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Vaccination against respiratory Pseudomonas aeruginosa infection.

Grimwood K, Kyd JM, Owen SJ, Massa HM, Cripps AW - Hum Vaccin Immunother (2014)

Bottom Line: Significant advances in identifying potential vaccine antigens have been made.Therefore, development of a therapeutic vaccine provides an alternative approach for treatment of chronic infection.Activation of mucosal immune responses may provide improved efficacy of vaccination for P. aeruginosa during both acute exacerbations and chronic infection.

View Article: PubMed Central - PubMed

Affiliation: a School of Medicine; Griffith University; Gold Coast, Queensland Australia.

ABSTRACT
Respiratory infections caused by Pseudomonas aeruginosa are a major clinical problem globally, particularly for patients with chronic pulmonary disorders, such as those with cystic fibrosis (CF), non-CF bronchiectasis (nCFB) and severe chronic obstructive pulmonary disease (COPD). In addition, critically ill and immunocompromised patients are also at significant risk of P. aeruginosa infection. For almost half a century, research efforts have focused toward development of a vaccine against infections caused by P. aeruginosa, but a licensed vaccine is not yet available. Significant advances in identifying potential vaccine antigens have been made. Immunisations via both the mucosal and systemic routes have been trialled in animal models and their effectiveness in clearing acute infections demonstrated. The challenge for translation of this research to human applications remains, since P. aeruginosa infections in the human respiratory tract can present both as an acute or chronic infection. In addition, immunisation prior to infection may not be possible for many patients with CF, nCFB or COPD. Therefore, development of a therapeutic vaccine provides an alternative approach for treatment of chronic infection. Preliminary animal and human studies suggest that mucosal immunisation may be effective as a therapeutic vaccine against P. aeruginosa respiratory infections. Nevertheless, more research is needed to improve our understanding of the basic biology of P. aeruginosa and the mechanisms needed to upregulate the induction of host immune pathways to prevent infection. Recognition of variability in the host immune responses for a range of patient health conditions at risk from P. aeruginosa infection is also required to support development of a successful vaccine delivery strategy and vaccine. Activation of mucosal immune responses may provide improved efficacy of vaccination for P. aeruginosa during both acute exacerbations and chronic infection.

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Figure 3. Vaccinating to clear an established chronic P. aeruginosa infection. This animal model was established in our laboratory to determine whether immunisation was effective in combating acute bacterial challenge in mice that had already been chronically infected with P. aeruginosa. (A) In this model, Balb/c mice received 104 colony forming units (cfu) of live P. aeruginosa in 0.5% agar intra-tracheally (IT) into the lungs on day 0. On day 7, they received a second dose of 104 cfu live P. aeruginosa in PBS (IT). One group of control non-immune mice⬜, received only agar on day 0 and PBS on Day 7, prior to acute live P. aeruginosa challenge at day 35, this provided a control group not previously exposed to an infection. The mice were then immunised sub-cutaneously on days 14 and 28 with either PBS (control mice) or vaccines formulated in IFA. On day 35, mice received an acute infection of 106cfu live P. aeruginosa (IT). The mice were killed at 4 h post this infection and bronchial lavage samples collected for testing. (B) This figure illustrates the clearance of P. aeruginosa in the bronchial lavage following acute bacterial IT challenge, 106cfu live P. aeruginosa or PBS, at day 35 in each of the groups. Non-immune mice received PBS (IT) and were sham immunised. All the filled symbol groups received P. aeruginosa in agar (IT) at day 0. ⬥Non-immunised control group (but did receive infections on days 0 and 7); ⬤KatA/Ad immunised group; ▲ heat-killed Pa. Kat A was mixed equally with Ad (10 µg each); and the heat killed P. aeruginosa (HKPa) group was immunised with heat-killed P. aeruginosa. Data presented as mean ± SEM of n = 5–6 mice per group.
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Figure 3: Figure 3. Vaccinating to clear an established chronic P. aeruginosa infection. This animal model was established in our laboratory to determine whether immunisation was effective in combating acute bacterial challenge in mice that had already been chronically infected with P. aeruginosa. (A) In this model, Balb/c mice received 104 colony forming units (cfu) of live P. aeruginosa in 0.5% agar intra-tracheally (IT) into the lungs on day 0. On day 7, they received a second dose of 104 cfu live P. aeruginosa in PBS (IT). One group of control non-immune mice⬜, received only agar on day 0 and PBS on Day 7, prior to acute live P. aeruginosa challenge at day 35, this provided a control group not previously exposed to an infection. The mice were then immunised sub-cutaneously on days 14 and 28 with either PBS (control mice) or vaccines formulated in IFA. On day 35, mice received an acute infection of 106cfu live P. aeruginosa (IT). The mice were killed at 4 h post this infection and bronchial lavage samples collected for testing. (B) This figure illustrates the clearance of P. aeruginosa in the bronchial lavage following acute bacterial IT challenge, 106cfu live P. aeruginosa or PBS, at day 35 in each of the groups. Non-immune mice received PBS (IT) and were sham immunised. All the filled symbol groups received P. aeruginosa in agar (IT) at day 0. ⬥Non-immunised control group (but did receive infections on days 0 and 7); ⬤KatA/Ad immunised group; ▲ heat-killed Pa. Kat A was mixed equally with Ad (10 µg each); and the heat killed P. aeruginosa (HKPa) group was immunised with heat-killed P. aeruginosa. Data presented as mean ± SEM of n = 5–6 mice per group.

