Evaluation of Adenylate Cyclase Toxoid Antigen in Acellular Pertussis Vaccines by Using a Bordetella pertussis Challenge Model in Mice

Boehm, Dylan T.; Hall, Joseph; Wong, Ting Y.; DiVenere, Andrea M.; Sen-Kilic, Emel; Bevere, Justin R.; Bradford, Shelby D.; Blackwood, Catherine B.; Elkins, Cody; DeRoos, Katherine; Gray, Mary C.; Cooper, C. Garret; Varney, Melinda E.; Maynard, Jennifer A.; Hewlett, Erik L.; Barbier, Mariette; Damron, F. Heath

doi:10.1128/iai.00857-17

Cited by 36 publications

(71 citation statements)

References 63 publications

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“…Two other autotransporters, Vag8 (250,251) and SphB1, when added to the current pertussis vaccine resulted in improved protection against B. pertussis infection (252). Adenylate cyclase toxin (ACT), when added to a current vaccine formulation significantly decreased inflammation and increased the generation of protective immunity (253,254). BcfA (colonization factor A) has been used as adjuvant in the current vaccine, and the preliminary data obtained with the murine model reveals that the addition of this adjuvant shifts the T cell response toward Th1/Th17 (255).…”

Section: Novel Vaccination Strategiesmentioning

confidence: 99%

Immunomodulation as a Novel Strategy for Prevention and Treatment of Bordetella spp. Infections

2019

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Well-adapted pathogens have evolved to survive the many challenges of a robust immune response. Defending against all host antimicrobials simultaneously would be exceedingly difficult, if not impossible, so many co-evolved organisms utilize immunomodulatory tools to subvert, distract, and/or evade the host immune response. Bordetella spp. present many examples of the diversity of immunomodulators and an exceptional experimental system in which to study them. Recent advances in this experimental system suggest strategies for interventions that tweak immunity to disrupt bacterial immunomodulation, engaging more effective host immunity to better prevent and treat infections. Here we review advances in the understanding of respiratory pathogens, with special focus on Bordetella spp., and prospects for the use of immune-stimulatory interventions in the prevention and treatment of infection.

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Section: Novel Vaccination Strategiesmentioning

confidence: 99%

Immunomodulation as a Novel Strategy for Prevention and Treatment of Bordetella spp. Infections

2019

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“…5c) that could result from the increased IL-17 expression in these mice. Stephen Morse observed dose-dependent leukocytosis in mice following vaccination with killed B. pertussis 31 . In this study, NECre luc mice were immunized with 1/5 th the human dose of WCV.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms of protection between DTaP and wP vaccines will be explored at length later in this chapter. Presently, human data exists suggesting differences in the long-term protection from individuals immunized with either wP or DTaP vaccines, suggesting that wP vaccines offer longer protection 31 . Studies in the US and Australia examining cohorts of children receiving either wP or DTaP priming immunizations, followed by DTaP booster immunizations have allowed for the study of the different responses 31 .…”

Section: Waning Dtap Vaccinementioning

confidence: 99%

“…Presently, human data exists suggesting differences in the long-term protection from individuals immunized with either wP or DTaP vaccines, suggesting that wP vaccines offer longer protection 31 . Studies in the US and Australia examining cohorts of children receiving either wP or DTaP priming immunizations, followed by DTaP booster immunizations have allowed for the study of the different responses 31 . A study comparing protection up to 2 years post-booster immunization found higher IgG titers, memory B-cell numbers, and T-cell cytokine responses in DTaP primed individuals compared to wP primed children shortly after booster immunization 32 .…”

Section: Waning Dtap Vaccinementioning

confidence: 99%

“…To determine vaccine induced protection, we utilized an established vaccine and challenge protocol. 31 CD-1 mice were immunized IN with either IN-aP or IN-caP. These groups were compared to pertussis immunizations that are known to be protective: DTaP (IP-aP) and whole-cell pertussis (IP-wP) administered intraperitoneally (IP).…”

Section: Intranasal Immunization Induces Production Of Anti-pt and Anmentioning

confidence: 99%

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Development of Improved Acellular Pertussis Vaccines Through Inclusion of the RTX Antigen or Induction of Mucosal Immunity

