BLACK MEDICINE IN PHILADELPHIA

COVID19 - What We Know so far

(William King, MD, MSEP-Vice President, worked in molecular biology labs at NIH, Stanford and Duke before becoming a general pediatrician...this summary is simplified from public academic and government sources

COVID19: it's nothing personal. It's a virus. (William F. King, MD, FAAP Vice President, Medical Society of Eastern PA)

COVID19 CORONA VIRUS-DISEASE 2019 (2019-nCoV) THE NOVEL (NEW) CORONA VIRUS AND YEAR IDENTIFIED



Most virus researchers believe this virus emerged when a natural coronavirus that lived in other mammals (bats, weasels, and pangolins (looks like an armadillo)), may have spread to other animals, but then spread to humans in or around Wuhan, China.  This is the third time a new coronavirus transferred to humans (SARS in 2003, MERS in 2012, now Covid19) in the past 20 years.  In addition to these epidemic coronaviruses, humans pass around human coronavirus strains. which are one of the viruses that cause the common cold (rhinovirus, adenovirus and parainfluenza are the other viruses).  All viruses are typically adapted to one species, but each time they infect they can mutate when they are copied incorrectly.  These random changes sometimes allow their proteins to change and better infect their host, or very rarely a new host.  This happens commonly with influenza, we believe this happened with HIV, and it has happened with Covid19.  When a virus typically carried by bats adapted to be able to infect human cells.  



HOW DOES THE COVID19 VIRUS WORK

The coronavirus is covered with a glycoprotein called the spike protein.   The spike proteins are the red knobby proteins that allow the covid19 virus to attach to human cells and begin invading them. The virus attaches, is taken up into our cells like a trojan horse, and takes over the cell’s genetic machinery to instruct the cell, like a village taken over by pirates, to make millions of copies of the viruses-dozens of different proteins and genes.  These copies assemble into millions of new virus particles that burst out of the now destroyed “zombie” cell, and infect new cells, first in the nose, then deeper in the respiratory system, then throughout the body.  The body mounts a defense within 3-4 days, but by then the battle is a race between the “shock and awe” attack of the full immune system and the billions of shock troops of the virus particles.  The human body usually has the reserves to overcome the destruction in the respiratory system, but Covid19 can also cause damage to the circulatory system, kidneys, and brain.  Inflammation from the battle appears to cause damage in any of these systems, but a severe viral pneumonia is often fatal.  


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The vaccines each present the spike protein to the human immune system.  The cells of the immune system (mainly B-cells and T-cells), patrol the tissues of the body and mark any foreign proteins with their own specialized antibodies.  These specialized immune cells and their antibodies are created in 3-4 days, and allow our immune system to immediately identify this foreign protein when it enters our body again, These unique proteins and the cells that recognize them now circulate through our body and provide immunity to the newly identified germ.  We have to generate immunity to each new germ, either by surviving a possibly deadly infection, or through vaccination. 



The genetic sequence for the novel coronavirus was identified in china and when it was released in February, scientists immediately began making vaccines that used the genetic sequence in 3 ways.



CURRENT NORTH AMERICA COVID19 VACCINES - COMPONENT VACCINES


Do not contain or use the Covid19 virus, instead they use 3 different gene techniques to present the spike protein to the immune system.

#1 mRNA Vaccines (Moderna, Pfizer/BioNTech)

The first vaccines to be approved for emergency use authorization use a technique that has been under development since the 1970’s, but had not been utilized for vaccination, primarily due to the very expensive development and manufacturing costs, however the pandemic gave this technology the green light.


Infographic GRAPHIC: V. ALTOUNIAN/SCIENCE


The gene for the spike protein is coded in mRNA.  The vaccine makers use sequencing machines to chemically “type out” the sequence for the spike protein, genetic letter by letter, using no cells or viruses.  This “master copy”  is copied as loops of DNA plasmids and grown in bacteria to make billions of DNA copies of the spike protein gene.  These DNA loops are translated back into mRNA in a process that uses biochemistry to make the pure mRNA strands.  The mRNA is coated in a bubble of fat that lets it get into our cells after injection.  In our cell the mRNA does not go into our nucleus (where our DNA is secured), but instructs those cells to make the Covid spike protein, but no other part of the covid19 virus.  Since mRNA vaccines don’t have any of the other genes or parts of viruses, they do not cause an infection or contain any viruses or live cells, then only stimulate our immune system to recognize the spike protein and develop an immune response. 

