Post-exposure immunization by capsid-modified AdC7 vector expressing Pseudomonas aeruginosa OprF clears P. aeruginosa respiratory infection

Abstract

Respiratory infections with Pseudomonas aeruginosa are major health problems, particularly in patients with cystic fibrosis (CF). No vaccine against P. aeruginosa is yet available. A vaccine that controls colonization of the respiratory tract with P. aeruginosa could be useful to prevent chronic infection and exacerbations. Replication-deficient adenoviral (Ad) vectors based on non-human serotypes are attractive vaccine platforms as they can circumvent the problem of pre-existing anti-Ad immunity in humans. The primate-based AdC7 vector AdC7OprF.RGD that expresses the outer membrane protein F (OprF) of P. aeruginosa (AdC7OprF) and that displays an integrin-binding arginine-glycine-aspartic acid (RGD) sequence is a potent inducer of lung mucosal and protective immunity. Here, we investigated the efficacy of immunization with AdC7OprF.RGD to clear an already established P. aeruginosa respiratory infection in mice (wild-type and CF) and rats. Intratracheal administration of the clinical P. aeruginosa strain RP73 embedded in agar beads was used to establish persistent infection. Subsequent intranasal immunization with AdC7OprF.RGD induced robust P. aeruginosa-specific systemic and mucosal, humoral and cellular immune responses. Importantly, the AdC7OprF.RGD immunized mice effectively cleared P. aeruginosa from the lungs. Likewise, immunization with AdC7OprF.RGD of CF mice and Sprague Dawley rats with established P. aeruginosa respiratory infection showed enhanced anti-Pseudomonas immune responses and increased clearance of P. aeruginosa from the lungs. These data suggest that AdC7OprF.RGD can be effective as a post-exposure vaccine and may be useful in clinical settings in particular for patients with CF who frequently harbor the bacteria over prolonged periods.

Understanding Pseudomonas aeruginosa–Host Interactions: The Ongoing Quest for an Efficacious Vaccine

“…Viral vector systems presenting protective epitopes of OprF have provided encouraging results with strong IgG and/or IgA antibodies titres and protection against P. aeruginosa challenge demonstrated in mice immunised with chimeric viruses expressing different epitopes. Influenza virus [278], cowpea mosaic virus [279,280], tobacco mosaic virus [281] and adenovirus [282][283][284][285] were used as vectors. Finally, a polyhydroxyalkanoate (PHA) nano-vaccine with P. aeruginosa cellular inclusions engineered to display OprF, OprI and AlgE antigens in the surface induced a protective Th1-cellular response associated with the production of antibodies that reacted with different strains and possessed opsonophagocytic killing activity [158].…”

Pushing beyond the Envelope: the Potential Roles of OprF in Pseudomonas aeruginosa Biofilm Formation and Pathogenicity

“…Due to the highly immunogenic nature of OprF, numerous studies have utilized the porin in pursuit of a P. aeruginosa vaccine (85,86). Many recent publications involving the administration of chimeric OprF fusion proteins have demonstrated acquired immunity to P. aeruginosa can be achieved in mammals (87)(88)(89)(90)(91). Hassan et al demonstrated that a recombinant trivalent OprF-OprI-flagellin vaccine significantly reduced mortality resulting from acute pneumonia in mice infected with mucoid and nonmucoid strains of P. aeruginosa (89).…”

“…Hassan et al demonstrated that a recombinant trivalent OprF-OprI-flagellin vaccine significantly reduced mortality resulting from acute pneumonia in mice infected with mucoid and nonmucoid strains of P. aeruginosa (89). In addition, Gomi et al showed that in a cystic fibrosis mouse model, mice with preexisting P. aeruginosa lung infections that were immunized with an OprF-adenoviral vector exhibited increased bacterial clearance relative to those that were not immunized (90). In contrast to these animal studies, Rello et al demonstrated that while an OprF-OprI vaccine in human subjects undergoing ventilator therapy produced a significant immune response, there was no observed difference in P. aeruginosa infection rates between vaccinated and nonvaccinated groups (91).…”

Immune responses and protective efficacy of a trivalent combination DNA vaccine based on oprL, oprF and flgE genes of Pseudomonas aeruginosa

“…The outer membrane protein, encoded by the oprL gene, oprF gene, and so on, is one of the major protective antigens of P. aeruginosa. A study by Gomi et al (2017) showed the oprF gene DNA vaccine could be used to treat respiratory infections caused by P. aeruginosa. Yu et al (2016) prepared a fusion DNA vaccine with the oprF gene of P. aeruginosa and the VP22 gene of herpes simplex virus and evaluated the immune effect.…”