Pertussis Challenge Research Articles

Responses to acellular pertussis vaccines and component antigens in a coughing-rat model of pertussis

Two acellular pertussis vaccines (SmithKline Beecham 3-component and Connaught 5-component), and a whole-cell pertussis vaccine (Evans), were similarly protective against paroxysmal coughing and leukocytosis in a coughing-rat model of pertussis. A two-dose immunization schedule was followed by sublethal intrabronchial challenge with Bordetella pertussis strain 18–323, encased in fine agarose beads, and the coughing monitored by sound-activated tape recorders. Pertussis toxoid by itself gave some protection against coughing, but lower than that afforded by the vaccines, despite inducing a higher serum anti-PT titre. The other component antigens, given individually, failed to protect against coughing although inducing antibodies. Immunization with the whole-cell and acellular vaccines and with their component antigens, as well as challenge with B. pertussis, caused significant elevation of total serum IgE antibodies. Antigen-specific IgG and IgA were detected in tracheobronchial washings from rats recovering from B. pertussis challenge, but vaccination prior to challenge had little influence on these antibody levels. The coughing-rat model of pertussis may be useful for the comparative testing of different formulations of pertussis vaccines before trials in human infants.

Effects of recombinant murine (rm) interleukin-12 and rm interferon-gamma in mice infected with Bordetella pertussis.

The recombinant cytokines interferon (IFN)-gamma and interleukin (IL)-12 stimulate several macrophage-mediated functions that are important in host defense. An experimental pertussis model showed that intraperitoneal (i.p.) administration of 10,000 U of recombinant murine (rm) IFN-gamma to mice at the time of Bordetella pertussis infection caused a marked and significant reduction in the number of colony-forming units of bacteria in the lungs. Administration i.p. of 1 microgram of rmIL-12 or 1 microgram of rmIL-12 at the time of and for 5 consecutive days after B. pertussis challenge also induced a significant reduction in the number. However, i.p. administration of 1 microgram of rmIL-12 with 10,000 U of IFN-gamma at the time of B. pertussis challenge did not provide protection. These findings indicate that exogenous administration of rmIL-12 and rmIFN-gamma enhances resistance of mice to B. pertussis infection.

Characterization of a Salmonella typhimurium aro vaccine strain expressing the P.69 antigen of Bordetella pertussis.

The P.69 Bordetella pertussis protective antigen was expressed by use of the trc promoter from the chromosome of a Salmonella typhimurium aro vaccine strain, BRD509, by integrating the prn gene, encoding the 93-kDa precursor of this protein, into the aroC locus. P.69 was detected on the cell surface of the S. typhimurium strain (BRD640) by agglutination and immunoelectron microscopy. BALB/c mice immunized orally or intravenously with BRD640 showed a significant level of protection against an aerosol challenge with virulent B. pertussis, compared with control animals. No anti-P.69 antibodies in the serum or anti-P.69 antibody-secreting cells in the lungs were detected in BRD640-vaccinated animals, although cells isolated from spleens showed a P.69-dependent cell proliferative response. In contrast, low levels of anti-P.69 antibodies in the serum and anti-P.69 antibody-secreting cells in the lungs were detected in immunized mice following a B. pertussis challenge.

The Status of Acellular Pertussis Vaccines: Current Perspective

Clinical studies of component ("acellular") pertussis vaccines have been undertaken in recent years, and several acellular vaccines have been used in Japan for 10 years. The Committee has reviewed these trials and related data and herein provides its assessment regarding the current status of the acellular vaccines and their possible use in the United States. The pertussis vaccines in current use in the United States are prepared from whole cells of a strain of Bordetella pertussis that is grown in broth medium, harvested by centrifugation, and killed or partially detoxified by heat or by the addition of a chemical agent, such as thimerosal, or by a combination of these methods. In contrast, the acellular vaccines developed in Japan and used in that country since 1981 contain one or more antigens derived from biologically active components of the B pertussis organism.1 An inactivated form of lymphocytosis promoting factor (LPF), also known as pertussis toxin and a variety of other synonyms, is a frequent component of acellular pertussis vaccines, as are filamentous hemagglutinins (FHA). Other constituents included in acellular vaccines are agglutinogens, a term denoting a variety of protein antigens on the surface of the B pertussis organism. Of the agglutinogens, a 69-kd outer membrane protein, when injected into neonatal mice, protects against B pertussis challenge.2 Acellular vaccines also have recently been derived from mutant pertussis toxin molecules prepared with recombinant DNA technology.3 The acellular vaccines produced in Japan have been classified into two types: B type, which contains LPF and FHA in roughly equal amounts; and T type, which contains mostly FHA but some LPF and agglutinogens.1,4

Characterization of the protective capacity and immunogenicity of the 69-kD outer membrane protein of Bordetella pertussis.

Immunization with the 69-kD outer membrane protein (OMP) of Bordetella pertussis protected neonatal mice against lethal respiratory challenge with B. pertussis 18323. Active immunization elicited a serum IgG anti-69-kD OMP response at the time of challenge, with IgG anti-69-kD OMP antibodies detected in bronchoalveolar lavage fluid after challenge. Intravenous administration of BPE8, a monoclonal IgG1 anti-69-kD OMP, also protected young mice against B. pertussis challenge. Intravenously injected BPE8 was detected in the lungs of mice at the time of aerosol challenge, suggesting that the presence of specific antibody in the lungs may mediate protection. Thus the 69-kD OMP of B. pertussis is a protective antigen in mice that elicits specific serum antibody that can transude to the lung. The 69-kD OMP was detected in a preparation of a Takeda acellular vaccine by immunoblot analysis and a serum antibody response to the 69-kD OMP was observed in 18-mo-old children boosted with this preparation of Japanese acellular vaccine. Our results demonstrate that the B. pertussis 69-kD OMP is a protective antigen in animals, is immunogenic in humans, and is present in a preparation of acellular pertussis vaccine that is widely used in Japan. These findings indicate that the 69-kD OMP should be seriously considered as a candidate for inclusion in new formulations of antigenically defined acellular pertussis vaccines.