CMCC 2568 / 3151 / 3154 / 3176 / 3260
Novel Age-Specific Adjuvants
Inventors: Simon D. Van Haren, David Dowling, Ofer Levy, Francesco Borriello
Invention Types: Therapeutics
Research Areas: Infectious Disease
Keywords: Drug Discovery, Neonatology/Pediatric, Peptide, Small Molecule/Drug, Vaccine
Despite monumental advancements in vaccinations, infectious diseases remain a leading cause of morbidity and mortality among the young and elderly, including diseases that are vaccine-preventable. Those at the extremes of age - i.e., newborns and young infants as well as elderly individuals - are particularly vulnerable due to differences in their innate immune systems compared to older children and middle-aged adults, making traditional vaccines less effective. The inclusion of adjuvants in vaccinations can broaden, enhance, and accelerate immune responses by activating additional immune pathways, yet there is an unmet need for age-specific vaccine adjuvants to enhance vaccine immunogenicity in these vulnerable populations and ensure protection.
Using novel human in vitro platforms, Boston Children’s Hospital’s Precision Vaccines Program, directed by Dr. Ofer Levy, has developed a portfolio of adjuvants with activity towards those at the extremes of age, including:
• Small molecule scaffolds that are potent activators of innate and adaptive immune responses. Some of these lead small molecules are agonists of pattern recognition receptors (PRRs), including Toll-like-receptors (TLRs); for others, receptor identification is on-going/pending. The small molecules were identified via high throughput screening in vitro, supported by the National Institute of Allergy & Infectious Diseases (NIAID) Adjuvant Discovery Program, and validated with respect to activity towards human leukocytes in vitro and animal models in vivo.
• Stimulator of interferon genes (STING) molecules, like 2’3’cGAMP, used alone or adsorbed to Alum, to induce expression of dendritic cell surface co-stimulatory molecules in newborns to levels comparable to adult cells.
• Combinations of TLR agonists with STING or C-type lectin receptor (CLR) agonists which synergistically activate human neonatal and infant antigen-presenting cells.
• Combinations of Alum-adjuvanted conjugate vaccines with TLR7/8 agonists
• Vaccine adjuvants to enhance, accelerate, and/or broaden immune responses in patients of varied ages, including neonates and elderly.
• Therapeutics to modify human immune responses with possible applications against tumors, allergies, and infection, either alone or in addition to standard therapy.
• Treatment and prevention for vulnerable neonate and elderly patient populations
• Demonstrated activities towards primary human cells in vitro and in animal models (mice and in some cases non-human primates) in vivo
• Small molecules are easily scaled
• In several instances amenable to and synergistic in formulation with Alum, a well-established adjuvant in many licensed vaccines.
• Two first-in-class small molecule drug scaffolds as vaccine adjuvants
• Agonists for diverse array of targets inducing a unique biological response with distinct patterns of cytokines
• Validated high-throughput screen (HTS) for additional small molecule discovery
• Biopharmaceutical and regulatory precedent- ie, other PRR/TLR agonists have been approved by FDA as stand-alone licensed agents (eg, imiquimod/TLR7) or as components of licensed adjuvanted vaccines (eg, CpG(TLR9)-adjuvanted Heplisav vaccine, MPLA_(TLR4) adjuvanted Cervarix vaccine, etc)
• Borriello F, van Haren SD, Levy O. First International Precision Vaccines Conference: Multidisciplinary Approaches to Next-Generation Vaccines. mSphere. 2018 Aug 1;3(4). pii: e00214-18.
• Borriello F, Piestrasanta C, Lai JCY, et al. Identification and characterization of stimulator of interferon genes as a robust adjuvant target for early life immunization. Front. Immunol. 2017 Dec 12;8.
• Dowling DJ, Scott EA, Scheid A, et al. Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of live BCG vaccine and enhance neonatal innate and adaptive immune responses. J. Allergy Clin. Immunol. 2017 Nov;140(5).
• Dowling DJ, van Haren SD, Scheid A, et al. TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth. JCI Insight. 2017 Mar 23;2(6).
• van Haren SD, Dowling DJ, Foppen W, et al. Age-specific adjuvant synergy: dual TLR7/8 and Mincle activation of human newborn dendritic cells enables Th1 polarization. J. Immunol. 2016 Dec 1;197(11)
• Pettengill MA, van Haren SD, Li N, et al. Distinct TLR-mediated cytokine production and immunoglobulin secretion in human newborn naϊve B cells. Innate Immun. 2016 Aug; 22(6).
• Dowling DJ and Levy O. Pediatric Vaccine Adjuvants: Components of the Modern Vaccinologist's Toolbox. Pediatr Infect Dis J. 2015 Dec;34(12):1395-8.
• Sanchez-Schmitz G, Levy O. Development of newborn and infant vaccines. Sci. Transl. Med. 2011 Jul 6;3(90).
• “Single-shot protection? Building a better hepatitis B vaccine for newborns”. https://vector.childrenshospital.org/2018/02/one-shot-hepatitis-b-vaccine-newborns/
• “New Adjuvant Permits Early Pneumococcal Immunization in Newborn Monkeys”. https://www.niaid.nih.gov/news-events/new-adjuvant-permits-early-pneumococcal-immunization-newborn-monkeys
IPStatus: Pat. Pend.