Schematic of mRNA-4650 design. 1.2.9 Risk for NCI-4650 Monotherapy The risk to subjects receiving NCI-4650 is expect ed to be low and primarily involving mild to moderate toxicities which have been observed in animal studies and generally observed and expected for other IM administered vaccines. Thes e local reactions may consist of transient and dose-dependent pain, swelling, and erythema. Possible mild to moderate systemic reactions, which are also transient, may include fever, fatigue, chills, headache, myalgias, and arthralgias. Such AEs may, in part, be due to the poor biodegradability of LNP formulations used in other vaccine studies; the LNP that comprises NCI-4650 is designed to have superior biodegradability and thus may have a further improved safety prof ile. Also, other AEs that have generally been associated with approved IM administered vaccines have included mild hematological and clinical chemistry abnormalities, which are usually reversible. Subjects receiving NCI-4650 could experience signs and symptoms compatib le with a C activati on-related pseudoallergy (CARPA) response, which has been observed in the administration of approved liposomal products, contrast agents, pegy lated proteins, and antibodies 24, as well as for small interfering RNA products formulated in LNPs25, 26. The signs and symptoms of CARPA resemble those of an acute hypersensitivity reaction. However, complement activation is far less likely to be associated with clinical signs for LNP products such as NCI-4650, which are administered IM at a much lower dose on a mg/kg basis than other clinical entities that cause CARPA in humans and nonclinical species. The design of this study allows an escalation of dose with intensive safety monitoring to ensure the safety of subjects, the study will use a traditional “3+3” design.