How do Self-Amplifying RNA Vaccines Work?

In late November 2023, regulatory authorities in Japan approved a new SARS-CoV-2 vaccine. Unlike earlier messenger RNA (mRNA) vaccines used to protect against COVID-19, this one relies on a technology called self-amplifying mRNA, or saRNA. Though researchers have long pursued saRNA-based vaccines, this represents the first full approval for the technology in humans and marks an exciting advance in the ongoing development of mRNA vaccines.

Continue reading for an overview of how saRNA vaccines work and some of their advantages relative to standard mRNA vaccines.

A syringe withdraws clear liquid from a sealed glass vial.
 A new type of COVID-19 mRNA vaccine, a self-amplifying RNA vaccine, was recently approved in Japan.
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Reviewing the Importance of circRNA

In recent years following the COVID-19 pandemic, RNA has gained attention for its successes and potential use in vaccines and therapeutics. One avenue of interest in RNA research is a non-coding class of RNA first identified almost 50 years ago, circular RNA (circRNA).

In 1976, Sanger et al. first identified circRNA in plant viroids, and later additions to the field found them in mice, humans, nematodes, and other groups. Unlike linear RNA, circRNA are covalently closed loops that don’t have a 5′ cap or 3′ polyadenylated tail. Following its discovery, researchers thought circRNA was the product of a rare splicing event caused by an error in mRNA formation leading to low interest in researching the subject (1).

In the early 2010s, following the development of high throughput RNA sequencing technology, Salzman et al. determined that circRNAs were not a result of misplicing, but a stable, conserved, and widely sourced form of RNA with biological importance. Since noncoding RNA makes up the majority of the transcriptome it’s an incredibly important field of study. We now recognize circRNAs for their potential as disease biomarkers and importance in researching human disease (2).

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mRNA Vaccine Manufacturing: Responding Effectively to a Global Pandemic

We’ve learned a few important lessons from the COVID-19 pandemic.

Perhaps the most significant one is the importance of an early and rapid global response to the initial outbreak. A coordinated response—including widespread use of masks and other personal protective equipment (PPE), travel restrictions, lockdowns and social distancing—could save lives and reduce long-term health effects (1). Widespread availability of effective vaccines goes hand in hand with these measures.

New Boosters to Fight Omicron

Last month, Pfizer/BioNTech announced the US Food and Drug Administration (FDA) had granted emergency use authorization (EUA) for a new adapted-bivalent COVID-19 booster vaccine for individuals 12 years and older. This vaccine combines mRNA encoding the wild-type Spike protein from the original vaccine with another mRNA encoding the Spike protein of the Omicron BA.4/BA.5 subvariants. Moderna also announced FDA EUA for its new Omicron-targeting COVID-19 booster vaccine. The Omicron variant of SARS-CoV-2 shows multiple mutations across its subvariants, and it is currently the dominant SARS-CoV-2 variant of concern across the world.

Genomic epidemiology of SARS-CoV-2 with subsampling focused globally over the past 6 months. This phylogenetic tree shows evolutionary relationships of SARS-CoV-2 viruses from the ongoing COVID-19 pandemic. Image from Nextstrain.org; generated September 20, 2022

Booster doses of vaccines have become a way of life, both due to declining effectiveness of the original vaccines especially in older adults (2), and the rapid mutation rate of SARS-CoV-2 (3). Clinical data for the new Pfizer/BioNTech booster vaccine showed superior effectiveness in eliciting an immune response against Omicron BA.1 compared to the original vaccine. Previously, Moderna published interim results from an ongoing phase 2-3 clinical trial, showing that the new bivalent booster vaccine elicited a superior neutralizing antibody response against Omicron, compared to its original COVID-19 vaccine (4).

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A One-Two Punch to Knock Out HIV

This schematic of HIV life cycle summarizes years of research to understand HIV and get to a potential cure for HIV infection
HIV-1 lifecycle illustration. Copyright Promega Corporation.

Scientists investigating the human immunodeficiency virus (HIV) have learned much about the retrovirus’s lifecycle, but their ultimate goals were to discover a cure and prevent infection. In the decades since HIV was discovered, basic research and pharmaceutical drug development have expanded the antiviral toolbox, but these HIV treatments do not provide a functional cure, only manage the infection. However, two techniques may offer a potential cure for HIV infection using CRISPR and a possible vaccine using mRNA.

CRISPR-Based Therapy May Cure HIV Infection

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