Three vaccines have passed Phase 3 tests, that last step before submitting the data to the FDA for an emergency use authorization. These are the two vaccines, made by Pfizer and by Moderna, both of which consist of an mRNA molecule wrapped in lipid. When injected into muscles, the vaccines produce large amounts of a spike protein that provoke the immune system. Both vaccines provide resistance to natural infection with SARS-CoV-2. There are two caveats: Only a few hundred people have been protected so far; and second, we are relying on a press release rather than data. My guess is that many officials have seen the data, which will become public at FDA meetings in mid-December.
A third vaccine, made by Oxford and AstraZeneca in which the spike gene is inserted into a crippled adenovirus, also works. When injected into humans, this hobbled virus provokes the immune system to make antibodies and T cells that destroy cells in which the virus is copying itself. It is not necessary to freeze this vaccine, and plants in India, the UK and the United States are pouring it out in hope of a coming EUA. It has had what is likely to be a short setback recently.
Novavax has made spike protein in cultured cells. It purified the spike protein, attached to a synthetic particle and used as a vaccine. This vaccine does not depend on expression of genes in humans. It seems to induce lots of antibody and many T cells. The bet on the immunogenicity of the spike protein seems to be paying off in these and other COVID-19 vaccines.
And yet there are mysteries about COVID-19, and in science, mysteries often contain clues. Why is there such a wide range of symptoms? What explains asymptomatic spreaders? Why do some people have mild disease while others are severely sick people and need oxygen and perhaps ventilators? Why do people who have had the disease recover but with lingering and exhausting symptoms (the so-called long-haulers)?
Suppose that a person with no underlying conditions just wants to have a drink and goes to a bar where a carrier (not apparently sick) breathes out droplets of coronavirus, each of which contains thousands of copies of the SARS-CoV-2 virus. Our victim inhales and a bolus of thousands of virus particles that escape from its lipid drop onto mucous membrane cells in the nose, throat or lung. The virus binds to a protein called ACE2, that has a role in controlling blood pressure, but in our case is a landing site for the spike protein on the outside of SARS-CoV-2. The virus is pulled into the cell, unwraps and starts to copy itself. This sounds ominous and it may turn out that way, but in immune cells lining the throat or the lungs, the alarms of the innate immune system are clanging.
The innate immune system is a collection of protective strategies and responds to threats immediately; it does not recognize them specifically as the adaptive immune system does (T cells and antibodies from B cells), but it does not require two weeks to ramp up against a threat like SARS-CoV-2. Its antennae are proteins called Toll-like receptors that face out of immune cells and sample the environment for viruses, bacteria, fungi or other invaders, which they can distinguish. The innate immune system alerts the adaptive immune system about the threat: Is it a bacterium or an RNA virus? It summons defensive cells to the site of the infection and is the source of inflammation, classically defined as redness, heat, swelling and pain. The innate immune system’s police force includes natural killer cells that blast holes in the membranes of virus-producing cells, doing to them what a mine does to the hull of a ship.
When the innate immune system recognizes an RNA virus, it activates many genes that produce interferon, cytokines and other molecules that limit viral damage to the host’s cells. If there is too much induction, a so-called cytokine storm occurs, the lung’s blood vessels leak and the air sacs of the lung fill with fluid and defensive cells. That leaves a mess that one of our medical students described as the remains of a barroom brawl.
If the innate immune system functions properly in the week or two after infection, it tends to limit SARS-CoV-2 and other infections. Not controlling the virus probably leads to growth of virus and severe disease. Could the DNA of very sick COVID-19 patients contain mutations in proteins of the innate immune system? That seems to be the case, at least for some patients. Other patients have antibodies against their own interferon, a critical component of innate immunity, and they also appear to be more vulnerable.
The dance between host and virus is complex. Viruses tend to have genes that they activate as weapons to turn off the host’s immune response (measles is a champ and SARS-CoV-2 has the genes too). All this viral offense can be circumvented if the human victim has antibodies to the virus, such as the new vaccines are producing.
Innate immunity is fascinating because it is not specific to a particular virus or bacterial infection. Is there a systematic way to induce a milder form of disease by prodding the innate immune system? Such knowledge could lead to emergency protections to apply during the months it takes to make a vaccine. We can be sure about this: COVID-19 is not going to be our last pandemic.
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Richard Kessin, Ph.D., is professor emeritus of pathology and cell biology at the Columbia University Irving Medical Center. Reach him at Richard.kessin@gmail.com. He will give a four-session Zoom course on COVID-19 at the Taconic Learning Center beginning Monday, Jan. 18, 2021, from 1 to 3 p.m.
