One of the most amazing aspects of the COVID pandemic was the speed with which the world was able to create and deploy effective vaccines. This was partly due to regulatory streamlining and funding (such as Operation Warp Speed in the US), but mainly because the necessary technology was available. It took only a few days once the virus was isolated to sequence the genome of SARS-CoV-2. Scientists were also able to track the development and spread of genetic variants throughout the world through continuous surveillance. This was only possible because of recent developments in molecular biology.

The world was also introduced to the concept of mRNA vaccines. Vaccines work by introducing either an inactivated infectious agents or a piece (antigen) of that agent (virus or bacteria, for example), usually along with some immune-stimulating adjuvants, to provoke an immune response. The body creates antibodies against the infecting organism and remembers, allowing for a more vigorous and rapid immune response if the recipient is ever exposed to the living infectious agent. It’s like getting infected without suffering the symptoms or risks of an actual infection. Vaccines can also be used to target cancer cells.

Scientists explored for a while making vaccines using DNA, the coding molecule that carries genetic information. The idea was to introduce DNA that codes for a viral or bacterial protein, the host’s cells would then incorporate that DNA into the nucleus and start making the protein. This approach, however, turned out to be too complicated and essentially did not work. So they next turned to RNA vaccines, specifically messenger RNA (or mRNA). RNA molecules can also encode for proteins, but they don’t have to enter the nucleus and do not run the risk of being incorporated into host DNA. They stay outside the nucleus where the proteins are made. Once proteins are transcribed from the mRNA, the molecule is broken down and recycled.

The mRNA approached worked extremely well. The Moderna and Pfizer COVID vaccines, for example, are both mRNA based. There are several advantages to the mRNA platform. Perhaps the most important is that mRNA vaccine can be made relatively quickly compared to other methods. Traditional vaccine require complex cell cultures and safety measure to prevent contamination, while mRNA technology is relatively clean and simple. We already have the technology to program and mass-produce mRNA molecules, so the production of a new vaccine involves mainly knowing the genetic sequence of the protein or proteins you wish to be antigens for the vaccine. This allows for rapid vaccine development and precise targeting.

The introduction of a new technology, however, especially one involving genetics lead to some popular anxiety about the safety of these vaccines. Scientifically the evidence is solid, but it was easy to scare people about a genetic vaccine. It is likely that we are about to see another advance in genetically based vaccines – the development of self-amplifying RNA vaccines (saRNA). This is an extension of the mRNA technology that may also lead to more rapid development of vaccines and more effective vaccines.

The saRNA vaccines include an RNA-dependent RNA polymerase (RdRP) complex accompanying the RNA that codes for the viral antigen. These amplifying gene sequences will replicate with RNA many times, so that even a small dose of saRNA can lead to many copies of RNA producing the desired antigen. There are also possible trans-amplifying RNA approaches that have the RdRP genes separate from the antigen-coding RNA.

What are the potential advantages to this approach? Vaccines based on saRNA technology could use a lower dose and require fewer subsequent boosters. This will reduce inconvenience and expense, and improve vaccine compliance. Preliminary research on candidate vaccines show that the saRNA vaccines (also called self-replicating or repRNA) can produce antigens for weeks or even months after a single injection.

This study also demonstrated the use of nanoparticles to deliver the saRNA package. These are then like psuedoviruses – an outer capsule containing the genetic package. The advantage here is that one nanoparticle capsule can contain multiple saRNA packages. Therefore with one injection an saRNA vaccine can produce immunity to multiple antigens. This itself is not new but the platform allows for it more easily.

It is also possible, although research is ongoing, that saRNA vaccines will produce better immunity. One reason is that the sustained release of antigen over time better replicates a natural infection than a single bolus of non-replicating vaccine. This may cause a greater immune response, allowing for later stages of immunity to kick in and produce greater and longer lasting immunity. There are a lot of technical details to work out, but the saRNA platforms currently under development appear to work and do not seem to present any unique safety concerns.

In the next 5-10 years we can likely expect saRNA based vaccines to be going through clinical trials and start getting approval. It’s also likely that the next pandemic that hits will be targeted, at least in part, by these vaccines. It is also likely that there will be another round of fear-mongering about the new technology. It probably best for scientists to get ahead of this, to introduce and explain the technology to the public, so that at least it will be somewhat familiar before the next COVID. Let’s also get all the conspiracy theories and misinformation out of the way, and at least produce the data and the analysis to respond to this misinformation before we are in the middle of a pandemic emergency.

This is probably wishful thinking, but there is no reason not to try.

Author

  • Founder and currently Executive Editor of Science-Based Medicine Steven Novella, MD is an academic clinical neurologist at the Yale University School of Medicine. He is also the host and producer of the popular weekly science podcast, The Skeptics’ Guide to the Universe, and the author of the NeuroLogicaBlog, a daily blog that covers news and issues in neuroscience, but also general science, scientific skepticism, philosophy of science, critical thinking, and the intersection of science with the media and society. Dr. Novella also has produced two courses with The Great Courses, and published a book on critical thinking - also called The Skeptics Guide to the Universe.

Posted by Steven Novella

Founder and currently Executive Editor of Science-Based Medicine Steven Novella, MD is an academic clinical neurologist at the Yale University School of Medicine. He is also the host and producer of the popular weekly science podcast, The Skeptics’ Guide to the Universe, and the author of the NeuroLogicaBlog, a daily blog that covers news and issues in neuroscience, but also general science, scientific skepticism, philosophy of science, critical thinking, and the intersection of science with the media and society. Dr. Novella also has produced two courses with The Great Courses, and published a book on critical thinking - also called The Skeptics Guide to the Universe.