Pathogen Clearance-based Correlates of Immunoprotection Reveal Insightful Features of Vaccine Immunity

Vaccination has significantly reduced the incidence of invasive infections caused by several bacterial pathogens, including Streptococcus pneumoniae , Haemophilus influenzae and Neisseria meningitidis . However, no vaccines are available for many other invasive pathogens. A major hurdle in vaccine development is the lack of functional markers to quantify vaccine immunity in eliminating pathogens in the process of infection. Based on our recent discovery of the liver as the major organ of vaccine-induced clearance of blood-borne virulent bacteria, we here describe a new vaccine evaluation system that quantitatively characterize important properties of effective vaccines in shuffling virulent bacteria from the blood circulation to the liver resident macrophage Kupffer cells (KCs) and sinusoidal endothelial cells (LSECs) in animal models. This system consists of three related correlates or assays: pathogen clearance from the bloodstream, pathogen trapping in the liver, and pathogen capture by KCs/LSECs. The readouts of these correlates were consistently associated with the serotype-specific immunoprotection levels of the 13-valent pneumococcal polysaccharide conjugate vaccine (PCV13) against lethal infections of S. pneumoniae , a major invasive pathogen of community-acquired infections in humans. Furthermore, these assays were able to identify a set of functional differences between two licensed PCV13 brands. Finally, the reliability and sensitivity of these correlates in reflecting vaccine efficacy were verified with whole cell vaccines of Klebsiella pneumoniae and Escherichia coli , two major pathogens in hospital-acquired invasive infections. This system may be used as cost effective readouts to evaluate the immunoprotective potential of vaccine candidates in the preclinical phase by filling the current technical gap in vaccine evaluation between the conventional in vitro approaches (e.g., antibody production and pathogen neutralization/opsonophagocytosis) and survival of immunized animals. ### Competing Interest Statement Patent applications have been filed on the basis of this work.