Predicting endemic viruses engaged in an evolutionary battle with the immune system

From the Bedford Lab, Vaccine and Infectious Disease Division

It’s flu season. You’ve probably already gotten your annual flu shot, perhaps coupled with another COVID-19 booster. For viruses like influenza that causes the flu, updated vaccines are required each year. However, others vaccines can be more of a “one and done” situation; after a single vaccine or closely spaced series of vaccines, we’ve acquired long-lasting immunity. How long immunization lasts, either from a vaccine or natural infection, can be influenced by how often a virus acquires mutations that enable it to evade immune recognition. “One of the many ways our bodies fight viral infections is to make antibodies that very specifically recognize viruses that infect us and, thus, block these viruses from being able to reinfect us in the future,” explained Dr. Katie Kistler, a postdoctoral researcher in the lab of Dr. Trevor Bedford, part of the Vaccine and Infectious Disease Division at Fred Hutch. She continued, “at the population level, this puts pressure on a virus to evolve such that it can escape detection by those antibodies. Of course, now the human immune system is prompted to make antibodies that detect this evolved form of the virus, and the virus, in turn, is under pressure to evade these new antibodies. This results in a continual arms race between the virus and our immune system, which we call antigenic evolution.”

According to Dr. Kistler, understanding if a virus undergoes this type of evolution is an important factor for “planning vaccines and public health measures. At the beginning of the SARS-CoV-2 pandemic, it was not known whether related coronaviruses evolve antigenically, and thus, it was difficult to speculate whether SARS-CoV-2 would evolve in this way.” Previously, the Bedford group found evidence of antigenic evolution in several seasonal coronaviruses which have been circulating in humans for many decades. In a recent study published in Cell Host & Microbe, “we sought to expand our knowledge of which viruses evolve in this way by comparing the relative rates of antigenic evolution among a panel of 28 viruses that commonly infect us.” These viruses that are in constant circulation are known as endemic viruses. Dr. Kistler explained that “endemic viruses can be contrasted with epidemic or pandemic viruses, which have just spread into humans. This distinction is important because we expect different evolutionary pressures to be at play in viruses that have just jumped into humans, versus those that have been in humans for a long time.” Early in a pandemic, new viruses adapt to their host species, while endemic ones are already optimized for replication and transmission.

Graphical depiction of approach used to identify endemic viruses undergoing antigenic evolution.
Graphical depiction of approach used to identify endemic viruses undergoing antigenic evolution. Image taken from original article.

Among the 28 endemic viruses analyzed in this study, the authors included fast-evolving influenza viruses and coronaviruses strains and antigenically stable viruses, like measles and hepatitis A. They ensured that the selected viruses had high-quality genome sequences available for circulating strains spanning at least 12 years in order to predict accurate adaptation rates. To identify viruses undergoing antigenic evolution, a type of adaptive evolution driven by positive selection to evade antibody recognition, Dr. Kistler employed a quantitative method which calculated adaptive amino acid substitutions per residue per year. Since, “antigenic evolution occurs through the virus acquiring antibody escape mutations,” it is predicted that these escape mutations will “occur in the viral protein that mediates receptor binding, which is located on the virion’s surface and is typically the primary target of neutralizing antibodies.” In other words, Dr. Kistler explained, “we look for an excess of protein-coding changes in the protein that mediates receptor-binding.” Across all viruses, Dr. Kistler analyzed 239 viral proteins, however she said, “we estimated that only 14 are evolving adaptively.” Thirteen of these were located on the virion surface and were “either the primary receptor-binding protein or are at least sometimes involved in receptor-binding,” while the rest of the genome showed little-to-no ongoing adaptation. These 14 protein-coding genes belonged to 10 of the 28 viruses analyzed in this work, suggesting that nearly a third of the endemic viruses analyzed are predicted to be undergoing antigenic evolution. However, Dr. Kistler acknowledged this panel is skewed towards viruses that have ample historical sequences available and may not reflect the overall proportion of antigenically-evolving endemic viruses. Consistent with our need for yearly flu vaccines, influenza A/H3N2 evolved roughly 2-3 times faster than the other viruses analyzed.

“An obvious question is where the evolution of SARS-CoV-2 falls with respect to these other viruses,” the authors explained in the article. They also noted the challenge of using this paper’s method for a virus with a short existence. Instead, the authors compared the rate of amino acid substitutions in the receptor-binding proteins between SARS-CoV-2 and the 10 viruses predicted to be evolving antigenically. Dr. Kistler found that SARS-CoV-2 accumulates amino acid substitutions at a rate 2-2.5 times faster than the fast-evolving influenza A/H3N2. While this may sound concerning, the authors point out that we don’t know whether SARS-CoV-2 can sustain such high rates of evolution or if the emergence of the highly fit Omicron variant was a one-time event. As to what makes viruses like influenza and SARS-CoV-2 evolve quickly and others evolutionarily stable, there are many possible reasons. Dr. Kistler explained that some factors influencing “antigenic evolution are mutation rate, mutational tolerance of the proteins targeted by neutralizing antibodies, the positions and co-dominance of epitopes, viral transmission dynamics, and existing population immunity.”

While “not ubiquitous, antigenic evolution is not uncommon amongst endemic viruses and immune evasion appears to be the primary driver of ongoing adaptation in viruses that have been circulating in humans for decades or longer,” Dr. Kistler stated. Because these antigenically evolving viruses “are particularly capable of causing repeat infections and escaping vaccine-mediated immunity,” identifying which viruses evolve this way and how fast they evolve “is directly relevant to vaccine design.” She added, “for instance, the strains included in the influenza vaccine have to be updated regularly to antigenically match the circulating strains. It is likely that vaccines targeting any antigenically-evolving protein will have to do the same.” Moving forward, Dr. Kistler aims to “expand this work further to compare an even wider panel of endemic viruses. The pandemic has spurred an increased interest in sequencing the circulating viruses and we hope to incorporate an analysis of more viruses in the future.”

This work was supported by Howard Hughes Medical Institute.

Kistler KE, Bedford T. 2023. An atlas of continuous adaptive evolution in endemic human viruses. Cell Host Microbe. 31(11):1898-1909.e3.