Efficacy of a Pseudomonas aeruginosa serogroup O9 vaccine

Abstract

There are currently no approved vaccines against the opportunistic pathogen Pseudomonas aeruginosa . Among vaccine targets, the lipopolysaccharide (LPS) O antigen of P. aeruginosa is the most immunodominant protective candidate. There are 20 different O antigens composed of different repeat sugar structures conferring serogroup specificity, and 10 are found most frequently in infection. Thus, one approach to combat infection by P. aeruginosa could be to generate immunity with a vaccine cocktail that includes all these serogroups. Serogroup O9 is 1 of the 10 serogroups commonly found in infection, but it has never been developed into a vaccine, due in part to the acid-labile nature of the O9 polysaccharide. Our laboratory has previously shown that intranasal administration of an attenuated Salmonella strain expressing the P. aeruginosa serogroup O11 LPS O antigen was effective in clearing bacteria and preventing mortality in mice following intranasal challenge with serogroup O11 P. aeruginosa . Consequently, we set out to develop a P. aeruginosa serogroup O9 vaccine using a similar approach. Here, we show that Salmonella expressing serogroup O9 triggered an antibody-mediated immune response following intranasal administration to mice and that it conferred protection from P. aeruginosa serogroup O9 in a murine model of acute pneumonia.

Optimization of the Synthesis and Conjugation of the Methyl Rhamnan Tip of Pseudomonas aeruginosa A-Band Polysaccharide and Immunogenicity Evaluation for the Continued Development of a Potential Glycoconjugate Vaccine

“…[α]D 25 1.0 (c 0.26, CH 3 OH) 1 H NMR (600 MHz, CD 3 OD): δ 5.15 (s, 4H, H1′, H1″, H1‴, H1‴′), 4.81 (d, 1H, J 1,2 = 1 4. Hz, H1), 4.14−4.12 (m, 1H, H2), 4.12−4.08 (m, 4H, H2′, H2″, H2‴, H2‴′), 3.96−3.91 (m, 1H, CHA, OCH 2 2 NH), 3.81−3.74 (m, 3H, H5′, H5″, H5‴), 3.75−3.67 (m, 2H, H5, H5‴′), 3.67−3.58 (5H, H4, H4′, H4″, H4‴, CHB, OCH 2 CH 2 NH), 3.55 (dd, 1H, J 3,2 = 3.1 Hz, J 3,4 = 9.1 Hz, H3), 3.50−3.46 (m, 4H, H4‴′, OCH 3 ), 3.46 (s, 3H, OCH 3 ), 3.45 (s, 3H, OCH 3 ), 3.44 (s, 3H, OCH 3 ), 3.42 (s, 3H, OCH 3 ), 3.42−3.38 (m, 3H, H3′, H3″, H3‴), 3.30 (dd, 1H, J 3‴′ , 2‴′ = 3.1 Hz, J 3‴′,4‴′ = 9.4 Hz, H3‴′), 3.26−3.15 (m, 2H, CHA, CHB, OCH 2 CH 2 NH), 1.34 (d, 3H, J 6,5 = 6.2 Hz, H6), 1.32−1.28 (m, 9H, H6′, H6″, H6‴), 1.27 (d, 3H, J 6‴′,5‴′ = 6.2 Hz, H6‴′)13 C NMR (150 MHz, CD 3 OD): δ 103.2 (C1‴′), 103.1 (C1‴), 103.0 (2C, C1″, C1′), 101.7 (C1), 83.1 (3C, C3′, C3″, C3‴), 82.8 (C3), 82.0 (C3‴′), 79.4 (C4‴), 79.3 (C4), 79.2 (2C, C4′, C4″), 72.6 (C4‴′), 70.5 (C5‴′), 69.1 (3C, C5′, C5″, C5‴), 68.7 (C5), 68.4 (C2′), 67.9 (3C, C2″, C2‴, C2‴′), 67.5 (C2), 64.6 (OCH 2 CH 2 NH), 57.3 (OCH 3 ), 56.7 (OCH 3 ), 56.6 (3C, OCH 3 ), 40.4 (OCH 2 CH 2 NH), 18.7 (C6), 18.6 (3C, C6′, C6″, C6‴), 17.9 (C6‴′).…”

