Modulation of the bone marrow landscape by vaccine adjuvants 2246451

Abstract Introduction Vaccination against influenza virus is currently the best strategy to lessen disease burden. The low immunogenicity of the subunit vaccines and variation in efficacy highlight the need for vaccine adjuvants. Rational vaccine design over the past decades has produced novel adjuvants, such as TLR7/8 agonists, aimed at eliciting Type 1 immune responses, like host responses against viral infections. TLR7/8 agonists induce type 1 IFNs which can have profound effects on hematopoietic stem and progenitor cells (HSPCs) in bone marrow. Methods We aimed to evaluate how the TLR7/8 agonist, IMDQ-PC, designed to adjuvant the inactivated influenza vaccine, affects HSPCs and hematopoietic output. C57BL/6 mice were vaccinated via the intramuscular route with the quadrivalent inactivated influenza vaccine (QIV) with or without IMDQ-PC or with PBS, and HSPCs in bone marrow were characterized using flow cytometry. Results Vaccination with IMDQ-PC significantly lowers the frequency of monocytes in bone marrow while increasing their frequency in the blood at day 5, indicative of increased egress into the periphery. IMDQ-PC also increased the number of phenotypic LSKs and upregulates Sca-1 expression on downstream progenitors for up to 14 days post vaccination, suggesting type 1 IFN signaling in the bone marrow. Furthermore, mice vaccinated with IMDQ-PC displayed a transient drop in phenotypically quiescent long-term HSCs compared to QIV or PBS vaccinated mice, potentially caused by a burst of increased differentiation. Conclusion These results suggest that IMDQ-PC triggers a type 1 IFN response that reaches HSPCs in the bone marrow, altering surface marker expression and inducing emergency myelopoiesis. Whether IMDQ-PC itself enters the bone marrow and whether HSPCs are being directly or indirectly signaled by type 1 IFNs is the focus of ongoing research. These findings provide insight into the working mechanism of vaccine adjuvants and their potential safety considerations. Funding Source 5T32AI078892-17 Topic Categories Vaccines and Immunotherapy (VAC)