We have watched SARS-CoV-2 develop for 18 months and have some idea of its trajectory. The Delta variant is the prime example of strains succeeding each other, becoming progressively worse in waves of infection. According to a recent report from the Scientific Advisory Group for Emergencies (SAGE) in the United Kingdom, the virus is very likely to evolve into a still more dangerous form. We must be prepared for this outcome, for we are already behind the curve as SARS-CoV-2 is outpacing our response.

Intended for reference by Prime Minister Boris Johnson and key public health decision-makers, the report compiled by leading physicians, scientists, and epidemiologists outlines what is known about viral evolution presents scenarios we are likely to encounter in the coming months and years as the Delta variant continues to evolve into something even more dangerous. The report assigns probabilities for each scenario and recommends strategies to limit the damage and control the pandemic.

The report outlines four scenarios: 

Scenario one: The Delta variant mutates to a point of increased lethality. Under this scenario, the virus has the potential to kill between 10 and 35% of people infected, as did SARS-CoV and MERS-CoV, up from the 1 to 2% lethality, characteristic of the current strains.

Scenario two: The Delta variant mutates to evade vaccines.

Scenario three: The Delta variant mutates to a point of multi-drug resistance, challenging antiviral treatments designed to prevent and treat disease. 

Scenario four: The Delta variant mutates to become less harmful, similar to the four coronaviruses circulating today, such as the common cold.

Before dissecting these scenarios, it is important to recognize the basis of their conclusions. The report is cognizant of the behavioral patterns of viruses and coronaviruses in particular. They can alter their genetic structures by mutation and recombination, leading to substantial changes in fundamental characteristics, including replication rate, transmission efficiency, and pathogenesis.

Wisely, the SAGE report considers the entire viral genome in its analysis, not just the potential changes in the Spike (S) protein, as is common in many other discussions on the topic. They note that the efficiency of transmission and evasion from immune surveillance is largely driven by the S protein. However, they also recognize that many other regions of the virus may contribute to both pathogenesis and transmission.

In considering how much more transmissible the virus can be, we note a study by Schreiber et al. that indicates that certain S mutations can increase avidity between the ACE2 receptor of the host cell and the virus by 600-fold, creating a far more transmissible variant. The progression from the original Wuhan virus to Alpha and then Delta seems to be following a path of increased avidity, as well as increased immune evasion. So far, the avidity appears to be increased by only four to eight-fold, far from the range that is theoretically possible. 

In what follows, we provide a detailed summary and analysis of each scenario.

Scenario One: Increased Lethality 

The SAGE report considers the development of strains with increased lethality a realistic possibility.

The Delta variant has driven a rise in cases to levels we have not observed in the United States since mid-February, and recent data shows a surge in deaths related to Delta variant infection in the UK, their highest rates since mid-March. The SAGE report highlights the possibility of recombination between two aggressive variants, resulting in a new, substantially more lethal and virulent virus. Specifically, the report highlights the possibility of an alpha and beta variant recombination. Were these variants to recombine, the variant could be comprised of the best of both worlds, forming a variant of dangerous transmission and immune evasion.

The report highlights another likely origin of a more pathogenic virus through the current advent of antigenic drift. Orf and structural proteins are particularly important in the suppression of host immune responses. Orf9b, for example, suppresses innate immunity by targeting mitochondria and the mitochondrial antiviral signaling protein (MAVS), TNF receptor-associated factor 3 (TRAF3), and TRAF6. In the alpha variant, a single amino acid mutation in the latter portion of the genome enabled the virus to replicate Orf9b mRNA to 80-fold greater amounts than in non-alpha variant samples. 

As the report notes, the “likelihood of genotypic change in internal genes…is high.” So long as infections continue, the virus will continue to mutate to better adapt to its host environment: us. If a single amino acid outside the S protein could enhance an immune suppression function by 80-fold, imagine the evolutionary capacity of dozens of other fine-tuned mutations down the line.

Scenario Two: Evading Vaccines

The SAGE report considers the possibility that the virus will develop into what I call “vaccine-busting variants” to be an almost certainty.

