Researchers in Science Advances present their work developing a “highly modular saponin-based nanoparticle platform”. The platform incorporates Toll-like receptor agonists (TLRas), including TLR1/2a, TLR4a, and TLR7/8a adjuvants and their mixtures. These induce “unique acute cytokine and immune-signalling profiles”, which facilitate specific T helper responses. In a murine vaccine, study the adjuvants “greatly improved” the potency, durability, breadth, and neutralisation of COVID-19 and HIV vaccine candidates. The authors believe their work highlights the potential of a modular TLRa-SNP adjuvant platform for improving vaccine design.
Adjuvant demands
Although prophylactic vaccine development has been “at the heart of intensive scientific research for the past hundred years”, the authors suggest that the emergence of global pandemics has “catalysed their development”. However, “many” commercial vaccines have “complex manufacturing processes and potential safety hazards”. Protein-based subunit vaccines offer “desirable” safety, cost-effectiveness, scalability, and manufacturability characteristics. They leverage adjuvants to promote the “magnitude and durability” of the immune response.
Although “only a handful” of adjuvants are clinically licensed in vaccine formulations, the authors identify potential in Toll-like receptor agonists (TLRas). These differ in physical and chemical properties but activate different Toll-like receptors (TLRs) commonly expressed by antigen-presenting cells to “drive distinct immune signalling pathways”. These adjuvants have been the “primary focus” in vaccine design, but other noon-TLR-based adjuvants also present interest, including saponins like Quil-A. When delivered in nanoparticles (NPs), such as ISCOMATRIX, they are “well tolerated”.
Although the mechanism of immune stimulation of self-assembled saponin-based nanostructure adjuvants has “not yet been fully elucidated”, research indicates that they increase lymph flow and lymph node (LN) permeability, enhancing antigen acquisition by B cells in the draining LNs (dLNs). Furthermore, there is a clear advantage in NPs formulation for “stability, solubility, cellular uptake, immunogenicity, and safety”.
What does this research add?
The paper reports a “library” of saponin-based NP adjuvants incorporating various single or multiple clinically relevant TLRas (TLRa-SNPs) to generate a “broadly applicable” modular platform. Four formulations were generated, and all four elicited “improved humoral immune responses”.
The adjuvant platform combines three approaches:
- Molecular TLRa adjuvants resembling pathogen-associated molecular patterns found on bacteria, viruses, and other foreign invaders our immune system is trained to recognise
- Saponin adjuvants from natural sources that improve lymphatic flow
- Particulate design displaying both adjuvants together with improved trafficking kinetics and cellular uptake
Although previous studies have reported the design of combined TLR4a MPLA and saponins into NP constructs, the authors highlight that a “tunable” platform approach should consider other clinically relevant TLRas. Therefore, they demonstrated that lipid TLRas like MPLA and Pam3CSK4 can be “readily incorporated with clinically relevant stoichiometric ratios due to the hydrophobic nature of SNPs”. Nonlipid TLRas can be incorporated by conjugating a cholesterol motif with hydrophobic interactions with SNPs.
Dr Eric Appel, associate professor of material science and engineering at Stanford, is senior author of the paper. He comments on the “stronger, more robust immune responses” and states that the “breadth” of the platform “allows us to readily tune the type of immune response in a way that just was not feasible with previous technologies”.
“This can be a tool to understand how different types of immune responses give rise to better or worse protection – it was impossible to even ask that question before.”
Dr Appel highlights two key benefits from the research.
“This platform approach will open up opportunities for people in the field to ask more probing questions about what immunology works better in different contexts. And it’s also making significantly better adjuvants.”
PhD student in Appel’s lab and first author of the paper, Ben Ou, wanted to create a highly potent adjuvant to “activate different immune pathways and improve vaccine responses”.
“All of our adjuvants improve overall vaccine responses, but the specific types of improvements are different. If we know that a specific type of immune activation will confer better protection, we now have a platform that will allow you to pick the specific formulation that will drive that distinct response.”
Several sessions at the Congress in Barcelona will enable discussions on adjuvant potential and how to achieve it; get your tickets to join us here and don’t forget to subscribe to our weekly newsletters for more vaccine updates.
