This is the first article in a 15-part series called “Relevance of Immune Suppression by SARS-CoV-2 to Understanding and Controlling the Covid-19 Pandemic,” which will explore an under-appreciated but highly significant aspect of SARS-CoV-2 replication. The ability of SARS-CoV-2 to delay, evade, and suppress the immune system has myriad implications for drugs, vaccines, and other aspects of our pandemic response. The first set of pieces in this series are intended for a general audience; the second set, for the medical community; and the third and final set, for biomedical researchers looking for a deeper understanding of variants, how they’re generated, and what we might do to control them.

Macavity’s a Mystery Cat: he’s called the Hidden Paw—

For he’s the master criminal who can defy the Law.

He’s the bafflement of Scotland Yard, the Flying Squad’s despair:

For when they reach the scene of crime—Macavity’s not there!

T.S. Eliot, The Naming of Cats (1939)

I write this series to celebrate the power of the science and medicine that provide us with deep insight into the nature of the virus that causes Covid-19 and the vaccines and drugs that prevent and treat the disease. But I also write this as a warning not to underestimate our adversary. 

Anyone who has engaged in hand to hand combat—for that is what it feels like—with cancer, AIDS, or any of the other great diseases of our time knows how formidable our foe is. Evolution, the same force that gifted us with the intelligence to understand our world, has crafted diseases of great subtlety that seem to slip through our grasp just as we think we have a firm grip. Yes, we have had success in developing Covid-19 vaccines, and new and effective treatments appear to be just around the corner. Yet at the same time, a chill wind of doubt disturbs our optimism, as viral variants begin to break through our vaccines and sicken and even kill a small fraction of those who seek protection.

This is the third major pandemic of my lifetime. I remember polio and all the forbidden summer activities—swimming in public pools, playing with more than two other friends, or enjoying the latest serials in the cool, dark movie theaters I loved. No doubt similar to what today’s children will remember of the restrictions around Covid-19. As a young Harvard researcher working on cancer and AIDS, I remember the War on Cancer and our hopes that we would vanquish the disease in a few short years or, conservatively, a decade or two at most. I remember the HIV epidemic, first for the sluggish reaction of our public health officials and leaders, then for the rapid science advances that led to a deep understanding of the virus and drugs to prevent and treat the disease. With some sadness, I see our dashed hopes for an early vaccine to end the pandemic and now, forty years and 35 million deaths later, see that HIV/AIDS lingers on with a million or more people dying each year.  

I have seen too many premature announcements of victory over disease that I hesitate to declare our imminent success in controlling Covid-19. I remain confident that a return to normal life can and will be the end result, but only if we remain dedicated to using the full power of our science, medicine, public health, and international organizations to understand and control SARS-CoV-2.

How do we understand what has happened? How and why SARS-CoV-2 infects so many, why it causes severe disease in some yet affects most others only mildly, how it confounds natural immunity, and what is behind the variants? It is a tale of stealth and disguise worthy of any great mystery novel. Each revelation offers not just insight into our collective experience but new hope that we might prevail against this most dangerous pathogen. 

First and foremost, SARS-CoV-2 is a master at evading both the defenses of an infected cell and the entire immune system. The primary story, perhaps paradoxically, is one of immune suppression—not hyper-activation, which is seen so strikingly in those who fall seriously ill. To establish infection all viruses must first defeat the body’s well-honed defenses. SARS-CoV-2, as we shall see, has proved exceptional at this task. Early on, the virus acts at multiple levels to counteract innate immunity, the first line of defense against microbial invaders, allowing enough time for the virus to enter and exit before the full set of antiviral defenses can mobilize.

Upon entry into a susceptible cell, the virus conceals its presence by creating a privileged subcellular organelle in which it replicates unseen by intracellular alarms and by camouflaging its messenger RNAs to resemble those of cellular RNAs. In addition, SARS-CoV-2 carries an impressive arsenal of proteins that actively suppress both the induction of interferon, the primary trigger of innate and adaptive immunity, and of interferon-induced genes and proteins. This early immune suppression may account for the generally weak antibody response in those infected, facilitating reinfection within months by variants that produce key neutralization epitopes.  

The second element of this tale is the puzzling pathogenesis of the virus. The peak of viral replication occurs before the onset of symptoms—meaning even mild symptoms occur only after the virus is on the wane. Perturbation of our initial immune defenses may be largely responsible for the violent reaction that seems to cause the most severe consequences of Covid-19.

Last but not least is the capacity SARS-CoV-2 has for evolution. SARS-CoV-2 is protean, capable of changing its exterior to re-enter previously infected hosts. New variants of SARS-CoV-2 have proven strikingly more infectious than the original strain, both because of spike proteins that enhance binding affinity and evade antibody detection, and because some variants are more potent in repressing innate immunity.

Troubling though these strategies to circumvent innate immunity may be, they offer exciting opportunities for prevention and treatment. The first bit of good news is that vaccines circumvent most viral defenses, inducing a much more robust and durable antiviral immune response than infection itself. The second piece of good news is discovery of new drugs that can overcome virus immune suppression. We can and will defeat Covid-19 by combining good public health practices with effective vaccines and new generations of antiviral drugs.