Sanofi’s protein-based vaccine, Nuvaxovid, defeated Moderna’s next-generation messenger RNA shot, mNexspike, in a head-to-head trial evaluating the tolerability of two coronavirus vaccines.
In a Phase 4, double-blind, real-world study of 1,000 adult participants in the United States, Nuvaxovid was shown to have statistically significantly fewer side effects across all prespecified endpoints.
Symptomatic reactions with Nuvaxovid were milder and shorter-lived than with mNexspike. Additionally, less than 10% of people who received Nubaxovid experienced severe side effects that interfered with their daily life, such as fatigue, headache, and fever, compared to less than 20% of people who received mNexspike. Injection site symptoms such as pain, redness and swelling were more than 75% more common in people who received the Moderna shot.
Almost twice as many people who received Nuvaxovid, without knowing which vaccine they received, said they would choose the same type of vaccine the following year.
“We observed that recombinant protein-based vaccines were consistently less reactogenic and less disruptive to patient activity than comparable mRNA vaccines in all measurements we evaluated,” Marcel Karlin, MD, Ph.D., the study’s principal investigator and professor at Oregon Health and Science University, said in the release. “Some people have cited side effects as a reason to avoid COVID-19 vaccination. These differences could have a significant impact on improving vaccination.”
The study met its primary endpoint with statistical significance, with 92% of patients taking mNexspike experiencing at least one systemic reaction within seven days, compared to 84% of patients taking Nuvaxovid. Moderate to severe side effects occurred in 61% of patients receiving mNexspike, compared with 43% of patients receiving Nuvaxovid.
This study was not designed to measure the effectiveness of two injections.
“A patient’s vaccination experience is essential because it determines not only whether they get vaccinated, but also whether they return annually for routine prophylaxis,” Thomas Triomf, Sanofi’s head of vaccines, said in a statement. “These results demonstrate that Nubaxovid can play a meaningful role in making routine COVID-19 vaccination a reality for more people. This is how we can help address the continued burden of this disease on patients and healthcare systems.”
With the help of $1.6 billion in government grants in 2020, Novavax developed Nuvaxovid. Novavax sold its vaccine to Sanofi for $500 million upfront and $700 million in potential milestones after a series of regulatory and commercial failures nearly bankrupted the Maryland biotech company.
Last year, Novavax reported sales of $625 million for Nuvaxovid, most of which related to the settlement of advance purchase agreements from the previous year. Sanofi took over vaccine distribution in Europe and the United States last fall.
Last May, Moderna received FDA approval for mNEXPIKE in adults 65 and older and people 12 to 64 with one or more underlying risk factors for severe coronavirus, such as asthma, diabetes or COPD. The shot was proven in a study against Spikevax, the predecessor to Moderna’s coronavirus vaccine.
The FDA also approved Nuvaxovid for use in the same population in May 2025, although it initially became available under emergency use authorization in 2022. Novaxovid has long been pitched as a traditional alternative to mRNA vaccines offered by Moderna and partners Pfizer and BioNTech.
