May 2018

For the past two years, drug-resistant typhoid has plagued Pakistan and is soon expected to make its way around the world. Typhoid fever is contracted through food or water contaminated with Salmonella Typhi. The vomiting, fever, and headaches caused by the bacterium are rarely fatal when treated — but now doctors are wondering how much longer our drugs will work against the pathogen. The strain from Pakistan resists five different kinds of antibiotics. Only one oral antibiotic, azithromycin, can still combat these bacteria, and scientists worry that resistance to this drug as well is just around the corner. Interestingly, a key weapon in the fight against drug resistant typhoid is vaccination. Salmonella Typhi evolves resistance to antibiotics quickly (in some cases, within two years), but has yet to evolve resistance to our vaccines, despite over a century of use.

Where's the evolution?

In fact, the case of typhoid fever generalizes: pathogen resistance to medications is common, while resistance to vaccines is rare. Malaria parasites have evolved resistance to at least nine different antimalarial drugs, and the speed with which bacteria like Staphylococcus aureus have evolved resistance to nearly every antibiotic we’ve thrown at them currently constitutes a major threat to global health. Yet our vaccines remain broadly effective, with just a few exceptions (e.g., the flu vaccine must be reformulated each year, in part, because of viral evolution). Why this difference? After all, both medications and vaccines represent selection favoring germs that are able to resist these interventions.

Understanding why pathogens evolve resistance under one form of selection but don’t under another requires going back to the basics of natural selection. This evolutionary process occurs anytime that the following four factors are all at work:

• Variation — There is variation in a population — i.e., individuals are not all identical to one another.
• Inheritance — Some of that variation is heritable — that is, it is passed down to offspring.
• Selection — Some of those heritable variations make the individuals carrying them better or worse at surviving and/or reproducing.
• Time — Together, the factors above cause evolutionary change from one generation to the next; as generations pass, harmful variations are weeded out and helpful ones become more common.

Recently, evolutionary biologists hypothesized that the differential effects of vaccines and drugs on pathogen evolution can be traced back to the way that these interventions affect two of these components: variation and selection.

First, vaccines reduce the ability of pathogen populations to accumulate genetic variation by working preventatively — that is, they prevent a germ from invading the human body and multiplying to a degree that causes illness. Medications like antibiotics, on the other hand, are usually given only after a germ has invaded and proliferated. Every time a pathogen reproduces, it’s another chance for random mutation to occur and potentially produce genetic variants that resist our medical interventions. The fact that vaccines keep pathogen populations small, and hence genetic variation low, at the time when the bugs are coming into contact with the effects of the vaccine (i.e., a well-prepared host immune system) helps slow the evolution of resistance to vaccines.

Second, vaccines increase the variety of selective forces at work on pathogen populations. Most drugs work by attacking or disabling a single, specialized part of the pathogen. For example, the antibiotic fluoroquinolone attacks a particular protein in typhoid bacteria — one that affects both DNA copying and the regulation of genes. However, the resistant typhoid strain in Pakistan produces a second molecule that binds to this key protein, protecting it (and hence, the entire bacterium) from the antibiotic. Vaccines, on the other hand, work by teaching the body’s immune system to recognize and attack many different parts of the pathogen. A tetanus shot, for example, can stimulate the immune system to recognize more than 100 different molecular bits associated with the tetanus bacterium. Resisting a drug may only require that a pathogen have one or a few small genetic quirks that confer resistance. But resisting a vaccine generally requires a pathogen that has the hundreds of different quirks that would allow it to elude the hundreds of different ways that the immune system has to identify it. A pathogen that carries a few of these quirks might be relatively common (given the large size of pathogen populations) — but one that carries all of those variants would be exceedingly rare. Hence, vaccines generally cause such strong selection on so many different traits that the variation to resist them all at the same time just isn’t present in the pathogen population.

In addition, different people’s immune systems will react to a vaccine in different ways, targeting different parts of the pathogen; whereas, drugs work against a pathogen in basically the same way in every patient. This means that even if some pathogen were to arise that happened to be able to resist the vaccine-stimulated immune system of one person, that disease strain wouldn’t necessarily be able to resist the vaccine-stimulated immune system of the next person it invaded. That is not the case when it comes to drug resistance. As occurred in Pakistan, bacterial strains resistant to many different antibiotics can run riot through a community, jumping from one victim to the next.

Third, vaccines reduce the opportunity for partially resistant pathogen strains to be favored by selection. To understand how, you need to know two things. First, full resistance often evolves through a series of smaller steps: one mutation might not confer full resistance to a drug, but might allow a pathogen to just occasionally reproduce even when a drug is present and so is favored, and later, another random mutation could amp up that effect and be favored, and so on. Through a series of mutation giving partial resistance, a fully resistant strain can evolve. Second, pathogens are generally only passed from one host to another when they have a large population size within the first host. Vaccines may selectively favor partially resistant pathogens but they usually keep the pathogen population within a single host small enough that new infections cannot occur — and hence, partially resistant strains cannot be passed on. Drugs on the other hand, select for partially resistant variants and may leave pathogen populations large enough that partially resistant strains are transmitted to others, setting up a situation in which it is easy for full resistance to evolve in a series of smaller steps.

All of this evolutionary theory underscores some important medical lessons. First, it highlights the importance of deploying drugs in ways that parallel the evolutionarily relevant effects of vaccines — for example, using combinations of different drugs on the same pathogen (i.e., increasing the variety of selective pressures) to slow the evolution of resistance, and using drugs preventatively (i.e., keeping population sizes and variation low) when appropriate without inordinate fear of the evolution of resistance (as in the case of HIV medications that are sometimes used preventatively in healthcare workers). Second, it provides lessons for the development of evolution-slowing vaccines: they must keep pathogen populations (and hence, genetic variation) low and cause a variety of selective pressures on the pathogen. The few cases in which vaccine-resistant pathogens have evolved have been cases in which the vaccine failed to keep the pathogen population low and did not attack a wide variety of sites on the pathogen. Most importantly though, viewing vaccines and drugs through an evolutionary lens showcases just how many different ways vaccinations saves lives: not only do they protect the vaccinated person from disease and reduce the burden of the disease within the larger population (including for those who cannot be vaccinated themselves) — but they can also reduce the need for drugs that strongly favor the evolution of dangerous, difficult-to-treat resistant pathogen strains, as in the case of typhoid in Pakistan. The low rate of typhoid vaccination in Pakistan may have contributed to that outbreak — and now vaccination is one of the few typhoid-fighting strategies that we know still works.