No one knows if, and when, there will be another variant of SARS-CoV-2. Nor can we make precise predictions about what that variant will be like if it does arise.
However, a surprising amount is currently known that can help us make informed guesses about variant emergence. This information suggests that new variants are extremely likely, and the best strategy is to prepare for their arrival.
Changes in the viral genome arise in large numbers in every individual who is infected. Most of these changes confer no advantage to the virus and disappear. New variants typically arise when multiple small changes result in altered viruses that can outcompete existing variants. These variants may spread locally or globally.
There are a number of factors that make variants successful. Important features involve potential changes in key viral properties including: the incubation period, the primary and secondary sites of replication, the ability to evade prior immunity from vaccination or infection, the amount of virus produced or viral load, the ability to suppress key immune functions, the ability to persist in airborne particles of various sizes, the ability to utilize new cellular receptors, the ability to infect multiple hosts, the ability to resist degradation in the environment including the ability to spread in different seasons, and drug resistance — the ability to resist current or future antiviral medications.
For some variants, researchers have determined the molecular basis for these new attributes. Some of these modifications require significant evolutionary challenges. That is to say they involve unlikely mutational events. Such rare events are more likely if many people are infected. This is why is it critical to limit the spread of the virus even among low-risk individuals. Other mutation changes, like those which allow immune escape, are relatively easy for the virus to achieve. That is because there are lots of possible changes in the spike protein that would allow the protein to elude the immune system but still maintain function.
We also know a number of factors that affect the speed with which variants emerge.
One key factor is the mutation rate. All RNA viruses mutate at very high rates. Compared to other RNA viruses Coronaviruses mutate at a much lower rate because of the presence of a replication proof-reading enzyme. Nevertheless, every time this large RNA virus replicates, there is likely to be at least one genetic change. Many of these will be deleterious to the virus and will not appear in the growing population of virus particles. Other changes will be benign and will not impact the ability of the virus to spread. But some rare mutations and collections of mutations will increase the fitness of the virus and facilitate replication and spread among humans.
A second factor is the rate at which viruses can recombine. Recombination allows different variants in the population to mix and match their genetic information. In effect, this can be thought of as viral sex. Compared to most RNA viruses, Coronaviruses encode a protein that makes them particularly good at recombining. Recombination can greatly increase the speed at which successful variants emerge. As a comparison, we might look at another group of viruses that is known for its prowess at recombining, namely the retroviruses including HIV. The large number of HIV variants has greatly increased the difficulty of controlling that ongoing pandemic.
A third factor is the number of times the virus replicates. Every infected cell, in every infected person provides a great many opportunities for variants to emerge. The opportunity to replicate can be controlled by limiting the number of people infected through the use of vaccination and other public health measures. In contrast, natural infection contributes to this problem. Another way to minimize this risk factor would be early and widespread use of antiviral medications. After two years, there are some effective medicines. However, they are expensive, in limited supply, have side effects, can be difficult to administer, and are usually not given in time to limit the spread of the virus. To understand this last point, it is important to note that these medications are given to symptomatic individuals who have had a positive test. By that time, many people have passed their period of maximum viral replication and spread.
A fourth factor affecting the speed of emerging is the immunological landscape. Once a potential variant has arisen, it will be subject to selection pressure. Some important selection pressures on the virus are 1) innate immunity or the ability to resist a virus without having been exposed to it before, 2) adaptive immunity, which is the immunity that arises due to vaccination or prior infection, and 3) the presence of other variants. For example, beta was a very successful variant, but it was outcompeted by delta. Similarly, delta was outcompeted by omicron. It should be noted that mixing and matching large numbers of infected and immune individuals is the ideal condition to select for escape variants. Any variant that can replicate in a previously immune individual will win the game of replication and spread. These are the conditions that are currently prevalent in the US and elsewhere. It is worth noting that immune escape variants can prevail even if they do not replicate as rapidly or as vigorously as the variants that preceded them. Recent studies by Baric and others indicate that the spike protein is evolving at a rate that is similar to influenza, a virus that has famously evading the immune response for more than a century.
A fifth factor is the duration of immunity. Some viruses like measles or smallpox are known to induce enduring immunity. Others like the Coronaviruses are known for their rapidly fading immunity. This successful strategy explains why a single person can be infected with the same Coronavirus multiple times. Because ALL of the SARS-CoV-2 variants are newcomers in evolutionary terms, we still do not know whether they may re-emerge repeatedly in the years to come. In just two years, there are already large numbers of individuals who have had COVID more than once. While is it not entirely known how coronaviruses limit the duration of immunity, it is likely to be due to the immunomodulatory nature of the coronavirus proteins. Coronaviruses are by far the largest RNA viruses to infect humans and the complete functionality of the various virus proteins has yet to be determined. It is intriguing to speculate that the most deleterious consequences of SARS-CoV-2 infection — including acute respiratory distress syndrome, multisystem inflammatory syndrome in children (MIS-C), and long COVID, may be inadvertent consequences of this immunomodulation. The inadvertent nature of these clinical complications is apparent because these conditions occur after the virus has been controlled and therefore, they do not impact the spread of the virus to other people or across the population.
A sixth factor is the ability to infect other animal hosts. Animal reservoirs exert significant selective pressure for the generation of new variants. These variants may subsequent cross back into humans with dire consequences especially if they recombine with human variants as described above. In addition, animal reservoirs may allow existing viral variants to hang out until immunity to those variants in humans has faded.
In light of what we know, we can make the following speculations about the next variant.
1) With the optimal conditions that currently exist, there will be more variants.
2) Emerging variants are most likely to be immune escape variants as these variants require minimal genetic change in the viral genetic information. While influenza viruses and Coronaviruses are distinct in many ways, this is what happens on a yearly basis for flu.
3) Since serious side effects of infection often have little impact on viral spread, we cannot predict whether future variants will be more or less virulent. The widespread narrative that variants will be increasingly more benign, and that SARS-CoV-2 will morph into a common cold virus is far from certain and this supposition is not supported by viral logic or precedent. Until the advent of effective vaccines, smallpox and measles were both highly endemic and unremittently deadly.
4) The best way to minimize the conditions that contribute to the emergence of variants is to implement rapid and pervasive vaccination along with extensive surveillance and other public health interventions that minimize spread.
5) The most effective vaccines in preventing the emergence of variants are those that minimize spread of the virus. This can be achieved through the use of vaccines that directly target currently circulating strains such as omicron, or preferably the use of multivalent vaccines. Disappointingly, the current vaccines still target the primordial strain that emerged in 2019. There has been a lot of talk about universal coronavirus vaccines. While this would be great, this approach has not yet been validated. On the other hand, the ability to make targeted multi-valent vaccines is currently available, facilitated by the use of mRNA vaccines and other modern vaccine technologies. Fortunately, human clinical trials with omicron specific vaccines are currently being conducted by Pfizer and Moderna.
6) The negative consequences (clinical, economic, psychological, political) of being unprepared for the next variant are far greater that the consequences of preparing for a variant that never emerges.
7) After two years of being outwitted by this virus, the least surprising outcome would be more surprises.
While we are all relieved by the recent rapid decline in the spread of omicron, the most prudent path further is to put in place effect measures to avert the next variant. To paraphrase Pasteur, fortune favors the prepared.
Robert David Siegel, MD, PhD
January 24, 2022
With minor revisions February 10, 2022