546 - Development of a TLR7/8 Agonist Adjuvant Formulation to Overcome Early Life Hyporesponsiveness to Acellular Pertussis Vaccine

Poster Number: 546
Publication Number: 546.328

Etsuro Nanishi, Boston Children's Hospital, Brookline, MA, United States; Soumik Barman, Boston Children's Hospital, Boston, MA, United States; Alyson J. Smith, Seagen, Snohomish, WA, United States; Francesco Borriello, Boston Children's Hospital, Arlington, MA, United States; Danielle M. Chaney, Boston Children's Hospital, Atlanta, GA, United States; Spencer Brightman, University of California, San Diego School of Medicine, San Diego, CA, United States; Gandolina Melhem, Boston Children's Hospital, Boston, MA, United States; Byron Brook, Boston Children's Hospital, Boston, MA, United States; Manisha Menon, Boston Children's Hospital, Boston, MA, United States; Dheeraj Soni, Boston Children's Hospital/Harvard Medical School, Brighton, MA, United States; Simone Schüller, Telethon Kids Institute, Perth, Western Australia, Australia; Karthik Siram, University of Montana, Missoula, MT, United States; Hélène Bazin, University of Montana, Missoula, MT, United States; David Burkhart, University of Montana, Missoula, MT, United States; Jay Evans, University of Montana, Missoula, MT, United States; Ofer Levy, Boston Children's Hospital, Cambridge, MA, United States; David Dowling, Boston Children's Hospital (BCH) / Harvard Medical School (HMS), Boston, MA, United States

Background: Infection is the most common cause of mortality early in life, yet the broad potential of immunization is not fully realized in this vulnerable population. Most vaccines are administered during infancy and childhood, but for some vaccines, such as acellular pertussis (aP) vaccines, immunogenicity is insufficient or wanes resulting in a need for multiple booster doses. New adjuvants are cardinal to further optimize current immunization approaches for early life. However, only a few classes of adjuvants are presently incorporated in vaccines approved for human use. Prominent among the growing toolbox of candidate adjuvants are synthetic small molecule Toll-like receptor (TLR) agonists, including TLR7/8 agonists that activate robust immune responses in early life. The development of an effective infant Bordetella pertussis vaccine is urgently required because of the resurgence of pertussis in many countries, contemporaneous to the switch from whole cell to aP vaccines.

Objective: We aimed to develop TLR7/8 adjuvant (TLR7/8A) based vaccine formulation as a tool to enhance and accelerate early life immunity by acellular B. pertussis vaccines.

Design/Methods: In the present study, we optimized a) the formulation delivery system, b) structure, and c) immunologic activity of novel small molecule imidazoquinoline TLR7/8As towards human infant leukocytes, including dendritic cells in vitro.

Results: Upon immunization of 7-day-old neonatal C57BL/6 mice, this TLR7/8A overcame neonatal hyporesponsiveness to acellular pertussis vaccination by driving a robust T helper (Th)1/Th17 biased T cell- and IgG2c-skewed humoral response to a licensed acellular vaccine (DTaP).Conclusion(s): This potent immunization strategy may represent a new paradigm for effective immunization against pertussis and other pathogens in early life.