Bordetella pertussis Whole Cell Immunization, Unlike Acellular Immunization, Mimics Naïve Infection by Driving Hematopoietic Stem and Progenitor Cell Expansion in Mice

Abstract

Hematopoietic stem and progenitor cell (HSPC) compartments are altered to direct immune responses to infection. Their roles during immunization are not well-described. To elucidate mechanisms for waning immunity following immunization with acellular vaccines (ACVs) against Bordetella pertussis (Bp), we tested the hypothesis that immunization with Bp ACVs and whole cell vaccines (WCVs) differ in directing the HSPC characteristics and immune cell development patterns that ultimately contribute to the types and quantities of cells produced to fight infection. Our data demonstrate that compared to control and ACV-immunized CD-1 mice, immunization with an efficacious WCV drives expansion of hematopoietic multipotent progenitor cells (MPPs), increases circulating white blood cells (WBCs), and alters the size and composition of lymphoid organs. In addition to MPPs, common lymphoid progenitor (CLP) proportions increase in the bone marrow of WCV-immunized mice, while B220+ cell proportions decrease. Upon subsequent infection, increases in maturing B cell populations are striking in WCV-immunized mice. RNAseq analyses of HSPCs revealed that WCV and ACV-immunized mice vastly differ in developing VDJ gene segment diversity. Moreover, gene set enrichment analyses demonstrate WCV-immunized mice exhibit unique gene signatures that suggest roles for interferon (IFN) induced gene expression. Also observed in naïve infection, these IFN stimulated gene (ISG) signatures point toward roles in cell survival, cell cycle, autophagy, and antigen processing and presentation. Taken together, these findings underscore the impact of vaccine antigen and adjuvant content on skewing and/or priming HSPC populations for immune response.

Evaluation of the Efficacy of the Brucella canis RM6/66 ΔvjbRVaccine Candidate for Protection against B. canis Infection in Mice

“…In the absence of significant inflammatory lesions in vaccinated mice, the transient EMH likely represents a strong immune response in reaction to the vaccine. Such a change has been reported in other vaccine studies in mice, with evidence that vaccines which induce EMH result in superior levels of protection, likely by providing stores of immature immune cells primed for response upon subsequent infection (38). This not only provides further support for the protective efficacy of B. canis RM6/66 ΔvjbR but also highlights the importance of histopathology in appropriately interpreting gross changes in vaccine studies.…”

Long-term analysis of pertussis vaccine immunity uncovers a memory B cell response to whole cell pertussis immunization that is absent from acellular immunized mice

“…We hypothesized that mice immunized with 1/10 th the human dose of wP and aP would be protected from challenge early on, but that protection would decrease over time in aP immunized mice. Mice were intranasally challenged with 2x10 7 pertussis over time and the importance of longitudinal studies to identify the optimal timeframe to study vaccine efficacy.…”

“…Blood was centrifuged at 14,000 x g for 2 minutes and sera were stored at -80 o C. Pierce™ high-binding 96 well plates (Thermo Scientific™, Cat. #15041) were coated with 5x10 7 Scientific, Cat. #37620) was added to each well to develop plates for 30 minutes in the dark at room temperature.…”

“…To study MBCs, we incubated splenocytes with fluorescently labeled B. pertussis. We then separated MBCs from the rest of the splenocytes using a proprietary kit (Miltenyi), followed by labeling with CD3e, CD45R, IgG, CD38, and CD80 75,7 . We analyzed MBC populations based on labeling with B. pertussis (antigen-specific) and further defined the B cell populations based on CD38 and CD80 surface expression [75][76][77] (Fig S2).…”

BCG vaccination improves DTaP immune responses in mice and is associated with lower pertussis incidence in ecological epidemiological studies

“…Whole-cell pertussis vaccines (wP) are reactogenic, limiting their acceptability and use beyond childhood [ 23 ]. Acellular vaccines (aP) have an improved safety profile but provide only relatively short-term protection, likely because of skewing of the immune response towards a Th2 profile [ 24 ], whereas wP vaccines favor Th1 immune responses, similar to natural infection [ 25 ]. A pertussis vaccination approach that combines the safety profile of aP with immunity induced by natural infection would thus be desirable.…”