“The opportunity to secure ourselves against defeat lies in our own hands, but the opportunity of defeating the enemy is provided by the enemy himself.”
- Sun Tzu, The Art of War
We are barely four months into the COVID-19 pandemic that erupted in Wuhan, China, and the analogy that fits the battle against SARS-CoV-2, the cause of COVID-19, is that of a global war. Perhaps because I spent almost all of my professional career studying various aspects of host defenses, the analogy seems apt. Therefore, an effective strategy to defeat this wily enemy depends on understanding not only the virus and how it operates but also our troops…cells of our immune system and how they defend us.
The nature of the enemy. Coronaviruses are named for the crown-like spikes on their envelope surface. Results of recent studies of of the spike protein (S) of SARS-CoV-2 are guiding both drug and vaccine development.
Coronaviruses have the longest genome of any of the RNA viruses—a single strand of nucleic acid that is roughly 26, 000 to 32,000 bases. The RNA of SARS-CoV-2 is also a target for vaccine development, and it is being monitored carefully for mutations as the virus sweeps the world. (While DNA-containing viruses cause their share of human infections, viruses that have RNA genomes have captured almost all of the attention as causes of emerging infections—not only three virulent coronaviruses, but also HIV/AIDS, Ebola, West Nile fever, dengue, and Zika, to name just a few.)
Other coronavirus enemies. Knowledge of the strategies of other coronaviruses that infect humans is a crucial element in understanding the behavior of SARS-CoV-2. While hundreds of types of coronaviruses have been known since the 1950s to circulate in animals, human coronaviruses were only identified in the mid-1960s. Of the seven human coronaviruses, several cause the “common cold.” But, it wasn’t until November 2002 when SARS-CoV, the etiology of severe acute respiratory syndrome (SARS), emerged that infectious diseases clinicians took coronaviruses seriously.
Fortunately, that pandemic, which also emerged in China, abruptly ended in July 2003, after it racked up a relatively small number of illnesses (8,098) and deaths (774). Civets (small cat-like mammals) were found to be an intermediate host for SARS-CoV; they were culled early on from wild animal markets in China. The primary reservoir of the virus, however, was subsequently found to be the Chinese horseshoe bat. (At that time, Chinese researchers also reported, rather eerily, that this bat species harbored several additional similar coronaviruses).
It didn’t take long for the next highly pathogenic coronavirus to strike humans—this time in April 2012 when Middle East Respiratory Syndrome (MERS) was first identified in Saudi Arabia. Subsequently, MERS spread throughout the Middle East. By the end of January 2020, MERS had spread to 27 countries, afflicted 2,519 people, and killed 866. Perhaps unsurprisingly, camels were identified as an intermediate host of MERS-CoV, but again bats seem to be the primary animal reservoir.
Enter SARS-CoV-2 (COVID-19). Our current enemy, SARS-CoV-2 was discovered and its genome sequenced by Chinese researchers within a month of its emergence in Wuhan, in the vicinity of a wild animal market. (Knowledge of its genome led to rapid development of a diagnostic test that plays a pivotal role in understanding who’s infected and who’s transmitting the virus.) As its name suggests, the genome of SARS-CoV-2 is most similar to SARS-CoV (about 80% identity), and its genome is 96% identical to bat coronavirus BATCoV. Although still unproven, pangolins, the most widely trafficked non-human mammal in the world, may be an intermediate host for SARS-CoV-2. Thus like a majority of emerging pathogens in the past 50 years, all three of these virulent coronaviruses are zoonotic—they somehow spilled over from animals (bats) to humans.
Bats: A Trojan Horse. By now, you’re probably wondering, what’s the deal with bats? While bats are absolutely marvelous creatures that, among other things, contribute several billion dollars a year to the agriculture economy, they harbor more than 60 human-infecting viruses. Yet, they don’t get sick because they’ve evolved several defense mechanisms against these viruses. An increased body temperature during night-time flight, related to an increased metabolism, may be one such tactic—some viruses just can’t stand the heat.