Influenza is an effective model for their concern. In addition to successive antigenic mutations that avoid immune suppression, a coronavirus has the evolutionary capability of antigenic shift, which involves substituting one or more genomic segments from a prevalent strain to an unrelated strain of animal origin. Such antigenic shifts of Influenza have occurred three times over the past century, each time giving rise to a new strain of flu, which evades existing prior immunity.

We note that a number of human and other animal retroviruses make use of the same ACE2 receptor as SARS-CoV-2, and given that hundreds of millions of people around the world have been and will be infected with SARS-CoV-2, it is highly likely that such a recombination event could take place.

At present, we are witnessing real-time antigenic drift, which could also result in “vaccine-busting variants.” Each variant, as they arise, contains a series of point mutations in the exterior spike protein, which serve to reduce the potency of extant vaccines and monoclonal antibodies. Observations based on the annual recurrence of cold-causing coronaviruses indicate that the virus has nowhere near exhausted its capacity to reduce recognition by antibodies produced by previous infection or vaccine.

Scenario Three: Anti-Viral Drug Resistance

The SAGE report considers the possibility that the virus will develop antiviral drug resistance to be likely.

The development of potent small-molecule antiviral drugs has been slower than originally anticipated. A problem plaguing the development of antiviral drugs is a long asymptomatic period prior to the onset of symptoms. By the time symptoms typically appear, the concentration of the virus has rapidly dropped in infected people and further treatment by anti-viral drugs yields limited efficacy. There are two strategies to counter. One is much more vigorous, which is the early identification of the infected, contact tracing, and use of antiviral drugs for prophylaxis. That has been a successful approach with monoclonal antibodies. The Regeneron combination monoclonal antibody was recently approved by the United States for preventing infections in nursing homes and other congregate living settings.

Resistance to single and, in some cases, multiple monoclonal antibodies is already apparent. Many of the variants can no longer be neutralized by monoclonal antibodies that were produced early in the pandemic. Reports from separate laboratory studies show that single combinations of small molecule drugs also result in rapid adaptation and resistance. The lessons learned from successful treatment and prophylaxis of HIV show that combinations of antiviral drugs are critical for both the prevention and treatment of HIV infections. Combination treatment with two or more drugs dramatically reduces the possibility that the virus would rapidly develop resistance. Currently, there are more than 25 drugs, focusing on at least five or five to six different HIV targets that are used in combination.

It is likely that a successful program for chemoprevention and treatment of coronaviruses requires a similar large pharmacopeia to cope with the virus’s propensity for developing resistance. The report urges dramatically increased research on the development of antiviral drugs. The model could be the recent drug, Xofluza, which was developed to prevent household transmission and length of influenza, and has been shown to reduce infection duration by 80% when administered promptly post-exposure to active Influenza infection. 

Scenario Four: Decreased Virulence

The SAGE report considers the possibility that the virus will develop decreased virulence to be a realistic possibility, only in the long term.

It is possible, but by no means certain, that over time the virus could mutate through a form that is highly transmissible but far less lethal. This may have been the case for the four coronaviruses currently in circulation, although there is no hard evidence to support this speculation. The report mentions that it is unlikely that the virus will mutate to become less lethal in the near future. They suggest that if the virus does mutate to a less lethal form, such mutations may occur over a period of many years to many decades.

This report is not entirely pessimistic. It offers a number of different approaches; many of these involve additional research and vaccines which may produce better immune responses, capable of protection from many different viruses. The report also calls for major increases in fundamental and applied research of coronaviruses to fill in glaring gaps in our knowledge necessary to create new generations of vaccines and antiviral drugs. Finally, the report mentions that we are not helpless in the face of these viral changes. Human behavior is a driving factor in the spread of the virus. Behavior modifications including mask-wearing, isolation, lockdowns, contact tracing, all combined with vaccines and antiviral drugs—something I am call Multimodal “Covid Control”—holds a prospect for effective management of the Covid-19 pandemic.