Safety of Matrix-M–adjuvanted COVID-19, seasonal influenza, combination influenza-COVID-19, and malaria vaccines: a review of the evidence

The saponin-based Matrix-M adjuvant induces potent and durable immunity through producing long-lasting memory B-cells and broad-based T-cell immunity, across a variety of vaccine platforms. Matrix-M–adjuvanted vaccines have a history of successful development for protection against a broad range of infectious diseases with high public health urgency. Two authorized Matrix-M–adjuvanted vaccines, NUVAXOVID (COVID-19) and R21/Matrix-M (Plasmodium falciparum malaria), have been administered to >10 million people worldwide. This review is a comprehensive evaluation of published reactogenicity and safety data from 66 clinical trials and post-marketing studies of Matrix-M–adjuvanted COVID-19, seasonal influenza, combination COVID-19-influenza (CIC), and malaria vaccines retrieved from PubMed and Embase with no restricted start date and last search on 1 November 2025. 64,101 participants received ≥1 Matrix-M–adjuvanted vaccine dose (143,170 doses): 55,939 COVID-19, 2477 influenza, 1422 CIC, and 4263 malaria vaccines. All authorized and candidate vaccines within each disease area were well-tolerated, including among a wide geographical distribution, immunocompromised populations, and children. Active-comparator clinical trials and post-marketing studies demonstrate favorable reactogenicity profiles of Matrix-M–adjuvanted vaccines versus licensed vaccines for the same diseases, particularly, lower reactogenicity rates post-NUVAXOVID versus mRNA COVID-19 vaccination. Research is ongoing to better characterize Matrix-M immune-stimulating mechanisms, continue technology improvements, and identify new applications to enhance vaccines and therapeutics.