COVID-19: Vaccine. What's the Deal?

Sep 29, 2020

I was spending a little time on Facebook, as one is wont to do, and one of my friends posted that the Johnson and Johnson vaccine was progressing and she was eager to get that one. As is typical of Facebook, there were reactions. “Never!” “Wouldn’t put that in my body!” “Would rather die!”

So, what’s the deal?

Let’s start at the beginning. Back in the last century people were dying or suffering severe complications from infectious diseases. Polio (paralysis, death). Cholera (diarrhea, death). Mumps (infertility). Whooping cough (cough, death). Tuberculosis (pneumonia, death) and many others. The century before that was ravaged by smallpox, a disease that caused a rash like chicken pox but much more deadly. In 1798(!) the first vaccine against smallpox was developed by Edward Jenner, and in 1980 – almost 200 years later! – the disease was considered eradicated from Earth.

Once we learned the root cause of infectious diseases – microscopic bacteria and viruses – we started to fix them through public health measures and individual treatments. Sanitation and water purification helped with cholera. Antibiotics helped with tuberculosis. Vaccines helped not only with smallpox but has also helped with polio, whooping cough and many others.

What is a vaccine? A vaccine is a substance used to stimulate the production of antibodies and provide immunity against a disease. They can be given orally (polio, cholera) or by a shot under the skin (MMR, meningitis) or into the muscle (flu, shingles, tetanus). These vaccines took years, decades to develop and have a long track record of safety and effectiveness. Once you get a vaccine you are likely protected from getting the illness. I say "likely" because a person may not respond to the inoculation ("vaccine non-responder") or the vaccine may not be 100% effective for a variety of reasons. Depending on how infectious a disease is, if enough people get vaccinated or are immune to the disease from prior infection (say 60-80%), we as a population develop herd immunity. This protects non-responders and those who are not able to get the vaccine (and those who refuse to take it.)

In this post I won’t get into the details of the body’s immune response to infectious agents and the difference between a T Cell response and a B Cell response. I want to focus on how the virus reproduces in our body and the ANTIBODY response to it. Antibodies bind to the spike protein to tag it for destruction. It is this antibody (aka humoral) response that is the basis of vaccines.

Vaccines are prepared in several different ways, and each of these methods is being used in the development of the Coronavirus vaccine (aka SARS CoV-2). There was an article in the NY Times that outlined these approaches that I thought was useful and instructive. The photos come from this article.

Top arrow is the Spike Protein and the bottom arrow is RNA for the Spike Protein

It is important to understand the structure of this virus, an RNA virus, in order to understand vaccine production. RNA is the genetic code that holds the blueprint to make more copies of itself. The RNA is protected from the host environment by a covering, a membrane; imagine it like the outside of a jellyfish (without the arms). The membrane is studded with a protein, the “spike protein” that helps the virus enter the host cell. These viruses are tiny: imagine 15,000 lined up end-to-end to cross the surface of the head of a pin.

The virus MUST enter the host cell to survive because SARS-CoV-2 does not have the tools to make copies of itself. Once it enters the cell it hijacks the host cell’s tools to make copies of itself and destroys the cell in its wake. These copies have the same strand of RNA, surrounded by the same membrane and the same spike protein.

The goal of a vaccine is to create an immune response that targets the virus for destruction. Some of the techniques for vaccine production have been used for a long time, and other approaches are completely new. In fact, some of the novel approaches to vaccine production hijack the same cellular tools to make proteins, but don’t destroy the cells as a byproduct.

1. Whole virus vaccines. TRADITIONAL. This approach to vaccine production involves growing full copies of the virus in chicken eggs or in tanks of other cell lines. The virus is then weakened (attenuated) or inactivated before packaging for administration. This is how the Flu vaccine, the Measles/Mumps/Rubella vaccine, and others are made.

For some of these, the live, attenuated vaccines, there is a slight risk of getting the disease for folks with weakened immune systems. This is why we don’t give “live, attenuated vaccines” to cancer patients, pregnant women, and others. The yearly Flu shot is an inactivated virus vaccine, not a live-attenuated vaccine. Because it is a killed form of a whole virus, people can get a flu-like illness when getting the flu shot. You cannot get the flu from the flu shot because all the flu virus is dead.

Back in the 18th century Jenner used a virus that was similar to smallpox – cowpox – to trigger the immune response in subjects. While they got a small welt at the location of the inoculation, they did not get cowpox (because people aren’t cows) yet the immune response to cowpox protected them from smallpox.

These types of vaccines have been proven safe and effective.

Companies investigating this form of Coronavirus vaccine: Sinovac (in late-stage/Phase 3 trials) and CNBG (Sinopharm)

2. Protein vaccines. TRADITIONAL. This method uses just the virus protein (here the spike protein) to trigger the immune response. The protein can be harvested from copies of real virus (Haemophilus influenza B (HiB) vaccine) or recombinant protein in the lab (Hepatitis B vaccine, Human Papilloma Virus (HPV) vaccine). These vaccines are safer in one respect because there is no chance that the protein itself can reproduce inside you, but because it’s just the amount of protein in the vaccine the response may not be strong. So, the protein (aka antigen) is often coupled to an adjuvant, another element that boosts the immune response to improve effectiveness. In our practice, the new shingles/Shingrix vaccine is the most common example of a recombinant protein vaccine that uses an adjuvant to boost the effectiveness of the antigen.

These types of vaccines have been proven safe and effective.

