Vaccine Resistance

Several weeks ago, while perusing the mental spewings of the Vermont Coalition for Vaccine Choice's Facebook page, I came across a post that actually got me thinking. It wasn't because the Vermont Coalition for Vaccine Choice was actually saying something based in science or reality for a change. Rather, it made me think about what evidence was actually out there on this particular subject. They shared a link to a news story about antibiotic resistant bacteria. The news story itself, A Wake-Up Call on Antibiotic Resistance, wasn't really controversial, being an NPR story about how resistant bacteria are becoming more common and how, if we don't figure something out soon, what once were treatable, relatively benign illnesses could become deadly. But then the VCVC had to tack on this comment: Will over-vaccination cause similar problems?

My initial, knee-jerk thought was, "Of course not!" But then I paused. My skeptical nature kicked in and made me ask, what does the science actually say on the subject? Was it possible? Maybe, but the comparison to antibiotics is flawed, since antibiotics and vaccines work in very different ways. Now, if I were the VCVC, I would have stopped right there. I would have just assumed my presumptions about vaccines being bad in every conceivable way were valid and therefore over-vaccination must inevitably lead to vaccine-resistant strains of bacteria and viruses. But, thankfully, I'm not among the membership of the Vermont Coalition for Vaccine Choice. I actually did go in search of answers, something I presume they did not bother doing, since I haven't seen any followup posts on the subject.

First, we should probably clarify what is meant by resistance in this context. With antibiotics, bacteria evolve the ability to survive the use of antibiotics. Resistance comes as a direct result of using the drug, rather than picking up genetic material from somewhere else that just happens to enable it to survive. This occurs largely because people use antibiotics when they don't need them (thereby killing off some [currently] non-pathogenic bacteria and leaving the survivors more genetically robust to resist antibiotics) and sometimes stop taking their antibiotics too early. In the latter case, a lot of the pathogenic bacteria are killed, but not all. The ones that weren't killed had the right genetic makeup to survive. They get to reproduce and pass on those resistant genes, making their descendants that much less likely to be killed by antibiotic treatments. This is a bit of a simplification of how it comes about (there's also random mutation during treatment [see pseudomonas], picking up new DNA a la MRSA and selecting for preexisting resistance like in TB), but I think it's a decent approximation of what we're talking about.

What about vaccines? How would bacteria or viruses develop resistance to the vaccine? The short answer is, they wouldn't. Because it's not actually the vaccine they would develop resistance to. That's because vaccines work by priming your own immune system to be able to recognize and respond to foreign invaders. So it's actually your immune system that the bugs would adapt to resist. This really isn't anything new. As long as bacteria and viruses and humans have been around, they've been in a constant arms race. Our immune systems get better at dealing with the diseases, the diseases work out some way to evade the immune system, forcing the immune system to learn how to deal with the disease. Those humans who survive the disease pass along their improved immune system genetics to their kids; and the bacteria and viruses that survive the onslaught of the immune system pass their genetics on to their progeny. As long as there are opportunities for the diseases to spread, they will be able to pass on those genes. But, that takes susceptible hosts. If there are no hosts, the disease can't spread and it dies out. See the example of smallpox.

In a very, very simple explanation, then, if enough people are vaccinated worldwide in a short enough time period with a sufficiently effective vaccine for a disease that only infects and spreads among humans, the disease will die out. It won't have a chance to develop resistance. Things are seldom so simple, though. What if the disease infects other animals (e.g., influenza infects pigs and birds, too)? What if the vaccine isn't very effective? What if not enough people are vaccinated? These all factor into whether or not a disease could become "resistant" to vaccines.

In theory (that's colloquial "theory", not "scientific" theory), bacteria and viruses could develop resistance, or evolve into vaccine escape variants. But it would take a number of different factors for that to happen. Let's start with diseases that infect more than just humans.

Diseases like the flu are pretty adept at picking up new genetic material as they jump from one species to another. Some of those things they pick up may make them much deadlier, but less able to spread (e.g., avian flu in humans). Some make them easier to spread, but not as deadly. The genetic material they pick up, when it isn't detrimental to the virus, helps it evade the immune system of its new host. But that's not really an escape variant. The vaccine is not really the thing that's driving its evolution; the vaccine isn't what's making the virus able to get past the immune system. It's just chance.

