This study, through systems vaccinology analysis, reveals the potential of platelet and cell adhesion-related transcriptional signatures in predicting antibody durability across multiple vaccines. It further demonstrates that TPO-activated megakaryocytes enhance vaccine-induced antibody persistence, providing new molecular mechanisms and predictive biomarkers for vaccine design.
Literature Overview
This paper, titled 'System Vaccinology Analysis of Predictors and Mechanisms of Antibody Durability to Multiple Vaccines in Humans', published in Nature Immunology, reviews and summarizes the mechanisms underlying antibody durability induced by various vaccines. Particularly, it highlights how the AS03 adjuvant significantly enhances the durability of antibody responses in the H5N1 influenza vaccine. Using multi-omics analysis, the research team identified platelet- and cell adhesion-related transcriptional signatures that can predict the durability of antibody responses. These findings were further validated in mouse and non-human primate models, which confirmed the critical role of TPO-activated megakaryocytes in bone marrow plasma cell survival and sustained antibody production. Additionally, the study applied machine learning methods to develop a classifier capable of predicting antibody durability across multiple vaccines, underscoring the conservation of this mechanism and offering theoretical foundations for future vaccine adjuvant and immune-enhancement strategies.Background Knowledge
Inducing long-term protective immunity remains one of the key challenges in vaccine research. Although adjuvants like AS03 are known to enhance antibody responses, their precise molecular mechanisms remain incompletely understood. Platelets, produced by megakaryocytes in the bone marrow, were traditionally viewed as primarily involved in hemostasis, but recent studies suggest their participation in immune regulation. This study, through systems-level analysis, first revealed a link between platelet-related transcriptional signatures and antibody durability. Animal and in vitro models further demonstrated that TPO-mediated megakaryocyte activation promotes plasma cell survival. This mechanism is conserved across multiple vaccines, except for the yellow fever vaccine YF-17D, which naturally induces durable antibody responses. The study also identified that cell adhesion-related genes, such as CTTN, CDHR5, and MYLK, along with platelet-highly expressed genes like SELP, PROS1, and PF4, are significantly associated with antibody durability. These findings provide new biomarkers and potential intervention targets for vaccine design, while also offering novel insights into the mechanisms of adjuvant action.
Research Methods and Experiments
The research team conducted a randomized controlled clinical trial in which 50 healthy adults received two doses of the H5N1 influenza vaccine in a 2:1 ratio. Among them, 34 individuals received the AS03 adjuvant, while 16 received the vaccine without adjuvant. Peripheral blood mononuclear cell (PBMC) samples were collected at baseline and at various time points post-vaccination (day 1, day 3, day 7, day 21, day 28, etc.) for transcriptomic profiling, flow cytometry, and SPR analysis. In addition, the team employed CITE-seq technology to analyze both transcriptional and protein expression profiles in PBMCs from individuals with durable versus waning antibody responses, and applied machine learning to develop a predictive model. In mouse models, the effects of TPO-activated megakaryocytes on antibody durability were evaluated. In vitro co-culture experiments further explored the cellular interaction mechanisms between megakaryocytes and plasma cells.Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to demonstrate the role of platelets and megakaryocytes in regulating vaccine-induced antibody durability, offering new molecular targets for adjuvant design. Future vaccine strategies may exploit platelet-related pathways or megakaryocyte activation to enhance long-term immunity. Furthermore, this transcriptional signature may serve as an early predictor in clinical vaccine trials, enabling optimization of vaccine development. The research team recommends further exploration of the mechanism’s applicability in other vaccines and disease models to assess its generality and specificity, and to evaluate its performance in diverse populations.
Conclusion
This study, employing multi-omics and systems vaccinology approaches, identified platelet- and cell adhesion-related transcriptional signatures as key predictors of vaccine-induced antibody durability. It demonstrates that megakaryocyte activation via TPO enhances plasma cell survival and sustains antibody responses. This mechanism is conserved across multiple vaccines, though not evident in YF-17D, likely due to its naturally durable immune response. Moreover, machine learning models based on day 7 transcriptional data can effectively forecast antibody durability, offering new biomarkers and intervention strategies for vaccine clinical trials. These findings provide important theoretical foundations for future vaccine design and adjuvant development, and highlight the underappreciated immunomodulatory role of platelets, warranting further investigation into their role in other immune responses.
