Key Highlights:
- Screening and Discovery: The team screened over 200,000 small molecules, identifying PVP-037 as the most active. This molecule belongs to imidazopyrimidines, known for their immunomodulatory properties.
- Mechanism of Action: PVP-037 targets the innate immune system by stimulating TLR7 and TLR8 receptors on antigen-presenting cells, enhancing the immune response. It demonstrated broad activation in donor immune cells but did not provoke the same response in cultured cell lines.
- In Vivo Efficacy: In live mice, PVP-037 boosted antibody responses against influenza and SARS-CoV-2 vaccine proteins.
- Stability and Usability: The compound is stable, easy to work with, and can be optimized for medical use, fitting into standard drug delivery systems like oil-in-water emulsions.
For over a decade, Ofer Levy, MD, PhD, and David Dowling, PhD, at Boston Children’s Hospital's Precision Vaccines Program, have been working to improve vaccine efficacy with the help of adjuvants. These compounds enhance immune responses, aiming to make vaccines more effective, especially for the very young and the elderly.
Recently, under a substantial contract from the National Institute of Allergy and Infectious Diseases (NIAID), the team discovered a new adjuvant, PVP-037. The discovery, published in Science Advances, shows great promise.
“Adjuvants are like rocket fuel for the immune system,” says Levy. “PVP-037 is one of the most active we’ve discovered, potentially enhancing any vaccine's action to induce a greater, more durable, and broader immune response.”
The discovery process was not straightforward. Screening small molecules against human primary cells is a complex task due to individual biological differences. However, this method is more reflective of human biology, making the findings more robust and applicable to diverse populations. “PVP-037 would not have been discovered by screening cell culture lines,” emphasizes Levy. This breakthrough highlights the importance of using human primary cells in vaccine adjuvant research.
Future Research:
Boston Children’s Hospital holds multiple patents on PVP-037. With NIAID support, further tests will be conducted across all age groups, focusing on enhancing immune responses to influenza and pertussis (whooping cough) vaccines, and an opioid vaccine aimed at preventing fentanyl overdose deaths. Additional research may explore using imidazopyrimidines for allergy and cancer treatments.
Levy and Dowling hope their precision vaccine approach will inspire similar innovative strategies for discovering and developing adjuvants and vaccines. “Our work essentially condensed the full vaccine development pipeline — including analog optimization, establishing the mechanism of action, and creating an optimized formulation,” says Dowling. This comprehensive approach may lead to faster and more effective vaccine development in the future.
Credit: Journal Science Advances | Boston Children’s Hospital