Plant-based edible vaccines that provide two-layered protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outweigh the currently used parenteral type of vaccines, predominantly causing a systemic immune response. Here we engineered and selected the transgenic tomato genotype (TOMOVAC), stably synthesising an antigenic S1 protein of SARS-COV-2. Two-course spaced force-feeding of mice with ≈5.4 µg/ml TOMAVAC increased up to 16-fold synthesis of RBD-specific NAbs in blood serums. TOMAVAC-induced NAbs had 15-25% viral neutralising activity in a surrogate virus neutralisation test. Results suggested early evidence of immunogenicity and protectivity of TOMAVAC against COVID-19 infection. Further, we observed a positive trend of statistically significant 1.2-fold (average of +42.28 BAU/ml) weekly increase in NAbs in the volunteers’ serum relative to the initial day. No severe side effects were observed, supporting the safety of TOMAVAC. TOMAVAC should be a cost-effective, ecologically friendly, and widely-applicable novel-generation COVID-19 vaccine, providing two-layered protection against SARS-CoV-2.