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Currently, limited data exist regarding the pathological changes occurring during the incubation phase of SARS-CoV-2 infection. We utilized proteomic analysis to explore changes in the circulatory host response in individuals with SARS-CoV-2 infection before the onset of symptoms. Participants were individuals from a randomized clinical trial of prophylaxis for COVID-19 in a workers' dormitory. Proteomic signatures of blood samples collected within 7 days before symptom onset (incubation group) were compared with those collected >21 days (non-incubation group) to derive candidate biomarkers of incubation. Candidate biomarkers were assessed by comparing levels in the incubation group with both infected individuals (positive controls) and non-infected individuals (negative controls). The study included men (mean age 34.2 years and standard deviation 7.1) who were divided into three groups: an incubation group consisting of 44 men, and two control groups—positive (n = 56) and negative (n = 67) controls. Through proteomic analysis, we identified 49 proteins that, upon pathway analyses, indicated an upregulation of the renin-angiotensin and innate immune systems during the virus incubation period. Biomarker analyses revealed increased concentrations of plasma angiotensin II (mean 731 vs. 139 pg/mL), angiotensin (1–7) (302 vs. 9 pg/mL), CXCL10 (423 vs. 85 pg/mL), CXCL11 (82.7 vs. 32.1 pg/mL), interferon-gamma (0.49 vs. 0.20 pg/mL), legumain (914 vs. 743 pg/mL), galectin-9 (1443 vs. 836 pg/mL), and tumour necrosis factor (20.3 vs. 17.0 pg/mL) during virus incubation compared with non-infected controls (all p < 0.05). Plasma angiotensin (1–7) exhibited a significant increase before the onset of symptoms when compared with uninfected controls (area under the curve 0.99, sensitivity 0.97, and specificity 0.99). Angiotensin (1–7) could play a crucial role in the progression of symptomatic COVID-19 infection, and its assessment could help identify individuals who would benefit from enhanced monitoring and early antiviral intervention. [ABSTRACT FROM AUTHOR]