Promising discovery and optimization of vaccine adjuvants

Many vaccines are only partially effective, have decreasing effectiveness, or do not work well in the very young or very old. For more than a decadeDoctor of Medicine and Doctor of Philosophy Ofer LevyAnd David Dowling, Ph.D.in the Precision Vaccine Program at Boston Children’s Hospital, have tried to improve vaccines by adding compounds known as adjuvants to boost immune responses in vaccine recipients.

Thanks to a major Adjuvant Discovery Program contract from the National Institute of Allergy and Infectious Diseases (NIAID), they identified a promising new adjuvant, called PVP-037. This discovery is published in Science Advances.

“In principle, this compound can be added to any vaccine to enhance its action,” said Levy, who leads the precision vaccines program. “Adjuvants are like fuel for the immune system. PVP-037 is one of the most active adjuvants we have discovered, and we believe it induces a larger, longer-lasting, and broader immune response to vaccines.”

Robust innate immune responses

The researchers began by screening more than 200,000 small molecules from a Harvard Medical School library in human immune cells, specifically primary peripheral blood mononuclear cells obtained from donors and cultured in their own plasma using a method developed within the framework of the Precision Vaccines programThis resulted in around 25 confirmed hits, with PVP-037 being the most active.

PVP-037 belongs to a family of molecules called imidazopyrimidines, which the study suggests are active immunomodulators. PVP-037 and its analogues target the innate immune system, stimulating pattern recognition receptors TLR7 and TLR8 on antigen-presenting cells such as monocytes and dendritic cells.

“Screening small molecules in primary human cells is more complicated than using a homogeneous cell line because every individual is different,” Levy says. “But that’s the point: it better reflects human biology. A good adjuvant should be able to work in 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 donor immune cells, inducing NF-κB and the production of TNF and other cytokines, signaling molecules that trigger a broader immune response. Notably, PVP-037 did not elicit such a response in cultured cell lines. In living mice, it enhanced antibody responses against influenza and SARS-CoV-2 vaccine proteins.

Levy and Dowling found it particularly interesting that in addition to inducing robust immune activity, the compound is stable, easy to use, and amenable to chemical optimization for medical use. It can be formulated into most commonly used drug delivery systems, such as oil-in-water emulsions.

“We have achieved something special with the discovery of PVP-037,” Dowling says. “Our work has essentially condensed the entire vaccine development process, including optimizing the analogue, establishing the mechanism of action, and creating an optimized formulation.”

On the program: tests against flu, whooping cough and fentanyl

Boston Children’s holds several patents on these discoveries, of which Levy and Dowling are inventors. With support from NIAID, they plan to evaluate PVP-037 across all age groups and test its ability to enhance immune responses to influenza and pertussis vaccines, as well as Opioid vaccine aims to prevent fentanyl overdose deathsThe patents also cover potential uses of imidazopyrimidines as immunomodulatory compounds for allergies and cancer — other future research directions.

“Overall, we hope that our approach to precision vaccines will inspire others to adopt a similar innovation strategy for adjuvant and vaccine discovery and development,” Dowling says.