Search

Despite high vaccine coverage in many parts of the world, pertussis is resurging in a number of areas in which acellular vaccines are the primary vaccine administered to infants and young children. This is attributed in part to the suboptimal and short-lived immunity elicited by acellular pertussis vaccines and to their inability to prevent nasal colonization and transmission of the etiologic agent Bordetella pertussis. In response to this escalating public health concern, the National Institute of Allergy and Infectious Diseases held the workshop “Overcoming Waning Immunity in Pertussis Vaccines” in September 2019 to identify issues and possible solutions for the defects in immunity stimulated by acellular pertussis vaccines. Discussions covered aspects of the current problem, gaps in knowledge and possible paths forward. This review summarizes presentations and discussions of some of the key points that were raised by the workshop.

Development of effective vaccines requires logical design and formulation of two main components: antigens and adjuvants. Some compounds, called immunogens, can assume both of these roles. Notably, Bordetella pertussis (Bp) and some of its antigenic products have been found to adjuvant immune responses to other vaccines or vaccine components. We chose to explore this ability by using B. pertussis and pertussis toxin as adjuvants for a whole cell vaccine (WCV) against Pseudomonas aeruginosa (Pa). Pa is a highly antibiotic resistant Gram-negative opportunistic pathogen for which there are no approved vaccines or immunotherapies. We formulated vaccines containing Pa with Bp or pertussis toxin to determine if these components could modulate the immune response to PaWCV, as measured by quantification of bacterial burden and immune cell response after an acute pneumonia challenge. We determined that these additions to the PaWCV were associated with increased clearance of bacteria after challenge and increased Pa-binding immunoglobulins in the blood and airway. Additionally, we determined that the BpWCV alone was sufficient to induce protection from acute Pa infection. This correlated with production of antibodies that bind Pa, indicating that there is at least one cross-reactive antigen that could be providing protection. Through utilization of immunoblotting of protein fractions of Pa and mass spectroscopy, we identified this protective antigen. It will be used to formulate a subunit vaccine and tested for efficacy in protection from Pseudomonas infection. This type of cross-protection is novel within the field and could lead to the identification of a protective antigen against P. aeruginosa in B. pertussis.

Pseudomonas aeruginosa (Pa) is an opportunistic Gram-negative pathogen that can lead to life-threatening pulmonary infections. Several promising vaccine candidates against Pa evaluated in clinical trials. However, there is still no commercial vaccine available against this pathogen, in part due to a lack of clarity of protective correlates of vaccine–induced immunity. To elucidate correlates of protection against Pa, we used an intranasal whole–cell Pa vaccine adjuvanted with curdlan WCV in a murine vaccination and challenge model. Immunization with WCV significantly decreased the bacterial burden and lung edema after Pa challenge. We found that WCV immunization leads to a significant increase in Th17 cellular immune response and Pa–specific serum IgG and IgA titers compared to naive animals. To identify mechanistic correlates of protection, we performed anti–CD4, – CD8, and –CD20 antibody mediated depletions prior to vaccination and challenge. Depletion of these populations did not affect the response to challenge in naive animals. Interestingly, we observed that depletion of B cells but not CD8+ or CD4+ T cells during WCV priming resulted in loss of protection against Pa. Furthermore, passive immunization of WCV sera was sufficient to protect naive mice against Pa. Taken together, vaccine-mediated humoral immune response was the critical component of immunity against Pa in acute lung pneumonia model. This study suggests that adjuvants stimulating humoral immune response may be used to enhance the efficacy of vaccine candidates against Pa.

Cadmium (Cd) is a carcinogen present at superfund sites, in battery manufacturing facilities, in and around zinc smelters, and in cigarettes (the most common exposure pathway). In humans, prenatal Cd exposure (preCd) is associated with differential DNA methylation patterns in blood leukocytes of mother-baby pairs. C57BL/6 mice chronically exposed to low doses of Cd in utero develop abnormal immune phenotypes including reduced regulatory T cell (Treg) numbers in the spleen, but not thymus, of adult animals. These data suggest that the probable immune consequences of preCd exposure are cause for alarm. To further define the mechanisms behind these phenotypic differences, we isolated Treg and CD4+ T conventional (Tconv) cells from the spleens of preCd offspring at 8 woa. Target cells were enriched using magnetic isolation prior to purification by flow cytometry. RNA-seq and Ingenuity Pathway analyses were conducted to define the Treg and Tconv transcriptomes and identify mechanisms dysregulated with preCd exposure. Treg cells exhibited more changes in gene expression than Tconv cells. In the splenic Tregs, there were 289 significantly changed genes (166 upregulated and 135 downregulated) in females and 135 (82 upregulated and 53 downregulated) in males. Of note, only 23 upregulated genes and 3 downregulated genes were shared between females and males. However, common pathways, including CREB1 signaling, were disrupted in both sexes. As CREB signaling plays an important role in TGFβ-mediated generation and maintenance of FoxP3 Tregs, inhibition of this pathway may promote Treg instability and contribute to the decrease in Treg numbers observed in the periphery of preCd-exposed mice.