By Susen Trail, CIH

A viral invader triggers an immune response that creates an antibody specific to the viral antigen.  The antibodies attack the antigens by binding to them to prevent them from binding to healthy body cells.  Antibodies remain in your system for several months after you recover, during this time you are immune to the virus.  The COVID-19 virus has been found to have a short post recovery antibody duration. 

You’ve seen pictures of COVID-19, it’s a ball with a lot of spikes all over it.  Those are the viral antigens.  Think of the protein spike on the virus as a hand and the antibody as a glove.  There is a glove receptor on the cell along with other receptors that fit feet, knees, ears, etc.  Only the hand spike will fit the cell’s glove.  A vaccine helps the body’s immune system to create antibody gloves so that, if we are exposed to the virus the glove antibodies are ready to get to that hand before it can get to the cell’s glove.  Resource.

You may have heard the term ‘Herd Immunity’. This occurs when a large percentage of the population becomes immune to the disease.  Basically, you starve the virus, you give it nowhere to go therefore it dies out.  There is a threshold proportion of the population that must be immune for herd immunity to work. 

The Mayo clinic says that, 70% of the US population, over 200 million people, would have to be infected and recovered so they were all immune at once to create herd immunity naturally.  The narrow post recovery immunity window creates serious barriers to natural herd immunity.

Vaccines have been successful in creating herd immunity for polio, smallpox, diphtheria, and other deadly and contagious diseases.  It is estimated that we will need to vaccinate 80% of the country almost all at once, given the short antibody production window.  This would be difficult for COVID-19 due to the short post infection.

There are two types of vaccines:

Protein based vaccines:

Deliver the immune system stimulating antigen to the body via several vector types.  Measles, mumps and rubella vaccines contain live but weakened viruses, polio vaccines contain inactivated, dead, viral material, and hepatitis B uses bits and pieces of the virus to generate an immune response.  However, there is a risk of preexisting immunity which means your immune system can clear the vector before it even gets started.  Several protein based vaccines developed in America and China have generated “less than impressive” antibody levels.

To get a protein based vaccine to the people who need it:

  1. Get a live virus
  2. Grow a culture
  3. Find the right genetic material
  4. Test it
  5. Insert it into a vector,
  6. Grow the vector,
  7. Test the vaccine
  8. Get Federal approval
  9. Grow cultures
  10. Start distribution of temperature sensitive cells.

Gene based vaccines:

Use the genetic instructions on how to make the antigen from the viral, DNA or mRNA stimulating antibody production.    DNA must wait until the cell is dividing, enter the cell’s nucleus, create mRNA, and then get it back out of the nucleus to form the antigens.  Much less efficient.  (I’ve worked with RNA, did you know the enzymes on your hands will eat your RNA sample?)  On the other hand, 95% of the cells that encounter the mRNA will take it up and make the antigen, a very efficient process. 

You can create a transport vector from a dead virus, a nanoparticle, or a less harmful virus that’s been engineered to not replicate.  From the articles it sounds like the nanoparticle is the best bet as the other 2 require cultures, etc. and controlled temperature delivery systems as well as concerns about preexisting antibodies disabling your vector.

These vectors can be used regardless of the original virus so you can generate a ‘fleet’ of vectors at the same time as you are isolating and replicating the genetic sequence for the target antigen.  For COVID-19 it’s the protein spike used by the virus to bind to a specific receptor spot on one of our body’s cells in order to inject its DNA.  And the gene based vaccine is more like a natural infection.

To get a gene based vaccine to the people who need it:

  1. Find the right genetic material
  2. Start replicating it
  3. Test it/manufacture nanoparticle vectors
  4. Insert the material into a vector to create the vaccine
  5. Test it
  6. Get federal approval, continue to create vaccine
  7. Potential for temperature stable vaccines

Gene-based vaccines are ‘plug and play’.  Once you have the genetic material of interest you can go immediately into testing.  Unlike the protein based vaccine this type of vaccine also stimulates the cytotoxic T cell response.  Imagine air support for your armored division. 

“You’re not giving them the protein—you’re giving them the genetic material that then instructs them how to make that spike protein, to which they make an antibody response that hopefully is protective,” University of Pennsylvania vaccinology professor Paul Offit, MD, explained in a JAMA livestream in June.

So far Americans have been using protein-based vaccines.  For example, Measles, mumps and rubella vaccines contain live but weakened viruses, polio vaccines contain inactivated, dead, viral material, and hepatitis B uses bits and pieces of the virus to generate an immune response.  The development, approval, and production time required for protein-based vaccines can take quite a while.

“This research has been going on since 2002 creating the genetic modifications to stabilize the spike protein for a robust and safe antibody response.  The people who jumped on this right away are the people who had vaccine platforms that were conducive for this that were simply sitting there,” said Louis Picker, MD, associate director of the Oregon Health & Science University’s Vaccine and Gene Therapy Institute. “All they had to do is basically figure out what part of [the virus] they were going to put in the vaccine and then run with it.”

These vectors can be used regardless of the original virus so you can generate a ‘fleet’ of vectors at the same time as you are isolating and replicating the genetic sequence for the target antigen.  For COVID-19 it’s the protein spike used by the virus to bind to a specific receptor spot on one of our body’s cells in order to inject its DNA.

January 10, 2020 Chinese researchers posted the mRNA sequence for COVID-19 on a preprint server making it available to everyone shaving weeks to months off the development of a vaccine.  The U.S. started its first clinical trials in April during which volunteers received the first vaccine developed by a private company, Moderna, Inc and a government agency, the National Institute of Allergy and Infectious Diseases (NIAID).  That’s the bright side.

