Acellular pertussis vaccine composed of genetically inactivated pertussis toxin: Safety and immunogenicity in 12- to 24- and 2- to 4-month-old children

doi:10.1016/S0022-3476(05)80227-6

The Journal of Pediatrics

Volume 120, Issue 5, May 1992, Pages 680-685

https://doi.org/10.1016/S0022-3476(05)80227-6 Get rights and content

To determine whether a nontoxic derivative of pertussis toxin obiained by recombinant DNA technology, PT-9K/129G, is a good candidate for a new pertussis vaccine, we examined the safety and the immunogenicity in children of a vaccine containing 15 μg of PT-9K/129G protein and 0.5 mg of aluminum hydroxide per dose. Fifty-three children 12 to 24 months of age and 21 infants aged 2 to 4 months were injected with two and three doses, respectively. The vaccine did not incude significant local or systemic reactions and elicited an increase of antibody titer in more than 98% of the children. The geometric mean of the toxin-neutralizing titers increased after each dose and was 85 units in children given two doses and 196 units in those given three doses. Two children who had detectable antibody levels before the first immunization had a high response (>320 units) to the first vaccine dose. The findings suggest that PT-9K/129G is a promising antigen to be included in the development of acellular pertussis vaccines.

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Long-lived immunity to genetically detoxified pertussis vaccines
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Most infections are caused by pathogens that access the body at mucosal sites. Hence development of vaccines to prevent local infection or invasion of pathogens represents a top global health priority. Because mucosal immunity requires priming at the mucosal site, mucosal vaccination has attracted much interest, but few mucosal vaccines have been developed. Although only a handful of mucosal vaccines have been approved for human use, many candidate vaccines are currently being tested in clinical trials. Most of these vaccines are live attenuated vaccines, whereas only a few recombinant protein/subunit-based vaccines are being developed. This is largely due to the lack of safe and potent mucosal adjuvants. Over the past decade, a number of immunomodulatory agents, including toxin-based adjuvants, Toll-like receptor mimetics, and non–TLR-targeting immunostimulators have shown promise for mucosal administration in experimental animal models. However, their possible use in humans remains to be established. Toxin-based adjuvants are among the most widely studied mucosal adjuvants today, but separating their toxicity from the adjuvant function is critical for their clinical use. This book chapter, albeit not exhaustively, provides an overview of the progress and challenges in the development of toxin-based adjuvants, since these could be viewed as prototype mucosal adjuvants for future mucosal vaccines.
Engineered bacterial toxin vaccines and adjuvants
2006, The Comprehensive Sourcebook of Bacterial Protein Toxins
Cloning and immunologic characterization of a truncated Bordetella bronchiseptica filamentous hemagglutinin fusion protein
1999, Vaccine
Filamentous hemagglutinin (FHA) is an outer-membrane associated adhesin conserved within the genus Bordetella. FHA provides protection against B. pertussis infections in humans and is a component of acellular whooping cough vaccines. Furthermore, FHA serves as a protective antigen in several animal models of infection with B. bronchiseptica and may serve as a protective antigen of canine bordetellosis. In this study, polyclonal anti-B. pertussis FHA antiserum was used to identify an immunoreactive clone from the genomic DNA library of a canine B. bronchiseptica field isolate. The nucleotide and predicted amino acid sequences of the immunoreactive clone were compared to fhaB and FhaB from B. pertussis revealing 94% identity at the nucleic acid level, and 86% identity at the protein level. A truncated fusion protein (FHAt) was prepared which included a conserved domain homologous to the immunodominant region in the FHA of B. pertussis [Leininger E, Bowen S, Renauld-Mongen G, Rouse JH, Menozzi FD, Locht C, Heron I, Brennan MJ. Immunodominant domain present on the Bordetella pertussis vaccine component filamentous hemagglutinin. J. Infect. Dis. 1997;175:1423–1431; Wilson DR, Siebers A, Finlay BB. Antigenic analysis of Bordetella pertussis filamentous hemagglutinin with phage display libraries and rabbit anti-filamentous hemagglutinin polyclonal antibodies. Infect. Immun. 1998;66:4884–4894]. FHAt was shown to be safe and antigenic in rabbits. FHAt induced the formation of antibodies that inhibit the hemagglutination associated with full length B. pertussis FHA, and inhibit adherence of B. bronchisepitca to canine fibroblasts by as much as 65%. This information may have implications for the development of safe and efficacious subunit vaccines for the prevention of canine bordetellosis and may contribute to future acellular whooping cough vaccines.
Genetically derived toxoids for use as vaccines and adjuvants
1999, Vaccine
Until very recently, development of vaccines has been based on an empirical approach. For example, bacterial toxins have been detoxified using empirical chemical treatment. Progress in biotechnology and molecular biology has allowed the fine knowledge of the structure-function relationship of several bacterial toxins. Thanks to this, the genetic attenuation of bacterial toxins has been made possible. Following this approach, a genetically detoxified pertussis toxin has been produced. This molecule is now the component of an acellular pertussis vaccine, which has been shown to be highly immunogenic and efficacious in infants. The same strategy of molecular detoxification of bacterial toxins has been applied to cholera toxin and to the Escherichia coli heat-labile enterotoxin. Toxin mutants devoid of any toxic activity have been produced and shown in animals to be highly immunogenic and to exhibit strong adjuvanticity when administered at mucosal sites in conjunction with several antigens. These successful results show that rational design of stronger and safer vaccines is feasible.
An acellular pertussis vaccine in healthy adults: Safety and immunogenicity
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Recent data indicate that Bordetella pertussis can be an important cause of illness in adolescents and adults. In a randomized observer- and subject-blinded study, adults (≥18 years of age) received an acellular pertussis (aP) vaccine containing genetically inactivated pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN), or a saline placebo, and were monitored for safety and immunogenicity. IgG antibodies to PT, FHA, and PRN were measured by enzyme-linked immunosorbent assay (ELISA) and PT neutralization by a Chinese hamster ovary (CHO) cell assay. Local reactions, more common in the aP group, were mild and transient. One month after immunization, geometric mean ELISA antibody concentrations for the aP and placebo groups, respectively, were: anti-PT, 463 and 7.6; anti-FHA, 417 and 18; and anti-PRN, 855 and 14. The anti-PT neutralization titers for the aP and placebo groups were 1:3439 and 1:58 respectively. This aP vaccine is a safe and immunogenic candidate booster vaccine against pertussis for adults.

