Introduction

The COVID-19 pandemic highlighted RNA vaccination as a rapid and flexible platform. However, the next generation is already here: self-amplifying RNA (saRNA). Derived from alphavirus genomes, saRNA uses a replicase complex to amplify the vaccine antigen in situ. A major benefit of this technology is significant dose reduction—potentially up to 100-fold less than mRNA. In a recent study published in Molecular Therapy Advances, AltraBio applied saRNA vaccine transcriptomics to blood samples from the COVAC1 phase I trial to dissect the human immune response to this promising platform.

The Challenge of saRNA Translation

Unlike traditional vaccines, saRNA must be translated within the body before the adaptive immune system can detect the antigen. A key hurdle is the Type I interferon (IFN) response, which can induce an anti-viral state and potentially inhibit protein translation. Our mission at AltraBio was to perform a comprehensive saRNA vaccine transcriptomics analysis to understand the interplay between these early innate signals and the final protective response.

Key Results: From Innate Signals to Antibodies

Using RNA-seq and systems vaccinology, we interrogated the blood of volunteers 24 hours after vaccination. The saRNA vaccine transcriptomics data revealed:

  • Potent Innate Signature: A significant overexpression of genes associated with Type I interferon signaling and innate immune cell recruitment.

  • Cellular Correlation: This molecular signature was reflected by an increase in monocytes and plasma cytokines.

  • Predictive Power: Most importantly, these acute responses significantly correlated with the subsequent antibody response to the vaccine.

Understanding Reactogenicity

The study also examined the molecular differences between individuals based on their degree of reactogenicity. While our saRNA vaccine transcriptomics analysis detected differences in gene expression related to immune responses in these groups, the results suggest a complex balance. As saRNA induces an acute inflammatory response similar to other RNA vaccines, further research is required to fully dissect the specific role of over-expressed genes in both immunogenicity and reactogenicity.

Collaboration & Publication

This groundbreaking research was conducted in collaboration with Béhazine Combadière and John Tregoning. AltraBio is proud to provide the bioinformatics expertise needed to optimize next-generation RNA therapies.