title: Rational design of small molecules as vaccine adjuvants.
abstract: Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants.
authors.affiliation: The Genomics Institute of Novartis Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Tom Y-H
authors.initials: TY
authors.lastname: Wu
authors.affiliation: Novartis Vaccines, 45 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Manmohan
authors.initials: M
authors.lastname: Singh
authors.affiliation: The Genomics Institute of Novartis Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Miller
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Doro
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: D'Oro
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: David A G
authors.initials: DA
authors.lastname: Skibinski
authors.affiliation: The Genomics Institute of Novartis Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: M Lamine
authors.initials: ML
authors.lastname: Mbow
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Bufali
authors.affiliation: The Genomics Institute of Novartis Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Herman
authors.affiliation: The Genomics Institute of Novartis Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Cortez
authors.affiliation: The Genomics Institute of Novartis Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Yongkai
authors.initials: Y
authors.lastname: Li
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: Nayak
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Elaine
authors.initials: E
authors.lastname: Tritto
authors.affiliation: The Genomics Institute of Novartis Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Christophe M
authors.initials: CM
authors.lastname: Filippi
authors.affiliation: Novartis Vaccines, 45 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Gillis R
authors.initials: GR
authors.lastname: Otten
authors.affiliation: Novartis Vaccines, 45 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Brito
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Monaci
authors.affiliation: The Genomics Institute of Novartis Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Aprea
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Valentini
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Calabrό
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Donatello
authors.initials: D
authors.lastname: Laera
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Brunella
authors.initials: B
authors.lastname: Brunelli
authors.affiliation: Novartis Vaccines, Via Florentina 1, 53100 Siena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Caproni
authors.affiliation: Novartis Vaccines, 45 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Padma
authors.initials: P
authors.lastname: Malyala
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA.
authors.forename: Rekha G
authors.initials: RG
authors.lastname: Panchal
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA.
authors.forename: Travis K
authors.initials: TK
authors.lastname: Warren
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA.
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.affiliation: Novartis Vaccines, 45 Sidney Street, Cambridge, MA 02139, USA. nicholas.valiante@novartis.com mcooke@gnf.org derek.ohagan@novartis.com.
authors.forename: Derek T
authors.initials: DT
authors.lastname: O'Hagan
authors.affiliation: The Genomics Institute of Novartis Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA. nicholas.valiante@novartis.com mcooke@gnf.org derek.ohagan@novartis.com.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cooke
authors.affiliation: Novartis Vaccines, 45 Sidney Street, Cambridge, MA 02139, USA. nicholas.valiante@novartis.com mcooke@gnf.org derek.ohagan@novartis.com.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Valiante
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D015195:Drug Design; D014612:Vaccines / Q000008:administration & dosage*
chemical_list: D000276:Adjuvants, Immunologic; D014612:Vaccines