Awarded Pilot Projects
2023-2024
Novel Nasal Vaccine Strategy Using Galectin-1
Minsoo Kim, Ph.D. – Professor, Department of Microbiology and Immunology, Center for Vaccine Biology and Immunology (SMD)
Summary: Despite the availability of antiviral drugs and vaccines against seasonal strains, the influenza virus causes widespread infection, leading to more than 35,000 deaths in the United States annually. Emerging data suggest that mucosal vaccination against respiratory pathogens can elicit tissue resident immunity to prevent or eliminate infection at the site of entry. Intramuscular vaccines do not elicit tissue resident memory T (TRM) cells, while intranasal delivery of the live attenuated vaccine generate both neutralizing antibodies and lung TRM cells. Indeed, current intramuscular SARS-CoV-2 vaccines can prevent severe illness and mortality but lack substantial efficacy in preventing upper respiratory infection and viral transmission. A live-attenuated influenza vaccine (LAIV), in the form of a nasal spray, mimics a natural infection, which brings the advantage of triggering mucosal immunity to block primary infections within the airway epithelia. However, immunization of the respiratory tract with LAIV often results in inadequate protection. For example, the CDC recommended against using LAIV for the 2016 -18 seasons, and the 2021-2022 nasal vaccine was only <10% effective. Therefore, new nasal vaccine strategies are needed to establish robust mucosal immune responses. In preliminary studies for this project, we tracked the fate of diverse myeloid cells in the lung after influenza infection and discovered that a subset of newly recruited monocytes differentiates and persists in the mouse lung for more than 4 months after infection. Surprisingly, selective depletion of the novel monocyte subset significantly reduced TRM formation. This long-lasting monocyte subset produces a high level of galectin-1 (Gal-1), which directly activates CD2 expressed on CD8 T cells and enhances TRM-mediated sensing of TGF-b, a key cytokine that promotes virus-specific memory T cell differentiation and tissue persistence. Based on these findings, we hypothesize that a long-lasting monocyte subset with characteristics similar to innate immune memory is formed in the lung after influenza infection and supports the development of effective T cell memory response by producing a key immune mediator, Gal-1. In this proposal, (1) we will investigate how Gal-1 induces a robust CD8 TRM formation in the lung after LAIV immunization. (2) We will also test whether a novel recombinant mutant Gal-1 variant (“Tri-PEG-Tri Gal-1”) improves the LAIV vaccine efficacy. The results of these studies will provide a useful scientific basis with which to design vaccine strategies capable of establishing productive crosstalk between components of innate and adaptive immunity, leading to the induction/maintenance of durable immunity. Such results may have a tangible and significant impact on vaccine strategies against other respiratory viruses.
Immunological Response Following mRNA-Based Vaccination in Subjects with Chronic Obstructive Pulmonary Disease
Manoj J. Mammen, M.D. - Associate Professor, Department of Medicine, Pulmonary Diseases and Critical Care (SMD)
Summary: Chronic obstructive pulmonary disease (COPD) is a global public health concern, ranking as the third leading cause of death. COPD exacerbations contribute significantly to morbidity, mortality, and healthcare utilization, with respiratory viruses implicated in up to one-third of exacerbations.
mRNA vaccines, encoding viral glycoproteins, offer potential protection against viral infections associated with COPD exacerbations, including influenza, COVID-19, and respiratory syncytial virus. The rapid production capacity of mRNA vaccines allows for timely strain matching. However, understanding the post-vaccination host responses, specifically the innate immunity pathways remain a critical research gap. This knowledge can enhance future vaccine trial design for COPD populations.
This work is directed at identifying the mechanistic underpinnings of these innate immune responses in response to mRNA vaccination in COPD patients. The mRNA vaccines have been optimized to balance the innate immune response in healthy controls, it is uncertain if there is an optimal balanced for patients with COPD given their dysregulated innate immunity. Better understanding of the response of the mRNA vaccine in individuals with COPD may optimize design of mRNA vaccines for better protection for that subpopulation.