Investigating the Mode of Action of Vaccine Adjuvants in Human Lymph Nodes Through High Parameter Imaging

Abstract

Adjuvants are added to vaccine formulations to steer and amplify immune responses, which is critical for inducing potent and robust responses to immunisation. Immune response priming after upper arm intramuscular vaccination takes place in axillary lymph nodes, where within the first 24 h, adjuvants act on innate immune cells. The Recombinant Zoster Vaccine (RZV) (Shingrix, GSK), is formulated with the adjuvant AS01 (GSK, Rixensart, Belgium), which contains MPL and QS-21 formulated in liposomes and is highly effective at preventing herpes zoster in older adults. In contrast, mRNA-lipid nanoparticle based vaccines do not adjuvants, but rather contain mRNA cargo within lipid nanoparticles. It is now appreciated that the lipid nanoparticles can also function as an adjuvant. mRNA vaccines can induce high levels of protective neutralising antibodies, but this response is not durable, waning over 6-8 months.

A more complete understanding of how human innate immune cells respond to these diverse adjuvants is crucial for their rational improvement. In isolated human blood derived antigen presenting cells, different lipid nanoparticle formulations induce similar low levels of cellular maturation and innate cytokine production, which may indicate that coordination with accessory cells in lymph nodes is required to induce more robust innate responses and subsequent optimal T cell priming.

In human lymph nodes, AS01-like liposomes are preferentially taken up by dendritic cells and macrophages, which is consistent with the initial events described in mice. Using an optimised Imaging Mass Cytometry panel, NK and CD8+ T cells were identified as an early (<24 h) source of IFNγ after AS01 treatment. Spatial analysis revealed an unexpected local relationship between IFNγ+ lymphocytes with plasmacytoid DCs. An expansive view of the interactions between different lymph node cell types, is vital for a more complete understanding of AS01’s mechanism of action in a human context.