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Viruses, variation, and vaccines

March 2021

Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases, receives the Moderna COVID-19 vaccine at the HHS/NIH COVID-19 Vaccine Kick-Off event at NIH on 12/22/20. Credit: NIH

Last month, we discussed new strains of SARS-CoV-2 and how they evolved, despite the relatively slow pace of coronavirus evolution. Since then, the new strains have continued to spread and more have popped up. This month, with over 15% percent of the US at least partially vaccinated, we all want to know how effective the existing vaccines will be against those new strains. Will we need another shot for the new viral varieties in six months? And then again in a year? And so on indefinitely? As we face down a future that almost certainly means learning to coexist with the virus in some way, it's worth asking a big-picture question: why do some vaccines successfully beat back a disease year after year and others do not?

Where's the evolution?

We've had a polio vaccine for 65 years, a measles vaccine for 57 years, and a rabies vaccine for more than 100 years ... and those viruses have never evolved resistance to the vaccines. They continue to work. The smallpox vaccine was so successful that, not only did no smallpox strains evolve resistance to it, but the virus was entirely eradicated. On the other hand, because of influenza's rapid evolution, the flu vaccine usually works for a year or less. And we've yet to develop an effective vaccine against HIV, despite 35 years of trying. While some of the differences come down to quirks of each virus and the immune system, evolutionary theory still helps explain important patterns.

A big part of the explanation is variation: both genetic variation in the viral population, and the variation that our vaccines and immune systems are able to throw at the virus. Variation in the viral population is important because this is the raw material for evolution. A highly variable viral population (or a very large population, as we've allowed to happen with SARS-CoV-2 by not controlling its spread) is more likely to contain a variant that can evade an immune system primed by a vaccine — just by chance alone. And of course, when many people are vaccinated, any vaccine-resistant variants will be favored by natural selection.

The amount of variation in a viral population is shaped by the virus' mutation rate and its population size. Influenza and HIV have very high mutation rates (as well as population sizes), leading to a lot of variability from one virus particle to the next. In the case of influenza, this means that we have to reformulate our vaccine every year to keep up with the virus as it evolves out from under the prior year's vaccine. And in the case of HIV, this means that we've never even gotten to the point of a broadly effective vaccine against the multitude of ever-changing strains circulating. SARS-CoV-2 has a lower mutation rate than those viruses, but its unchecked spread has led to a vast population of viruses. We are now learning that some of those virus particles carry mutations that allow them to spread more easily. Consequently, descendants of those variants, which also carry the now beneficial mutations, are on the rise.

The other half of the equation is the diversity of defenses that a vaccine can equip our immune systems with. The polio, measles, and rabies vaccines are all based on entire virus particles (either inactivated or disabled so that they cannot cause serious disease). Such vaccines teach our immune systems to recognize many different viral proteins, not just one. Imagine a polio virus that carries a mutation making one of its proteins unrecognizable to a vaccine-primed immune system. That virus would still be attacked by the immune system on the basis of its other proteins. To get past the immune system, a single virus particle would have to carry the right the mutations in all the different proteins the immune system recognizes. And that is extremely unlikely, making the evolution of a resistant strain similarly unlikely. (Note that the flu vaccine is a notable exception to this general pattern; it is also based on the entire virus particle, but the virus is still able to evolve out from under the vaccine.)

The approved COVID-19 vaccines, on the other hand, all target a single protein — and two of them only a short stretch of that protein. If mutations change the shape of that protein, it could easily make our vaccines less effective. Studies of this question are still underway, but the initial evidence is worrying. At least some of our vaccines seem to be somewhat less effective against some coronavirus strains now in circulation. Focusing on a single protein contributed to the record-breaking pace of COVID-19 vaccine development. But it also produced narrowly focused vaccines that could falter in the face of viral variation.

We may wind up in an evolutionary arms race with SARS-CoV-2, in which we produce new vaccines to deal with new strains as they arise, much as we do with influenza. Researchers are already working to adjust COVID vaccines and vaccination strategies to account for emerging strains. But this problem is not just up to medical researchers to solve. The virus acquires mutations, the raw material of evolution, when it replicates. We can all help limit the variation available to SARS-CoV-2 by slowing its spread and, hence, its replication. Masking, social distancing, and getting vaccinated not only help keep us and our families healthy. They also reduce the evolutionary potential of the virus.

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Discussion and extension questions

  1. The article above says that genetic variation is the raw material for evolution.  In your own words, explain what this means.
  2. How does a virus' mutation rate and its population size affect the amount of variation in the viral population?  How do these, in turn, affect the chances of the virus evolving adaptations via natural selection?
  3. What is a key difference between the polio vaccine and the approved COVID vaccines described in the article above? Explain how this impacts the human immune response to each.
  4. In your own words, explain how and why a multipronged immune system attack could slow the evolution of resistant viral strains.
  5. HIV infections are challenging to treat because the virus evolves so quickly, even diversifying and adapting within a single infected patient. Drug cocktails (a treatment composed of several different drugs that work in different ways) are commonly used to treat HIV infections, which would quickly evolve resistance to a single drug. Explain the evolutionary strategy behind this treatment. Then list some similarities and differences between the drug cocktail strategy and whole-virus vaccines, making sure to address impacts on the evolution of the virus in each case.
Related lessons and teaching resources

  • Teach about variation and natural selection: This short film and exercise for grades 9-12 reinforce the concepts of variation and natural selection using the rock pocket mouse system.
  • Teach about the evolution of resistance: This case study for the college level examines the evolution of toxin resistance in clams.
  • Teach about vaccines and evolution: This news article for high school and college students explores how evolutionary theory can help us understand the different impacts of medications and vaccines on pathogen evolution and human health. Discussion questions are included.


  • Callaway, E. (2020). The coronavirus is mutating — does it matter? Nature. 585: 174-177.
  • Williams, T. C., and Burgers, W. A. (2021). SARS-CoV-2 evolution and vaccines: cause for concern? The Lancet. DOI: https://doi.org/10.1016/S2213-2600(21)00075-8

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