JENNIFER L. Gordon
$613,059
UNIVERSITY OF TEXAS MED BR GALVESTON
Texas
National Institute of Allergy and Infectious Diseases (NIAID)
SUMMARY: The Coronavirus disease 2019 virus (COVID-19) pandemic has made a devastating impact on global public health and economy over the past three years. Despite the success in rapid progress of COVID-19 vaccine development, increasing rates of variants of concern (VOCs) with enhanced viral transmission and disease severity, and/or ability to escape vaccine-induced immunity have challenged the global vaccine efficiency efforts. Continuous work toward optimizing existing vaccine platforms and development of more effective novel vaccines is needed. Intranasal immunization can lead to the induction of antigen-specific immunity in both the mucosal and systemic immune compartments, and thus is effective in control of SARS-CoV-2 infection and disease. However, most SARS-CoV-2 vaccines granted for emergency use authorization or in clinical trials are limited to parenteral delivery as soluble antigens do not breach the nasal epithelial barrier but are transported by microfold cells. We recently reported that a modified porous silicon microparticle (mPSM) adjuvant to SARS-CoV-2 receptor-binding domain (RBD) vaccine triggered potent and durable systemic humoral and type 1 helper T cell- mediated immune responses following parenteral vaccination. mPSM also facilitated mucosal uptake of SARS-CoV-2 RBD antigens. Two doses of parenteral and intranasal combined vaccinations with mPSM-RBD elicited more potent lung resident T and B cells and mucosal IgA responses than parenteral vaccinations alone, which led to markedly diminished viral loads and inflammation in the lung following SARS- CoV-2 Delta variant challenge. Our results suggest that mPSM is an effective adjuvant for SARS-CoV-2 subunit vaccine in both systemic and mucosal vaccinations. We also found that combinatorial mRNA- S+Nucleocapsid (N) vaccination provided stronger protection against Delta and Omicron variants infection than the clinically approved S-expressing mRNA vaccine alone. Thus, to further optimize the immunogenicity of mPSM-adjuvanted subunit vaccine, we will modify the formulation of antigens. Here, we hypothesize that parenteral and intranasal vaccination with mPSM-based subunit vaccine triggers durable systemic and mucosal immune responses which provide cross protection against SARS-CoV-2 VOCs infection and transmission. We will initially optimize the immunogenicity and test the safety of m-PSM subunit vaccines in mice (Aim 1). Next, we will study the protective efficacy of parenteral and intranasal vaccination with m-PSM subunit vaccine against SARS-CoV-2 VOCs infection in young and aged mice and identify the immune correlates of host protection (Aim 2). Lastly, we will confirm the immunogenicity of m-PSM subunit vaccine in hamsters and evaluate its efficacy on prevention of SARS-CoV-2 VOCs transmission and enhanced control of infection (Aim 3). The result of this project will be an effective SARS-CoV-2 vaccine candidate that induces balanced systemic and mucosal immunity, provides long-lived cross-reactive host protection against SARS- CoV-2 VOCs, and prepares us for future coronavirus outbreaks.