The researchers began by screening more than 200,000 small molecules from a Harvard Medical School library in human immune cells — specifically, in primary peripheral blood mononuclear cells, obtained from donors and cultured in their own plasma using a method developed within the Precision Vaccines Program. This yielded about 25 confirmed hits, with PVP-037 being the most active.
PVP-037 belongs to a family of molecules called imidazopyrimidines, which the study found to be active immunomodulators. PVP-037 and its analogs target the innate immune system, stimulating the pattern-recognition receptors TLR7 and TLR8 on antigen-presenting cells such as monocytes and dendritic cells.
“Screening small molecules against human primary cells is messier than using a homogenous cell line, because each individual is different,” says Levy. “But that’s the whole point: It’s more reflective of human biology. A good adjuvant needs to be able to work across diverse populations. PVP-037 would not have been discovered by screening cell culture lines.”
An optimized version of PVP-037 demonstrated broad innate immune activation in the donor immune cells, inducing NF-κB and production of TNF and other cytokines, signaling molecules that rally a wider immune response. Notably, PVP-037 did not provoke such a response in cultured cell lines. In live mice, it enhanced antibody responses against influenza and SARS-CoV-2 vaccine proteins.
Especially exciting to Levy and Dowling is that in addition to inducing robust immune activity, the compound is stable, easy to work with, and lends itself to chemical optimization for medical use. It can be formulated in most standardly-used drug delivery systems, such as oil-in-water emulsions.
“We did something special with the discovery of PVP-037,” says Dowling. “Our work essentially condensed the full vaccine development pipeline — including analog optimization, establishing the mechanism of action, and creating an optimized formulation.”