These mRNA are very simple in their ingredients, no live cells, but are very fragile, the fat bubbles with the mRNA have to be stored frozen, and fall apart in less than a day once defrosted.  

#2 Viral Vector DNA Vaccines (Johnson&Johnson, AstraZeneca)



Instead of using a non-living fat bubble to carry the instructions for the spike protein, Viral vector vaccines use another virus to deliver instructions as DNA.  J&J uses a cold virus adenovirus that has been inactivated to not be able to grow.  AstraZeneca uses an inactivated chimpanzee adenovirus to deliver the DNA.  This technology is more complicated to develop, but is less expensive to manufacture and store, since viruses are naturally able to tolerate less gentle handling, so these vaccines are able to be stored in a refrigerator.   Although easy to store, these vaccines appear to have more unpredictable side effects, since there is the desired immunity to the spike protein, and the less predictable interaction of immunity or reaction to the whole adenovirus that carries the coronavirus spike protein.  

Hyperactive' platelets behind mysterious blood clotting in COVID-19 patients | NHLBI, NIH

The AstraZeneca viral vector appears to cause a rare blood clotting reaction in about 10 in 1 million doses.  The J&J viral vector also appears to cause a similar blood clotting reaction about 1 in 1 million doses.  The reaction of the immune system to the covid19 spike protein (1 gene coding 1 protein) and the adenovirus that carries it (38 genes for 50 proteins) is more unpredictable.

The blood clotting reaction appears to occur when the adenovirus vector vaccines generate an immune system reaction creating an antibody against the patients own platelets.  As you remember, platelets are a part of our blood clotting system, to help stop bleeding after injury.  This vaccine triggered reaction leads to low platelet counts and appears to cause the platelets to stick together more, generating blood clots, particularly in the vessels of the brain.  

This platelet autoantibody blood clotting reaction is similar to another rare reaction of patients taking the blood thinner, Heparin (Warfarin), who develop an anti-heparin antibody, which causes more blood clots instead of thinning.  Therefore it is very important to know that a patient who received the J&J or AstraZeneca vaccine and is thought to be having blood clots NOT receive Heparin (warfarin).


#3  Protein subunit - Nanoparticle vaccine (Novavax)

The Novavax vaccine does not use genetic material to instruct our cells to make the spike protein like the mRNA vaccines (Pfizer or Moderna) or DNA delivered by a viral vector (J&J or AstraZeneca or the Russian Sputnik V).  The Novavax vaccine is more traditional, by making the protein itself to show the immune system the Spike Protein.  


This approach is one of the oldest ways of making a vaccine, similar to the tetanus shot, hepatitis vaccines or many others.  The Spike protein is engineered and then grown in a lab by cells from a silkworm cousin, actually an army moth.  The army moth cells are engineered to make spike protein instead of silk protein.  These spike proteins are not attached to a live virus, but presented by being attached to a nananoparticle, made of lipids (a fat droplet, this time with spike proteins on the outside, instead of mRNA on the inside).  They add another compound, called an adjuvant, this compound, saponin, is plant-based (from a tree bark), the adjuvant activates the immune system better.  These fat-droplet attached spike proteins and saponin, are stable at refrigerator temperatures, and make up the Novavax spike protein nanoparticle vaccine.  

Making vaccines from the protein of an infectious germ is a very traditional way of making a vaccine.  Unfortunately, when producing any protein, such as cheese or soy protein, it takes extra time to work out the details of growing the protein to manufacture the vaccine.  Novavax is currently seeking the emergency authorization for use, but the clinical studies show it to be highly effective, above 90% with two doses, and it can be stored with normal refrigeration.  These protein subunit vaccines, once the manufacturing is worked out, are often less expensive to produce and store than the more technological mRNA vaccines.  Protein vaccines like Novaxax’s, shouldn’t have the safety issues of the viral vector vaccines, but will take time to reach the 100 millions of doses safety record of the proven mRNA vaccines by Pfizer and Moderna.  We’ll update you when we all have more data.  


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