Attenuated Bordetella pertussis Vaccine Protects against Respiratory Syncytial Virus Disease via an IL-17–Dependent Mechanism

Abstract

Rationale: We attenuated virulent Bordetella pertussis by genetically eliminating or detoxifying three major toxins. This strain, named BPZE1, is being developed as a possible live nasal vaccine for the prevention of whooping cough. It is immunogenic and safe when given intranasally in adult volunteers.Objectives: Before testing in human infants, we wished to examine the potential effect of BPZE1 on a common pediatric infection (respiratory syncytial virus [RSV]) in a preclinical model.Methods: BPZE1 was administered before or after RSV administration in adult or neonatal mice. Pathogen replication, inflammation, immune cell recruitment, and cytokine responses were measured.Measurements and Main Results: BPZE1 alone did not cause overt disease, but induced efflux of neutrophils into the airway lumen and production of IL-10 and IL-17 by mucosal CD4 1 T cells. Given intranasally before RSV infection, BPZE1 markedly attenuated RSV, preventing weight loss, reducing viral load, and attenuating lung cell recruitment. Given neonatally, BPZE1 also protected against RSV-induced weight loss even through to adulthood. Furthermore, it markedly increased IL-17 production by CD4 1 T cells and natural killer cells and recruited regulatory cells and neutrophils after virus challenge. Administration of anti-IL-17 antibodies ablated the protective effect of BPZE1 on RSV disease.Conclusions: Rather than enhancing RSV disease, BPZE1 protected against viral infection, modified viral responses, and enhanced natural mucosal resistance. Prevention of RSV infection by BPZE1 seems in part to be caused by induction of IL-17. Clinical trial registered with www.clinicaltrials.gov (NCT 01188512).

Acute bronchiolitis: Influence of viral co‐infection in infants hospitalized over 12 consecutive epidemic seasons

“…Laboratory data analysis highlighted a higher neutrophil count and higher C‐RP levels in infants with a single infection than in multiple infection. Although this finding has to our knowledge never been reported in humans, Schnoeller et al found similar results in neonatal mice in which a Bordetella pertussis respiratory infection seemed to protect against RSV‐induced disease in adult life, through a still incompletely understood mechanism involving interleukin‐17 and 10.…”

Development of improved pertussis vaccine

“…The use of an attenuated B. pertussis strain administered intranasally has been successfully tested in animal models and moved to Phase I clinical trials. 39,40 Although this is a promising application that has shown some advantages, 41,42 it shares the potential safety concerns related to the use of attenuated pathogens. 39 An interesting alternative that combines some of the above-mentioned strategies is the use of outer membrane vesicles, also called nanoparticles, which contain bacterial surface antigens.…”

Investigating Pertussis Toxin and its Impact on Vaccination

“…In addition to provide full protection against pertussis challenge in mice, this vaccine also cross-protects against challenge with Bordetella parapertussis and Bordetella bronchiseptica [106]. In addition, it has interesting bystander effects, as it also protects against influenza virusinduced pneumonia [107] respiratory syncytial virus disease [108] and allergic asthma [109]. This live nasal vaccine has now undergone a human Phase I clinical trial and was found to induce immune responses in all colonized individuals without causing any vaccine-related adverse event [110].…”