Vaccination of Cystic Fibrosis Patients Against Pseudomonas aeruginosa Reduces the Proportion of Patients Infected and Delays Time to Infection

Lang, Aloïs B.; Rüdeberg, A; Schöni, Martin H.; Que, John U.; Fürer, E; Schaad, Urs B.

doi:10.1097/01.inf.0000129688.50588.ac

Cited by 91 publications

(54 citation statements)

References 29 publications

(22 reference statements)

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“…This vaccine was found to elicit good serum immune responses (16,17) and reduced the proportion of patients infected with P. aeruginosa, as well as delayed the time to infection (18). This same group is developing passive reagents (19); however, a clinical trial using i.v.…”

Section: Discussionmentioning

confidence: 99%

Intranasal immunization with heterologously expressed polysaccharide protects against multiple Pseudomonas aeruginosa infections

DiGiandomenico

Rao

Harcher

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Surface-expressed bacterial polysaccharides are often immunodominant, protective antigens. However, these antigens are chemically and serologically highly heterogeneous, and conjugation to protein carriers is often necessary to enhance their immunogenicity. Here we show the efficacy of intranasal immunization of mice with attenuated Salmonella enterica serovar Typhimurium expressing the O antigen portion of Pseudomonas aeruginosa lipopolysaccharide. P. aeruginosa is an ideal model system because it can cause a myriad of localized and systemic infections. In particular, this bacterium is a leading cause of hospital-acquired pneumonia and is responsible for infections after burns and after eye injury. In addition, there are mouse models of infection that mimic the clinical manifestations of P. aeruginosa infections. Immunized mice were highly protected against infection, with long-lasting immunity to acute P. aeruginosa pneumonia, whereas mice immunized with Salmonella containing only the cloning vector or PBS were not. Prophylactic and therapeutic administration of sera from vaccinated animals protected naive mice. Intranasal vaccination also provided complete protection from infections after burns and reduced pathology after corneal abrasions. These results indicate that intranasal delivery of heterologously expressed polysaccharide antigens provides protection at distinct sites of infection. This approach for the expression and delivery of polysaccharide antigens as recombinant immunogens could be easily adapted to develop vaccines for many infectious agents, without the need for complicated purification and conjugation procedures.antibody ͉ Salmonella ͉ vaccine B acterial surface polysaccharides make effective components for vaccines against serious infections because they are generally immunodominant. However, their utility is limited by significant chemical, and hence serologic, variability that requires a large number of components for comprehensive coverage against pathogens capable of expressing different polysaccharide serotypes. Also, purified polysaccharides are often poorly immunogenic, necessitating synthesis of protein-polysaccharide conjugate vaccines. These problems could potentially be overcome by use of recombinant DNA to induce synthesis of the polysaccharides in a heterologous antigen-delivery system. We evaluated this potential by expressing the Pseudomonas aeruginosa LPS O antigen in attenuated Salmonella enterica serovar Typhimurium SL3261 and used this construct to immunize mice intranasally (IN) to evaluate protective immunity against P. aeruginosa infection in the lung and eye, as well as systemic infection emanating from burn wounds.The model polysaccharide that we have used for this study is the P. aeruginosa serogroup O11 O antigen. This serogroup is one of the most prevalent (1) and has been associated with acute infections (2), burns (3), and ulcerative keratitis (4). In addition, P. aeruginosa serogroup O11 strains are among the most pathogenic and lethal because of the expression ...

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Section: Discussionmentioning

confidence: 99%

Intranasal immunization with heterologously expressed polysaccharide protects against multiple Pseudomonas aeruginosa infections

DiGiandomenico

Rao

Harcher

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Antibodies are the most likely major effectors of such immunity, as the role of the cellular immune system involving T lymphocytes is unclear, although animal data have suggested they might be an important factor [70]. Many virulence factors of P. aeruginosa have been targeted for active immunization against this bacterium, and two vaccines reached phase III clinical trial studies [71,72]. One vaccine was composed of 8 different LPS O antigens, each conjugated to the P. aeruginosa toxin A carrier protein, but recently released results did not show any efficacy of this vaccine (http://investors.crucell.-com/C/132631/PR/ 200607/1064252_5_5.html).…”