Because of the speed with which the gene virus can be developed having the mRNA sequence greatly accelerated the process.  In fact, the first four vaccines submitted for FDA approval are mRNA vaccines.  Due to the shortened approval process the number of

To date the FDA has only approved protein-based vaccines, which are grown.  This takes time and resources and can be difficult to scale up, especially in a pandemic situation.  Protein based vaccines must be kept at a specific temperature creating problems in transport and delivery.  The logistics of growing and distributing several hundred million vaccinations in a few months in order to create herd immunity are daunting.  Especially as the process may still be ongoing when the earlier immunized people now need their booster`

As discussed, the gene based vaccine can go in several different types of transport including manufactured nanoparticles that can be stored until needed.  The genetic material can be duplicated on a massive scale by PCR and then inserted into the transport medium.  Some studies show that mRNA, messenger RNA, can be stored at room temperature greatly decreasing large scale distribution to places without refrigeration trucks or on site refrigeration.

“This research has been going on since 2002 creating the genetic modifications to stabilize the spike protein for a robust and safe antibody response.  The people who jumped on this right away are the people who had vaccine platforms that were conducive for this that were simply sitting there,” said Louis Picker, MD, associate director of the Oregon Health & Science University’s Vaccine and Gene Therapy Institute. “All they had to do is basically figure out what part of [the virus] they were going to put in the vaccine and then run with it.”

In order to safely speed up the vaccine testing process it is necessary to enroll a much larger number of volunteer participants in the clinical trials.  Over the last 10 years the usual number of volunteers in studies when going for Food and Drug Administration approval tops out under 16,000 while accelerated testing requires many more.  The mRNA tests used by Pfizer and BioNTech will enroll approximately 60,000 volunteers.

Before federal approval is sought vaccine development follows specific stages, or phases:

  1. Pre-clinical testing, using cells or animals, if the vaccine produces an immune effect it goes on to
  2. Safety Trial, also called Phase 1.  The vaccine is tested on a few human and if it works
  3. Expanded Safety Trials, Phase 2.  The vaccine is given to hundreds of people of different races, genders, and age.
  4. Efficacy trials, Phase 3.  Thousands of people are given the vaccine or a placebo and watched for side effects and immunity.

A recent research letter in the Journal of American Medical Association described the U.S. Food and Drug Administration, FDA, approval process to license a total of 21 new vaccines over the last 10 years.  This process is called the Biologics Licensing Applications, BLA.

There are three parts to this approval

  • Investigational New Drug Submission, for human testing, involving a clinical development period between 6.1-10.5 years, with a median of 8 years (median means most of the submissions took 8 years)
  • BLA submission for FDA review a process taking 10.8-21 months
  • FDA approval

Average time from start to market was 8 years, 12 of the vaccines were for well understood illnesses, influenza, meningitis, and whooping cough.  The follow up period to identify adverse health effects was 6-12 months, median 6 months.  The vaccines were approved based on the results of between 5 and 13 clinical trials, median 7, including:

  • 1-3 pivotal effectiveness, median 1, results for the approved vaccines were between 79.6 and 98%
  • 1 lot to lot consistency

The number of patients included in these trials ranges from 4,576 to 15,997.  The trials used a variety of methods to prevent bias, including

  • Randomized participant selection
  • Masking  – keeping the study group assignment hidden after the vaccine is administered
  • Placebo comparator groups
  • Clinical primary endpoint, either lab confirmed infection or antibody immune response.

Of the 21 approved vaccines, 4 were granted accelerated approval; however, this letter did not provide any information on that process.  The FDA published a “Development and Licensure of Vaccines to Prevent COVID-19” guidance document on June 30, 2020.  It requires at least a 50% efficacy in preventing or decreasing the severity of COVID-19.  Where there are known or potential serious risks from the approved vaccine the FDA may require post marketing studies.

The New York Times Coronavirus Vaccine Tracker shows 55 clinical trials, on humans, and 87 vaccines in pre-clinical trials, on cells or animals, as of November 27, 2020.  Because of the mRNA sequence provided in early January Chinese researchers to other countries the development of the gene based vaccine was on the fast track. 

By March pre-clinical trials were in progress with 13 of the vaccines reaching the final testing stage.  Other methods used to speed up research include conducting trials to test safety and trials to test dosage were conducted simultaneously instead of consecutively.  To offset the faster Emergency Use Authorization process, the number of trial participants is greatly increased, up to 60,000/trial, starting in the pre-human trials instead of starting small, 15,000/trial, and then moving to expanded testing if the vaccine is effective. 

The reason most of you are reading this blog is because you want to know

  1. Can the accelerated authorization of COVID-19 approval provide a vaccine that works?
  2. Will the accelerated process provide enough time for the vaccines to be sufficiently tested for adverse health effects?
  3. How long will the immunity last for COVID-19 from a vaccine given the relatively short immunity after recovering from the illness?  In other words,
    • Will we be required to get booster shots?
    • How many and how frequently?
  4. How long will it take to create and deliver the vaccine?

Not all of the answers are available right now.  There are 260 COVID-19 vaccines in development with over 70 in the approval process.  We have our questions and we do have resources to find the answers for the ‘winners’ in the COVID-19 vaccine race.

The FDA has provided a webpage for it’s Coronavirus Treatment Acceleration Program, CTAP, and the National Institutes of Health, NIH, has a website for the partnership between the government and private and public research labs working on creating a COVID vaccine. The NIH website has an April 2020 article that answers a lot of questions and describes an unprecedented partnership with goals and guidelines.  I recommend bookmarking both sites and using the above questions when reviewing the data.

My source for factual information on COVID is the JAMA Network.  It requires a membership but I’m not a doctor and I found it easy to set up a free membership for a lot of access.  You can also set up an email service that provides links to the main articles being released.

A great deal of my information on Gene based vaccines came from this article.