Affinity Constants of Naturally Acquired and Vaccine-Induced Anti-Pseudomonas aeruginosa Antibodies in Healthy Adults and Cystic Fibrosis Patients

Bruderer, Urs; Cryz, Stanley J.; Schaad, Urs B.; Deusinger, Markus; Que, John U.; Lang, Aloïs B.

doi:10.1093/infdis/166.2.344

Cited by 47 publications

(23 citation statements)

References 34 publications

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“…The average affinity constants for such antibodies were determined [8]. The ability of sera to neutralize the cytotoxicity of toxin A was determined in a HEp-2 cell assay [9].…”

Section: Resultsmentioning

confidence: 99%

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Immunization of Noncolonized Cystic Fibrosis Patients against Pseudomonas aeruginosa

Cryz

Wedgwood

Lang

et al. 1994

Journal of Infectious Diseases

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The long-term safety and immunogenicity of a polyvalent Pseudomonas aeruginosa conjugate vaccine was evaluated in 30 noncolonized cystic fibrosis patients. Four doses were administered over 3 years, and patients were followed for a mean of 38 months. No acute or long-term adverse effects were noted. Immunization engendered a significant antibody response to all vaccine components. A decline in titers during year 3 of observation was associated with a marked rise in the isolation of P. aeruginosa. This organism was isolated repeatedly from the respiratory tract of 4 patients and only once from 7 patients. The remaining patients were repeatedly culture-negative. Only 1 patient showed clinical deterioration associated with multiple isolations of P. aeruginosa.Pseudomonas aeruginosa is the leading cause of bronchopulmonary infection in patients with cystic fibrosis (CF) [1]. A substantial proportion of morbidity and mortality in this patient population is the result of recurrent pulmonary exacerbations subsequent to colonization. Rarely can P. aeruginosa be eradicated through antibiotic treatment. Further complicating treatment is the fact that multiply resistant strains often arise after repeated or prolonged drug therapy or prophylaxis.Colonization of the lower respiratory tract by mucoid variants of P. aeruginosa is preceded by infection of the upper respiratory tract by smooth strains [2]. Such natural exposure to P. aeruginosa stimulates a vigorous humoral antibody response to many somatic and extracellular antigens [3,4]. However, such antibodies do not prevent or even ameliorate subsequent infections. In fact, several laboratories [5,6] have noted a positive correlation between elevated anti-P aeruginosa antibody titers and a more severe disease course. This may be the result ofimmune complexes being deposited in the lungs and other organs.Anti-P. aeruginosa lipopolysaccharide (LPS) antibodies acquired after natural exposure are not effective at promoting opsonophagocytic killing [7]. We have found that anti-P. aeruginosa LPS antibodies acquired subsequent to colonization had very low average affinity constants, which These studies have been expanded to include 30 noncolonized patients followed for an average of38 months after vaccination. Various clinical. serologic, and bacteriologic parameters were analyzed. Materials and MethodsOver 31 months, 30 CF patients (13 males, 17 females) aged 1.6-24.0 years (mean, 8.3) were enrolled. All were in good health and clinically stable and had no history of infection with P. aeruginosa. On entry. sputum or throat swabs (or both) were negative for P. aeruginosa.Patients were immunized intramuscularly at O. 2, 12, and 36 months with a low (12.5 J.lg ofO-PS per serotype, n = 19) or a high (25 J.lg of O-PS per serotype, n = 11) dose of octavalent O-PS-toxin A conjugate vaccine [9] that contained the following International Antigen Typing System (IATS) LPS serotypes: 1.2/5.3.4,6,7. 10, and 16. Patients were observed for 60 min after immunization. For assessment of adverse r...

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“…The average affinity constants for such antibodies were determined [8]. The ability of sera to neutralize the cytotoxicity of toxin A was determined in a HEp-2 cell assay [9].…”

Section: Resultsmentioning

confidence: 99%

“…We have found that anti-P. aeruginosa LPS antibodies acquired subsequent to colonization had very low average affinity constants, which correlate with poor opsonic activity [8]. In contrast, vaccineinduced antibodies are opsonic and of high affinity [8].…”

mentioning

confidence: 90%

Immunization of Noncolonized Cystic Fibrosis Patients against Pseudomonas aeruginosa

