Document text
Principal Investigator: Gundeep Singh Dhillon
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $412,076
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY / ABSTRACT
Lung transplantation (LT) recipients suffer from life-threatening pulmonary infections that can trigger acute
rejection and death. Although vaccination is the most effective way for preventing infections, vaccine efficacy is
limited in immunocompromised solid organ transplant recipients. Two recent JAMA studies suggest that most
transplant recipients fail to mount antibody responses to SARS-CoV-2 mRNA vaccines; anti-metabolite
immunosuppressants further dampened this response. To facilitate more effective vaccination strategies,
there is an urgent unmet need to understand vaccine responses in immunosuppressed LT recipients.
Adopting a system vaccinology approach, this grant characterizes complex vaccine-elicited immune responses
to address the problem of deficient vaccine immunogenicity in LT recipients. As the COVID-19 pandemic
heightens focus on the vulnerability of LT recipients, the creation of a vaccine-oriented biobank to facilitate
system biology analyses can strengthen the newly-formed NIH LT Consortium.
In this proposal, we unite physicians/scientists from Stanford, Inova-Fairfax, and Houston Methodist to build a
vaccination-oriented biorepository as the focus of a clinical center (CC). Responding to the RFA to explore
center-specific hypotheses, our CC seeks an answer to the pressing question: ‘how do LT recipients respond to
vaccinations?’ The grant hypothesis is that a vaccination-oriented biorepository will facilitate the holistic
analysis of influenza vaccine-induced immune responses in LT recipients from geographically distant
regions and that the use of an anti-metabolite immunosuppressant predicts reduced protective innate
and adaptive responses in these patients. In Aim 1, biospecimens from patients immunized by vaccines
against COVID-19, varicella-zoster, pneumococcus, and influenza will be prospectively collected and banked to
generate the biorepository. To address hypothesis-driven questions achievable with a modest budget, Aim 2
uses system vaccinology tools to evaluate the influenza vaccines, the most common vaccinations administered
to LT patients. Aim 2a characterizes humoral and innate immunity, Aim 2b focuses on cellular immunity, and
Aim 2c builds a vaccine response network with bioinformatics tools. Aim 2 will also assess whether the use of
an anti-metabolite as immunosuppression reduces influenza vaccine immunogenicity. The rationale for focusing
on influenza over COVID-19 is that most patients will be vaccinated against the latter when this project begins.
However, our CC is well-equipped to test other types of vaccinations when future initiatives are available. In
addition to fostering interactions and shared resources within the LT Consortium, the main purpose of the
Stanford CC is to improve vaccine designs, adjuvants, and administration protocols in at-risk LT patients through
an improved understanding of immune responses. Information gleaned here can inform and improve vaccination
efforts for all immunosuppressed patients.
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