Boehm¹

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Pertussis is a human respiratory disease, primarily caused by the Gram-negative pathogen Bordetella pertussis. The infection is most severe and can be life-threatening in young children and infants where it manifests as a series of paroxysmal coughs. The disease is more commonly known as whooping cough, due to the whoop omitted during a massive inspiratory effort to bring air back into the lungs. Pertussis is a toxin-mediated disease that persists due to an early release of toxins that allow that bacteria to evade the cells of the innate immune response. The inhibition of the host response continues as toxin activity disrupts the signaling generating an adaptive immune response. Fortunately, two generations of vaccines have been developed to combat the spread of the highly contagious disease. The whole-cell pertussis (wP) vaccine was implemented in the 1950s and was successful in controlling cases. However, due to adverse side effects associated with the immunization, wP vaccines were replaced with acellular protein (aP) vaccines absorbed to an alum adjuvant. The second generation aP vaccines induced an immune response capable of neutralizing key virulence factors contained in the vaccine, thereby controlling the symptoms of the disease. Unfortunately, there has been a re-emergence of pertussis incidence in countries using the aP vaccines. Included in this resurgence is an increased number of adolescents and adults with unrecognized pertussis, leading to the potential of adult and adolescent reservoirs of the infection. We reasoned that a pertussis vaccine capable of inducing sterilizing immunity, rather than controlling the symptoms, would decrease the spread of pertussis. In this work, we propose two directions towards this goal. The first was through the neutralization of a key virulence factor not included in any current vaccine formulations, adenylate cyclase toxin (ACT). This was accomplished through the optimization of a mouse immunization and challenge model. In initial experiments using a neutrophil reporter mouse, NeCre luc, we visualized the spatiotemporal localization of neutrophils after B. pertussis challenge in wP or aP immunized mice with a vaccine dose known to be protective. In these experiments wP immunized mice elicited an exaggerated immune response, that persisted after clearance of the pathogen, raising concerns to the relevance of the high vaccine dose in characterizing the immune response. In subsequent experiments, we addressed these concerns, by titrating the concentration of a Diphtheria-Tetanus-acellular Pertussis (DTaP) subunit vaccine to a dose that did not induce a protective response in a murine model. In defining a suboptimal protective dose for mice, the additive effects of potential antigens could be evaluated, that were previously masked by the higher concentrations of vaccine. This model was confirmed through the addition of an ACT toxoid, RTX. The inclusion of RTX into a DTaP vaccine produced an antibody response that neutralized the toxin in vitro, and upon challenge with B...

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Role of Major Toxin Virulence Factors in Pertussis Infection and Disease Pathogenesis

Scanlon

Skerry

Carbonetti

2019

Advances in Experimental Medicine and Biology

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Bordetella pertussis produces several toxins that affect host-pathogen interactions. Of these, the major toxins that contribute to pertussis infection and disease are pertussis toxin, adenylate cyclase toxin-hemolysin and tracheal cytotoxin. Pertussis toxin is a multi-subunit protein toxin that inhibits host G protein-coupled receptor signaling, causing a wide array of effects on the host. Adenylate cyclase toxin-hemolysin is a single polypeptide, containing an adenylate cyclase enzymatic domain coupled to a hemolysin domain, that primarily targets phagocytic cells to inhibit their antibacterial activities. Tracheal cytotoxin is a fragment of peptidoglycan released by B. pertussis that elicits damaging inflammatory responses in host cells. This chapter describes these three virulence factors of B. pertussis, summarizing background information and focusing on the role of each toxin in infection and disease pathogenesis, as well as their role in pertussis vaccination.

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Evaluation of Adenylate Cyclase Toxoid Antigen in Acellular Pertussis Vaccines by Using a Bordetella pertussis Challenge Model in Mice

Cited by 36 publications

References 63 publications

Immunomodulation as a Novel Strategy for Prevention and Treatment of Bordetella spp. Infections

Immunomodulation as a Novel Strategy for Prevention and Treatment of Bordetella spp. Infections

Development of Improved Acellular Pertussis Vaccines Through Inclusion of the RTX Antigen or Induction of Mucosal Immunity

Role of Major Toxin Virulence Factors in Pertussis Infection and Disease Pathogenesis

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