The First Optimized Self-Replicating RNA (srRNA) Technology

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EP: 1.The First Optimized Self-Replicating RNA (srRNA) Technology

The pivotal paper series brings to a wider audience a sharp focus on important advances in the biomedical field. This particular paper comes at a troubling time in the vaccine industry, which is currently beset by misinformation and disinformation. In our inaugural "Pivotal Paper" we hear from a panel of vaccine heavyweights which comprises Philip Dormitzer, MD-PhD, Hospitalist Physician, Coastal Medical Associates, Phil Felgner, PhD, Professor, UC Irvine, Andy Geall, PhD, Co-founder and Chief Development Officer, Replicate Bioscience, Inc. and Chairman of the board, Alliance for mRNA Medicines, and Jeffrey Ulmer, PhD, President, TechImmune LLC.

The scientific paper discussed is titled “Safety and immunogenicity of an optimized self-replicating RNA platform for low dose or single dose vaccine applications: a randomized, open label Phase I study in healthy volunteers” and was published January 2, 2025 by Springer Nature.¹

From the paper’s introduction we learn:

Self-replicating RNA (srRNA) technology, in comparison to mRNA vaccines, has shown dose-sparing by approximately 10-fold and more durable immune responses. However, no improvements are observed in the adverse events profile. Here, we develop an srRNA vaccine platform with optimized non-coding regions and demonstrate immunogenicity and safety in preclinical and clinical development.

As overview comments we hear directly from the panelists:

Andy Geall, PhD: “I'd say our therapeutic index stands out. It's greater than 100. Most other vaccines, whether they are first generation self-amplifying or linear mRNA are in the range of one to 10, so outstanding. The fact that we didn't reach a maximum tolerated dose means we can dose higher, and this comes into play with multivalent vaccines. What we found with linear vaccines, say in the context of Seasonal flu, we have 4 HOA antigens [HLA-A, HLA-B, HLA-C, and HLA-DR antigens, which are part of the Human Leukocyte Antigen (HLA) system, also known as the human Major Histocompatibility Complex (MHC)] we're trying to encode, and they encode each HA [HA antigens, or hemagglutinin] on a separate strand, and they can only dose basically 1/4 at the maximum dose. The overall immune responses are less, or weakened. We're not in that place. With this technology, we can encode all of the antigens on the one vector to start, and we have the ability to dose escalate further, before we hit that maximum tolerated dose, [which is] a huge advantage.”

Phillip Felgner, PhD: “One of the targets in vaccine science in general is for the field to develop single dose vaccine technology. The self-replicating RNA has the potential for doing just that.”

Phillip Dormitzer, MD-PhD: “We've long known that at lab scale, if you focus on making a small amount of the best self-replicating RNA you can make, it outperforms everything else. The question was, could you scale it and get it to the point where you can actually manufacture with that kind of quality? And I think that's been the barrier that sort of prevented the self-replicating RNA from being the dominant RNA. But it does appear with this paper that those barriers really have been overcome.”

Jeffrey Ulmer, PhD: “As you said, up to now there's been some uncertainty about the prospects. If the technology could be making high quality [drug product], could we make it potent enough? We see in humans what we've seen in the animal models, and I think what this paper clearly demonstrates is yes, it has. The technology has arrived. The implications are that it's been shown to be safe and immunogenic to the point where it would be protective in the context of rabies; this provides a clear path forward for the technology, for applications broader to other infectious diseases and non-infectious diseases.”

From the discussion section we learn:

This is the first report on the clinical use of next-generation, optimized srRNA technology. We conducted a Phase I clinical trial to assess safety and immunogenicity of a srRNA rabies vaccine in healthy volunteers. In contrast to prior srRNA vaccines for SARS-CoV-28–11, this study is the first demonstration of priming de novo immune responses by a srRNA vaccine, i.e., in participants with no confirmed prior history of antigen exposure or vaccination; an important step in the validation of a vaccine platform. De novo priming of immune responses as measured by RVNA titers above the WHO measure of indirect protection was detected in the majority of participants at all dose levels, including the lowest dose level tested of 0.1 mcg. The vaccine demonstrated a dose-dependent priming effect with no saturation, suggesting that higher doses of RBI-4000 may be well tolerated and result in even more striking immune responses.

We also hear:

Data shown here and from others show that srRNA technology is not inherently more reactogenic than mRNA-based vaccines incorporating modified nucleotide bases to avoid innate immune sensors.¹ RBI-4000 was well tolerated at all dose levels with no serious adverse events reported and a maximum tolerated dose was not defined in this study. In some instances, dose-limiting toxicities have been reported by other groups with srRNA vaccines administered at comparable doses.¹ This increase in bioactivity, over first-generation srRNA, is a result of higher levels of protein expression from vector engineering and optimization. Thus, we have shown that vaccines utilizing optimized srRNA technology show a substantial improvement in bioactivity for multiple antigens. Importantly, in a first-in-human study, RBI-4000 achieved clinical bioactivity, while maintaining a favorable safety profile, across the tested dose range of 0.1–10 mcg. These findings broaden the TI of RNA technology which has wide-ranging implications. A superior bioactivity at low doses can favorably impact deployability and accessibility for widespread use, such as in pandemic settings.¹ Additionally, a broadened therapeutic window suggests expanded use of this platform outside of simple vaccines. For example, for multigenic formultivalent vaccines, this technology can be multiplexed with no compromise on its effective dose based on safety. Furthermore, for alternative therapeutic uses outside infectious disease vaccines, such as cancer vaccines and protein replacement therapies, where high, repeat dosing is expected to achieve the required levels of antigen or protein expression, a broad therapeutic window is critical to avoid toxicity.¹ We have generated preclinical and clinical evidence that improvements to srRNA vectors can greatly expand their potential applications. Coupled with a favorable safety profile, these next generation vectors have a broader utility for future vaccine and drug development.

Reference:

1. Aliahmad, P, Goldberg, Z, Geall, A, Safety and immunogenicity of an optimized self-replicating RNA platform for low dose or single dose vaccine applications: a randomized, open label Phase I study in healthy volunteers, Nature Communications, January 07, 2025, Springer Nature Limited