Nature communicationsDec 6, 2025

How existing immunity against viral replication affects self-amplifying mRNA vaccine effectiveness

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

In female mice, prior self-amplifying mRNA vaccination created anti-replicase immunity that weakened later vaccine expression and Th1 responses but did not block H5N1 protection.

Evidence

Preclinical female-mouse vaccination and passive-transfer experiments tested sequential saRNA dosing, anti-replicase antibodies and T cells, and influenza saRNA challenge protection.

Caveat

The protection result is limited to an influenza saRNA H5N1 challenge in female mice, so effects may differ by antigen, schedule, sex, or humans.

Simplified

Self-amplifying mRNA vaccines use a viral replicase for self-amplification. It is currently unclear whether anti-replicase immunity occurs after saRNA vaccination, and whether such pre-existing anti-replicase immunity impacts the efficacy of subsequent saRNA vaccines. Using female mice, this study demonstrates that an initial saRNA vaccination schedule elicits replicase-specific immunity, which reduces the in vivo expression and impairs the Th1 cell responses of subsequent saRNA vaccines. Passive transfer experiments demonstrate that the suppression of T cell responses is driven by a synergistic effect of both anti-replicase antibodies and anti-replicase T cells. Interestingly, pre-existing anti-replicase immunity does not affect the ability of an influenza saRNA vaccine to provide full protection against an H5N1 challenge in female mice. Taken together, these results provide crucial insights on the effects of anti-replicase immunity induced by a first saRNA vaccination schedule on the expression, immunogenicity and protection efficacy of a subsequent saRNA vaccine.