The COVID-19 pandemic began at the end of 2019 in Wuhan, China, and has spread throughout the world. Vaccination is still the most effective method of prevention of pathogenic infections, including viral infections. However, there is little evidence that vaccination can protect against SARS-CoV-2 virus for a long time. Thus, regular re-vaccination is necessary to control COVID-19. Vaccination by injection is invasive, and is one of the reasons people refuse to get re-vaccinated. Therefore, we developed a less invasive vaccine based on oral or nasal administration. The gene encoding the high conserved region (HCR) spike protein was inserted into pNZ8149 and expressed in NZ3900. Mice were immunized at 3-week intervals with oral or nasal routes. Anti-SARS-CoV2 spike antibody (IgG and IgA) level were measured using ELISA method before and after treatment. Plasma cells population in lymph were analyzed using flowcytometry and the CD4 + and CD8 + cells in lymph and intestine were analyzed using immunofluorescence method. The results of nasal and oral administration in experimental animals showed that carrying the HCR gene could induce a humoral immune response, as indicated by increased levels of IgG and IgA against SARS-CoV-2 (IgG/IgA-SARS-CoV-2). The plasma cell population after nasal and oral vaccination in mice were significantly different with control group (p < 0.05). The CD4 + and CD8 + cells in intestine were significantly higher in orally immunized group mice than control group. The CD8 + cells in lymph were significantly higher in intranasal immunized group mice than control group. Our data demonstrate expressing spike protein can be developed into a less invasive alternative to nasal and oral vaccination.