troublesome targets. Whilst microorganisms are annoyingly adept at mutating and altering their appearance, they (hopefully!) cannot change something as fundamental as how they produce mRNA. If further studies bear out, using bacterial mRNA to boost the efficacy of killed vaccines may give us the edge we need to fight and eradicate yet more of these microscopic killers.

Sander, L., Davis, M., Boekschoten, M., Amsen, D., Dascher, C., Ryffel, B., Swanson, J., Müller, M., & Blander, J. (2011). Detection of prokaryotic mRNA signifies microbial viability and promotes immunity Nature, 474 (7351), 385-389 DOI: 10.1038/nature10072