Innate immune cell subtypes involved in infant responses to protein-conjugate and whole-cell pneumococcal vaccines. - Project Summary/Abstract: Streptococcus pneumoniae is a leading killer of infants throughout the world. While a conjugated vaccine (invented by members of the mentorship team on this application) has enabled successful vaccination of infants, not all infants mount a protective response to vaccination. 1 in 9 children do not mount protective responses to half of the vaccines in their primary series. This work will define why this is occurring. Studies in adults showed that an elevated frequency of natural killer (NK) cells is associated with low pneumococcal vaccine responses. In contrast, adult vaccine trials found an elevated frequency of inflammatory antigen presenting cells (APCs) was associated with higher vaccine responses. This work will test the hypothesis that infants with low vaccine responses to pneumococcal vaccines have high NK cell frequency and functionality and low inflammatory APC frequency with impaired functionality. This work compares the role of these populations in responses to the licensed conjugated vaccines and a killed whole-cell Streptococcus pneumoniae vaccine being tested in US infants. The principal investigator, Dr. Andrew Cox, completed his MD/PhD at the University of Rochester, his residency and fellowship at Cincinnati Children’s Hospital Medical Center and has now joined the Rochester General Hospital Research Institute where he will learn under the mentorship of Dr. Michael Pichichero. Dr. Cox’s career goal is to become a leading pediatric vaccine clinical trialist conducting translational immunology with infant samples to discover new pathways of enhancing vaccine efficacy. During the award period, he will obtain additional training through formal coursework in vaccine immunology and bioinformatics, and directed study in infant immunology and clinical trial design, execution, and oversight. He will participate in this Phase IIb clinical trial and in doing so gain real world experience in an infant vaccine clinical trial. His primary mentor will be Dr. Michael Pichichero, Director of the Rochester General Hospital Research Institute, co-inventor with Drs. Insel and Anderson of the Haemophilus influenzae type b protein conjugated polysaccharide vaccines that have saved millions of infant lives. Over the past two decades, Dr. Pichichero has amassed an invaluable biorespository of prospectively collected infant samples that will permit analysis of infant vaccine responses. Dr. Cox’s mentorship team also includes: (a) Dr. Richard Malley, Professor of Pediatrics at Harvard Medical School, co-inventor the whole-cell pneumococcal vaccine and expert in mucosal immune responses, (b) Dr. Richard Insel, Professor of Pediatrics at the University of Rochester, expert in infant vaccine responses, (c) Dr. Stephen Waggoner, Associate Professor of Pediatrics at Cincinnati Children’s Hospital Medical Center, expert in natural killer cell immunoregulation, (d) Dr. Dan Weinberger, Professor of Epidemiology at the Yale School of Public Health, expert in advances statistical methods for understanding pneumococcal vaccine responses, (e) Dr. Simon van Haren, Assistant Professor of Pediatrics at Harvard/Boston Children’s Hospital expert in in vitro assays of human vaccine responses and (f) Dr. Porter Anderson, inventor of multiple infant vaccines, pioneer of protein conjugate polysaccharide vaccines and expert in bacterial pathogenesis.
