How Will SARS-COV-2 Continue to Evolve?
A report in Nature examines why Omicron was such a surprise, and how the possible evolutionary pathways available to SARS-CoV-2 shape future scenarios of the COVID pandemic.
Currently, Delta and its descendants still dominate worldwide, and they were expected to eventually outcompete the last holdouts. But Omicron has undermined those predictions. “A lot of us were expecting the next weird variant to be a child of Delta, and this is a bit of a wild card,” said Aris Katzourakis, a specialist in viral evolution at the University of Oxford, UK.
The Omicron surge in South Africa suggests that the new variant has a fitness advantage over Delta, said Tom Wenseleers, an evolutionary biologist and biostatistician at the Catholic University of Leuven in Belgium. Omicron has some of the mutations associated with Delta’s high infectivity – but if increased infectivity alone explained its rapid growth, it would mean an R0 (reproduction number) in the 30s, said Wenseleers. “That’s very implausible.”
At present, Omicron appears to have an R0 of 1.36, after its initial surge, based on a continually updated estimate by Louis Rossouw, head of research and analytics at Gen Re. Weneseelers and other researchers instead suspect that Omicron’s rise may be due to its re-infection and vaccine evasion ability.
If Omicron is spreading, in part, because of its ability to evade immunity, it fits in with theoretical predictions about how SARS-CoV-2 is likely to evolve, says Sarah Cobey, an evolutionary biologist at the University of Chicago in Illinois.
As SARS-CoV-2’s infectivity gains start to slow, the virus will maintain its fitness by overcoming immune responses, said Cobey. If mutation halved a vaccine’s transmission blocking ability, this could open up a vast number of hosts. It’s hard to imagine any future infectivity gains providing the same boost.
The evolutionary path towards immune evasion and away from infectivity gains, is common among established respiratory viruses such as influenza, said Adam Kucharski, a mathematical epidemiologist at the London School of Hygiene and Tropical Medicine. “The easiest way for the virus to cause new epidemics is to evade immunity over time. That’s similar to what we see with the seasonal coronaviruses.”
Analysis has shown a wealth of Spike protein mutations that weaken the potency of neutralising antibodies resulting from infection and vaccination. Variants like Beta that have such mutations, have degraded – but not destroyed – vaccine effectiveness particularly against severe disease.
Compared with other variants, Omicron contains many more of these mutations, particularly in the region of spike that recognises host cells. Preliminary analysis from evolutionary biologist Jesse Bloom suggests that these mutations might render some portions of Spike unrecognisable to the antibodies raised by vaccines and previous infection with other strains. But lab experiments and epidemiological studies will be needed to fully appreciate the effects of these mutations.
Evolutionary costs and benefits
Evolving to evade immune responses such as antibodies could also carry some evolutionary costs. A Spike mutation that dodges antibodies might reduce the virus’s ability to recognise and bind to host cells. The receptor-binding region of Spike, the main target for neutralising antibodies. is relatively small, explained Jason McLellan, a structural biologist at the University of Texas at Austin. Thus, the region might tolerate only small changes if it retains its main function of attaching itself to host cells’ ACE2 receptors.
Repeat exposures to different Spike versions, through infection with different virus strains, vaccine updates or both, eventually might build up a wall of immunity that SARS-CoV-2 will have difficulty overcoming. Mutations that overcome some individuals’ immunity might not work on the whole population, and T-cell-mediated immunity, another arm of the immune response, seems to be more resilient to changes in the viral genome.
SARS-CoV-2’s evasion of immunity might be slowed by these constraints, but they are unlikely to stop it, said Bloom. Evidence shows that some antibody-dodging mutations do not carry large evolutionary costs, said McLellan. “The virus will always be able to mutate parts of the Spike.”
A virus in transition
How SARS-CoV-2 evolves in response to immunity has implications for its transition to an endemic virus. There wouldn’t be a steady baseline level of infections, says Kucharski. “A lot of people have a flat horizontal line in their head, which is not what endemic infections do.” Instead, the virus is likely to cause outbreaks and epidemics of varying size, like influenza and most other common respiratory infections do.
To predict what these outbreaks will look like, scientists are investigating how quickly a population becomes newly susceptible to infection, says Kucharski, and whether that happens mostly through viral evolution, waning immune responses, or the birth of new children without immunity to the virus. “My feeling is that small changes that open up a certain fraction of the previously exposed population to reinfection may be the most likely evolutionary trajectory,” said Rambaut.
The best outlook for SARS-CoV-2, but also the least likely, would be for it to follow measles. Lifetime protection results from infection or vaccination and the virus circulates largely on the basis of new births. “Even a virus like measles, which has essentially no ability to evolve to evade immunity, is still around,” said Bloom.
A more likely, but still relatively hopeful, parallel for SARS-CoV-2 is a pathogen called respiratory syncytial virus (RSV). Most people get infected in their first two years of life. RSV is a leading cause of hospitalisation of infants, but most childhood cases are mild. Waning immunity and viral evolution together allow new strains of RSV to sweep across the planet each year, infecting adults in large numbers, but with mild symptoms thanks to childhood exposure. If SARS-CoV-2 follows this path – aided by vaccines that provide strong protection against severe disease – “it becomes essentially a virus of kids,” Rambaut said.
Influenza offers two other scenarios. The influenza A virus, which drives global seasonal influenza epidemics each year, is characterised by the rapid evolution and spread of new variants able to escape the immunity elicited by past strains. The result is seasonal epidemics, propelled largely by spread in adults, who can still develop severe symptoms. Flu jabs reduce disease severity and slow transmission, but influenza A’s fast evolution means the vaccines aren’t always well matched to circulating strains.
But if SARS-CoV-2 evolves to evade immunity more sluggishly, it might come to resemble influenza B. That virus’s slower rate of change, compared with influenza A, means that its transmission is driven largely by infections in children, who have less immunity than adults.
How quickly SARS-CoV-2 evolves in response to immunity will also determine the need for vaccine updates. The current offerings will probably need to be updated at some point, says Bedford. In a preprint5 published in September, his team found signs that SARS-CoV-2 was evolving much faster than seasonal coronaviruses and even outpacing influenza A, whose major circulating form is called H3N2. Bedford expects SARS-CoV-2 to eventually slow down to a steadier state of change. “Whether it’s H3N2-like, where you need to update the vaccine every year or two, or where you need to update the vaccine every five years, or if it’s something worse, I don’t quite know,” he says.
Although other respiratory viruses, including seasonal coronaviruses such as 229E, offer several potential futures for SARS-CoV-2, the virus may go in a different direction entirely, say Rambaut and others. The sky-high circulation of the Delta variant and the rise of Omicron, aided by inequitable vaccine roll-outs to lower-income countries and minimal control measures in certain large developed countries such as the US, offer fertile ground for SARS-CoV-2 to take additional surprising evolutionary leaps.
For instance, a document prepared by a UK government science advisory group in July raised the possibility that SARS-CoV-2 could become more severe or evade current vaccines by recombining with other coronaviruses. Continued circulation in animal reservoirs, such as mink or white-tailed deer, brings more potential for surprising changes, such as immune escape or heightened severity.
It may be that the future of SARS-CoV-2 is still in human hands. Vaccinating as many people as possible, while the jabs are still highly effective, could stop the virus from unlocking changes that drive a new wave. “There may be multiple directions that the virus can go in,” said Rambaut, “and the virus hasn’t committed.”
Source: Nature