In a related example, look at pneumococcal vaccine. There are dozens of strains of the pneumococcus bacterium. The first vaccine (PCV7) included 7 of those strains, while the newer version includes 13 strains. The strains that aren't included aren't "vaccine-resistant". The vaccine never included them to begin with. None of the strains targeted by the vaccine evolved into one of those other strains. They were already there, so we can't include those in the discussion, really, when we ask "does over-vaccination lead to vaccine resistance?"

What about vaccine efficacy. This does play a role. Suppose we have a less-than-robust immune response. It works, but not quite well enough to take care of the infection before you spread it to someone else. While the bug might be the same strain that's included in the vaccine, there's something just slightly different about it that makes it less recognizable to your immune system as something bad that needs to be attacked. So no we have the wild type (against which the vaccine is designed to work) and a mutant (which evades the immune response). That mutant might eventually become a vaccine-resistant variant and become the dominant strain in circulation. But...(there's always a "but".)

We need to consider how tailored the vaccine is. Does it provide a good deal of cross-immunity? Or does it focus on only a single part of the bacterium/virus? Some vaccines use the entire bug. Live virus vaccines like MMR or varicella use the whole virus. That provides a lot more cross-immunity to any mutants that might arise. Some, like pertussis vaccine, use a handful of parts from the bacterium. And still others are even more narrowly focused, and so provide less cross-immunity. Hep B and HPV fall in this latter category. If the vaccine produces broad immunity, then both the wild type and the mutant will be recognized and eliminated by the immune system. If the vaccine is more narrowly focused, the wild type will be effectively targeted and eliminated, but the mutant might not be recognized and flourish in the gap left by the demise of the wild type. But...

Vaccine uptake adds another layer to this. If vaccine uptake is very low or nonexistent, then the wild type will remain the dominant strain; resistance won't evolve. If vaccine uptake is very high, chances are good that the bacterium or virus will be eliminated before it has an opportunity to evolve, even if the vaccine produces a very narrowly focused immune response. But if uptake is in the middle, high enough to kill off the wild type but low enough that mutant escape variants have a chance to evolve, then we could see a resistant strain come about. But even then, it would likely take a couple decades for the variant to become the dominant strain.

Now that we know what kinds of conditions need to be in place on the vaccine side of things for vaccine resistance to develop, how likely is it? How easy is it for the bacteria/viruses to evolve resistance? The short answer is, not very. When talking about diseases, antigens are the parts of viruses and bacteria that kick our immune systems into action. They're usually polysaccharides or proteins, and these polysaccharides and proteins have these things called epitopes. It's those epitopes that our antibodies bind to; they are what allow our immune system to latch onto and attack an invading bug. Antigens generally have multiple epitopes, and our antibodies are often able to act against more than one epitope. The more epitopes on an antigen that an antibody can bind to, the stronger the bond and the less chance the invader has of surviving. So even if we have a very narrowly designed vaccine that uses only a single protein from the target bacteria, for instance, the bacteria would need to change lots of epitopes in order to be able to evade the immune system. It's certainly possible that the bug could do that, but (so many "buts" in all this, aren't there?) the genetic changes necessary to alter protein expression to make the epitopes different enough to make the invader unrecognizable by our bodies would also have to not be detrimental to the bacteria. Genes seldom code for just a single thing, so a change that might favorably alter the epitopes could make reproduction a problem, or damage nutrient uptake, or any number of other things that would keep the bacteria from passing on the mutation that allow them to escape the vaccine-induced immune response. This is, perhaps, oversimplifying things (even this small area of immunology is incredibly complex), but it's good enough for the question at hand.