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^†: Supported in part by a grant from Centro Nazionale Ricerche (CNR 91/00229/PF41).

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The Journal of Pediatrics

References (20)

Secondary analyses of the efficacy of two acellular pertussis vaccines evaluated in a Swedish phase III trial

Vaccine

Development of a pertussis component vaccine in Japan

Lancet

Immunogeneicity and safety of a pertussis vaccine composed of pertussis toxin inactivated by hydrogen peroxide, in 18- to 23-month-old children

J Pediatr

Modern vaccines: Haemophilus influenzae infections and whooping cough

Lancet

Report of the Task Force on Pertussis and Pertussis Immunization

Pediatrics

Pertussis immunization and serious acute neurological illness in children

BMJ

Pertussis vaccine encephalopathy: it is time to recognize it as the myth that it is

JAMA

Pertussis: epidemiology and control

Bull World Health Organ

Placebo-controlled trial of two acellular pertussis vaccines in Sweden: protective efficacy and adverse events

Lancet

The efficacy of acellular pertussis vaccine

JAMA

Cited by (39)

Long-lived immunity to genetically detoxified pertussis vaccines

Toxin-Based Mucosal Adjuvants

Engineered bacterial toxin vaccines and adjuvants

Cloning and immunologic characterization of a truncated Bordetella bronchiseptica filamentous hemagglutinin fusion protein

Genetically derived toxoids for use as vaccines and adjuvants

An acellular pertussis vaccine in healthy adults: Safety and immunogenicity

Original articleAcellular pertussis vaccine composed of genetically inactivated pertussis toxin: Safety and immunogenicity in 12- to 24- and 2- to 4-month-old children†

Vaccine

Lancet

J Pediatr

Modern vaccines: Haemophilus influenzae infections and whooping cough

Lancet

Report of the Task Force on Pertussis and Pertussis Immunization

Pediatrics

Pertussis immunization and serious acute neurological illness in children

BMJ

Pertussis vaccine encephalopathy: it is time to recognize it as the myth that it is

JAMA

Pertussis: epidemiology and control

Bull World Health Organ

Placebo-controlled trial of two acellular pertussis vaccines in Sweden: protective efficacy and adverse events

Lancet

The efficacy of acellular pertussis vaccine

JAMA

Original article
Acellular pertussis vaccine composed of genetically inactivated pertussis toxin: Safety and immunogenicity in 12- to 24- and 2- to 4-month-old children†