Nuvaxovid Lowers Systemic Reactogenicity Compared With mRNA COVID-19 Vaccine

Sanofi’s protein-based COVID-19 vaccine, Nuvaxovid, demonstrated significantly lower systemic reactogenicity compared to Moderna’s latest mRNA vaccine, mNEXSPike, in a first-of-its-kind head-to-head phase 4 study. The results of the COMPARE (NCT07051031) study, presented at the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Global Congress in Munich, Germany, revealed that Nuvaxovid met its primary end point by showing a lower probability of systemic reactions within seven days of vaccination.¹

“This study was designed to answer a question that matters deeply to clinicians and patients alike: how do different COVID-19 vaccines compare in terms of reactogenicity and patient experience? The answer is clear," Marcel E. Curlin, MD, professor of medicine at Oregon Health & Science University, said in a news release.

Specifically, 83.6% of Nuvaxovid recipients experienced a systemic reaction compared with 91.6% of those who received mNEXSPIKE. These findings are particularly relevant for pharmacists, as concerns regarding side effects remain a top reason cited by adults for declining COVID-19 immunization.

About The Trial

The randomized, double-blind study of 1000 US adults highlighted that when adverse effects did occur with Nuvaxovid, they were generally less severe and shorter in duration than those associated with the mRNA comparator. Severe systemic symptoms, such as fever or headache intense enough to prevent daily activities, were more than 50% less frequent in the Nuvaxovid group, affecting fewer than 1 in 10 recipients compared with 1 in 5 for mNEXSPike.

Furthermore, severe local reactions at the injection site were over 75% less frequent with Nuvaxovid. This improved patient experience led to Nuvaxovid recipients being nearly twice as likely as those in the mRNA group to state they would definitely choose the same vaccine type for 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,” Curlin said. “Individuals cite side effects as a reason they avoid COVID-19 vaccination. These differences could have a significant impact on improving vaccination uptake."

In 2025, the FDA approves the updated 2025-2026 formulations for several vaccines, including Nuvaxovid, Spikevax, and Comirnaty. For the current respiratory season, Nuvaxovid is indicated for adults 65 years and older, as well as for patients aged 12 through 64 years who have at least 1 underlying condition placing them at high risk for severe disease.²

The updated protein-based vaccine has shown the ability to induce immunity across the JN.1 lineage, including subvariants like LP.8.1, which the FDA’s advisory committee recommended for the 2025-2026 formulations. Having a variety of vaccine platforms is increasingly seen as a vital strategy for addressing vaccine hesitancy in the current endemic phase of the virus.

What Pharmacists Should Know

For pharmacists on the front lines, navigating these clinical updates is complicated by a shifting regulatory landscape and conflicting recommendations. Although the FDA has approved the new formulations, the CDC’s Advisory Committee on Immunization Practices (ACIP) recently removed COVID-19 vaccine recommendations for healthy children and pregnant women from its official schedule. This move has caused significant confusion among both providers and patients, especially as the American Academy of Pediatrics has diverged from federal guidance by continuing to recommend the vaccine for all infants and children aged 6 to 23 months. Pharmacists find themselves in the difficult position of explaining these discrepancies while managing an increased workload and navigating state-specific laws that often tie a pharmacy's vaccination authority directly to ACIP recommendations.³

The availability of a well-tolerated, non-mRNA option like Nuvaxovid provides a meaningful alternative for patients who are wary of the reactogenicity associated with mRNA platforms. Ultimately, providing a better tolerability experience may be the key to improving long-term vaccination uptake and reducing the ongoing burden of COVID-19 on the health care system.¹

READ MORE: COVID-19 Resource Center

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REFERENCES

1. Press release: ESCMID: Sanofi's Nuvaxovid COVID-19 vaccine showed better tolerability than mNEXSPIKE in head-to-head study. News release. Sanofi. April 18, 2026. Accessed April 20, 2026. https://www.sanofi.com/en/media-room/press-releases/2026/2026-04-18-10-00-00-3276558

2. Gallagher A. FDA approves COVID-19 vaccine for patients 65 years and older. Drug Topics. August 28, 2026. Accessed April 20, 2026. https://www.drugtopics.com/view/fda-approves-covid-19-vaccines-for-patients-65-years-and-older

3. Gallagher A. HHA and American Academy of Pediatrics differ on COVID-19 vaccine recommendations. Drug Topics. September 10, 2025. Accessed April 20, 2026. https://www.drugtopics.com/view/hhs-and-american-academy-of-pediatrics-differ-on-covid-19-vaccine-recommendation