Quantitative Priming with Inactivated Pertussis Toxoid Vaccine in the Aerosol Challenge Model

Abstract

Serum antibodies to pertussis toxin (PT) have been shown to be protective against severe pertussis disease, although a specific level of anti-PT antibody that correlates with protection has not been demonstrated. Current animal models such as the intracerebral challenge model have significant limitations in correlating protection to a specific level of anti-PT antibody. This study examines the protective effects of priming with tetranitromethane-inactivated pertussis toxoid (PTx) vaccine in the aerosol challenge model and whether a measurable response to a priming dose of PTx is enough to initiate a protective secondary response when challenged with infection. The correlation of priming with markers of illness such as leukocytosis, weight loss, bacterial proliferation, and mortality after established infection with Bordetella pertussis was explored. BALB/c mice were immunized with PTx vaccine on day 6 of life and then challenged with B. pertussis using the aerosol challenge model. Data were analyzed according to the primary immunologic response, differentiating responders (anti-PT immunoglobulin G [IgG] >1 g/ml) from nonresponders (anti-PT IgG <1 g/ml). Mice that showed evidence of priming on the day of aerosol challenge were able to mount a secondary response to the challenge with a >2-fold rise in anti-PT IgG antibody by day 7 and a >10-fold rise by day 14 post-aerosol challenge. These primed mice were significantly better protected against leukocytosis, weight loss, and proliferation of B. pertussis in the lungs following aerosol challenge than the nonprimed group. This protection correlated with levels of anti-PT antibody in serum present on the day of aerosol challenge.

Association of Interacting Genes in the Toll-Like Receptor Signaling Pathway and the Antibody Response to Pertussis Vaccination

“…Unfortunately the functional significance of this SNP is still unknown. This antibody response correlates with protection against disease both in humans [14] – [16] and in mice [17] .…”

Lipopolysaccharide Analogs Improve Efficacy of Acellular Pertussis Vaccine and Reduce Type I Hypersensitivity in Mice

“…Ptx-specific IgG levels have been shown to correlate with protection in both humans (11,41,42) and mice (7). Cell-mediated immunity, however, also critically contributes to protection in both humans (1, 9, 24) and mice (30).…”

Antibodies Recognizing Protective Pertussis Toxin Epitopes Are Preferentially Elicited by Natural Infection versus Acellular Immunization

“…We suggest that antibodies recognizing specific protective epitopes with high affinity, as opposed to overall titers against individual virulence factors, may aid in identification of serological correlates of protection. For instance, the failure of P-IGIV passive immunization trials to demonstrate a clear effect on clinical outcome (5,6,19) may have been due to low concentrations of clinically relevant antibodies binding key neutralizing epitopes. Here we have presented evidence that serum responses to two protective epitopes are significantly higher following exposure to native PTx than following vaccination with PTd.…”

“…There, the molecule ADP ribosylates the alpha subunit of Gi/o receptors, altering cellular signaling processes. Experiments have demonstrated the following: (i) reduced virulence of bacteria lacking PTx genes for mice (37,(41)(42)(43), (ii) efficacy of the acellular pertussis vaccines (comprised of PTx and 0 to 4 additional virulence factors) in preventing human disease (6,20,35,39,40), and (iii) protection and even reversal of disease postinfection upon passive administration of antiPTx antibodies in mice and humans (4,5,15,16,30,31,33). Furthermore, in highly vaccinated populations, circulating strains have emerged with increased virulence, correlating with increased PTx production due to promoter mutations (23).…”