Self-amplifying mRNA (samRNA) vaccines, which promise to deliver extended efficacy with lower doses than their mRNA predecessors, have faced a slow start in gaining widespread approval and adoption. Despite the initial excitement surrounding the technology, regulatory resistance and scientific challenges have prevented samRNA vaccines from dominating the vaccine landscape.
Challenges in samRNA Vaccine Development
Large vaccine companies have been hesitant to invest heavily in samRNA technology due to knowledge gaps compared to mRNA therapeutics. Gritstone Bio, a leader in samRNA, recently filed for bankruptcy, highlighting the financial challenges faced by companies in this space. The technical complexity of samRNA vaccines, combined with increasing confidence in established mRNA vaccines, makes it difficult for smaller companies to establish the attractiveness of these approaches.
Gennova Biopharmaceuticals' Gemcovac was the first samRNA vaccine to enter the market, gaining emergency approval in India against SARS-CoV-2 Omicron in 2022. Kostaive (ARCT-154), developed by Arcturus Therapeutics and CSL Behring, was the first samRNA vaccine to gain full marketing approval in Japan for the Wuhan-Hu-1 strain of SARS-Cov-2 in November 2023. However, no other samRNA vaccine or therapeutic approvals have followed since.
Arcturus' Success and Strategic Timing
According to Joseph Payne, CEO of Arcturus, Kostaive's success was due to unique circumstances. The pandemic accelerated its development, and Arcturus was the only company to complete a placebo-controlled efficacy trial during that time. The Phase I/II/III trial ARCT-154-01 (NCT05012943) enrolled over 19,000 participants and found that Kostaive offered 56.6% protection against infection in participants who were neither previously infected nor vaccinated against SARS-Cov-2, meeting the trial's primary endpoint.
Payne also attributed the company's success to "good fortune and strategic timing." Vietnam, with a large population naive to Covid-19 antigens, was ideal for a large-scale trial. Additionally, Japan allowed a direct comparison Phase III trial with Pfizer's Comirnaty vaccine. In this study, Kostaive elicited higher geometric mean titers of Wuhan-Hu-1 neutralizing antibodies than Comirnaty (5,641 vs 3,934, respectively), as per (Oda et al.; Lancet Infect Dis 2024 Apr;24(4):351-360).
The Impact of COVID-19 and Absence of Major Players
The COVID-19 pandemic accelerated mRNA technology, which is the foundation of samRNA therapeutics, by focusing global resources and regulatory attention. SamRNA therapeutics have the potential to address cost and reactogenicity issues associated with mRNA vaccines.
Dr. Gorben Pijlman, professor of Arbovirology & Medical Biotechnology at Wageningen University, noted that the pandemic positively impacted mRNA technology, particularly the development of lipid nanoparticle (LNP) technologies. He also pointed out that while Kostaive is the only approved human vaccine based on samRNA, veterinary applications have been approved for much longer.
Despite the promise, many major players in vaccinology are notably absent from the samRNA field. Dr. Cristian Smerdou Picazo, director of Gene Therapy and Regulation of Gene Expression at the University of Navarre, explained that Pfizer and BioNTech initially developed a samRNA COVID-19 vaccine together but decided to proceed with mRNA vaccines due to existing experience and the perception of an easier path to approval.
Technical Hurdles and Future Development
Smerdou noted that experience with mRNA vaccines may not translate to samRNA. Concerns remain about the replicon-encoded protein in samRNA potentially eliciting its own immune response, which could limit the long-term efficacy of booster doses.
Andreas Suhrbier, PhD, head of the Inflammation Biology Group at QIMR Berghofer, highlighted two technical hurdles to achieving efficacy with samRNA therapeutics. One is the need to modify mRNA nucleosides to prevent the induction of type I interferons that inhibit replication. The other is the RNA size, as even small degradation or alteration can reduce the efficiency of the entire construct.
While solutions to these challenges are being found, a limited understanding of RNA in general is hindering therapeutic development. Despite its potential, the future of samRNA vaccines is uncertain. Pijlman anticipates samRNA vaccines against cancers and infectious diseases in the coming years, but they may not always be the preferred choice. If samRNA technology is to succeed, it must overcome not only technical challenges but also demonstrate clear advantages over existing approaches.
In the ARCT-154-01 study, 89.6% of vaccinated participants reported at least one adverse event after one Kostaive dose. However, similar to many mRNA COVID-19 vaccines, these reactions were mostly mild and resolved within a few days. Smerdou questions whether the demonstrated efficacy of candidates like Kostaive justifies these side effects, noting that the 56.6% protection rate is relatively low. However, Arcturus's Payne points out that Kostaive demonstrated 95.3% protection against severe COVID-19 in the same trial, which is a greater priority for regulatory authorities.
