Sanofi’s protein-based vaccine Nuvaxovid has conquered Moderna’s next-generation messenger RNA shot mNexspike in a head-to-head trial assessing the tolerability of the two COVID vaccines.
In the phase 4 double-blind, real-world study, which included 1,000 adult participants in the United States, Nuvaxovid showed statistically significant fewer side effects across all pre-specified endpoints.
Symptomatic reactions with Nuvaxovid were both milder and shorter than with mNexspike. Additionally, less than 10% of those who received Nuvaxovid experienced severe side effects—such as fatigue, headache or fever which prevented them from conducting their daily activities—compared to 20% of those who got mNexspike. As for injection site symptoms such as pain, redness and swelling, they were more than 75% more frequent for those who received Moderna’s shot.
Without knowing which shot they received, nearly twice as many recipients of Nuvaxovid said they would choose the same vaccine type the following year.
“Across every measure we evaluated, we observed that the recombinant protein-based vaccine consistently exhibited lower reactogenicity and less disruption to patient activities than the comparator mRNA vaccine,” Marcel Curlin, M.D., the principal investigator of the study and a professor at Oregon Health & Science University, said in a release. “Individuals cite side effects as a reason they avoid COVID-19 vaccination. These differences could have a significant impact on improving vaccination uptake.”
The study achieved its primary endpoint with statistical significance, as 92% of those who took mNexspike experienced at least one systemic reaction within seven days, as opposed to 84% of those who had Nuvaxovid. Moderate-to-severe side effects occurred in 61% of mNexspike recipients compared to 43% of those who got a shot of Nuvaxovid.
The study was not designed to measure the two shots’ efficacy.
“The patient experience with vaccination is essential, because it determines not only whether people get vaccinated, but also whether they come back year after year for routine protection,” Thomas Triomphe, Sanofi’s vaccine chief, said in a statement. “These results show that Nuvaxovid can play a meaningful role in making routine COVID-19 vaccination a reality for more people, which is how we can help address the continued burden of this disease on patients and health systems.”
With the help of a $1.6 billion government grant in 2020, Novavax developed Nuvaxovid. After a series of regulatory and commercial missteps left the Maryland biotech on the brink of bankruptcy, Novavax sold the vaccine to Sanofi for $500 million up front and $700 million in potential milestones.
Last year, Novavax reported $625 million in Nuvaxovid sales, most of which were associated with the settlement of advanced purchase agreements from previous years. Sanofi took over marketing of the vaccine in Europe and the U.S. in the fall of last year.
Moderna gained FDA approval of mNEXPIKE in May of last year for adults 65 and older and for those ages 12 to 64 who have one or more underlying risk factors for severe COVID, such as asthma, diabetes or COPD. The shot proved itself in a study against Moderna’s COVID vaccine predecessor Spikevax.
The FDA also signed off on Nuvaxovid in May of 2025 in the same population, though it was originally made available under an emergency use authorization in 2022. Novavax has long pitched its shot as a traditional alternative to the mRNA vaccines offered by Moderna and partners Pfizer and BioNTech.