It is becoming increasingly clear, however, that it is the bat’s revved up immune system that protects them. Sadly, this also appears to play a role in their generating viruses that when spilled over to humans cause such havoc. As you would likely imagine, studies of the bat’s immune system and related matters are under intensive investigation in several prominent research laboratories.
The war against SARS-CoV-2. SARS-CoV, MERS-CoV, and SAR-CoV-2 are all highly virulent coronaviruses. But, perhaps surprisingly, SARS-CoV-2 is the least lethal. In a March 27 publication in the Lancet (“The many estimates of the COVID-19 case fatality rate”), it was suggested that the case fatality rate (CFR) of COVID-19 is about 1.0%, which is considerably lower than reported with SARS (CFR 9.5%) and MERS (CFR 34.4%). (What this also means is that on average, 99% of people infected with SARS-CoV-2 don’t die of their infection.)
All three of these highly virulent coronaviruses behave similarly in finding their way to us, their target. Transmission between humans is primarily by respiratory droplets generated through coughing and sneezing. And once these viruses arrive, they can cause great damage to the respiratory tract of some of the humans they infect. But SAR-CoV-2 appears to have additional “tricks” up its sleeve that may help explain why it has spread so widely, so quickly. And multiple studies are underway to come up with this explanation.
It is already known that SARS-CoV-2 has a relatively prolonged incubation period (the period of time between contracting the virus and developing symptoms)—about 5 days. Preliminary studies suggest that the incubation periods of SARS-CoV and MERS-CoV are similar to that of SARS-CoV-2, so this factor alone doesn’t explain why we’re in a global war against SARS-CoV-2.
We also know, that when humans are incubating this virus, they can transmit it to others. SARS-CoV-2 also appears to causes a disproportionately large number of asymptomatic infections—some studies suggest that up to half of people don’t get sick when infected. But these asymptomatic carriers can transmit the virus to unwitting contacts. Thus, it is extremely important that we all stay at home and practice social distancing.
It appears that in addition to being spread by respiratory droplets, SARS-CoV-2 can also be transmitted through contact with contaminated surfaces. A study published on March 17 in the New England Journal of Medicine showed that while the virus could infect people by aerosols for at least three hours, when it was on plastic or stainless steel it remained viable for more than 3 days. (On cardboard and copper it didn’t fare as well.) Because these characteristics were similar for SARS-CoV, however, the authors of the study suggested other factors must explain the widespread transmission of SARS-CoV-2—perhaps its high rate of transmission by asymptomatic people.
This virus has also been detected in stools of infected people. This finding caused the Federal Drug Administration to warn that SARS-CoV-2 could be transmitted via fecal microbiota transplants. But there is little, if any, evidence supporting fecal-oral transmission. (And the paucity of gastrointestinal symptoms of COVID-19 patients should deter the berserk run on toilet paper experienced recently in the United States.)
Another interesting aspect of SARS-CoV-2 transmission is that some infected people are “super-spreaders.” That is, about 1 in 5 people transmit far more virus than the majority. This phenomenon, called the “20/80 rule,” was also seen in the SARS pandemic. (Some readers may have heard of “Typhoid Mary,” an asymptomatic cook for wealthy New York families in the early 20th century, who transmitted the bacterium that causes typhoid fever to an estimated 51 individuals.) The underlying mechanism behind superspreading SARS-CoV-2, however, remains unknown.
By now, you may have heard of what is called the basic reproduction number or Ro. The formal definition of a disease’s Ro is the number of cases, on average, that an infected person will cause during their incubation period. This a measure of just how contagious a pathogen is. Researchers in the Imperial College group have estimated the Ro of SARS-CoV-2 to be somewhere between 1.5 and 3.5. This means that each infection from the virus is expected to result in 1.5 and 3.5 infections when no members of the community are immune and no preventive measures are taken. This reproduction number is somewhat higher than that of seasonal flu (Ro 1.28), but nowhere near that of the most contagious virus of all—the measles virus (Ro between 12-18).
Our troops (the immune system). While the human body is equipped with a number of defense systems against foreign invaders, including the skin and mucous membranes of various body sites and a microbiome (comprised of many trillions of microbes that share our body surfaces), it is the immune system that we lean on most heavily to keep us safe from enemies, like SARS-CoV-2. Studies of the immune response to this novel, as in “never seen before by the human immune system,” coronavirus are in an early stage of discovery. Nonetheless, much can be anticipated from what’s been seen before with similar pathogens.
