Molecular therapy : the journal of the American Society of Gene TherapyJul 30, 2026

Self-amplifying mRNA vaccine without a cap protects mice against H5 bird flu virus using lower doses

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 3, 2026

Abstract

A minimal 0.01 µg dose of capless self-amplifying mRNA (CLsamRNA) conferred complete protection against lethal H5N8 influenza virus challenge in mice.

CLsamRNA vaccines can induce potent immune responses at lower doses compared to conventional non-replicating mRNA vaccines.
Systematic optimization of genetic elements enhanced antigen expression from the CLsamRNA platform.
LNP-formulated CLsamRNA demonstrated rapid early expression and RNA amplification, with distinct kinetics compared to other mRNA platforms.
In mouse models, CLsamRNA induced strong neutralizing antibody responses and cross-reactive activity against related H5N1 viruses.
Platform-specific immune gene signatures were observed, indicating early inflammatory responses and cellular immune priming.

Simplified

Self-amplifying mRNA (samRNA) vaccines can induce potent immune responses at lower doses than conventional non-replicating mRNA vaccines; however, large RNA size and manufacturing considerations associated with 5' capping remain important challenges. Here, we developed a capless samRNA (CLsamRNA) vaccine platform derived from a Coxsackievirus B5 replicon that uses IRES-mediated cap-independent translation. Systematic optimization of key genetic elements enhanced antigen expression from the CLsamRNA backbone. Using reporter RNAs, LNP-formulated CLsamRNA showed rapid early expression and RNA amplification, with expression kinetics distinct from VEEV-based saRNA and nucleoside-modified mRNA comparators. When encoding the hemagglutinin antigen of highly pathogenic avian influenza clade 2.3.4.4 H5 viruses, CLsamRNA induced potent immune responses after LNP formulation. In mouse models, CLsamRNA induced potent neutralizing antibody responses, cross-reactive activity against clade 2.3.4.4b H5N1 virus, Th1-skewed humoral immunity, and strong antigen-specific cellular immune responses. CLsamRNA also elicited platform-specific early inflammatory and lymph-node immune gene signatures associated with antigen presentation, costimulation, and cellular immune priming. Notably, a minimal 0.01 μg dose of CLsamRNA conferred complete protection against lethal H5N8 influenza virus challenge in BALB/c mice. These findings support CLsamRNA as a distinct cap-independent RNA vaccine platform with dose-sparing protective efficacy against HPAI H5 viruses.

Full Text

Full text is available at the source.

View Full Text ↗

Self-amplifying mRNA vaccine without a cap protects mice against H5 bird flu virus using lower doses

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the mrna technology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the mrna technology brief