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Peer-reviewedCC BY-NC-ND 4.0Nature Communications

Extended dosing intervals enhance the durability of a self-amplifying mRNA vaccine against pandemic H5N1 influenza: a randomized, observer-blind, dose-finding Phase I study

  • Antoinette A. Pragalos1
  • Filippo Pacciarini2
  • Hongfan Jin2
  • Terri Hopkins2
  • Ye Zhang2
  • Roberto Bugarini2
  • Xuexuan Liu2
  • Brian M. Sullivan2
  • Carole Verhoeven2
  • Igor Smolenov2
  1. 1CTI Clinical Trial and Consulting Services, Covington, Kentucky USA
  2. 2Arcturus Therapeutics, San Diego, USA
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Abstract

Avian influenza poses a persistent pandemic threat, yet traditional vaccines face production delays. Self-amplifying mRNA (sa-mRNA) technology offers potential advantages, including rapid development, dose sparing, and enhanced, durable immunity. We evaluated ARCT-2304, a bicistronic sa-mRNA vaccine encoding H5N1 hemagglutinin (HA) and neuraminidase (NA), in a Phase 1 randomized, observer-blind trial (NCT06602531). Healthy adults (N = 212) received two doses of ARCT-2304 (1.5, 5, or 12 mcg) or control/placebo on a 4- or 8-week schedule. Primary outcomes evaluated safety and reactogenicity (solicited/unsolicited/serious adverse events [AEs]) and immunogenicity (HA inhibition and NA enzyme-linked lectin assays 28 days post-second dose). Immunogenicity results were benchmarked using serum from a prior study supporting licensure of an H5N1 vaccine. ARCT-2304 was well-tolerated, displaying mostly mild-to-moderate, transient, dose-dependent solicited AEs, with no safety concerns identified. Two doses elicited robust HA and NA humoral responses. An 8-week interval yielded higher magnitude and greater durability than a 4-week schedule, with neutralizing and anti-NA antibodies remaining significantly elevated 6–7 months post-second dose. ARCT-2304 also induced dose-dependent, Th1-polarized T-cell responses peaking at Day 29. These findings support advancing sa-mRNA platforms for pandemic influenza preparedness.

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Cite

BibTeXRIS
BibTeX
@article{pragalos2026extended,
  title = {{Extended dosing intervals enhance the durability of a self-amplifying mRNA vaccine against pandemic H5N1 influenza: a randomized, observer-blind, dose-finding Phase I study}},
  author = {Antoinette A. Pragalos and Filippo Pacciarini and Hongfan Jin and Terri Hopkins and Ye Zhang and Roberto Bugarini and Xuexuan Liu and Brian M. Sullivan and Carole Verhoeven and Igor Smolenov},
  journal = {Nature Communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-78031-9},
  url = {https://doi.org/10.1038/s41467-026-78031-9},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Extended dosing intervals enhance the durability of a self-amplifying mRNA vaccine against pandemic H5N1 influenza: a randomized, observer-blind, dose-finding Phase I study
AU  - Antoinette A. Pragalos
AU  - Filippo Pacciarini
AU  - Hongfan Jin
AU  - Terri Hopkins
AU  - Ye Zhang
AU  - Roberto Bugarini
AU  - Xuexuan Liu
AU  - Brian M. Sullivan
AU  - Carole Verhoeven
AU  - Igor Smolenov
PY  - 2026
DA  - 2026/09/24
JO  - Nature Communications
DO  - 10.1038/s41467-026-78031-9
UR  - https://doi.org/10.1038/s41467-026-78031-9
AB  - Avian influenza poses a persistent pandemic threat, yet traditional vaccines face production delays. Self-amplifying mRNA (sa-mRNA) technology offers potential advantages, including rapid development, dose sparing, and enhanced, durable immunity. We evaluated ARCT-2304, a bicistronic sa-mRNA vaccine encoding H5N1 hemagglutinin (HA) and neuraminidase (NA), in a Phase 1 randomized, observer-blind trial (NCT06602531). Healthy adults (N = 212) received two doses of ARCT-2304 (1.5, 5, or 12 mcg) or control/placebo on a 4- or 8-week schedule. Primary outcomes evaluated safety and reactogenicity (solicited/unsolicited/serious adverse events [AEs]) and immunogenicity (HA inhibition and NA enzyme-linked lectin assays 28 days post-second dose). Immunogenicity results were benchmarked using serum from a prior study supporting licensure of an H5N1 vaccine. ARCT-2304 was well-tolerated, displaying mostly mild-to-moderate, transient, dose-dependent solicited AEs, with no safety concerns identified. Two doses elicited robust HA and NA humoral responses. An 8-week interval yielded higher magnitude and greater durability than a 4-week schedule, with neutralizing and anti-NA antibodies remaining significantly elevated 6–7 months post-second dose. ARCT-2304 also induced dose-dependent, Th1-polarized T-cell responses peaking at Day 29. These findings support advancing sa-mRNA platforms for pandemic influenza preparedness.
SN  - 2041-1723
ER  -