From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation

  • Sci Adv. 2024 Jul 5;10(27):eadg3747. doi: 10.1126/sciadv.adg3747.
Dheeraj Soni  1  2 ,  Francesco Borriello  1  2 ,  David A Scott  2  3 ,  Frederic Feru  2  3 ,  Maria DeLeon  1  2 ,  Spencer E Brightman  1 ,  Wing Ki Cheng  1  2 ,  Gandolina Melhem  1  2 ,  Jennifer A Smith  2 ,  Juan C Ramirez  1  2 ,  Soumik Barman  1  2 ,  Michael Cameron  4 ,  Aisling Kelly  1 ,  Kristina Walker  1 ,  Etsuro Nanishi  1  2 ,  Simon Daniel van Haren  1  2 ,  Tony Phan  5 ,  Yizhi Qi  5 ,  Robert Kinsey  5 ,  Michal M Raczy  6 ,  Al Ozonoff  1  2  7 ,  Matthew A Pettengill  1  2 ,  Jeffery A Hubbell  6 ,  Christopher B Fox  5  8 ,  David J Dowling  1  2 ,  Ofer Levy  1  2  7
Affiliations
  • 1. Precision Vaccines Program, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
  • 2. Harvard Medical School, Boston, MA, USA.
  • 3. Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
  • 5. Access to Advanced Health Institute (AAHI), Seattle, WA, USA.
  • 6. Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.
  • 7. Broad Institute of MIT & Harvard, Cambridge, MA, USA.
  • 8. Department of Global Health, University of Washington, 3980 15th Ave NE, Seattle, WA 98195, USA.
PMID: 38959314 DOI: 10.1126/sciadv.adg3747
Abstract

Vaccination can help prevent Infection and can also be used to treat Cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)-activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor Immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-κB and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037's in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses.

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