Defining vaccine immunogenicity and adoptive transfer in hematopoietic stem cell transplant recipients - PROJECT SUMMARY Allogeneic hematopoietic stem cell transplant (HCT) recipients are at high risk of severe morbidity and mortality due to respiratory viral illnesses, including COVID-19. Despite two mRNA SARS-CoV-2 vaccines that are highly effective for the general population, HCT recipients have reduced immune responses to vaccines and remain at risk. This population’s ongoing risk is amplified by the emergence and circulation of SARS-CoV- 2 variant strains, relaxation of mask mandates and other public health measures, and waning effectiveness of SARS-CoV-2 monoclonal antibodies. New vaccination strategies are urgently needed for patients with hematologic malignancies, both to protect these patients and to reduce viral reservoirs that otherwise would allow for generation of new variants. To inform these strategies, we will evaluate the unique role of adoptive transfer of humoral and cellular immunity in HCT recipients, which will simultaneously use vaccine response as a mechanism to evaluate immune reconstitution. These studies will test our overarching hypothesis that these patients have distinct and altered immune responses to mRNA SARS-CoV-2 vaccination, resulting from their underlying disease, past immunomodulatory therapies, and the unique donor-to-recipient immune dynamics. The Specific Aims of this proposal are: Aim 1: Characterize the relationship between donor and recipient SARS-CoV-2 immunity in matched-related donor allogeneic HCT patients through analysis of humoral responses and transfer of immunity post-transplant from banked samples; Aim 2: Describe the correlation between donors’ pre-harvest cellular responses and recipients’ post-transplant humoral SARS-CoV-2 vaccine responses through creation of a prospective study of HCT recipients and their matched-related donors; and Aim 3: Evaluate donor v. recipient Ag-specific T and B cells and SARS-CoV-2 clonal breadth and depth after re-vaccination post-transplant to assess immune reconstitution, using T and B cell receptor repertoire analyses methods. We expect that completion of these aims and the associated training objectives will generate clinically applicable preliminary data to inform vaccine development and policy for patients with hematologic malignancies. My long-term career goal is to become an independently funded clinician-scientist and leader in translational vaccinology with a focus on developing precision vaccines for immunocompromised adults. I will achieve this through: 1) investigation of immunologic pathways that promote or inhibit vaccine-induced responses for patients with hematological malignancies, and 2) translation of these findings into novel vaccines via early-phase clinical trials. Brigham and Women’s Hospital and the Precision Vaccines Program at Boston Children’s Hospital are highly collaborative research environments within the broader Harvard Medical School community that will provide abundant resources and institutional support to complete the described aims.
