A year after emerging in the midst of an RNA renaissance, scientific challenges and regulatory resistance have prevented self-amplifying messenger RNA (samRNA) vaccines from taking over the vaccine space. But experts say that time may be coming soon.
Major vaccine companies are reluctant to invest heavily in emerging technologies due to knowledge gaps, especially compared to mRNA therapeutics. Nevertheless, those familiar with samRNA are confident that these treatments and vaccines will inevitably enter the market, especially for infectious diseases and cancer.
But it hasn’t been smooth sailing for the biotech companies investing in the technology. Earlier this month, Emeryville, California-based samRNA leader Gritstone Bio filed for bankruptcy, undergoing a major financial restructuring. Additionally, growing confidence and technical complexity in established mRNA vaccines means that small and medium-sized companies leading the samRNA field face an uphill climb in establishing the attractiveness of these approaches to approval. It means there is.
Pune, India-based Gennova Biopharmaceuticals’ Gemcovac was the first samRNA vaccine to enter the market, winning emergency approval for SARS-CoV-2 Omicron in India in 2022. In November 2023, Arcturus Therapeutics and CSL Behring were the first samRNA vaccine to receive full marketing authorization in Japan to treat the Wuhan-Hu-1 strain of SARS-Cov-2. Since its approval by Japan’s Pharmaceutical Affairs and Food Sanitation Council, no other samRNA vaccines or therapeutics have been approved.
Arcturus CEO Joseph Payne said Kostaive benefited from special circumstances. “That’s simply because our vaccines were accelerated by the pandemic,” he said, adding that “all the major vaccine companies have strong or very strong interest in samRNA vaccines.” However, we were the only company to complete a placebo-controlled efficacy trial during the pandemic. ”
The Phase I/II/III study ARCT-154-01 (NCT05012943) enrolled more than 19,000 participants to study the safety and efficacy of Arcturus’ candidate. In participants who had never been infected with SARS-Cov-2 and who had not been vaccinated, Kostave was found to be 56.6% effective in protecting against infection, meeting the trial’s primary endpoint.
Payne attributed the company’s success in part to “luck and strategic timing.” Vietnam effectively isolated itself against the initial wave of the pandemic, and many of its citizens remain free of coronavirus antigens, making it uniquely eligible for large-scale trials. Ta.
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Payne also pointed out that “Japan is the first country to allow a direct comparison Phase III trial with the Pfizer vaccine.” This refers to the Phase III trial (jRCT2071220080) comparing Kostave and Pfizer’s mRNA vaccine Comirnaty (Tojinamelan). In this study, as in (Oda et al.; Lancet Infect Dis 2024 Apr;24(4):351-360), Kostaive elicited higher geometric mean titers of Wuhan-Hu-1 neutralizing antibodies than Comirnaty. (5,641 vs. 3,934, respectively). ).
samRNA therapeutics are built on standard mRNA vaccines, where the mRNA strand encodes a protein presented by a specific virus, cancer cell, or other target. This protein is produced within host cells during vaccination and induces an immune response. samRNA therapeutics also include RNA that encodes replicons, which are complexes of proteins that produce additional copies of the immunizing mRNA.
The COVID-19 pandemic has accelerated mRNA technology, the basis of smRNA therapeutics, by concentrating resources and regulatory attention globally. Compared to mRNA vaccines, samRNA is theoretically thought to overcome the cost and reactogenicity drawbacks found in the former.
When asked about the impact of COVID-19 on samRNA development, Dr. Goben Peilman, professor of arbovirology and medical biotechnology at Wageningen University in the Netherlands, said that the pandemic has brought positive attention to mRNA as a technology. He said he had gathered. In particular, the development of lipid nanoparticle (LNP) technology would not have happened without the pandemic, he added.
However, Pijlman also points out that while Kostave is the only human vaccine approved based on samRNA, vaccines for veterinary use have been approved for much longer. For example, Harrisvaccines, based in Ames, Iowa and now part of MSD Animal Health, received USDA approval in 2012 for a samRNA vaccine against swine influenza H3N2 based on the company’s “SirraVax” replicon technology. .
Gritstone Bio (NCT05141721), whose cancer vaccine GRANITE-001 is in Phase II/III trials for colorectal cancer, and VLP Therapeutics, whose COVID-19 vaccine is in Phase III trials (jRCT2051230141). Companies such as Arcturus are close behind. Therapeutic drugs in the samRNA field. A number of other companies also have candidates in preclinical development, including Philadelphia, Pennsylvania-based Chimeron Bio, New Westminster, Canada-based Eyam Vaccines and Immunotherapeutics, and Zwijnaarde, Belgium-based Ziphius vaccine. I’m holding it. However, many of the usual world leaders in vaccinology, particularly mRNA vaccines, are conspicuously absent.
This is probably due to a critical lack of experience, says Dr. Cristian Smerdu Picasso, director of gene therapy and gene expression regulation at the University of Navarra in Spain. He pointed out that Pfizer and BioNTech initially jointly developed a samRNA-type coronavirus vaccine. We had approval, but we had no experience with samRNA. ”
Even several years of experience with mRNA vaccines “may not translate into samRNA,” Smerdu said. Additionally, he says there are still potential unresolved concerns surrounding samRNA technology. In particular, he emphasizes that samRNA “does more than just express antigens.” He said replicon-encoded proteins can trigger their own immune responses independent of the antigen payload, potentially limiting the long-term efficacy of booster samRNA administration.
Dr. Andreas Suhrbier, head of the inflammation biology group at QIMR Berghofer in Brisbane, Australia, says there are “two technical hurdles” to achieving efficacy for samRNA therapeutics. One is the need to modify mRNA nucleosides to prevent the induction of type I interferons, which interfere with replication. Many modified nucleosides, such as N1-methylpseudiuridine, are effective in standard mRNA vaccines but not in samRNA.
Another hurdle, Suhrbier said, is the size of the RNA. Approximately 4,000 nucleosides encode the replicon components of samRNA. Even small degradations or changes can reduce the efficiency of the entire construct and, in turn, the effectiveness of the vaccine, he explains.
Suhrbier believes that although solutions to these challenges are being found, the development of treatments is limited by a lack of understanding of RNA in general. “There are just so many unknowns in place that you can invest money in,” he says, adding that traditional leaders in the industry are becoming indecisive as a result.
As a complex, cutting-edge technology, samRNA is similarly subject to many safety concerns. For example, in the ARCT-154-01 study, 89.6% of vaccinated participants reported at least one adverse event after one dose of Kostaive. However, like many mRNA Covid-19 vaccines, this seemingly high reactogenicity consisted of mild reactions that mostly resolved within two to four days.
Still, Smerdu asks whether the proven efficacy of candidates like Kostayb justifies these side effects. “(The 56.6% protection rate) is low,” he says. But Arcturus’s Payne noted that Kostaev demonstrated 95.3% protection against severe COVID-19 infection in the same trial, a metric he said is more of a priority for regulators. There is.
Although experts emphasize its potential, the future of samRNA is uncertain. SamRNA vaccines for cancer and infectious diseases are expected to appear within the next few years, Pijlman said, but in many cases this approach may not be the first choice. For samRNA technology to be successful, more than technical difficulties may need to be overcome.
“Slow Start for Self-Amplifying mRNA Vaccines” was originally created and published by Pharmaceutical Technology, a brand owned by GlobalData.
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