Next-generation COVID-19 vaccine shows stronger protection against new variants

An international clinical study, one of the first international vaccine trials using next-generation COVID-19 vaccines and mRNA technology, has shown that a new COVID-19 vaccine offers stronger protection against Omicron and can be given safely alongside the flu shot.

The vaccine ARCT-2303 uses self-amplifying mRNA (sa-mRNA) technology to instruct the body’s cells to make more of the viral protein that trains the immune system, resulting in a stronger and longer-lasting immune response compared with traditional mRNA vaccines.

Doherty Institute researchers from the Vaccine Research Group, led by the University of Melbourne’s Professor Michelle Giles, were among the contributors of the landmark study published in eClinical Medicine. Professor Giles, first author of the paper, said that developing updated vaccines is crucial to keeping pace with the changing virus.

“While vaccines using mRNA technology have played a major role in controlling the COVID-19 pandemic, their effectiveness is challenged by the evolving nature of the virus,” she explained.

“Sa-mRNA vaccines have emerged as a promising new platform, but until now research had mostly focused on early-stage trials against the original strain of the virus. For the first time, we conducted a large phase 3 clinical trial to test a Sa-mRNA vaccine updated for a circulating variant of SARS-CoV-2.”

Between March 2024 and April 2025, nearly 1,500 volunteers from Australia, Costa Rica, Honduras and the Philippines, took part in the large-scale, randomised, placebo-controlled study. Participants were randomly assigned to receive the updated ARCT-2303 vaccine with or without coadministration of influenza vaccine.

“The findings are clear,” said Professor Giles.

“ARCT-2303 produced a stronger immune response against Omicron than the original vaccine, and when given with a licensed influenza vaccine, the vaccine’s safety and immune response was not compromised.”

The vaccine was safe and well tolerated, with only mild, short-lived side effects similar to those seen with other COVID-19 and influenza vaccines, making it a suitable candidate as a booster.

“These findings could simplify seasonal vaccination, allowing people to receive their COVID-19 and flu shots in a single visit,” said Professor Giles.

“It’s a practical step forward in protecting communities as the virus continues to evolve.”

Peer-review: Giles M, et al. Immunogenicity and safety of self-amplifying mRNA COVID-19 vaccine (ARCT-2303), with or without co-administration of seasonal inactivated influenza vaccine in adults: a phase 3, randomised, controlled, observer-blind, multicentre study. eClinical Medicine (2025). DOI: https://doi.org/10.1016/j.eclinm.2025.103428

Collaboration: This work is the result of a collaboration between the Doherty Institute (Australia), the Tropical Disease Foundation Inc. (Philippines), Arcturus Therapeutics (USA), Inversiones en Investigacion Medica S.a (Honduras), Clinica San Agustin Mostt S.a (Costa Rica), Far Eastern University Nicanor Reyes Medical Foundation (Philippines), Emeritus Research Melbourne (Australia), Griffith University Clinical Trials Unit (Australia), Momentum Clinical Research (Australia), CSL (USA) and Walson Consulting (USA).