(a-b) BALB/cJ mice (n=10/group) immunized at weeks 0 and 3 with 0.01 (green), 0.1 (blue), or 1 μg (red) of mRNA-1273 or PBS, were challenged with mouse-adapted SARS-CoV-2 five weeks post-boost. (c) Other groups were immunized with single doses of 0.1 (blue),1 (red), or 10 (purple) μg of mRNA-1273 and challenged 7 weeks post-immunization. Two days post-challenge, at peak viral load, mouse lungs (a,c) and nasal turbinates (b) were harvested from 5 mice/group to measure viral titers. (a-c) Data are presented as GMT+/−geometric SD, and dotted lines represent assay limits-of-detection. Group comparisons were made by Kruskal-Wallis ANOVA with Dunn’s multiple comparisons test. **=p-value<0.01, ***=p-value<0.001. (d) At days 2 and 4 post-challenge, Hematoxylin and eosin-stained lung sections were examined from 5 mice per group, and representative photomicrographs (4X and 10X) from each group with detectable virus in lung are shown. Day 2 lungs from PBS control mice demonstrated moderate-to-severe, predominantly neutrophilic, inflammation present within, and surrounding, small bronchioles (arrowheads); alveolar capillaries were markedly expanded by infiltrating inflammatory cells. In the 0.01 μg two-dose group, inflammation was minimal to absent. In the 0.1 μg two-dose group, occasional areas of inflammation intimately associated with small airways (bronchioles) and adjacent vasculature (arrowheads) were seen, primarily composed of neutrophils. In the single-dose 0.1 μg group, there were mild patchy expansion of alveolar septae by mononuclear and polymorphonuclear cells. At day 4, lungs from PBS control mice exhibited moderate to marked expansion of alveolar septae (interstitial pattern) with decreased prominence of adjacent alveolar spaces. In the 0.01 μg two-dose group, inflammation was minimal to absent. Lungs in the 0.1 μg two-dose group showed mild, predominantly lymphocytic inflammation, associated with bronchioles and adjacent vasculature (arrowheads). In the single-dose 0.1 μg group there was mild, predominantly lymphocytic, inflammation around bronchovascular bundles (arrowheads).