The quickening pace of COVID-19 vaccine delivery, and a question not answered

Three vaccines have passed Phase 3 tests — that last step before submitting the data to the FDA for an Emergency Use Authorization (EUA). 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 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. Data will come at FDA meetings in December.  

A third vaccine made by Oxford and AstraZeneca, in which the Spike gene is inserted into a crippled adenovirus that normally infects chimpanzees, also works. When injected into humans, Spike protein provokes the immune system to make antibodies and T-cells that provide immunity to SARS-CoV-2 infection. It is not necessary to freeze this vaccine, and plants in India, the UK and the United states are pouring it out in the expectation of a coming EUA.  

A fourth vaccine by Novavax in Maryland is made from Spike protein in insect cells. The Novavax people purify the Spike protein, attach it to a synthetic particle about the size of a virus, and use it as a vaccine. It does not depend on expression of the Spike gene in humans.  The bet on the immunogenicity of the Spike protein seems to be paying off.

These and a number of other clever vaccines produced by the tools of molecular biology should deliver a large amount of vaccine, starting in December and increasing in January, February and beyond.  

And yet, there are mysteries about Covid-19. One that seems productive to think about is why are there such a wide range of symptoms? There are asymptomatic spreaders, there are people with mild disease, there are severely sick people who need oxygen and ventilators, and finally there are people who have had the disease and who recover, but with lingering and exhausting symptoms, the so-called long-haulers. 

Let’s follow the course of an infection and suppose that a person with no underlying conditions just wants to have a drink with friends and goes to a bar where a carrier (not apparently sick) breathes out some droplets of coronavirus, each of which contains thousands of copies of the SARS-Cov-2 virus. Or perhaps a smaller particle is circulating in an aerosol, which can keep the virus in the air for hours. 

Our victim inhales and a bolus of virus escapes from its lipid raft onto the 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 convenient landing site for the Spike protein on the outside of the virus.  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 other cells lining the lung or throat, the alarms of the innate immune system are clanging.  

The innate immune system responds immediately to threats. It does not recognize them specifically as the adaptive parts of the immune system do (T cells and B cells), but it is always on duty and does not require 2 weeks to ramp up. Its receptors (detectors) face out of our cells and sample the environment for viruses, bacteria, fungi or worms, which it can distinguish and signal what is coming to the adaptive immune system (B and T cells). The innate immune system’s police force includes Natural Killers cells, which recognize virus infected host cells and destroy them by blasting holes in the cells’ membranes.  

When the innate immune system recognizes an RNA virus, it activates many genes that produce cytokines, interferon and other proteins that limit viral damage to the host’s cells.  If there is too much induction, the lung’s blood vessels leak and the lung can fill with fluid, as in the case of a cytokine storm. If the innate immune system is functioning, it tends to control early SARS-CoV-2 and other infections. We might infer that the DNA of very sick Covid-19 patients contains mutations in important proteins of the innate immune system and that seems to be the case, at least for some patients. 

The dance between host and virus is complex. Viruses have genes that they can activate as weapons to turn off the host’s immune response. All this feint and jab is circumvented if the human victim has antibodies to the virus, as we hope to have soon. That does not make the innate immune response uninteresting. There may be some systematic way to turn other new viral infections into a milder form of any disease, perhaps by prodding the innate immune system. Covid-19 is not going to be our last pandemic.  

Richard Kessin is Emeritus Professor of Pathology and Cell Biology at Columbia University’s Irving Medical Center. 

He lives in Norfolk. Email him at Richard.Kessin@gmail.com. He will give a course on Covid-19 at The Taconic Learning Center in January.

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