AbstractThe relationship between SARS-CoV-2 dose, infection, and COVID-19 outcomes remains poorly understood. This review summarizes the existing literature regarding this issue, identifies gaps in current knowledge, and suggests opportunities for future research. In humans, host characteristics including age, sex, comorbidities, smoking, and pregnancy are associated with severe COVID-19. Similarly in animals, host factors are strong determinants of disease severity although most animal infection models manifest clinically with mild to moderate respiratory disease. The influence of variants of concern as it relates to minimal infectious dose, consequence of overall pathogenicity, and disease outcome in dose-response remain unknown. Epidemiologic data suggest a dose-response relationship for infection contrasting with limited and inconsistent surrogate-based evidence between dose and disease severity. Recommendations include the design of future infection studies in animal models to investigate inoculating dose on outcomes and the use of better proxies for dose in human epidemiology studies.