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HOLLYWOOD, FLORIDA – AUGUST 07: Lisa Taylor receives a COVID-19 vaccination from RN Jose Muniz as … [+]
An article published on July 8, 2024 in the magazine Nature Biotechnology presents promising data that provide a basis for the development of future vaccines and treatments. Researchers Joshua McGee, lead author, senior authors Mark Grinstaff, Wilson Wong and Florian Douam and other colleagues from Boston University have solved a long-standing problem with self-amplifying RNA. They used modified building blocks called NTPs to build their saRNA. After establishing proof-of-concept in cells, they tested their method in vaccinated mice against a lethal SARS-CoV-2 challenge. Their vaccine delivered much higher antibody levels and better protection against the challenge than a comparable mRNA-based vaccine.
mRNA vaccines explained
Most readers are aware that messenger RNA technology was used in the vaccines given to protect against SARS-CoV-2, the virus that causes Covid-19 disease. If we look at some basic principles: our genetic material is encoded in DNA. To make vital proteins in the body, such as enzymes to perform cellular functions or build tissue, cells translate DNA into mRNA and mRNA into proteins. Both DNA and RNA are made up of building blocks called NTPs.
Like any transport vessel, once injected into muscle, mRNA can transport sequences of NTPs, called cargoes, into cells. The mRNA is then translated into proteins of interest by the body’s cellular machinery. If the payload sequence is intended as a vaccine, proteins against the pathogen in question are generated and the body then mounts an immune response against those proteins, ultimately protecting us from the pathogen.
Challenges of mRNA vaccines
There are a few challenges with mRNA vaccines. First, they induce a robust immune response, which can be assessed by measuring interferon levels. This robust response limits the time they remain viable, which in turn reduces the amount of protein they can produce, creating a need for additional booster doses of the vaccines. Second, mRNA has a short half-life and requires high doses. The high doses combined with a robust immune response can lead to inflammation and unappealing side effects, such as fever, body aches and fatigue that many of us have experienced. Third, the mRNA carries only a single cargo and thus codes for only a single protein of interest.
How are saRNAs different?
The promise of using saRNA as an alternative to mRNA is that it offers “the gift that keeps on giving.” Because saRNA is self-replicating, it requires a much smaller dose than mRNA, as they could essentially turn cells into protein production factories, and continue to produce proteins over a longer period of time than mRNA. By doing this, they could lead to a much better immune response and long-term protection over time. Unfortunately, because saRNA self-replicates, it triggers a robust interferon response, quickly shutting down protein production.
The scientific approach used
Boston University’s data overcomes this hurdle. The BU researchers started by creating a ‘library’ with several modifications to the NTP building blocks for saRNA. They then performed a screening process in cells to determine which of their modified saRNAs maintained robust protein production – they found three. They selected for further study the one that entered cells most efficiently and found that this led to higher protein production in different types of cells compared to natural, unmodified saRNA and mRNA. Basically, they were looking for the sweet spot of a saRNA that caused a robust protein response along with a dampened inflammatory response.
All good so far. They then had to demonstrate proof-of-concept in living animals. They compared three different platforms to vaccinate mice with SARS-CoV-2’s spike protein as payload: their new modified saRNA versus mRNA versus an unmodified saRNA. They gave an initial vaccine and 21 days later a booster vaccine to different groups of mice to test the response of three doses: 10 ng, 100 ng and 1000 ng. They then challenged the mice with a lethal dose of SARS-CoV-2 virus via the nose 35 days after the first vaccine.
At the 1000 ng dose, all mice survived. The real difference occurred at the lowest dose of 10 ng: 25% of those given mRNA survived, versus 45% with an unmodified saRNA and compared to 75% survival with their modified saRNA. More excitingly, the antibody response in the mice that received their modified saRNA was 121 times higher than in the mRNA-vaccinated mice. They also found that interferon I levels induced by their saRNA were lower than those of the mRNA mice and disappeared within 48 hours. They had found their sweet spot. Grinstaff states, “The unexpected finding that modified saRNA works at ultra-low doses and with reduced immune response changes the way we think about RNA engineering and therapeutics.”
What could the future bring?
This is not the first use of saRNAs – research into similar vaccine platforms has been going on for more than two decades, with significant challenges. The tide is turning. A vaccine using saRNA was recently licensed as a Covid-19 booster in Japan. The ARCT-154 vaccine (Arcturus Therapeutics, San Diego) works at a dose of one six compared to other mRNA Covid-19 vaccine doses. Having this as a precedent could spur the development of other new vaccines based on a saRNA platform to advance to clinical testing. Modified saRNA takes the use of saRNA one step further: it doses one-hundredth of the existing doses.
Wong and Grinstaff also successfully tested a saRNA construct containing up to four protein cargo sequences. “This result opens the door to potentially evaluating multiple vaccines administered at once,” said Dr. Douam of the BU National Emerging Infectious Diseases Laboratories. Wouldn’t that be great? There are also other potential benefits of a vaccine that works at a significantly lower dose than current mRNA vaccines. The amount of production needed to vaccinate a population would be lower. In addition, a vaccine could potentially be generated lower cost per person and therefore perhaps more affordable for wider distribution. Reducing the need for boosters would be a plus, in addition to fewer unwanted side effects at a lower dose.