Toll-like receptor (TLR) and saponin adjuvants have each improved vaccine potency and safety. Now, researchers at Stanford University report that combining them in a nanoparticle format improves not only potency, but also durability, target breadth, and degree of virus neutralization.
A modular approach makes it possible to fine-tune adjuvants by mixing and matching saponin nanoparticles (SNPs) and TLR adjuvants in the same nanostructure to elicit tailored immune responses, according to a recent paper by Eric Appel, PhD, associate professor of materials science and engineering at Stanford University, senior author, and Ben Ou, first author and a doctoral student in the Appel Lab.
The TLRa-SNP adjuvants “elicited different levels of IgG isotypes,” the scientists reported. Some, for example, generated IgG1 responses comparable to those generated by SNPs, while one caused an order of magnitude greater IgG1 response. All TLRa-SNP adjuvants, however, elicited at least five-fold higher IgG2c titers than SNPs, however.
The scientists created four types of TLRs: Pam3CSK4, Monophosphoryl-Lipid A (MPLA), an imidazoquinoline derivative, and a combination of the imidazoquinoline derivative and MPLA. Each was combined with a saponin and used as an adjuvant in SARS-CoV-2 and HIV vaccines. In mice, each formulation elicited more robust humoral responses than either the saponin nanoparticles (ISCOMATRIX™) or aluminum hydroxide/alum adjuvants without the TLRs.
Broad, durable binding
“We expected an increase of broadly neutralizing antibodies and better breadth of responses,” Ou says. “Nonetheless, we were pleasantly surprised…that our nanoparticle adjuvant could bind strongly to even the most immune-evasive variants, such as the beta and omicron variants [of SARS-CoV-2].
Compared to SNP adjuvants, the TLRa-SNPs adjuvants caused about 50% more antigen to accumulate in the draining lymph nodes. Additionally, the immunized mice showed “significantly higher anti-RBD IgG endpoint titers at all time points after [the boost]” with little variation among animals.
Even one year later, the average titer concentration values (EC50) among mice immunized using the TLRa-SNP adjuvants were an order of magnitude higher than those of SNP or aluminum hydroxide/alum adjuvants. For context, titers for the aluminum/alum adjuvant declined 24-fold and those of saponin nanoparticles declined 13-fold during the year. TLRa-SNPs’ titers remained high, however, declining only by five- to seven-fold.
Importantly, researchers found zero infectivity at week five among mice receiving the TLRa-SNPs vaccines. Infectivity of human convalescent plasma, in contrast, averaged 15%.
“Nanoparticle-based vaccine adjuvants already exist in the market, so adopting our adjuvant should not affect vaccine manufacturing,” Ou says. They fit into the normal pharmaceutical temperature supply chain, too, remaining stable for several months at -20°C, and for at least six weeks at 4°C.