In a seriously overly-simplistic view of the immune system, we have troops that are immediately battle-ready (referred to as innate immunity)—comprised of natural killer cells and phagocytic cells (neutrophils and macrophages). But it is another group of warriors (referred to as cell-mediated immunity), made up of T and B lymphocytes, that confer immunity. Once they’ve experienced an enemy, they never forget it (they’ve developed memory), and if confronted again, they are immediately called into action, that is, the host is now “immune.”
As discussed earlier, a majority of people don’t get sick when they become infected with SARS-CoV-2. These are the lucky ones (for them, but not for others since they are able to transmit the virus for some time after infection). It appears that asymptomatic people are equipped with robust innate immunity, and it is hypothesized that once they have been infected they are immune to re-infection.
Most people with symptomatic SARS-CoV-2 infections develop a fever as their immune system fights to clear the virus. (Generally “fever is your friend” because many microbes can’t stand the heat, and some cells of the immune system are more efficient at an elevated body temperature.)
Waning of the immune system associated with aging (referred to as immunosenescence) seems to explain, at least in part, why elderly people are at an increased risk of serious disease. (The CFR of people over 80 is about 13.4%.) While comorbid (coexisting) medical conditions dramatically increase mortality in some of the elderly victims of SARS-CoV-2, there is emerging evidence that an age-related decline in the number or capacity of some of our troops (T and B lymphocytes) plays a role. While a blunted immune response may be involved in the development of more severe infections, an overly robust immune response (referred to as a cytokine storm) plays a role in tissue damage, such as in the lungs of people who develop acute respiratory distress syndrome (ARDS), a complication that requires respiratory support and is commonly fatal. Whether elderly people have dysregulated cytokine production, however, is unknown.
This brief overview of the immune system may help explain herd immunity, a term borrowed from veterinary medicine, that is referred to as community immunity in human medicine. Once a sufficient number of people in a community (or country) have developed immunity, the virus no longer finds a welcome home. And at that point people can carry on with a normal lifestyle. (In the case of measles, which is extraordinarily contagious, experts suggest that about 95% of people in a given community need to be immune to prevent spread. Fortunately, a highly effective vaccine is available that can, if used properly, accomplish the task.)
A key goal of immunization is to increase herd immunity by vaccination with an attenuated virus or a component of SARS-CoV-2. The good news is that a number of research projects are already underway to develop a vaccine. The first to go into a clinical trial of safety was launched by the company Moderna in Seattle on March 16. It is testing a vaccine comprised of viral RNA. Many estimate, however, that if the trial is proved successful it will take at least a year before a vaccine is available for large-scale clinical trials.
Finally, this brief overview of the immune system may also help explain the basis of a treatment trial using human plasma from infected patients who have recovered. This plasma contains antibodies produced by B lymphocytes that should neutralize SARS-CoV-2. On March 27, an uncontrolled treatment trial of five critically ill patients with ARDS with plasma from convalescent patients was reported in the Journal of American Medical Association. Encouragingly, the clinical condition of all five patients improved.
Also, because antibodies to SARS-CoV-2 indicate that a person is immune to infection, assays that measure them in blood serum samples are potentially useful in decisions about who won’t transmit the virus and who can return to work.
Strategy. In my opinion, the strategy proposed by both the National Institute of Allergy and Infectious Diseases (NIAID) and the Center for Disease Control and Prevention (CDC) makes sense—social distancing, rigorous attention to covering coughs and handwashing, disinfecting potentially contaminated surfaces, surgical masks for those who are sick, as well as N95 respirators for healthcare workers who are exposed to infected patients. This strategy has been adopted by most, if not all, states. It is also clear to me that to win this war, all leaders in public health, medicine, and the scientific community, as well as in governments, both here and abroad need to be on the same page for this strategy to work.
And, all of us need to be on board. At the same time that we are social distancing, we need to work together to defeat this enemy. We are all in the army now!
