“The only true wisdom is in knowing you know nothing.”
“The greatest of all the accomplishments of 20th century science has been the discovery of human ignorance.”
- Lewis Thomas, M.D., American physician, researcher, and poet
Recently, yet another SARS-CoV-2 variant emerged. The Omicron subvariant BA.2 (nicknamed “the stealth variant”), is unleashing more uncertainties about the course of this pandemic. In this Germ Gems post I provide an accounting both of what we do and don’t know about COVID-19. As you will see, we have come a long way but still have a lot to learn.
The known unknowns. First, a bit about Epistemology—a branch of philosophy devoted to the study of the nature, origin and limits of human knowledge. The word is derived from the Greek episteme (“knowledge”) and logos (“reason”).
Perhaps some of you are familiar with former Secretary of Defense Donald Rumsfeld’s famous take on epistemology: “There are known knowns, things we know we know, and there are known unknowns, things that we know we don’t know. But there are also unknown unknowns, things we do not know we don’t know.” Apparently, in Secretary Rumsfeld’s view, the “unknown unknowns” are the ones that can really wreak havoc.
Within the context of this Germ Gems post on the uncertainties of COVID-19, I’d like to add that there are both epistemic uncertainties (those that can be eliminated with more knowledge) and aleatory uncertainties (those that are never knowable). For me, the latter category of uncertainties is the most formidable.
What are the COVID-19 known unknowns? Here is a short list that immediately comes to my mind:
Where did the pandemic start (a “natural” infection, that is, a spillover of SARS-CoV-2 from a wild animal in a wet market in Wuhan, vs a manipulated virus in the Wuhan Institute of Virology)?;
Will new variants of SARS-CoV-2 ever stop emerging (while writing this Germ Gem post, two new subvariants, BA2.1 and BA2.2, and a recombinant virus XE debuted)?;
Will white-tailed deer infected with SARS-CoV-2 become a major zoonotic reservoir?;
Will the current vaccines protect against the Omicron subvariants?;
Why do some people seem to never get infected, and why is it that infection is asymptomatic in most people?;
Why does immunity after an infection or post-vaccination wane?;
How important are T cells in the immune response to SARS-CoV-2?
Many of these known unknowns represent epistemic uncertainties, that is, as I mentioned earlier, they can be eliminated with more knowledge. We might question, however, whether any, or perhaps all of them are aleatory uncertainties, that is, they’re inherently unknowable. Let’s hope not.
The known knowns. Thanks to the work of a multitude of talented and dedicated researchers, we have learned an extraordinary amount about SARS-CoV-2 in a relatively short period of time. Here is a brief summary of what we now know.
The Pathobiology of SARS-CoV-2. Within the first two months of the emergence of the COVID-19 pandemic in late 2019, researchers identified the nature of SARS-CoV-2, the RNA virus that causes COVID-19. Scientists also discovered that the binding of SARS-CoV-2’s spike protein to ACE2 receptors on cells throughout the body played a pivotal role in pathogenesis of the disease.
Early on, scientists also determined the importance of emergence of genetic variants of the SARS-CoV-2’s spike protein. This phenomenon wasn’t surprising given that RNA viruses are infamous for mutating quickly to serve their own ends (that is, to avoid recognition by cells of the immune system).
SARS-CoV-2 is constantly evolving. Over the past two years, genetic variants in SARS-CoV-2’s spike protein continuously cropped up precipitating a dizzying series of waves, surges, and upticks of infection. In many cases, the genetic changes of these variants conferred increased infectivity and transmissibility of the virus and in some instances increased viral virulence. These mutations were designated Variants of Concern (VOC). To refresh your memory, here is a list of the VOC to date:
In the past few months, the highly contagious Omicron BA.2 (stealth) subvariant has emerged as the primary VOC. In early 2022, BA.2 swept across regions in the Far East, such as, China, Hong Kong, New Zealand, and South Korea—countries that previously prided themselves on their excellent containment of the pandemic. By early April, BA.2 was responsible for about 90% of COVID-19 cases in the U.S. and it is now causing mounting concern throughout the nation.
Immunology of COVID-19. When pandemics take off, it is often difficult to determine who’s holding the steering wheel—the pathogen or the host’s immune system. In the case of COVID-19, a bevy of immunologists throughout the world jumped at the chance to decipher the contribution of various components of the immune system to the body’s defense against SARS-CoV-2. They found that both antibodies and T cells are involved, and they also discovered that an overactive immune system, generated largely by activated monocytes and macrophages, produced a “cytokine storm” that caused collateral tissue damage.
