In vaccinology, inducing durable protective immunity is a major challenge. It is generally believed that protection against infection is mainly achieved through antibodies, which prevent host cells from becoming infected. Some live attenuated vaccines (such as smallpox and yellow fever vaccines) induce durable antibody responses that can last a lifetime; however, in other types of vaccines, including inactivated subunit vaccines for seasonal influenza, pertussis vaccines, Salmonella typhi, Neisseria meningitidis vaccines, as well as RTS,S malaria vaccines and some candidate vaccines against HIV, the phenomenon of waning antibody responses has been widely documented. Why some vaccines provide lifelong protection while others only protect for a few months remains a major unsolved mystery in immunology.

An adjuvant is a component of a vaccine that enhances the strength and durability of the immune response. For more than 70 years, insoluble aluminum salts (alum) have been the only approved adjuvants. However, the number of adjuvants approved for use in vaccines has grown significantly over the past three decades. These adjuvants include oil-in-water emulsion adjuvants for influenza vaccines (such as MF59 and AS03), adjuvants containing the TLR4 agonist 3-O-deacylated-4'-monophosphoryl lipid A (MPL) (such as AS01 and AS04, widely used in respiratory syncytial virus, herpes zoster and human papillomavirus vaccines), TLR9 agonist CpG oligonucleotides (CpG 1018, used in hepatitis B vaccine HepB-CpG), and recently applied to recombinant COVID vaccines and R21 malaria vaccines. The saponin-based adjuvant Matrix M. Despite such great developments in adjuvant technology, the molecular mechanisms of most adjuvants are still poorly understood.

On January 2, 2025, Bali Pulendran's team at Stanford University published an article titled System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans in Nature Immunology. This study revealed the key role of platelets and megakaryocytes in enhancing the durability of vaccine antibody responses through systematic vaccinology analysis, and developed a transcriptional signature-based model that can predict the persistence of antibody responses across multiple vaccines.

The authors randomly divided 50 healthy volunteers (aged 21-45 years) into two groups and received two doses of H5N1 vaccine (21 days apart), of which 34 received AS03 adjuvanted vaccines and 16 received unadjuvanted vaccines. Peripheral blood mononuclear cell (PBMCs) samples were collected to analyze gene expression, immune cell activation, antibody levels, and neutralizing capacity at different time points before and after vaccination. The results showed that the AS03 adjuvanted vaccine induced a stronger early transcriptional response, higher levels of neutralizing antibodies, and faster T and B cell activation. The immune response of the unadjuvanted group was significantly weaker than that of the adjuvanted group, and a second vaccination was required to achieve a lower level of immune activation.

The authors then explored the molecular features associated with the durability of antibody responses through transcriptomics and gene set enrichment analysis. Using machine learning methods, models were trained on clinical trial data of multiple vaccines to predict antibody durability. The generalization ability of the model was verified, including applications in other vaccines (such as COVID-19 mRNA vaccines, malaria vaccines, etc.). The authors found a gene module related to platelet activation and cell adhesion (such as the M196 module) that can be used to predict the durability of antibody responses. This platelet-related molecular feature is a universal durability prediction marker across vaccines.

In a mouse model, megakaryocytes in the bone marrow were activated by injection of TPO (thrombopoietin). In in vitro experiments, bone marrow megakaryocytes and bone marrow plasma cells isolated from humans or mice were co-cultured to evaluate the support of megakaryocytes for plasma cell survival and antibody production. Anti-APRIL and anti-IL-6 neutralizing antibodies and Transwell experiments were used to verify whether the interaction between megakaryocytes and plasma cells depends on direct contact and secreted factors. The analysis found that megakaryocytes significantly enhanced the survival and antibody production of plasma cells by secreting APRIL and IL-6. TPO injection to activate megakaryocytes can significantly improve the persistence and titer of antibodies after vaccination.

The authors also used CITE-seq technology to analyze single-cell transcriptome and proteome data from H5N1 vaccine subjects (persistent and attenuated antibody response groups). Single-cell gene expression in the persistent response group and the attenuated response group was compared to identify key differential genes and modules. The results showed that the transcriptional signature of antibody durability was mainly derived from platelet gene expression, especially genes related to cell adhesion and activation. Plasma cells in the persistent response group showed higher metabolic activity and mitochondrial function, such as enhanced oxidative phosphorylation, which is closely related to antibody production.

Finally, the authors tested platelet-related predictive gene signatures in the rhesus monkey model. The changes in antibody persistence after vaccination were compared to verify the applicability of the predictive model. The results showed that platelet-related gene signatures were once again verified as reliable predictors of antibody durability in the rhesus monkey model. The consistency of results in different experimental systems further supports the core role of platelets and megakaryocytes in vaccine durability.

These experiments revealed the core role of platelets and megakaryocytes in antibody durability, and developed molecular signatures for predicting antibody durability across vaccines through multi-omics and machine learning models. This provides new strategies for designing more effective and long-lasting vaccines.

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