Dear Editor,
An upcoming influenza virus A(H5N1) pandemic poses incredible challenges to the vaccine manufacturers community. At least 20 H5N1‐based vaccines have been already authorized for human use across the globe [1], but in animal models, they only provide partial immunity against the currently dominant 2.3.4.4b clade [2]. Of note, only Arepanrix, Aflunov, and Zoonotic Influenza Vaccine are updated on the currently circulating 2.3.4.4b clade, even considering that the two latter are based upon H5N8 and not H5N1 virus. In addition, 84% of the vaccine manufacturing capability relies over 11‐day‐old fertilized hen eggs (whose procurement is likely to suffer shortages during a bird flu pandemic), and only 16% relies over cell cultures (mostly MDCK cells). Further complicating scaling up, to spare antigen dose most vaccines require adjuvants (whose availability also represents a bottleneck), and it takes 4–6 months to have the first doses available since the WHO defines the candidate vaccine virus (CVV) [3]. There is then huge demand for alternative, faster vaccine manufacturing platforms.
In this regard, mRNA vaccines have built their success upon the COVID‐19 pandemic, when modified RNA (mod‐RNA) vaccines have been providing timely updates to the boosts, and many manufacturers are already testing in clinical trials mod‐RNA vaccines against different respiratory pathogens [4], including seasonal influenza [5]. A new generation of mRNA vaccines, named self‐amplifying mRNA (sa‐mRNA), has recently gained approval, with the promise of providing more doses, higher, and more durable immunogenicity [6]. In addition to the antigen cassette included in the mod‐RNA vaccines, sa‐mRNA constructs incorporate the replicase gene within the Alphavirus replicon [5], lowering the mRNA requirement per single vaccine dose from 30 μg down to 1 μg: A single manufacturing center can theoretically provide 8 billion doses of sa‐RNA vaccines [7]. The main hurdle for sa‐RNA vaccines is that uridine cannot be replaced by less immunogenic nucleosides, which rises the risk of both higher reactogenicity and immune responses against the replicase protein, which could impair the efficacy of boosts: Codon optimization is then required to minimize immunogenicity.
Table 1 summarizes the state of the art of H5N1 vaccine pipeline, which will likely translate into approvals in the upcoming months. It is clear that the majority of manufacturers is moving to mRNA platforms, and H5N1 sa‐mRNA vaccines are already in early clinical trials. Although the final CVV will likely be different from those currently tested in clinical trials, immunobridging will likely facilitate the authorization of updated vaccines. Moderna is also developing mRNA vaccines against pandemic candidates other than H5N1, such as H10N8 (VAL‐506440/mRNA‐1440) and H7N9 (VAL‐339851/mRNA‐1851).
TABLE 1.
H5N1‐based vaccine pipeline.
| Manufacturer | Country | Name | Vaccine type | Advancement |
|---|---|---|---|---|
| CSL | Australia | CSL406 Influenza (H5N1) Vaccine | sa‐mRNA | Phase I (NCT06028347) |
| CSL400 (TIV) Trivalent influenza vaccine | sa‐mRNA | Phase I | ||
| Pfizer | USA | pdmFlu | mod‐RNA | Phase I (NCT06179446) |
| Moderna | USA | mRNA‐1018 (against H5 and H7, and soon against 5 serotypes upon BARDA funding) | mod‐RNA | Phase I/II (NCT05972174) |
| CureVac/GSK | Germany | mRNA influenza A (H5N1) prepandemic vaccine candidate | (codon‐)optimized mRNA | Phase I/II (NCT06382311) |
| Sanofi | France | SP0289 | mRNA | Phase I |
| Arcturus Therapeutics | USA | ARCT‐2304 (aka LUNAR‐H5N1) | sa‐mRNA (STARR) into LUNAR LNP | Phase I (NCT06602531) |
Cost per dose remains the main issue with mRNA vaccines, and again, sa‐RNA vaccines have the potential to lower this cost. H5N1mRNA vaccines for low‐and‐middle income countries have been sponsored by the WHO since July 2024 [8]. Outside pandemic settings, sa‐mRNA technology has the potential to translate the promise of universal influenza vaccines into reality.
Author Contributions
Daniele Focosi: conceptualization, writing – original draft. Emanuele Nicastri: writing – review and editing. Fabrizio Maggi: writing – review and editing, conceptualization.
Conflicts of Interest
The authors declare no conflicts of interest.
Peer Review
The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer‐review/10.1111/irv.70113.
References
- 1. Taaffe J., Zhong S., Goldin S., Rawlings K. S., Cowling B. J., and Zhang W., “An Overview of Influenza H5 Vaccines,” Lancet Respiratory Medicine 3, no. 4 (2025): e20–e21. [DOI] [PubMed] [Google Scholar]
- 2. Hawman D. W., Tipih T., Hodge E., et al., “Clade 2.3.4.4b but Not Historical Clade 1 HA Replicating RNA Vaccine Protects Against Bovine H5N1 Challenge in Mice,” Nature Communications 16, no. 1 (2025): 655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Taaffe J., Goldin S., Lambach P., and Sparrow E., “Global Production Capacity of Seasonal and Pandemic Influenza Vaccines in 2023,” Vaccine 51 (2025): 126839. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Troncoso‐Bravo T., Ramírez M. A., Loaiza R. A., et al., “Advancement in the Development of mRNA‐Based Vaccines for Respiratory Viruses,” Immunology 173, no. 3 (2024): 481–496. [DOI] [PubMed] [Google Scholar]
- 5. Lokras A. G., Bobak T. R., Baghel S. S., Sebastiani F., and Foged C., “Advances in the Design and Delivery of RNA Vaccines for Infectious Diseases,” Advanced Drug Delivery Reviews 213 (2024): 115419. [DOI] [PubMed] [Google Scholar]
- 6. Chang C., Patel H., Ferrari A., et al., “Sa‐mRNA Influenza Vaccine Raises a Higher and More Durable Immune Response Than mRNA Vaccine in Preclinical Models,” Vaccine 51 (2025): 126883. [DOI] [PubMed] [Google Scholar]
- 7. Kis Z., Kontoravdi C., Shattock R., and Shah N., “Resources, Production Scales and Time Required for Producing RNA Vaccines for the Global Pandemic Demand,” Vaccine 9, no. 1 (2021): 3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Terao C., Bayoumi N., McKenzie C. A., et al., “Quantitative Variation in Plasma Angiotensin‐I Converting Enzyme Activity Shows Allelic Heterogeneity in the ABO Blood Group Locus,” Annals of Human Genetics 77, no. 6 (2013): 465–471. [DOI] [PubMed] [Google Scholar]