Companies investigating this form of Coronavirus vaccine: Medicago, Novavax

3. Genetic code vaccines. NEW. Using gene technology to create vaccines is a novel approach. These types of vaccines use the genetic code of SARS-CoV-2 to mount the immune response. The benefit of vaccines of this type are the speed at which vaccines can be produced, avoiding the time it takes to grow the cell lines/eggs for traditional vaccines.

a. DNA Vaccines: NEW. To nerd out a bit more, remember that in humans, the genetic code is maintained in DNA, compressed, folded and packaged into 46 chromosomes. In different cells who have different purposes, different parts of the genetic code are opened up to code molecules (short strips) of RNA that are then used to code proteins. This is much more complex because humans are much more complex than viruses!

In a DNA vaccine, the RNA genetic information of the Coronavirus spike protein is used to manufacture a strip of DNA. This DNA is then integrated into a longer strand of engineered DNA (aka plasmid) isolated from bacteria that knows how to infect cells. This bacteria plasmid DNA + spike protein DNA is produced in great quantities and then packaged into the vaccine for delivery. Once injected, the plasmid DNA is delivered to the host cells where our own cells’ machinery is used to manufacture many copies of the spike protein. Our body then creates an immune response to the spike protein, theoretically creating immunity. There is a risk in these vaccines that the plasmid DNA gets across the membrane of the nucleus (the heart of the cell where our DNA/chromosomes are) and integrates into our own DNA.

There are NO human DNA vaccines such as this, but they are being studied for Zika and influenza. There are some DNA vaccines in veterinary use at this time.

Companies investigating this form of Coronavirus vaccine: Inovio.

b. RNA Vaccines: NEW. Instead of using DNA, these vaccines use the RNA for the spike protein directly. The strips of RNA are engineered from a synthetic copy of DNA in the lab. The strips of RNA are isolated, purified, into the vaccine and delivered to the subject. The manufactured RNA gets taken up by the host cells where the host manufactures the spike protein in great quantities triggering the humoral response. Given the vaccine is only RNA and not DNA, the RNA cannot get into the nucleus nor can it get integrated into the subject’s DNA. Theoretically, the RNA virus would be safer than the DNA vaccines.

There are NO human RNA vaccines such as this, but they are being studied for MERS (Middle-East Respiratory Syndrome).

Companies investigating this form of Coronavirus vaccine: Moderna, Pfizer (US) w/BioNTech (Germany), Curevac

c. Virus Vector Vaccines: NEW. There are many viruses that infect us, but do not kill us. For 20 to 30 years scientists have been studying the use of viruses to deliver genes into cells to vaccinate people against diseases. Adenovirus, which when it reproduces itself in humans causes illnesses such as the common cold and pink eye, is a virus commonly used for these vaccines. The adenovirus genetic material is modified so it does not cause illness, and the genetic material for the spike protein is added. When the vaccine is administered, the virus delivers the genetic material to cells where our own cells then use the genetic material to make the spike protein and trigger the immune response.

There are NO human virus vector vaccines approved for human use. Johnson & Johnson has developed HIV and Ebola vaccines with this technique and are under study. There are some virus vector vaccines in veterinary use at this time.

Companies investigating this form of Coronavirus vaccine: Astra Zeneca/Oxford, Janssen/Johnson & Johnson, Merck, CanSino.

Aside from the type of vaccine, there are other variables that will influence the type of vaccine that will be distributed around the world. Some of the vaccines require refrigeration. Others require a freezer. Some are one shot and others are two. We have refrigerators. We have freezers. We can coordinate multiple shots. So these won't be issues for us, but may be for practices without the tools we have.

Distribution: This is another big unknown. It is not clear how the vaccine(s), when it (they) come(s) available, will be distributed to practices. Will the government buy it all and distribute? Will we be able to get it like we purchase our other vaccines? Will there be limited supplies to offices? All of this is unknown at this point, and we'll update you as we learn more.

So, what’s our take on the Coronavirus vaccine overall? First, we still believe that one of these types of vaccines will finish its safety and effectiveness studies and be approved by the end of 2020. Since pharmaceutical companies are making vaccine at the same time the vaccine is being studied, once there’s approval there will be some vaccine available for distribution. Those first doses will likely be reserved for those at highest risk. It is my belief that a vaccine manufactured in the U.S. won't be available for wider distribution until the end of Q1 2021.

However, one concern we have is safety. It is critical that the vaccine has been proven safe before we can unequivocally recommend it to our patients. This is different than recommending a new medication for cancer, where you are giving it to sick people who would otherwise die if they did not get the treatment. We give vaccines to healthy people to prevent illness; the last thing we want to do is cause harm through prevention.

We are concerned that a trial of only 30,000 (Moderna) up to 60,000 people (Janssen Pharmaceutical Companies of Johnson & Johnson) may not be enough to identify potential complications. As a vaccine gets administered to millions, may new issues be identified?

This is particularly relevant for the genetic code vaccines as there are NO vaccines of this type yet approved for human use. While the science of these is intellectually intriguing, we will be extra-careful before we recommend those for ourselves and for our patients.

If one of the whole virus or protein vaccines gets approved, we'll likely recommend that one a bit quicker. In fact, the Chinese CNGB vaccine, an inactivated whole virus vaccine, may be the first vaccine approved. It is not clear whether it will be available in the US.

I hope this was educational for you. Please let us know if you have any questions or comments.