Cryz

Wedgwood

Lang

et al. 1994

Journal of Infectious Diseases

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“…The host response to P. aeruginosa is a complex immune and inflammatory reaction that results in damage to the respiratory tract (1,2). Antibodies as well as cell-mediated immunity seem to be associated with protective immunity, but an efficient vaccine against pulmonary colonization with P. aeruginosa is not yet available (39)(40)(41)(42)(43)(44)(45)(46). Various components of P. aeruginosa have been tested as vaccine candidates in animal studies and humans, among them the outer membrane protein OprF.…”

Section: Figurementioning

confidence: 99%

Protection against P. aeruginosa with an adenovirus vector containing an OprF epitope in the capsid

Worgall¹,

Krause²,

Rivara³

et al. 2005

J. Clin. Invest.

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Pseudomonas aeruginosa is an important opportunistic pathogen that can cause chronic and often life-threatening infections of the respiratory tract, particularly in individuals with cystic fibrosis (CF). Because infections with P. aeruginosa remain the major cause of the high morbidity and mortality of CF, a vaccine against P. aeruginosa would be very useful for preventing this disorder. The outer membrane protein F (OprF) of P. aeruginosa is a promising vaccine candidate and various B cell epitopes within OprF have been identified. Given that adenovirus (Ad) vectors have strong immunogenic potential and can function as adjuvants for genetic vaccines, the present study evaluates the immunogenic and protective properties of a novel replication-deficient Ad vector in which the Ad hexon protein was modified to include a 14-amino acid epitope of P. aeruginosa OprF (Epi8) in loop 1 of the hypervariable region 5 of the hexon (AdZ.Epi8). Immunization of C57BL/6 mice with AdZ.Epi8 resulted in detectable serum anti-P. aeruginosa and anti-OprF humoral responses. These responses were haplotype dependent, with higher serum anti-OprF titers in CBA mice than in BALB/c or C57BL/6 mice. AdZ.Epi8 induced Epi8-specific IFN-γ-positive CD4 and CD8 T cell responses and resulted in protection against a lethal pulmonary challenge with agar-encapsulated P. aeruginosa. Importantly, repeated administration of AdZ.Epi8 resulted in boosting of the anti-OprF humoral and anti-Epi8 cellular response, whereas no boosting effect was present in the response against the transgene β-galactosidase. These observations suggest that Ad vectors expressing pathogen epitopes in their capsid will protect against an extracellular pathogen and will allow boosting of the epitope-specific humoral response with repeated administration, a strategy that should prove useful in developing Ad vectors as vaccines where humoral immunity will be protective.

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“…The isotypes of both specific antibodies and NAbs that bind to LPS include IgA, IgG and IgM, although NAbs are predominantly IgM. Although germinal centers typically do not form in response to LPS, specific antibodies still have a higher affinity to LPS than NAbs (Bruderer et al, 1992). In mice, an age-associated decrease in antibody responses to Tindependent antigens, including LPS, has been reported (Chelvarajan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Humoral immune responses are maintained with age in a long-lived ectotherm, the red-eared slider turtle

Zimmerman

Clairardin

Paitz

et al. 2012

Journal of Experimental Biology

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SUMMARYAging is typically associated with a decrease in immune function. However, aging does not affect each branch of the immune system equally. Because of these varying effects of age on immune responses, aging could affect taxa differently based on how the particular taxon employs its resources towards different components of immune defense. An example of this is found in the humoral immune system. Specific responses tend to decrease with age while non-specific, natural antibody responses increase with age. Compared with mammals, reptiles of all ages have a slower and less robust humoral immune system. Therefore, they may invest more in non-specific responses and thus avoid the negative consequences of age on the immune system. We examined how the humoral immune system of reptiles is affected by aging and investigated the roles of non-specific, natural antibody responses and specific responses by examining several characteristics of antibodies against lipopolysaccharide (LPS) in the red-eared slider turtle. We found very little evidence of immunosenescence in the humoral immune system of the red-eared slider turtle, Trachemys scripta, which supports the idea that non-specific, natural antibody responses are an important line of defense in reptiles. Overall, this demonstrates that a taxonʼs immune strategy can influence how the immune system is affected by age.

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Affinity Constants of Naturally Acquired and Vaccine-Induced Anti-Pseudomonas aeruginosa Antibodies in Healthy Adults and Cystic Fibrosis Patients

Cited by 47 publications

References 34 publications

Immunization of Noncolonized Cystic Fibrosis Patients against Pseudomonas aeruginosa

Immunization of Noncolonized Cystic Fibrosis Patients against Pseudomonas aeruginosa

Protection against P. aeruginosa with an adenovirus vector containing an OprF epitope in the capsid

Humoral immune responses are maintained with age in a long-lived ectotherm, the red-eared slider turtle

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