Epidemiology of COVID-19. Epidemiology is defined as the study of the distribution and determinants (causes, risk factors) of health-related conditions in specified populations (neighborhood, school, city, state, country, global). The COVID-19 pandemic has engaged an untold number of epidemiologists around the world working within government and academic institutions. Their advice about who’s at risk of COVID-19 and who should be vaccinated is generally followed by most public health officials and medical professionals. As with all aspects of knowledge about COVID-19, however, what we know changes. (For an excellent overview, I highly recommend the article, “The changing epidemiology of SARS-CoV-2,” in Science in March 2022).
Prevention and Treatment of COVID-19. What we know about how to prevent and treat SARS-CoV-2 infections have been subjects of a voluminous literature, some of which I featured in my previous Germ Gems posts. The COVID-19 vaccine story is perhaps the most thrilling scientific and logistical achievement of the pandemic. Although less exciting, important measures to prevent SARS-CoV-2 infection, such as, wearing a mask and social distancing, are known to help prevent COVID-19. These practices, along with getting vaccinated and boosted, are also recommended in preventing Omicron BA.2 infections.
Much scientific “know-how” also has gone into the production of effective drugs to treat COVID-19. Currently, the main drugs for outpatient therapy, aimed at preventing progression of mild or moderate disease, are: Pavlovix, Molnupavir, and the monoclonal antibody preparation, Evusheld. And, more drugs are in the pipeline.
Will herd immunity play a role? From the outset, many research groups were interested in knowing what role “herd immunity” would play in protection against infection. The central idea here is that as a virus sweeps through a community, more and more people become infected and develop immunity, either “naturally” or, when available, by vaccination. At some point the number of protected (immune) people reaches a high enough level that the whole community (the “herd”) is benefitted.
The public health strategies of some countries, such as Sweden in 2020 and most recently, Iceland, have been predicated on this concept. In fact, as of late March, Iceland dropped all of its COVID-19 restrictions relying instead on herd immunity to end the pandemic. (It should be noted, however, that Iceland has a heavily COVID-19 vaccinated population and that this fact played a significant role in that country’s decision to drop restrictions.)
In a March, 2022 Journal of Infectious Diseases article, “The Concept of Classical Herd Immunity May Not Apply to COVID-19,” Anthony Fauci and his colleagues at the National Institute of Allergy and Infectious Diseases suggest that SARS-CoV-2 is so different from polio and measles (two viral infections in which herd immunity has been achieved) that such classical herd immunity may not apply to it. It therefore remains to be seen what role herd immunity will play in ending this pandemic.
It’s still a pandemic. By definition the worldwide distribution of SARS-CoV-2 infections is a pandemic (impacting all countries and territories on Earth). In the past several months, increased attention has focused on the so-called “new normal” phase of life when SARS-CoV-2 settles down and becomes an endemic infection—an infection in a population that is constantly maintained at a baseline level in a geographic area. Influenza is perhaps the most relevant example of an endemic infection. Only time will tell when COVID-19 will be endemic rather than pandemic or what endemic COVID-19 will look like. (My February 16, 2022 Germ Gems post, “COVID-19 and the ‘New Normal’: Are We There Yet?,” provides my perspective on this burning issue.)
It’s been a humbling experience. Within my 45 plus-years as an infectious diseases specialist, I’ve never read as many articles and books about previous pandemics for guidance about how to deal with the COVID-19 pandemic as I have in the past two years. One of the most recent articles was Gina Kolata’s publication in the New York Times titled “Past Pandemics Remind Us Covid Will Be an Era, Not a Crisis That Fades.” In it, Kolata concludes, “If nothing else, the Covid-19 virus has humbled experts who once confidently predicted its course, disregarding the lessons of history.”
Although dealing with the SARS-CoV-2 virus has indeed been a humbling experience for all of us in the scientific community, it has also provided us with enormous opportunities for discovery. And the joy of discovering new knowledge about the natural world or, in the case of medicine, of the disordered body, is one of the things that drives most scientists and clinical investigators. But science also requires an ongoing admission of ignorance—especially about the prognosis of a disease or ailment.
We must face the fact that nobody can predict the future of the COVID-19 pandemic. As professed by the 6th century BCE Chinese scholar, Lao Tzu, “Those who have knowledge don’t predict. Those who predict don’t have knowledge.” It is something for all of us to remember as we continue to live with the uncertainties of this pandemic.