“…2,3 Antibiotic-resistant Pa is often respiratoracquired and affects especially patients afflicted with cystic fibrosis, causing pneumonia and also a range of acute infections that can lead to sepsis. 4 There is currently no vaccine on the market against Pa; however, a range of vaccines are being developed. 5,6 Glycoconjugate vaccines are historically robust, safe, and efficient in preventing infections.…”

“…The aqueous layer was collected, evaporated, and purified by HPLC (C-18, H 2 O/MeOH) to generate 1 tri (7.4 mg, 10.8 μmol, 12%) as a white powder. 1 H NMR (600 MHz, CD 3 OD): δ 5.16−5.13 (m, 2H, H1′, H1″), 4.75 (d, 1H, J 1,2 = 1 4. Hz, H1), 4.41 (t, 0.73H, CH(OCH 3 ) 2 ), 4.13−4.08 (m, 2H, H2′, H2″), 4.07 (dd, 1H, J 2,1 = 1.9 Hz, J 2,3 = 3.0 Hz, H2), 3.84−3.71 (m, 3.5H, H5′, H5″, CHA, OCH 2 CH 2 NH), 3.71−3.65 (m, 1H, H5), 3.64−3.55 (m, 2.8H, H4, H4′), 3.55−3.37 (m, 17H, H3, H3′, H4″, CHB, OCH 2 CH 2 NH, CHA, CHB, OCH 2 CH 2 NH, 3x OCH 3 ), 3.34 (m, 4H, 2x OCH 3 ), 3.29 (dd, 1H, J 3″,2″ = 3.2 Hz, J 3″,4″ = 9.4 Hz, H3″), 2.26 (t, 1.6H, COCH 2 ), 1.73−1.66 (m, 1.6H, COCH 2 CH 2 ), 1.66−1.60 (m, 1.66H, COCH 2 ,CH 2 CH 2 ), 1.31 (d, 3H, J 6,5 = 6.1 Hz, H6), 1.30 (d, 3H, J 6′,5′ = 6.2 Hz, H6′), 1.27 (d, 3H, J 6″,5″ = 6.2 Hz, H6″) 13 C NMR (150 MHz, CD 3 OD): δ 176.1 (CO), 105.8 (CH(OCH 3 ) 2 ), 103.2 (C1′), 103.1 (C1″), 101.3 (C1), 83.1 (C3′), 83.0 (C3), 82.0 (C3″), 79.7 (C4), 79.2 (C4′), 72.6 (C4″), 70.5 (C5″), 69.0 (C5′), 68.4 (C2″), 68.3 (C5), 68.0 (C2′), 67.6 (C2), 67.0 (OCH 2 CH 2 NH), 57.3 (OCH 3 ), 56.7 (2x OCH 3 ), 53.5 (OCH 3 ), 53.4 (OCH 3 ), 40.2 (OCH 2 CH 2 NH), 36.6 (COCH 2 ), 33.1 (COCH 2 CH 2 CH 2 ), 22.0 (COCH 2 CH 2 ), 18.7 (C6), 18.6 (C6′), 17.8 (C6″).…”

“…Pseudomonas aeruginosa ( Pa ) is a pathogen that has become of considerable concern due to its resistance to most commonly used antibiotics, including carbapenems . This antimicrobial resistance (AMR) has prompted the World Health Organization and others to state that priorities include preventing infections by developing novel vaccines against AMR bacteria such as Pa due to the high mortality risk and the economic cost of these infections. , Antibiotic-resistant Pa is often respirator-acquired and affects especially patients afflicted with cystic fibrosis, causing pneumonia and also a range of acute infections that can lead to sepsis . There is currently no vaccine on the market against Pa ; however, a range of vaccines are being developed. , …”

“…Glycoconjugate vaccines are historically robust, safe, and efficient in preventing infections. ,− When developing a glycoconjugate vaccine against a bacteria, a range of carbohydrates on the surface of the bacteria can be targeted, such as the capsule and lipopolysaccharides . In Pa , as the B-band polysaccharide is highly variable, while the A-band polysaccharide is conserved in many clinical isolates, the A-band polysaccharide could therefore be of interest to develop as an antigen to target for a vaccine. − …”