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What’s Up Doc column: What’s the difference between COVID-19 vaccines?

Dr. Jeff Hersh
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Cheboygan Daily Tribune

Columns share an author’s personal perspective.


Q: What’s the difference between the different COVID-19 vaccines?

A: Our immune system, both the innate and adaptive parts of it, is designed to identify and attack “non-self,” that is proteins - whether on the surface of a virus, bacteria, fungi, parasite or other cell, or other protein - called antigens. When these antigens attach to special receptors on certain specialized immune system cells, the body’s immune response is stimulated.

The innate immune system is a nonspecific defense, where immune cells (natural killer cells and phagocytes) identify and then directly destroy invading substances (so this part of the immune system is especially active on the skin and in the gastrointestinal tract).

The adaptive (acquired or learned) system utilizes cells that produce antibodies (certain types of lymphocytes) to tag and destroy invading substances/cells (each antibody is specific for a particular antigen), which are then engulfed by other cells of the immune system (macrophages). The immune system will “remember” this antigen (the length of this memory depends on many things), so the body is prepared to fight off this invader again in the future. The goal is to have these be neutralizing antibodies, which will effectively destroy the invading antigen.

A vaccine works by “presenting” an antigen to the immune system to “prime” it so that it is ready to mount a response to a specific “invader.” For the SARS-CoV-2 virus that causes the COVID-19 disease, the spike protein on the surface of the coronavirus has been a key candidate for an antigen to be used in a vaccine. So, how can the vaccine antigen be “presented” to the immune system?

Inactivated/killed virus vaccine: This approach uses a weakened/attenuated (the target virus is modified so it no longer causes illness) or inactivated (“killed”) virus (the target virus is treated so it can no longer invade cells and reproduce) in the vaccine. After injection, this manipulated virus presents itself (and its surface proteins, etc.) to the immune system. This is the approach used in the yearly flu (because the flu virus mutates rapidly a new vaccine is prepared each year), hepatitis A, inactivated poliovirus, rabies, MMR (Measles/Mumps/Rubella), chickenpox and many other vaccines. The challenge in this approach is to inactivate/kill the virus in a way that still allows the vaccine to stimulate a robust immune response.

Protein-based: This approach uses a specific protein in the vaccine to stimulate the immune system, and is used in the hepatitis B, shingles, human papillomavirus and many other vaccines. This approach can also be used to “prime” the immune system to respond to a disease-causing toxin that is produced by an invading organism (such as with tetanus or diphtheria). The challenge in this approach is to select an appropriate protein that allows the vaccine to stimulate a robust immune response.

mRNA and DNA plasmid-based: In order to understand this approach (a new, novel approach to vaccine development) we need to understand how our cells produce proteins (the workhorses which control and execute the cell’s functions). The DNA in the nucleus of our cells (whether our own DNA or DNA that gets inside the cell’s nucleus by DNA plasmid transfer or even from a virus entering the nucleus) is an instruction set on how to build a protein The code for a specific protein in these instructions is transcribed (copied) to messenger RNA, mRNA, to be carried from the nucleus to the ribosomes (the protein manufacturing site in cells). This information is then translated (read and decoded) so the correct amino acid sequence can be manufactured (and then have some post-manufacturing manipulation done) to create the desired protein. Once the mRNA has done its job, it degrades.

This approach “teaches” some of the body’s own cells to produce a protein (or proteins) that will then prime the body’s immune system. One benefit of this approach is that the mRNA/DNA plasmid can be created simply by knowing the genetic sequence of the pathogenic virus (and figuring out the specific sequence that codes for a protein that would make an appropriate antigen), so the virus does not need to be inactivated/killed nor a specific protein manufactured in the laboratory. However, the specific protein selected must still be one that will stimulate an appropriate immune response. And the specifics of how to transfer the mRNA (the mRNA must be encapsulated in a lipid covered nanoparticle) or DNA plasmid into some of the body’s cells is a fairly new technology (although one that has been successfully used in other therapeutic approaches).

Viral vector: In this approach a modified (so it carries the DNA of an antigenic protein from the target virus), inactivated virus (not the pathogenic target virus) is used to infect some of the body’s cells, getting into the cell’s nucleus but NOT integrating into the patient’s own DNA, to utilize the normal cell protein manufacturing apparatus (as described above) to create a desired protein to stimulate the immune system. The virus vector selected is one that most patients will not have been exposed to in the past, so their immune system does not respond to the viral vector itself. Conceptually this is similar to the mRNA/plasmid DNA approach above, except the cells are being used to produce an appropriate antigenic protein with the instructions transferred by the modified virus. Although this is also a fairly new approach for a vaccine, this technological approach has been used for a couple of decades in other therapeutic treatments.

All four of these approaches are being pursued to develop a vaccine for SARS-CoV-2. Since only the genetic sequence of the pathogen virus is needed to begin development of the mRNA/DNA and viral vector approaches, it is not surprising that these are the approaches furthest along in the development process, specifically the clinical trials utilized to verify that the vaccine is safe and effective.

Bottom line: a safe and effective vaccine is likely to be approved very soon. When that happens, I urge everyone to get vaccinated as soon as it is available for them. That is clearly the pathway to get us out of this pandemic and back to a more normal situation.

Jeff Hersh, Ph.D., M.D., can be reached at