Mentions: Parenteral immunisation studies have demonstrated that KatA appears to be just as effective in mice as the homologous killed P. aeruginosa whole cell vaccine, and slightly better than the leading vaccine candidate OprF-OprI (provided by Dr von Specht) (Fig. 1). We have also demonstrated that KatA combined with Ad is protective in a chronic lung infection model (Figs. 2 and 3), significantly reducing the number of bacteria recovered 4 h after acute challenge with P. aeruginosa. In this model, there was visually much less epithelial thickening in the bronchiole wall, less cellular infiltration, less alveolar wall damage and less lung consolidation in immunised animals compared with non-immunised controls (Fig. 4). Indeed, the extent of epithelial damage 4 h after bacterial challenge was still evident 24 h after administration of the bacterial challenge, with the alveoli exhibiting significant damage and bleeding in non-immunised animals. The presence of clear mucus in some smaller bronchioles provides evidence of localized mucosal responses within the KatA/Ad immunised animals. Most importantly, this study demonstrated that, parenteral immunisation was effective against an acute exacerbation of a chronic lung infection in mice when immunisation occurred after the infection was firmly established (Fig. 3). In most chronic pulmonary disorders, individuals suffer episodes of acute exacerbations. Thus, in this model, both the day 7 and day 35 P. aeruginosa challenges represent acute exacerbation situations, with day 35 being a severe episode. These results show potential for candidate antigens, such as KatA and Ad, to enhance clearance of an acute P. aeruginosa-associated exacerbation of an established chronic P. aeruginosa infection.


Vaccination against respiratory Pseudomonas aeruginosa infection.

Grimwood K, Kyd JM, Owen SJ, Massa HM, Cripps AW - Hum Vaccin Immunother (2014)

Figure 3. Vaccinating to clear an established chronic P. aeruginosa infection. This animal model was established in our laboratory to determine whether immunisation was effective in combating acute bacterial challenge in mice that had already been chronically infected with P. aeruginosa. (A) In this model, Balb/c mice received 104 colony forming units (cfu) of live P. aeruginosa in 0.5% agar intra-tracheally (IT) into the lungs on day 0. On day 7, they received a second dose of 104 cfu live P. aeruginosa in PBS (IT). One group of control non-immune mice⬜, received only agar on day 0 and PBS on Day 7, prior to acute live P. aeruginosa challenge at day 35, this provided a control group not previously exposed to an infection. The mice were then immunised sub-cutaneously on days 14 and 28 with either PBS (control mice) or vaccines formulated in IFA. On day 35, mice received an acute infection of 106cfu live P. aeruginosa (IT). The mice were killed at 4 h post this infection and bronchial lavage samples collected for testing. (B) This figure illustrates the clearance of P. aeruginosa in the bronchial lavage following acute bacterial IT challenge, 106cfu live P. aeruginosa or PBS, at day 35 in each of the groups. Non-immune mice received PBS (IT) and were sham immunised. All the filled symbol groups received P. aeruginosa in agar (IT) at day 0. ⬥Non-immunised control group (but did receive infections on days 0 and 7); ⬤KatA/Ad immunised group; ▲ heat-killed Pa. Kat A was mixed equally with Ad (10 µg each); and the heat killed P. aeruginosa (HKPa) group was immunised with heat-killed P. aeruginosa. Data presented as mean ± SEM of n = 5–6 mice per group.
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Related In: Results  -  Collection

