Innate Immune Memory Modulation Through Vaccination

The traditional view that only adaptive immunity can form long-lasting memory has been upended by evidence that innate cells also undergo persistent functional reprogramming following an initial stimulus. Vaccines such as Bacillus Calmette-Guérin (BCG) or novel pattern recognition receptor ligands initiate metabolic and epigenetic changes that endow monocytes, macrophages and dendritic cells with enhanced responsiveness on re-encountering pathogens. This “trained immunity” leverages shifts in cellular metabolism—commonly from oxidative phosphorylation to aerobic glycolysis—and histone modifications at key cytokine gene loci. Globally, the capacity to modulate innate immune memory has profound implications for reducing all-cause mortality in neonates, augmenting responses to unrelated infections and improving efficacy of next-generation vaccine formulations. By harnessing non-specific protective effects through rational design of adjuvants and prime-boost schedules, researchers aim to deliver broad-spectrum resistance against emerging pathogens and to refine strategies for combating chronic inflammatory and autoimmune conditions.

Research from Nature Portfolio

Outcomes of a controlled human malaria infection trial demonstrate that BCG vaccination accelerates clinical and cellular responses during Plasmodium falciparum challenge. Vaccinated volunteers exhibited earlier natural killer cell activation and monocyte phenotypic changes, with an inverse correlation between innate activation markers and parasitaemia, confirming that BCG can reprogramme innate defences in vivo to affect disease course. In parallel, an experimental immunisation study has shown that dendritic cells can be imprinted with memory-like features. Following protective vaccination against a fungal pathogen, isolated dendritic cells displayed sustained upregulation of interferon signalling pathways and produced heightened cytokine responses upon restimulation—an effect abrogated by inhibitors of specific histone modifications—thereby providing proof of principle that vaccination strategies can deliberately induce durable innate memory in antigen-presenting cells.

Research from all publishers

A longitudinal multi-omics study of healthy adults receiving BCG mapped chromatin accessibility and transcriptional changes over three months, revealing that baseline epigenetic landscapes predict the magnitude of trained immunity. Individuals with a quiescent chromatin state at rest experienced a more pronounced heterologous innate boost, highlighting the potential for personalised vaccine regimens based on epigenetic profiling. In a high-mortality Ugandan birth cohort, early administration of BCG at birth was associated with a significant reduction in non-tuberculous infections during the neonatal period compared with delayed vaccination. This protection correlated with inhibition of developmental increases in histone trimethylation at pro-inflammatory cytokine promoters, supporting the prioritisation of neonatal BCG to harness non-specific innate memory for public-health benefit.

Innate Immune Memory Modulation Through Vaccination publication trend

The graph below shows the total number of articles in innate immune memory modulation through vaccination across all publications each year (not limited to Nature Index journals).

Technical terms

Trained immunity: A form of innate immune memory in which prior stimulation induces persistent functional enhancement of innate cells.

Epigenetic reprogramming: Durable alterations in chromatin structure or DNA modifications that regulate gene expression without changing the DNA sequence.

Pattern recognition receptors (PRRs): Germline-encoded receptors on innate cells that detect conserved microbial or damage-associated molecular patterns to initiate immune responses.

Histone modifications: Post-translational chemical changes to histone proteins (for example, methylation or acetylation) that influence chromatin accessibility and gene transcription.

References

1. The Intersection of Epigenetics and Metabolism in Trained Immunity. Immunity (2020).
2. Trained Immunity-Based Vaccines: A New Paradigm for the Development of Broad-Spectrum Anti-infectious Formulations. Frontiers in Immunology (2018).
3. Outcomes of controlled human malaria infection after BCG vaccination. Nature Communications (2019).
4. Induction of memory-like dendritic cell responses in vivo. Nature Communications (2019).
5. Multi-omics analysis of innate and adaptive responses to BCG vaccination reveals epigenetic cell states that predict trained immunity. Immunity (2024).
6. BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial. The Lancet Infectious Diseases (2021).