Long-term Functional and Epigenetic Changes in Adult Monocytes Induced by AS01-adjuvanted Vaccine

Background:

Vaccine adjuvants are widely used to enhance the immune response of vaccines. In particular, the AS01 adjuvant, a key component in several approved vaccines, has demonstrated high immunogenicity and efficacy. AS01 exerts its adjuvant effect by activating the innate immune system, but its specific impact on innate cell function and epigenetic remodeling remains unclear. Therefore, Bechtold et al. focused on investigating the long-term functional changes and epigenetic alterations in monocytes and dendritic cells (DCs) induced by AS01-adjuvanted vaccines.

Paper Source:

This paper was written by Viviane Bechtold, Kinga K. Smolen, et al., from GSK, Université Libre de Bruxelles, and other research institutions. It was published in Science Translational Medicine on July 31, 2024, with the paper number eadl3381.

Research Process:

The study involved healthy adults and used a model vaccine containing hepatitis B surface antigen and AS01, with an aluminum-adjuvanted vaccine as a control. The research was conducted in multiple steps, including:

a) Workflow: The study included multiple steps from vaccination to blood sample collection, and gene expression and epigenetic analysis. The main techniques used were: 1. Sample collection and processing: Participants received vaccinations on Day 0 and Day 30, followed by periodic blood sample collection. 2. Flow cytometry analysis: Used to detect changes in the number and phenotype of monocytes and DCs after vaccination. 3. RNA sequencing (RNA-seq): Used to analyze gene expression changes in monocytes after vaccination. 4. Single-cell ATAC sequencing (scATAC-seq): Used for chromatin accessibility detection at the single-cell level to analyze epigenetic changes.

b) Main Results: 1. Changes in monocyte numbers and phenotype: Two days after AS01-adjuvanted vaccination, the number of intermediate monocytes increased significantly, with phenotypic changes showing increased HLA-DR expression, correlating with the strength of CD4+ T cell memory responses.

1. Gene expression changes: RNA-seq analysis showed that on Day 32 after the second dose of vaccine, gene expression in monocytes was generally downregulated, involving inflammatory responses, NF-κB signaling pathways, and oxidative phosphorylation.

2. Functional changes: The study found that after AS01-adjuvanted vaccination, monocytes showed reduced pro-inflammatory responses to TLR activation but enhanced responses to IFN-γ.

3. Epigenetic changes: scATAC-seq analysis revealed that after AS01-adjuvanted vaccination, especially on Day 32, chromatin accessibility in CD14+ monocytes and DCs changed, reflected in the accessibility of key transcription factors, with some epigenetic changes persisting for up to 6 months.

Conclusions and Research Value:

The study shows that AS01-adjuvanted vaccines can not only enhance adaptive immune responses through antigen-specific protection but also produce lasting innate responses by reprogramming monocytes. These changes enhance monocytes’ response to IFN-γ and promote antigen presentation, potentially significant for long-term vaccine protection and non-specific protection.

Research Highlights:

• Monocyte reprogramming: First demonstration of AS01-adjuvanted vaccines achieving reprogramming by affecting gene expression and chromatin accessibility in monocytes.
• Persistence of epigenetic changes: Epigenetic alterations can persist for up to 6 months, revealing the long-term impact of vaccines.
• Enhanced IFN-γ response: This may explain how AS01-adjuvanted vaccines improve innate immune system function while enhancing adaptive immunity (such as CD4+ T cell responses).

Other Valuable Information:

The study also showed that aluminum-adjuvanted vaccines did not demonstrate the same degree of innate immune system activation and epigenetic changes compared to AS01-adjuvanted vaccines. This finding may guide future vaccine adjuvant design and application, especially in research on enhancing vaccine long-term efficacy.

Bechtold et al.’s research, through detailed experimental design and multiple analytical methods, brings important findings about AS01-adjuvanted vaccines, enriching our understanding of the mechanisms of vaccine adjuvants, and has significant scientific and application value.