To recap, in order for vaccine-resistance strains of bacteria and viruses to come about, we would need middling (but not super-low/nonexistant) vaccine uptake, low cross-immunity, very narrowly focused vaccines and a lot of very fortunate (from the bugs' perspective) mutations and enough time for that to happen. In the history of vaccines (since Jenner's first use of cowpox to innoculate against smallpox), no vaccine-resistant bacteria or viruses have emerged. The closest we've seen so far is pertactin-negative pertussis, though this may result in less severe disease than infection with wild type. While we do not (yet) have a vaccine resistant strain of pertussis in active circulation, it might be heading that way. The vaccine still provides some cross-protection to these mutant strains, but it isn't perfect, and uptake of the vaccine, particularly among adults, has not been very good. Add to this that immunity to pertussis, whether from natural infection or from immunization, wanes with time. At any rate, we have yet to see any emergence of vaccine escape variants. And remember, it's not really the vaccine that they would develop resistance to, but rather the immune system itself, and that's something that would occur whether the immunity comes from vaccines or infection; the difference is simply a matter of time.

While researchers should keep a close eye on the genotypes of circulating strains of viruses and bacteria to make sure our vaccines stay closely matched, and therefore, remain effective, over-vaccination is not likely to cause the emergence of vaccine-resistant strains. Rather, middling uptake will be a larger contributor to the evolution of vaccine-resistant bacteria and viruses. If anti-vaccine advocates like the Vermont Coalition for Vaccine Choice are effective in their efforts (which recent measles outbreaks in the U.S. certainly suggest they are), and immunization rates drop to a mid-range, then we might see resistant strains crop up. But if people actually get vaccinated, and we keep herd immunity high, then these bugs won't stand a chance. Even better, we could actually completely eliminate a good number of the ones we vaccinate against, since their only hosts are humans. And then we wouldn't need the vaccines anymore.

The vaccine resistance that we should really be worried about isn't with the bacteria and viruses, it's with people.
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References and further reading:

• McLean AR. (1995). Proc Biol Sci. Vaccination, evolution and changes in the efficacy of vaccines: a theoretical framework. 261(1362):389-93.
• McLean AR. (1998). Br Med Bull. Vaccines and their impact on the control of disease. 54(3):545-56.
• Wilson JN, Nokes DJ, Carman WF. (1999). Vaccine. The predicted pattern of emergence of vaccine-resistant hepatitis B: a cause for concern?. 17(7-8):973-8.
• Wilson JN1, Nokes DJ, Carman WF. (2000). Epidemiol Infect. Predictions of the emergence of vaccine-resistant hepatitis B in The Gambia using a mathematical model. 124(2):295-307.
• Scherer A, McLean A. (2002). Br Med Bull. Mathematical models of vaccination. 62:187-99.
• Echevarría JM, Avellón A. (2006). J Med Virol. Hepatitis B virus genetic diversity. 78 Suppl 1:S36-42.
• Iwami S, Suzuki T, Takeuchi Y. (2009). PLoS One. Paradox of vaccination: is vaccination really effective against avian flu epidemics?. 4(3):e4915.
• Komatsu E, Yamaguchi F, Abe A, Weiss AA, Watanabe M. (2010). Clin Vaccine Immunol. Synergic effect of genotype changes in pertussis toxin and pertactin on adaptation to an acellular pertussis vaccine in the murine intranasal challenge model. 17(5):807-12.
• Bondi T, Canessa C, Lippi F, Iacopelli J, Nieddu F, Azzari C. (2012). J Prev Med Hyg. Streptococcus pneumoniae: elusive mechanisms of the body's defense systems. 53(2):89-93.
• Mishra RP, Oviedo-Orta E, Prachi P, Rappuoli R, Bagnoli F. (2012). Curr Opin Microbiol. Vaccines and antibiotic resistance. 15(5):596-602.
• Bodilis H, Guiso N. (2013). Emerg Infect Dis. Virulence of pertactin-negative Bordetella pertussis isolates from infants, France. 19(3):471-4.
• Medici MC, Tummolo F, Guerra P, Arcangeletti MC, Chezzi C, De Conto F, Calderaro A. (2014). Virus Genes. Evidence of VP9 and VP4 intra-lineage diversification in G4P[8] Italian human rotaviruses. 48(2):361-5.