A Future of Living With COVID-19: Defining the Known Unknowns

As 2022 begins, the world again finds itself wrapped in a heavy blanket of COVID-19, driven by the remarkably infectious Omicron variant. How many times can we go through the same pattern? Individuals are fatigued and confused as overpromises and misunderstandings about the degree of protection from vaccines do not live up to their understandably inaccurate expectations. Acceptance of a future with COVID-19 is settling in. Building strategies that improve quality of life as we live with this viral disease requires addressing the unknowns that still exist after 2 years of COVID-19. It is unclear what a future with endemic SARS-CoV-2 will look like. Will it be seasonal, like many other respiratory viruses? This seems likely, although so far changes in dominant variants have affected infection incidence at least as much as the weather has, so it is difficult to measure. Will SARS-CoV-2 be circulating at the same time as influenza and respiratory syncytial virus?

Variants

Future variants are inevitable, but their impact on society is difficult to predict. The combination of increased transmissibility and immune evasion led to the rapid dominance of Omicron. The plan to vaccinate the world and decrease the amount of mutable circulating virus needs to be scaled rapidly to protect us all.

Long COVID-19

“Long COVID-19” is an enormous unknown. Our diminished ability to control Omicron infection means most individuals will likely be exposed to it, with significant proportions of them becoming infected. Will the somewhat milder course of infection with Omicron, whether innate to the virus or due to partial immunity, attenuate cases of long COVID-19? What is the mechanism of long COVID-19, and can we come to a consensus on its definition? This problem may require resources for many years to come.

Antiviral benefits and pathways to access

A significant step forward in 2022 is the availability of oral antivirals. These therapies, highlighted in this issue of Contagion®, have prevented progression to hospitalization in clinical trials, with nirmatrelvir/ritonavir (Paxlovid) looking particularly promising. However, we know that starting antiviral therapy early in the course of infection is key to its success. How useful will these therapies be in real-world use? When availability improves, will test-to-treat protocols be established that shorten time from symptom development to clinician assessment to prescription to dispensing? Because at-home antigen tests are (intermittently) available, can patients utilize them in clinician-aided self-diagnosis to expedite this process?

Vaccine durability and improvement

Our vaccines had been a home run before Delta and Omicron each took some of the shine from their luster. They are still proving highly effective in preventing hospitalization, but can we improve their ability to prevent transmission? Will changing variants require constantly updated vaccines or can a pan–COVID-19 vaccine be created? And how long are they protective? We have learned much in these 2 years, but understanding COVID-19 is a work in progress. Filling the remaining knowledge deficits starts with identification.