Time to Unleash Transmissive Vaccines?

Nine months ago the world came to a halt. Returning from a conference in Orlando, I had to quarantine for 2 weeks due to the Covid 19 virus. Soon after non-essential businesses had to close and we all watched the CDC website reporting daily the spread of SARS-Cov-2. Never would I have imagined that 9 months later, my kids are sitting at the kitchen table for Google meetings instead of going to school. A mask mandate is in effect and due to another "surge" businesses are being told to shut down again. On Thanksgiving my sister and I spoke on the phone. How long will it will take until the world reached that critical concentration for herd immunity against Covid 19?

I am currently participating in the phase III clinical by Astrazeneca #Covid19Vaccine. Their vaccine against SARS-Cov-2 is based on a chimpanzee adenovirus carrying genetic material to express the SARS-Cov-2 spike protein. The spike protein, harmless on its own, can trigger a potent immune response resulting in the building of SARS-Cov-2 antibodies in the weeks following vaccination. The adenovirus vector has been rendered harmless by deletion of its E1 region. I am excited to participate in the process of bringing a vaccine to market, bringing awareness to people on how they are work and if they are safe.

Before signing up to be injected with a vaccine lacking FDA approval, I need to know exactly what it is, how its made, and its affect on me. The high level process for making a recombinant vector vaccine involves two major stages:

Stage 1. Creating a plasmid with the gene for the antigen:

1. Identify the target antigen. In the case of an RNA virus like SARS-COV-2, the RNA for the spike protein will do.

2. Synthesize complimentary DNA (cDNA) from the viral RNA using a reverse transcriptase enzyme.

3. The cDNA and a plasmid with an antibiotic resistant gene are cut using the same restriction endonuclease creating matching "sticky ends".

4. The DNA and the plasmid are mixed and recombine with the help of DNA ligase inserting the cDNA into the plasmid.

5. A quick heat shock to Escherichia coli (E. Coli) and plasmids will trigger the E. Coli. to take up the new plasmids.

6. Now grow the E. Coli. in the presence of antibiotic and only the E. Coli. with the antibiotic resistant gene containing plasmid will survive.

7. Colonize the E. Coli with the proper plasmid to create more clones.

Stage 2. Construction and production of a recombinant vector vaccine:

1. The plasmid is cut or linearized and adenoviral DNA is digested.

2. Adenovirus DNA and plasmid are transfected into a "producer" cell

3. In an HEK293 producer cell, recombination of the DNA takes place leading to production of adenovirus virus capable of expressing SARS-Cov-2 spike protein.

4. Purify and isolate the recombinant adenovirus vector for use in a vaccine.

It is truly incredible what modern biology and molecular cloning is capable of. In what some may call a "Frankenstein style" experiment, there are research groups who have even been able to synthesize live viruses in the lab. Their approach was to take viral RNA, make a complimentary DNA template (cDNA). That DNA brought viruses to life after delivery into producer cells via electroporation!

However, its becoming clear that there are additional hurdles to controlling this virus. It is estimated that the general population could see a vaccine for distribution in March of 2021. Unfortunately, it is also very likely that the world will still need to follow safety protocols (masks, social distancing, restaurant closings, concert cancellations, etc..) as it will take time for vaccination. During this time, the virus will continue to spread.

Another problem is that it is estimated that ~50% of the worlds population may not want to get vaccinated even if one becomes available. In Michigan, a poll determined around 60% of adults are willing to get vaccinated but half wanted to wait and see first. Add to that the reports from news media around the world that much of the population is refusing to social distance, wear masks, quarantine, or limit travel.

It does not appear the planet will reach a state of herd immunity any time soon. The virus has a huge advantage; its contagious....It is difficult to model all the factors that influence a global pandemic but it is estimated that a transmissible vaccine could cut the time to reach herd immunity of a naive population by more than 50%. A transmissible vaccine is a vaccine which can spread from one host to another, just like the virus.

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"..a transmissible vaccine could cut the time to herd immunity of a naïve population by more than 50%.."

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Why a transmissible vaccine now? Besides addressing the immediate concern of hospitalization and mortality due to Covid 19, there are also growing concerns that pandemic related restrictions are causing other serious social consequences. The CDC is reporting 40% of adults are struggling with with mental health or substance abuse. Suicide, depression, and health issues due to a delay of medical treatment are all up. Not to mention problems of world economies, business closings , and the rise of unemployment. One need not look further than their own community to see toll the virus has had on employment. I have friends and neighbors who have been on furlough for months, if their job has not already been terminated permanently.

One solution to both concerns could be a more rapid approach to achieving herd immunity to the virus. In the field of veterinary medicine, there are interesting case studies we may learn from with goals ranging from immunocontraception to disease prevention. There has been an effort to eradicate rabbit hemorrhagic disease in wildlife via transmissive vaccination. It is not realistic to think you can vaccinate wildlife against diseases like Lyme's or rabies....Or is it? Imagine eradicating rabies in wild animals by simply baiting wildlife areas with transmissible vaccines. Its being working on right now....

The Astrazeneca vaccine uses a modified chimpanzee adenovirus which cannot reproduce in a human host (replication-incompetent) due to a purposeful genetic modification. This is done for safety. But what if we created a vaccine which used a virus which could replicate and be transmitted from one person to another?

What if this virus (vector) was one with mild cold symptoms to enhance how vaccinated individuals would transmit the viral vaccine to others? The inoculated individuals becoming a temporary "super-spreader", if you will.

One could design a transmissible vaccine by inserting the gene for the SARS-CoV-2 spike glycoprotein (antigen) into the human adenovirus Serotype 5 (AdHu5). AdHu5 is well understood and easy to manipulate. This serotype mainly causes mild upper respiratory infections. In this case, irritation causing coughing and/or sneezing could actually aid in transmissibility to new hosts.

One potential problem with using AdHu5 is that there are sub-populations having a pre-existing immunity to it (as high as 40%). Janssen Pharmaceuticals is using Adenovirus serotype 26. It is much more rare with 10-20% of populations in US and Europe already carrying the antibody. Again, their vaccine is specifically designed to be replication-incompetent for safety.

Would we be helping the world more if Janssen and Astrazeneca made vaccines which were replication-competent? The advantage viruses have over vaccines today is the ability to replicate and transmit. If we have the advanced technology to create transmissive vaccines, should we leverage it?

Some will feel that this is too dangerous an approach and pharmaceutical companies will be cautious to explore. I agree, there will be resistance from big pharma. But safety is not the only reason…

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