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A COVID-19 Vaccine - Betting on the Hare or the Tortoise?

There is no question about it. Remarkable progress has been made in developing a number of vaccines against COVID-19 in a very short time. However, while short-cuts can be taken with production methods, there can be no short-cuts when it comes to human testing. 

The race is on! Pharmaceutical companies and assorted academic researchers around the world are engaged in the quest for the current version of the Holy Grail, a vaccine against the SARS-CoV-2 virus that hopefully will restore some degree of normalcy to our lives. Given that no vaccine has ever been produced in less than four years, the challenge is a mighty one. However, with many brilliant minds cooperating in an unprecedented fashion, there is a good chance that at least some of the close to two hundred projects now underway will bear fruit. Just when we will be able to pick that fruit and safely consume it is very difficult to predict unless you are a politician looking for votes.

In theory, designing a vaccine seems quite straight forward, but theory is not the same as practice. The basic idea is to trick the body into mounting an immune reaction against the virus without exposing it to “live” virus. An immune reaction has essentially two components. White blood cells called B cells produce “antibodies,” specific proteins capable of binding to and neutralizing the virus. Another type of white blood cell, the T cell, seeks out and destroys cells that have been infected by a virus. This prevents the virus from replicating inside the cell, spilling out, and infecting other cells.

There are four different technologies that are being actively pursued by vaccine researchers. The simplest idea is to introduce the virus itself into the body, let the body recognize it as a foreign invader, and start producing antibodies and T cells that then stay in the system, ready to swing into action in case of a future attack by the same virus. Of course, this priming of the system has to be done without causing disease through the introduction of a virus capable of reproducing. This requires either inactivating the virus by destroying its genetic machinery with chemicals such as formaldehyde, or “attenuating” it by introducing it into a foreign host such as an embryonated egg or a live animal. In this case, the virus adapts to the host and loses its ability to infect humans. Whether killed or attenuated, the virus retains its surface proteins which are the “antigens” that are recognized by the immune system.

For coronaviruses, those surface proteins take the shape of spikes that the virus uses to attach to receptors on the cells they eventually infect. These receptors are also proteins, known as ACE2 (angioconverting enzyme 2), and attachment to them is a necessary prelude to the virus invading a cell and hijacking its reproductive machinery to produce more viruses. Since the spike protein is what the immune system recognizes as the foreign invader, another possibility for a vaccine is the introduction into the body of just the spike protein detached from the virus. Last January, Chinese researchers published the entire genetic code of the SARS-CoV-2 virus so the genes that code for the spike protein are known. Through genetic engineering, these can be inserted into the genome of cells that can then be grown in the lab. They will crank out the desired protein that can then be used to produce what is called a “subunit protein vaccine.” Many companies are hitching their horse to this wagon.

A third method aims at activating the immune system through exposure to spike protein that is actually produced in the body by cells that have been equipped with the genetic instruction to crank out this protein. The necessary genes are introduced either into DNA or messenger RNA, nucleic acids that can then be delivered by vaccines and taken up by cells. This is the scheme being used both by Moderna and Pfizer and has shown encouraging results with documented production of neutralizing antibodies.

Yet another technique uses “viral vectors” to introduce the genes needed to produce the spike protein. A harmless virus, such as a chimpanzee adenovirus that cannot replicate in humans, has the gene that codes for the spike protein implanted in its genome. When this virus infects human cells, it transfers the gene into the cell’s DNA with the result that the cell starts to churn out the protein that triggers the production of T cells the formation of antibodies. Astra-Zeneca in cooperation with Oxford University is pursuing this approach, but the Phase 3 trials that involve thousands of patients in the U.K. and the U.S. have been temporarily halted due to a significant adverse reaction in one subject. Obviously, vaccine research is a precarious business.

Aside from these major themes, there are other subtle interventions that are being explored. The spike protein actually alters its shape when it attaches to the ACE2 receptor and evidence indicates that it can stimulate antibody production more effectively in its unbound form. This form can be stabilized by incorporating the rigid amino acid proline at appropriate positions in the protein structure. If the gene for this mutated form is introduced into a cell, the spike protein produced provokes a better immune response. Researchers are also looking at which fragment of a spike protein is most likely to be targeted by an antibody and are exploring the possibility of using just this fragment to trigger an antibody reaction.

There is no question that remarkable progress has been made in developing a number of vaccines against COVID-19 in a very short time. However, while short-cuts can be taken with production methods, there can be no short-cuts when it comes to human testing. Different age groups may react differently, pre-existing health conditions may present problems, and there may be rare side effects that are not picked up in small-scale studies. Proper testing for both safety and efficacy takes time. Years, not months. The path to a useful vaccine is lined with curves, pitfalls, and possible dead ends. Let’s remember the fable of the hare and the tortoise. The race is not always to the swift. Slow and steady gets to the finish line first.


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