As experienced in the SARS-CoV-2 pandemic, intramuscular immunization does not provide sufficient protection against breakthrough infection and transmission, especially regarding emerging virus variants. Therefore, optimized vaccine approaches should induce – besides systemic immunity - local immunity in the respiratory tract in the form of secretory IgA antibodies and tissue-resident memory T cells. Currently, the main obstacle of mucosal immunizations is to elicit a robust and long-lasting immune response. Preclinical studies have shown that a combination of an intramuscular mRNA prime with an adenoviral mucosal boost immunization results in both systemic and mucosal immunity against SARS-CoV-2 variants. Based on these experiments, we want to investigate the functionality and longevity of the induced immune response in this heterologous prime-boost model in mice. Furthermore, we want to optimize mucosal immunization by expanding the breadth and intensity of the humoral and cellular response by immunizing against different virus variants and proteins, and exploring adenoviral vectors encoding cytokines/chemokines as adjuvants in the mucosal boost immunization. As alternative to the adenoviral vector vaccines, live-attenuated viruses will be exploited as mucosal booster component. We will thereby investigate the T-cell and antibody response against different epitopes and SARS-CoV-2 variants. Furthermore, functionality of the immune response will be analyzed in homologous and heterologous challenge experiments. Our detailed determination of the stimulated immune response will serve as basis for clinical studies and for the development of vaccination strategies against other pathogens that enter the organism via the mucosal barrier.
