Antibody responses induced by long-term vaccination with an octovalent conjugate<i>Pseudomonas aeruginosa</i>vaccine in children with cystic fibrosis

Zuercher, Adrian W.; Horn, Michael P.; Que, John U.; Ruedeberg, Anna; Schoeni, Martin H.; Schaad, Urs B.; Marcus, Paul; Lang, Aloïs B.

doi:10.1111/j.1574-695x.2006.00103.x

Cited by 48 publications

(22 citation statements)

References 32 publications

(47 reference statements)

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“…Indeed, we have shown previously that naturally (i.e., infection induced) anti-LPS antibodies mostly were of low affinity and specific for LPS-core determinants rather than O-polysaccharide epitopes. Consequently, on May 11, 2018 by guest http://aac.asm.org/ they were ineffective in mediating clearance of P. aeruginosa infection (46). Thus, the approach of using immunized volunteers as the source of human lymphocytes for the generation of hybridomas was clearly useful.…”

Section: Discussionmentioning

confidence: 99%

PreclinicalIn VitroandIn VivoCharacterization of the Fully Human Monoclonal IgM Antibody KBPA101 Specific forPseudomonas aeruginosaSerotype IATS-O11

Horn¹,

Zuercher²,

Imboden³

et al. 2010

Antimicrob Agents Chemother

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Pseudomonas aeruginosa infection in ventilator-associated pneumonia is a serious and often life-threatening complication in intensive care unit patients, and new treatment options are needed. We used B-cell-enriched peripheral blood lymphocytes from a volunteer immunized with a P. aeruginosa O-polysaccharide-toxin A conjugate vaccine to generate human hybridoma cell lines producing monoclonal antibodies specific for individual P. aeruginosa lipopolysaccharide serotypes. The fully human monoclonal antibody secreted by one of these lines, KBPA101, is an IgM/ antibody that binds P. aeruginosa of International Antigenic Typing System (IATS) serotype O11 with high avidity (5.81 ؋ 10 7 M ؊1 ؎ 2.8 ؋ 10 7 M ؊1 ) without cross-reacting with other serotypes. KBPA101 specifically opsonized the P. aeruginosa of IATS O11 serotype and mediated complement-dependent phagocytosis in vitro by the human monocyte-like cell line HL-60 at a very low concentration (half-maximal phagocytosis at 0.16 ng/ml). In vivo evaluation of KBPA101 demonstrated a dose-response relationship for protection against systemic infections in a murine burn wound sepsis model, where 70 to 100% of animals were protected against lethal challenges with P. aeruginosa at doses as low as 5 g/animal. Furthermore, a high efficacy of KBPA101 in protection from local respiratory infections in an acute lung infection model in mice was demonstrated. Preclinical toxicology evaluation on human tissue, in rabbits, and in mice did not indicate any toxicity of KBPA101. Based on these preclinical findings, the first human clinical trials have been initiated.

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Section: Discussionmentioning

confidence: 99%

PreclinicalIn VitroandIn VivoCharacterization of the Fully Human Monoclonal IgM Antibody KBPA101 Specific forPseudomonas aeruginosaSerotype IATS-O11

Horn¹,

Zuercher²,

Imboden³

et al. 2010

Antimicrob Agents Chemother

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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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“…Although here we demonstrated that LPS core-targeted antibodies with opsonic-killing activity were associated with better protection against acute fatal lung infection, it is not clear whether antibodies with this specificity would also help prevent and/or eradicate chronic P. aerguinosa infection in CF patients. Based on cross-inhibition enzyme-linked immunosorbent assay (ELISA) analysis, it has been reported that antibodies induced by a P. aeruginosa LPS O-antigen-based octavalent conjugate vaccine that was tested in CF patients bound monospecifically to individual O antigens of each serotype, but during chronic lung infection with the pathogen, there was acquisition of antibodies that bound to common epitopes within the core region of LPS (19,32,38). As neither the LPS O-antigen-based octavalent vaccine nor the induced core-specific antibodies confer protection against either acquisition or progression of chronic infection, it appears unlikely that targeting these epitopes with a vaccine would have a high chance of success in the setting of CF.…”

Section: Discussionmentioning

confidence: 99%

Mucosal Vaccination with a Multivalent, Live-Attenuated Vaccine Induces Multifactorial Immunity against Pseudomonas aeruginosa Acute Lung Infection

et al. 2011

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Many animal studies investigating adaptive immune effectors important for protection against Pseudomonas aeruginosa have implicated opsonic antibody to the antigenically variable lipopolysaccharide (LPS) O antigens as a primary effector. However, active and passive vaccination of humans against these antigens has not shown clinical efficacy. We hypothesized that optimal immunity would require inducing multiple immune effectors targeting multiple bacterial antigens. Therefore, we evaluated a multivalent live-attenuated mucosal vaccination strategy in a murine model of acute P. aeruginosa pneumonia to assess the contributions to protective efficacy of various bacterial antigens and host immune effectors. Vaccines combining 3 or 4 attenuated strains having different LPS serogroups were associated with the highest protective efficacy compared to vaccines with fewer components. Levels of opsonophagocytic antibodies, which were directed not only to the LPS O antigens but also to the LPS core and surface proteins, correlated with protective immunity. The multivalent liveattenuated vaccines overcame prior problems involving immunologic interference in the development of O-antigen-specific antibody responses when closely related O antigens were combined in multivalent vaccines. Antibodies to the LPS core were associated with in vitro killing and in vivo protection against strains with O antigens not expressed by the vaccine strains, whereas antibodies to the LPS core and surface proteins augmented the contribution of O-antigen-specific antibodies elicited by vaccine strains containing a homologous O antigen. Local CD4 T cells in the lung also contributed to vaccine-based protection when opsonophagocytic antibodies to the challenge strain were absent. Thus, multivalent live-attenuated vaccines elicit multifactorial protective immunity to P. aeruginosa lung infections.Pseudomonas aeruginosa lung infections cause substantial morbidity and mortality in humans, manifesting as acute lifethreatening infection, often with bacteremia, in hospitalized and/or immunocompromised patients or as chronic localized lung infection in patients with cystic fibrosis (CF). In hospitalacquired lung infections, which are most commonly ventilatorassociated pneumonias, P. aeruginosa is the leading Gramnegative causative bacterial agent (31). In these infections, the crude mortality rate associated with the bacterium is higher than that due to other bacterial etiologies (30). Despite the widespread and significant impact of P. aeruginosa infections, along with the increasing rates of antibiotic treatment failure due to drug resistance (33), vaccines and immunotherapeutic agents for the disease are still in the early stages of preclinical and clinical development (7).In animal studies, lipopolysaccharide (LPS) O antigens of P. aeruginosa induce potent serogroup-specific protection (i.e., protection against P. aeruginosa strains within the same LPS O-antigen serogroup) (23, 24). However, even within a serogroup there are structural, and hence antige...

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Antibody responses induced by long-term vaccination with an octovalent conjugatePseudomonas aeruginosavaccine in children with cystic fibrosis

Cited by 48 publications

References 32 publications

PreclinicalIn VitroandIn VivoCharacterization of the Fully Human Monoclonal IgM Antibody KBPA101 Specific forPseudomonas aeruginosaSerotype IATS-O11

PreclinicalIn VitroandIn VivoCharacterization of the Fully Human Monoclonal IgM Antibody KBPA101 Specific forPseudomonas aeruginosaSerotype IATS-O11

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

Mucosal Vaccination with a Multivalent, Live-Attenuated Vaccine Induces Multifactorial Immunity against Pseudomonas aeruginosa Acute Lung Infection

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