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Figure 3: Figure 3. Vaccinating to clear an established chronic P. aeruginosa infection. This animal model was established in our laboratory to determine whether immunisation was effective in combating acute bacterial challenge in mice that had already been chronically infected with P. aeruginosa. (A) In this model, Balb/c mice received 104 colony forming units (cfu) of live P. aeruginosa in 0.5% agar intra-tracheally (IT) into the lungs on day 0. On day 7, they received a second dose of 104 cfu live P. aeruginosa in PBS (IT). One group of control non-immune mice⬜, received only agar on day 0 and PBS on Day 7, prior to acute live P. aeruginosa challenge at day 35, this provided a control group not previously exposed to an infection. The mice were then immunised sub-cutaneously on days 14 and 28 with either PBS (control mice) or vaccines formulated in IFA. On day 35, mice received an acute infection of 106cfu live P. aeruginosa (IT). The mice were killed at 4 h post this infection and bronchial lavage samples collected for testing. (B) This figure illustrates the clearance of P. aeruginosa in the bronchial lavage following acute bacterial IT challenge, 106cfu live P. aeruginosa or PBS, at day 35 in each of the groups. Non-immune mice received PBS (IT) and were sham immunised. All the filled symbol groups received P. aeruginosa in agar (IT) at day 0. ⬥Non-immunised control group (but did receive infections on days 0 and 7); ⬤KatA/Ad immunised group; ▲ heat-killed Pa. Kat A was mixed equally with Ad (10 µg each); and the heat killed P. aeruginosa (HKPa) group was immunised with heat-killed P. aeruginosa. Data presented as mean ± SEM of n = 5–6 mice per group.
Mentions: Parenteral immunisation studies have demonstrated that KatA appears to be just as effective in mice as the homologous killed P. aeruginosa whole cell vaccine, and slightly better than the leading vaccine candidate OprF-OprI (provided by Dr von Specht) (Fig. 1). We have also demonstrated that KatA combined with Ad is protective in a chronic lung infection model (Figs. 2 and 3), significantly reducing the number of bacteria recovered 4 h after acute challenge with P. aeruginosa. In this model, there was visually much less epithelial thickening in the bronchiole wall, less cellular infiltration, less alveolar wall damage and less lung consolidation in immunised animals compared with non-immunised controls (Fig. 4). Indeed, the extent of epithelial damage 4 h after bacterial challenge was still evident 24 h after administration of the bacterial challenge, with the alveoli exhibiting significant damage and bleeding in non-immunised animals. The presence of clear mucus in some smaller bronchioles provides evidence of localized mucosal responses within the KatA/Ad immunised animals. Most importantly, this study demonstrated that, parenteral immunisation was effective against an acute exacerbation of a chronic lung infection in mice when immunisation occurred after the infection was firmly established (Fig. 3). In most chronic pulmonary disorders, individuals suffer episodes of acute exacerbations. Thus, in this model, both the day 7 and day 35 P. aeruginosa challenges represent acute exacerbation situations, with day 35 being a severe episode. These results show potential for candidate antigens, such as KatA and Ad, to enhance clearance of an acute P. aeruginosa-associated exacerbation of an established chronic P. aeruginosa infection.

Bottom Line: Significant advances in identifying potential vaccine antigens have been made.Therefore, development of a therapeutic vaccine provides an alternative approach for treatment of chronic infection.Activation of mucosal immune responses may provide improved efficacy of vaccination for P. aeruginosa during both acute exacerbations and chronic infection.

View Article: PubMed Central - PubMed

Affiliation: a School of Medicine; Griffith University; Gold Coast, Queensland Australia.

ABSTRACT
Respiratory infections caused by Pseudomonas aeruginosa are a major clinical problem globally, particularly for patients with chronic pulmonary disorders, such as those with cystic fibrosis (CF), non-CF bronchiectasis (nCFB) and severe chronic obstructive pulmonary disease (COPD). In addition, critically ill and immunocompromised patients are also at significant risk of P. aeruginosa infection. For almost half a century, research efforts have focused toward development of a vaccine against infections caused by P. aeruginosa, but a licensed vaccine is not yet available. Significant advances in identifying potential vaccine antigens have been made. Immunisations via both the mucosal and systemic routes have been trialled in animal models and their effectiveness in clearing acute infections demonstrated. The challenge for translation of this research to human applications remains, since P. aeruginosa infections in the human respiratory tract can present both as an acute or chronic infection. In addition, immunisation prior to infection may not be possible for many patients with CF, nCFB or COPD. Therefore, development of a therapeutic vaccine provides an alternative approach for treatment of chronic infection. Preliminary animal and human studies suggest that mucosal immunisation may be effective as a therapeutic vaccine against P. aeruginosa respiratory infections. Nevertheless, more research is needed to improve our understanding of the basic biology of P. aeruginosa and the mechanisms needed to upregulate the induction of host immune pathways to prevent infection. Recognition of variability in the host immune responses for a range of patient health conditions at risk from P. aeruginosa infection is also required to support development of a successful vaccine delivery strategy and vaccine. Activation of mucosal immune responses may provide improved efficacy of vaccination for P. aeruginosa during both acute exacerbations and chronic infection.

Show MeSH
Related in: MedlinePlus