Section: Preventing or Limiting The Development Of Infectionmentioning

confidence: 99%

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Campodónico

Gadjeva

Paradis-Bleau

et al. 2008

Trends in Molecular Medicine

100

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Defective expression or function of the cystic fibrosis transmembrane conductance regulator (CFTR) underlies the hypersusceptibility of cystic fibrosis (CF) patients to chronic airway infections, particularly with Pseudomonas aeruginosa. CFTR is involved in the specific recognition of P. aeruginosa, thereby contributing to effective innate immunity and proper hydration of the airway surface layer (ASL). In CF, the airway epithelium fails to initiate an appropriate innate immune response, allowing the microbe to bind to mucus plugs that are then not properly cleared because of the dehydrated ASL. Recent studies have identified numerous CFTR-dependent factors that are recruited to the epithelial plasma membrane in response to infection and that are needed for bacterial clearance, a process that is defective in CF patients hypersusceptible to infection with this organism. Pseudomonas aeruginosa in cystic fibrosisCystic fibrosis (CF) is unique among human genetic disorders in that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a protein whose primary function described to date has been to regulate conductance of ions in and out of cells and intracellular vacuoles, lead to hypersusceptibility to chronic lung infection. Human diseases wherein individuals homozygous for mutant genes are predisposed to infections serve as a firm foundation for understanding the molecular, cellular, physiologic and immunologic aspects of normal and compromised resistance to infection. CF is not just a prime example of how we can learn about normal and pathologic states; it could, in fact, be the only known human genetically determined disease wherein infection with a single pathogen -Pseudomonas aeruginosa -drives the vast majority of morbidity, clinical deterioration and ultimately life-shortening mortality encountered in this disease. In humans with significant compromises to their immune system, such as advanced AIDS, we would normally expect to see a plethora of pathogens take advantage of this debilitated state, but this is not the case in CF.CF is characterized by the emergence and persistence of (and, ultimately, the inability to clear) chronic infection with a variant of P. aeruginosa (mucoid P. aeruginosa) that overproduces a surface polysaccharide known as alginate. The organism undergoes other significant genetic adaptations and selections within the CF lung, and it is the emergence of mucoid P. aeruginosa that is the primary determinant of the clinical course of this disease [1,2]. In those individuals with either an uncommon but fortuitous protective immune response to specific P. aeruginosa antigens [3,4] Histopathologic basis for defining relevant interactions between P.aeruginosa and the CF airway epitheliumAlthough CF is a multisystem disease characterized by GI and nutritional abnormalities, salt loss syndromes and male urogenital abnormalities, the major clinical problem for CF patients is chronic sinopulmonary disease. Therefore, relying on observations made fr...

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“…KBPA-101 is a human MAb obtained from a volunteer immunized with a P. aeruginosa O-polysaccharide toxin A conjugate vaccine (10,11). It is of IgM/ isotype and directed against the LPS O-polysaccharide moiety of P. aeruginosa serotype IATS O11.…”

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confidence: 99%

Pharmacokinetics and Safety Profile of the Human Anti- Pseudomonas aeruginosa Serotype O11 Immunoglobulin M Monoclonal Antibody KBPA-101 in Healthy Volunteers

Lazar¹,

Horn²,

Zuercher³

et al. 2009

Antimicrob Agents Chemother

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Vaccination of Cystic Fibrosis Patients Against Pseudomonas aeruginosa Reduces the Proportion of Patients Infected and Delays Time to Infection

Cited by 91 publications

References 29 publications

Intranasal immunization with heterologously expressed polysaccharide protects against multiple Pseudomonas aeruginosa infections

Intranasal immunization with heterologously expressed polysaccharide protects against multiple Pseudomonas aeruginosa infections

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Pharmacokinetics and Safety Profile of the Human Anti- Pseudomonas aeruginosa Serotype O11 Immunoglobulin M Monoclonal Antibody KBPA-101 in Healthy Volunteers

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