Intradermal vaccination with a Pseudomonas aeruginosa vaccine adjuvanted with a mutant bacterial ADP-ribosylating enterotoxin protects against acute pneumonia

• Published in: Vaccine 2019-02, Vol.37 (6), p.808-816
• Main Authors: Baker, Sarah M., Pociask, Derek, Clements, John D., McLachlan, James B., Morici, Lisa A.
• Format: Article
• Language: English
• Subjects: Acute Disease; Adenosine diphosphate; Adjuvants; Adjuvants, Immunologic - administration & dosage; Animal models; Animals; Antibodies; Antibodies, Bacterial - blood; Antibodies, Neutralizing - blood; Antigens; Bacteria; Bacterial infections; Bacterial Outer Membrane Proteins - genetics; Bacterial Outer Membrane Proteins - immunology; Bacterial Toxins - genetics; Bacterial Toxins - immunology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell adhesion & migration; Cell migration; Dendritic cells; Disease Models, Animal; dmLT; Drug resistance; E coli; Enterotoxins - genetics; Enterotoxins - immunology; Escherichia coli Proteins - genetics; Escherichia coli Proteins - immunology; Female; Helper cells; Immunity; Immunization; Immunoglobulin G; Immunoglobulin G - blood; Immunoglobulins; Immunologic Memory; Immunological memory; Infections; Injections, Intradermal; Interferon-gamma - immunology; Interleukin 17; Interleukin-17 - immunology; Intradermal; Laboratory animals; Lung; Lung - immunology; Lung - microbiology; Lungs; Lymphatic system; Lymphocytes; Lymphocytes T; Membrane proteins; Memory cells; Mice; Mice, Inbred C57BL; Morbidity; Mucosal immunity; Multidrug resistance; Mutation; Opportunist infection; Outer membrane proteins; Pathogens; Pneumonia; Pneumonia, Bacterial - prevention & control; Proteins; Pseudomonas aeruginosa; Pseudomonas Infections - prevention & control; Pseudomonas Vaccines - administration & dosage; Pseudomonas Vaccines - immunology; Respiratory diseases; Toxins; Tuberculosis; Vaccination - methods; Vaccine; Vaccines; Ventilator-associated pneumonia; γ-Interferon
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2018.12.053

Respiratory infections are a leading cause of morbidity and mortality globally. This is partially due to a lack of effective vaccines and a clear understanding of how vaccination route and formulation influence protective immunity in mucosal tissues such as the lung. Pseudomonas aeruginosa is an opportunistic pathogen capable of causing acute pulmonary infections and is a leading cause of hospital-acquired and ventilator-associated pneumonia. With multidrug-resistant P. aeruginosa infections on the rise, the need for a vaccine against this pathogen is critical. Growing evidence suggests that a successful P. aeruginosa vaccine may require mucosal antibody and Th1- and Th17-type CD4+ T cells to prevent pulmonary infection. Intradermal immunization with adjuvants, such as the bacterial ADP-Ribosylating Enterotoxin Adjuvant (BARE) double mutant of E. coli heat-labile toxin (dmLT), can direct protective immune responses to mucosal tissues, including the lungs. We reasoned that intradermal immunization with P. aeruginosa outer membrane proteins (OMPs) adjuvanted with dmLT could drive neutralizing antibodies and migration of CD4+ T cells to the lungs and protect against P. aeruginosa pneumonia in a murine model. Here we show that mice immunized with OMPs and dmLT had significantly more antigen-specific IgG and Th1- and Th17-type CD4+ memory T cells in the pulmonary environment compared to control groups of mice. Furthermore, OMPs and dmLT immunized mice were significantly protected against an otherwise lethal lung infection. Protection was associated with early IFN-γ and IL-17 production in the lungs of immunized mice. These results indicate that intradermal immunization with dmLT can drive protective immunity to the lung mucosa and may be a viable vaccination strategy for a multitude of respiratory pathogens.