selection

What does the future hold for SARS-CoV-2? Will it remain in its current configuration, with 20% of infections causing serious damage? Will everyone on Earth need to be vaccinated regularly to prevent infection? Allow me to indulge in some speculation and suggest that SARS-CoV-2 will eventually become the fifth common cold coronavirus (CoV).

There are five CoV that regularly cause mild upper respiratory tract infections in most humans. Called OC43, HKU1, 229E and NL63, they infect children in their first years of live and cause little disease. Immunity wanes within a year and reinfections occur regularly, but with little consequence.

OC43, HKU1, 229E and NL63 were originally viruses that infect bats and rodents. Hundreds of years ago these viruses spilled over into humans and eventually became the viruses we know today. It is likely that the initial emergence of these viruses from bat and rodent reservoirs led to epidemics that were not noticed. There was no medicine or science or public health to record such epidemics, and given the much smaller human population, they likely spread slowly and were not noticed amid the generally poor state of human health.

It is likely that since their emergence hundreds of years ago, OC43, HKU1, 229E and NL63 slowly underwent change and became less pathogenic for humans. I base this assumption on the fact that contemporary spillovers of CoVs have led to serious disease in humans. In 2003, SARS-CoV emerged from bats into humans and caused severe atypical respiratory disease; however we were able to eradicate this virus after only 8000 known human infections. In 2013, MERS-CoV emerged from camels into humans, but this virus has never been able to establish itself in humans. Every small outbreak is, for the most part, the consequence of a new spillover of virus from camels into humans. These short chains of infection eventually terminate.

However in late 2019 SARS-CoV-2 emerged from bats into humans and established itself as a human virus. It transmits very well among humans and because 80% of infections are mild, it spreads silently. The more serious infections that require hospitalization contribute little to transmission of the virus in the human population. Indeed, these seriously ill patients have problems because their own immune response has gone awry. SARS-CoV-2 is no longer their problem.

It seems likely that with time, SARS-CoV-2 will change so that infected patients no longer develop serious disease. This assumption is based on the fact that causing serious disease is absolutely not required for virus transmission. As the virus moves through humans over the years, its genome will slowly accumulate mutations as a consequence of error-prone replication. Some of these mutations will be lethal and cause viral replication to cease. Other mutations will be tolerated, and among these will be changes that alter the viral reproduction cycle so that serious disease no longer occurs in 20% of infected patients. Although viral reproduction in seriously ill patients is very low, it is likely that some virus-mediated event early in infection sets the stage for the later immune dysregulation. I submit that mutations will eventually accumulate in the viral genome that prevent these late sequelae.

There is good reason to think that SARS-CoV-2 will eventually lose the ability to cause serious disease. The main selective force for viral evolution is transmission; little else matters (viruses can be selected to become drug resistant but such events play a minuscule role in the bigger scheme of viral evolution). Put another way, there is simply no selective advantage for the virus to remain pathogenic as this property contributes nothing to transmission. With no selection to maintain pathogenicity, SARS-CoV-2 will eventually become benign. It will become the fifth common cold CoV.

Why does SARS-CoV-2 cause severe disease in 20% of infected people? Recall that the ancestors of this virus originated in bats where have likely circulated for many thousands of years. These viruses became well adapted to their bat hosts, such that they replicated efficiently and were transmitted effectively to new hosts. Their genome had evolved to co-exist with the unusual immune system of bats, which is tuned to deal with the damage caused by high oxygen usage during flight. Then one day late in 2019 one of these viruses encounters a human host. It replicates well in that host but in the face of a very different immune response, problems such as cytokine storms arise. It will be some years before the genome of SARS-CoV-2 changes sufficiently so that it no longer triggers aberrant immune reactions in the human host.

How long it will take before SARS-CoV-2 changes sufficiently to become common cold CoV #5 is unknown. It depends in part on how well the experimental vaccines currently under development work. I suspect that none of these vaccines will completely block viral reproduction, although they may mitigate disease. Consequently SARS-CoV-2 will continue to circulate and the mutations that will eventually reduce its virulence will arise. I do think that at one day in the future we will no longer need any of the SARS-CoV-2 vaccines that are currently in development, because the virus will no longer cause serious disease. For this reason we do not have vaccines against the four common cold CoVs – there is no medical need for them.

To put this another way, here we have a pandemic virus whose emergence could have been stopped had we invested a few billion dollars in development of pan-CoV antiviral drugs. Instead, many companies and governments are spending billions of dollars to develop vaccines that will one day be obsolete. This lack of vision should infuriate every human on Earth.

Pandemic viruses will continue to emerge from animal reservoirs in the coming years. Will we be ready for them? I doubt it.