Thanks in large part to the efficacy of the Pfizer-BioNTech and Moderna mRNA vaccines, mask mandates, social distancing, and other COVID-19-related precautions have eased in many countries. Even so, many countries did not reach the global goal of 40% of the population receiving at least one dose of a vaccine by 2021, and significantly fewer countries achieved the next targeted milestone of 70% of the population by mid-2022.
Some of the lagging vaccination rates are due to attitudes toward vaccination, but for much of the world, access to vaccines remains a major contributing factor. With two of the common barriers to access being cost and storage along the supply chain, a COVID-19 mRNA vaccine based on self-amplifying RNA (saRNA) technology may offer a solution. As reported in Science, Arcturus Therapeutics of San Diego recently completed a placebo-controlled trial of their self-amplifying COVID-19 mRNA vaccine, ARCT-154, in Vietnam.
Self-Amplifying RNA Technology
In conventional mRNA COVID-19 vaccines, mRNA coded for the SARS-CoV-2 spike protein is introduced into cells, initiating production of the spike protein to trigger an immune response. Within a few days, all mRNA from the vaccine is cleared from the body. Self-amplifying mRNA vaccines, on the other hand, include enzymes from alphaviruses to support ongoing replication of the mRNA, so it is present for twice as long. This ability to replicate means that a smaller dose of the drug is needed to achieve the desired immune response. In the case of COVID-19 mRNA vaccines, the dose used in trials for ARCT-154 was six times smaller than the Pfizer-BioNTech dose and 20 times smaller than a dose of the Moderna vaccine.
The smaller dosage requirements of the saRNA-based vaccine may contribute to a lower cost, but a greater impact on cost and access is that the vaccine would be significantly easier to distribute. The ARCT-154 manufacturing process includes freeze-drying the medicine before distribution. The freeze-dried powder can be shipped and reconstituted before administration, which doesn’t require the extreme freezing or refrigeration needs associated with conventional mRNA COVID-19 vaccines.
If it receives emergency-use authorization, the affordability resulting from the smaller dose and ease of transport could make ARCT-154 a contender – but all of this hinges upon the full results of the clinal trials. Some researchers expressed doubts about the self-amplifying technology, stating the vaccines cannot employ an mRNA modification: the replacement of the natural RNA building block uridine with pseudouridine. Studies have shown this modification leads to higher levels of the spike protein and lower production of cytokines, immune chemicals that can cause side effects. Initial reports of efficacy of ARCT-154, however, may assuage those concerns.
Efficacy Measures in the Age of Omicron
The clinical trial, completed in collaboration with Vinbiocare Biotechnology, involved over 17,000 participants. Those who received the ARCT-154 vaccine were given two doses of the self-amplifying mRNA vaccine, 28 days apart, at 5 micrograms per dose.
The trials demonstrated that the vaccine had 55% efficacy when it came to symptomatic infection. While this may seem low in comparison to the 90 – 95% efficacy against symptomatic COVID-19 reported in trials of the for the Pfizer-BioNTech and Moderna vaccines, it is important to note that the Arcturus trial reflected efficacy against the variants that were not in circulation during the other vaccine trials. While it was not specified in the preview of the initial findings, the timing of the trials suggests participants were likely exposed to Delta and Omicron variants. The efficacy of the Arcturus vaccine against severe illness or death in this trial was 95%.
Deborah Fuller, vaccinologist at the University of Washington School of Medicine and advisor to HDT Bio, which is currently conducting its own human studies of an saRNA COVID-19 vaccine, acknowledged the milestone. “It’s a huge accomplishment that for the first time a self-amplifying RNA vaccine has been shown to be safe and effective,” Fuller said, and went on to explain that the current real-world effectiveness of existing mRNA vaccines may be “in the same ballpark” as ARCT-154.
In terms of safety, there were no reports of myocarditis or pericarditis documented in either the ARCT-154 or placebo group, though Arcturus did state in their press release that “the study is not large enough to reliably observe these events given their extremely rare frequency of occurrence.”
Too Late to the Game?
As vaccination rates rise around the world, some wonder if the ARCT-154 will be too late to have a significant impact on COVID-19, but Chief Scientific Officer and Chief Operating Officer of Arcturus Therapeutics, Dr. Pad Chivukula, says he “is confident it will find a market in countries that have far lower vaccination rates,” and stresses it will be at “a price point that everyone can afford.” Meanwhile, the investor community says the true impact of this next-generation technology will be felt when we face the next pandemic. In the meantime, Arcturus is waiting to hear about emergency use authorization and initiating research into the ARCT-154’s efficacy as a booster.
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