Self-Amplifying Messenger RNA COVID-19 Vaccine Demonstrates Efficacy and Tolerability

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The novel vaccine, ARCT-154, is a self-amplifying messenger RNA (sa-mRNA) vaccine and now has the first published demonstration of clinical efficacy for this type of vaccine.

clinician holding up a vaccine. Image Credit: Unsplash

Late last year, Japan approved ARCT-154, for initial vaccination and booster for adults 18 years and older.

Image Credit: Unsplash

The ARCT-154, a self-amplifying messenger RNA (sa-mRNA) vaccine demonstrates that 2 5 μg doses against severe COVID-19 was 100% efficacious in healthy persons aged 18-59 and more than 90 percent in persons at risk of severe consequences of the disease due to co-morbidities or older age.1

The results were pooled from phase 1, 2, 3a, and 3b randomized, controlled trials, and published recently in Nature Communications.This is the first published demonstration of the clinical efficacy of an sa-mRNA vaccine according to the investigators.

These results add to recently published data on ARCT-154 demonstrating superior immunogenicity to Omicron BA 4/5 compared to conventional mRNA COVID-19 vaccine booster and follow-up data demonstrating longer duration of immunity compared to traditional COVID-19 mRNA vaccine booster.1

"The results published in Nature Communications demonstrate the efficacy and tolerability of ARCT-154 and add to a growing body of evidence that our sa-mRNA vaccine has the potential to provide significant protection against the pervasive virus, reinforcing our promise to protect public health," said Jon Edelman, MD, senior vice president, Vaccines Innovation Unit, CSL.1

Arcturus Therapeutics is in an exclusive partnership with CSL Seqirus, CSL’s vaccine subsidiary, and is manufacturing the ARCT-154 vaccine. The ARCT-154 vaccine is a novel protection platform. Its self-amplifying mRNA vaccine instructs the body to make more mRNA and protein to boost the immune response;1 whereas, the mRNA vaccine platform protects against infectious diseases by instructing cells in the body to make a specific protein, stimulating the immune response, and leaving a blueprint to recognize and fight future infection. The companies report the technology has the potential to create more potent cellular immune responses and increase duration of protection, while using considerably lower doses of mRNA.2

At the end of November, Japan's Ministry of Health, Labor and Welfare granted approval for ARCT-154, for initial vaccination and booster for adults 18 years and older.2

What You Need to Know

The ARCT-154 vaccine demonstrated 100% efficacy in preventing severe COVID-19 among healthy individuals aged 18-59. It also showed more than 90% efficacy in those at higher risk due to age or comorbidities.

Compared to conventional mRNA COVID-19 vaccine boosters, the ARCT-154 vaccine has shown superior immunogenicity against the Omicron BA.4/5 variant and provides a longer duration of immunity.

Across multiple phases of the clinical trials, the ARCT-154 vaccine was found to be safe and well-tolerated, with most adverse events being mild or moderate. This reinforces the vaccine's potential for broader clinical use, offering a promising alternative to traditional mRNA vaccines with the advantage of requiring lower doses for similar or enhanced efficacy.

Study Parameters and Results
During the observer-blind, randomized, controlled phase 1, 2, 3a and 3b integrated study, adults ≥18 years old receive two 5 μg doses of ARCT-154 or saline placebo 28 days apart. Phase 2/3a/3b participants were stratified by age (< 60 or ≥ 60 years of age) and by risk of severe COVID-19 prior to being randomized 3:1 (phase 1/2/3a) or 1:1 (phase 3b) to vaccine or placebo groups.1

The primary endpoints were vaccine efficacy up to 2 months after dose 2, reactogenicity within up to 7 days of each dose, safety within up to 28 days after each dose, and immunogenicity measured 28 days after each dose From August 15 to January 12, 2023, 1001 participants were randomized (748 ARCT-154 and 253 placebo) in the integrated phase 1/2/3a study, and 16,100 participants (8,056 ARCT-154 and 8,044 placebo) in the phase 3b study.1

In the phase 1/2/3a studies, ARCT-154 was safe and well tolerated. Most solicited adverse events were mild or moderate and resolved quickly, and rates of related or severe unsolicited adverse events were similar in the ARCT-154 and placebo groups. The phase 3b study confirmed these observations.1

Four weeks after the second ARCT-154 dose in phase 3b, the neutralizing antibody seroconversion rate was 94.1% (95% CI: 92•1–95•8). There were 640 confirmed, protocol-defined COVID-19 cases, mainly of the Delta variant, that were determined to be eligible for analysis, including 43 severe cases and 10 deaths attributed to COVID-19.1

ARCT-154 absolute efficacy was 56.6% (95% CI: 48.7– 63.3) against any COVID-19, 95•3% (80.5–98.9) against severe COVID-19 and 86.5% (-7.4–98.3) against death due to COVID-19.1

Efficacy against severe COVID-19 was 100% in healthy 18-59-year-olds and 91.9% (37.9-98.9) in participants in that age group with underlying co-morbidities, which put them at risk for severe disease.1

In adults aged 60 years or older, efficacy was 54.3% (28.2–70.9) against COVID-19 of any severity and 94.4% (58.2–99.3) against severe COVID-19.1

Final Takeaways
The investigators see the sa-mRNA vaccine platform as a complementary modality. “This first demonstration of the clinical efficacy of the ARCT-154 sa-mRNA vaccine against COVID-19, together with acceptable safety and reactogenicity in a large study population, establishes the potential of sa-mRNA vaccines for future clinical use, and complements the other study that showed boosting with ARCT-154 provides superior immunogenicity against Omicron than an mRNA vaccine,” the investigators wrote.3


References
1. Nature Communications Publishes Pivotal Data Demonstrating Efficacy and Tolerability of CSL and Arcturus Therapeutics' COVID-19 Vaccine. CSL news statement. May 20, 2024. Accessed May 21, 2024.
https://www.prnewswire.com/news-releases/nature-communications-publishes-pivotal-data-demonstrating-efficacy-and-tolerability-of-csl-and-arcturus-therapeutics-covid-19-vaccine-302149979.html
2. Parkinson J.First Self-Amplifying mRNA COVID-19 Vaccine Approved in Japan. December 17, 2023. Accessed May 21, 2024.
https://www.contagionlive.com/view/first-self-amplifying-mrna-covid-19-vaccine-approved-in-japan
3. Hồ NT, Hughes SG, Ta VT, et al. Safety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a and 3b randomized, controlled trials. Nat Commun. 2024;15(1):4081. Published 2024 May 14. doi:10.1038/s41467-024-47905-1



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